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Effects of dopaminergic drugs on working and reference memory in rats
Abstract
Changes in dopaminergic function have been associated with alterations in motor and cognitive function in man and in animals. This study was designed to assess the effects of dopaminergic drugs on these aspects of conditioned behavior in animals. Male Long-Evans rats were trained to perform an appetitive operant task that allowed daily quantification of working memory (accuracy of spatial delayed nonmatching-to-position), reference memory (accuracy of visual discrimination) and motor function [choice lever-press latency and nosepoke interresponse time (IRT) during delay]. The indirect dopamine agonist d-amphetamine (0.3–1.0 mg/kg) reduced nonmatching accuracy without significantly affecting discrimination accuracy, response latency, or nosepoke IRT. The D2/D3 agonist quinpirole (0.01–0.056 mg/kg) also decreased nonmatching accuracy without changing discrimination accuracy, but increased choice response latency and nosepoke IRT as well. The D1 agonist SKF 38393 (1.0–3.0 mg/kg) and the D1 antagonist SCH 23390 (0.01–0.03 mg/kg) only affected nosepoke IRT, at doses below those causing response failure. The D2 antagonist raclopride (0.056–0.177 mg/kg) exerted no significant effects at doses that did not suppress responding completely. The selective reduction of nonmatching accuracy by d-amphetamine and quinpirole indicates a mnemonic impairment specific to working memory (relative to reference memory). These results suggest further 1) that stimulation of D2/D3, but not D1, receptors may account for the d-amphetamine-induced deficit in working memory; 2) that stimulation of D2/D3 receptors alone by quinpirole may also impair spatial working memory, but only in conjunction with motor slowing; and 3) that antagonism of either receptor type (by SCH 23390 or raclopride) does not significantly affect memory at doses causing motor slowing and response failure.
... Drugs commonly used for the treatment of symptoms related to ADHD, such as amphetamine and methylphenidate, are psychomotor stimulants that promote dopamine activity (Martinez et al., 2003;Volkow et al., 1998). Low to moderate doses of d-amphetamine relieve impaired attention in animal models (Bizot et al., 2015;Sagvolden & Xu, 2008) while moderate to high doses of d-amphetamine have been shown to inhibit short-term memory (Bushnell & Levin, 1993;Shoblock et al., 2003). ...
... Further validation of the nature of the memory procedure used in this study arises from observations that not only was there a delay-dependent inhibition of accuracy as described by White (2001) but memory was impaired, dose-dependently, by the dopamine agonist d-amphetamine (Bushnell & Levin, 1993). Previous reports have shown variable interactions between developmental MeHg exposure and alterations in memory dependent on the regimen of exposure, the model, and the task of memory used (Albores-Garcia et al., 2016;Gilbert et al., 1993;Goulet et al., 2003;Liu et al., 2009;Newland et al., 2008;Sakamoto et al., 2004;Tian et al., 2016). ...
... Memory in the current procedure was unaffected by MeHg. Further, short-term memory for all rats in this study was impaired as the dose of d-amphetamine increased, an effect that has been previously reported (Bushnell & Levin, 1993;Sahgal, 1987). Of greatest interest is the similarity in effects observed in the current study as compared to those results reported by Bushnell and Levin (1993) where there were no notable alterations in accuracy at a dose of 0.3 mg/kg d-amphetamine but significant impairments in accuracy at 1.0 mg/kg. ...
Methylmercury (MeHg) is an environmental neurotoxicant known to disrupt behavior related to dopamine neurotransmission in experimental models. Such disruptions are sensitive to dopamine agonists when administered acutely after exposure to MeHg has ended or when administered concurrently with MeHg exposure. Sustained attention and short-term remembering, components of attention-deficit/hyperactivity disorder (ADHD), are partially mediated by dopamine neurotransmission. In order to observe MeHg-related alterations in sustained attention and short-term memory, as well as determine sensitivity of MeHg exposed animals to dopamine agonists commonly used in the treatment of ADHD symptoms, rats were exposed to 0, 0.5, or 5 ppm MeHg throughout adolescence and trained in a hybrid sustained attention/short term memory visual signal detection task in adulthood. Behavior was then probed with acute i.p. injections of the dopamine agonist, d-amphetamine, which improves impaired attention and inhibits short-term memory in clinical syndromes like ADHD. Acute d-amphetamine dose-dependently decreased short-term memory as well as sustained attention. While MeHg alone did not impair accuracy or memory, it did interact with d-amphetamine to produce baseline-dependent inhibition of behavior. These findings further show that changes in behavior following low-level exposure to MeHg during adolescence are augmented by dopamine agonists. Observed impairments in memory following acute d-amphetamine are consistent with previous findings.
... Other psychostimulants are known to have deleterious effects on working memory at higher doses, 1 both acutely (e.g., Shoblock, Maisonneuve, & Glick, 2003) and when administered during vulnerable periods of neural development (Cutler, Wilkerson, Gingras, & Levin, 1996;Jablonski, Williams, & Vorhees, 2016;Melnick, Kubie, Laungani, & Dow-Edwards, 2001;Santucci et al., 2004). For example, Baron, Wright, and Wenger (1998) found that both dextroamphetamine and cocaine disrupted performance in spatial alternation and matching-to-position tasks in rats; Baron and Wenger (2001) found similar effects of both drugs in a matching-to-sample task with squirrel monkeys; Bushnell and Levin (1993) found disruptive effect of dextroamphetamine in a nonmatching-to-position task with rats; and Shoblock et al. (2003) found disruption of delayed-alternation behavior in the T-maze using both amphetamine and methamphetamine. One recent study by Xi, Yang, Zeng, Hu, and Wang (2012) suggests that TDF may have similar effects on learning and reference memory, as well as decreasing retinoic acid concentration in the hippocampus. ...
... Our results suggest that TDF is effective in disrupting spatial working memory in this task. In this aspect, it is similar to other psychostimulants (Baron & Wenger, 2001;Baron et al., 1998;Bushnell & Levin, 1993;Shoblock et al., 2003). ...
... In their study of dopaminergic drugs and working memory, Bushnell and Levin (1993) suggest that the mechanism by which d-amphetamine and quinpirole have the effects on working memory is through stimulation of D 2 /D 3 receptors, as D 1 agonists did not produce similar disruption in working memory. One possible site for TDF's disruptive effects on memory is the dorsolateral prefrontal cortex, an area strongly implicated in working memory and dopamine's effect on working memory (Arnsten, Girgis, Gray, & Mailman, 2017); however, lacking measurement data for neurological activity, our study cannot confirm that this is the case. ...
Triadimefon (TDF) is a fungicide which has psychostimulant properties similar to cocaine and amphetamine. Past studies with psychostimulants suggests that acute exposure leads to disruptions in working memory. In this study, we examined the effects of TDF exposure (relative to corn oil control) on performance in the delayed matching-to-position task in two separate studies using Sprague-Dawley male rats. In both studies, TDF exposure led to significantly poorer performance across delays. TDF shows similar properties to cocaine and amphetamine in terms of disrupting working memory.
... It is widely recognized that dopaminergic agents may not exclusively affect processes related to time discrimination. For example, there is considerable evidence that dopaminergic drugs such as amphetamine affect nontemporal working and reference memory (Bushnell & Levin, 1993;Packard & White, 1989). Nevertheless, it is important to know precisely what experimental conditions are necessary in order to produce selective clock effects such as those reported by Meck (1996). ...
... The 0.08-mg/kg dosage of quinpirole was selected on the basis of previous research conducted by Bushnell and Levin (1993). They found that a 0.056-mg/kg dose of quinpirole and a I.OO-mg/kg dose of d-amphetamine produced a similar disruption of spatial delayed nonmatching-to-position in rats. ...
... In previous studies of timing in rats, a 1.5-mg/kg dose of methamphetamine has been used (Maricq et aI., 1981;Meck, 1983;Meck & Church, 1983;Santi et aI., 1995). Consequently, the 0.056-mg/kg dose of quinpirole used in the Bushnell and Levin (1993) study was increased by approximately 50% in order to approximate the behavioral effects of a 1.5-mglkg dose of amphetamine. ...
Three groups of rats were trained to discriminate between 2 sec and 8 sec of darkness by responding to either the left or the right lever. Following acquisition of this temporal discrimination, psychophysical functions were obtained by presenting unreinforced signals of intermediate duration. Two groups of rats were trained with saline and subsequently tested with the specific D2 dopamine agonist quinpirole (0.08 mg/kg). One of these groups was naive to the drug prior to testing (DN), whereas the other had exposure to the drug but not during training sessions (DE). A third group (DT) was trained under quinpirole and tested with saline. The temporal discrimination was acquired rapidly and equivalently in Groups DN and DE. However, rats in Group DT were severely impaired in acquiring the discrimination. During psychophysical testing, quinpirole disrupted the accuracy of temporal discrimination equivalently in Groups DN and DE. Both the Weber fraction (WF) and the difference limen (DL) increased significantly in Groups DN and DE; however, the point of subjective equality (PSE) was not affected. In Group DT, the shift to saline during psychophysical testing did not result in any changes to the PSE, DL, or WF. These findings are not consistent with the hypothesis that the speed of the internal clock is selectively affected by D2 dopaminergic manipulations. Prior exposure to the drug does not appear to be a critical variable in the failure to observe a selective adjustment of the internal clock. The D2 agonist quinpirole appears to affect the accuracy of temporal discriminations generally, without altering the speed of the internal clock.
... However, some disruptive effects of amphetamine cannot be explained in this way. Bushnell and Levin (1993) have directly compared the effects of amphetamine on working memory (accuracy of spatial delayed nonmatching-to-position), reference memory (accuracy of visual discrimination), and motor function in rats. Amphetamine reduced the accuracy of nonmatchingto-position without significantly affecting visual discrimination accuracy or motor function. ...
... This suggests that there is an enhanced sensitivity of working memory tasks to disruption by amphetamine, a finding which parallels the re-Copyright 1995 Psychonomic Society, Inc. 224 suits already well-established for-eholinergic blockade (Beatty & Bierley, 1985;Buresovli, Bolhuis, & BureS, 1986;Santi, Bogies, & Petelka, 1988;Wirsching, Beninger, Jhamandas, Boegman, & EI-Defrawy, 1984). In addition, as in the research literature on anticholinergics, Bushnell and Levin (1993) found that the disruptive effects of amphetamine were delay independent. They concluded that amphetamine did not disrupt the maintenance of sample information as much as its encoding prior to the delay. ...
... This permitted an examination of drug effects on both temporal and nontemporal memory in pigeons. Previous timing research in rats suggested a direct effect of amphetamine on clock processes (e.g., Maricq & Church, 1983;Maricq et aI., 1981;Meck, 1983), whereas other research indicated that amphetamine has additional effects both on temporal discriminations (Rapp & Robbins, 1976;Spetch & Treit, 1984;Stubbs & Thomas, 1974) and on other nontemporal memory tasks (e.g., Beatty & Rush, 1983;Bushnell & Levin, 1993). If amphetamine simply increased the speed of the internal clock, it was expected that a choose-long bias would be demonstrated. ...
In Experiment 1, pigeons were trained to match short (2-sec) and long (8- sec) sample durations to red and green comparison stimuli and red and green samples to vertical and horizontal line comparisons. They received injections of d-amphetamine (2.0 mg/kg) or saline, and the delay interval was manipulated (0, 1, 3, and 9 sec). In Experiment 2, rats were trained to discriminate short (2-sec) or long (12-sec) durations of either houselight illumination (light group) or tone (tone group), using a choice procedure. During the test phase of each trial, the left and right levers were presented with the cuelight above one of them on (cued lever) while the other was off (uncued lever). For some of the rats, the correct response following the short sample was to press the cued lever, whereas following the long sample, it was to press the uncued lever. This was reversed for the remaining rats. The rats received injections of methamphetamine (1.5 mg/kg) or saline, and the delay interval was manipulated (0, 1, 3, and 9 sec). Memory for color samples in pigeons was not affected by amphetamine. However, for both rats and pigeons, amphetamine reduced the accuracy of event duration memory even at the 0-see delay but did not increase the slope of the retention functions. In addition, in neither experiment was there any evidence that amphetamine produced an overestimation of perceived sample duration. Amphetamine predominantly affected temporal memory in both pigeons and rats by disrupting attention to temporal samples rather than by simply increasing the speed of the internal clock.
... Cortical dopaminergic transmission has been found to act in an inverted U-shaped manner, deficits in working memory can be induced by either inflated or deficient dopaminergic transmission (Zahrt et al., 1997;Cools and D'Esposito, 2011) mainly by postsynaptic effects in the PFC (Williams and Goldman-Rakic, 1995;Seamans and Yang, 2004;Vijayraghavan et al., 2007;Cools and D'Esposito, 2011). Imbalanced receptor activations can induce opposite effects on working memory compared to within-range levels (Luciana et al., 1992;Bushnell and Levin, 1993;Murphy et al., 1996;Cai and Arnsten, 1997;Wilkerson and Levin, 1999). However temporal effects, in terms of subsequent training sessions, of dopamine receptors on working memory are rarely reported. ...
... Similar to our study working memory was mainly modulated by D1R but not D2R blockade. In contrast to the present study working memory was impaired at all drug concentrations and all test delays used, however session (day) specific effects were not determined (Bushnell and Levin, 1993;Wilkerson and Levin, 1999). Dose related impairments of spatial working memory by intra-PFC injections of D1R receptor agonists have been found (Williams and Goldman-Rakic, 1995) that were attenuated by pretreatment with an D1R antagonist (Zahrt et al., 1997), however no session specific effect was analyzed. ...
The dopaminergic system is known to be involved in working memory processed by several brain regions like prefrontal cortex (PFC), hippocampus, striatum. In an earlier study we could show that Levodopa but not Modafinil enhanced working memory in a T-maze only during the early phase of training (day 3), whereas the later phase remained unaffected. Rats treated with a higher dose performed better than low dose treated rats. Here we could more specifically segregate the contributions of dopamine type 1- and 2- like receptors (D1R; D2R) to the training state dependent modulation of spatial working memory by intracerebroventricular (ICV) application of a D1R-like (SKF81297) and D2R-like agonist (Sumanirole) and antagonist (SCH23390, Remoxipride) at a low and high dose through 3 days of training. The D1R-like-agonist at both doses enhanced working memory at day 1 but only in the low dose treated rats enhancement persists over training compared to control rats. Rats treated with a high dose of a D1R-like-antagonist show persistent enhancement of working memory over training, whereas in low dose treated rats no statistical difference at any time point could be determined compared to controls. The D2R-like-agonist at both doses does not show an effect at any time point when compared to control animals, whereas the D2R-like antagonist at a low dose enhanced working memory at day 2. For the most effective D1R-like agonist, we repeated the experiments in a water maze working memory task, to test for task dependent differences in working memory modulations. Treated rats at both doses did not differ as compared to controls, but the temporal behavioral performance of all groups was different compared to T-maze trained rats. The results are in line with the view that spatial working memory is optimized within a limited range of dopaminergic transmission, however suggest that these ranges vary during spatial training.
... DA signaling is involved various cognitive and affective functions, which depend on brain areas where DA neurons innervate. The mesocortical and mesolimbic DA projections in the PFC and ventral striatum (including the NAcc), respectively, are involved in cognitive functions such as working memory (Sawaguchi and Goldman-Rakic, 1991;Bushnell and Levin, 1993;Zahrt et al., 1997;Muller et al., 1998;Kahkonen et al., 2001;Mehta et al., 2004;Von Huben et al., 2006), behavioral flexibility (Floresco et al., 2006;Coppens et al., 2010;Klanker et al., 2013), attention regulation (Chudasama and Robbins, 2004;Von Huben et al., 2006;Pezze et al., 2007;Agnoli et al., 2013), and decision making (Kurniawan et al., 2011;Humphries et al., 2012;Guitart-Masip et al., 2014). The mesolimbic DA pathway in limbic structures such as the amygdala has also been shown to contribute to affective function such as fear conditioning (Pezze and Feldon, 2004). ...
... One such cognitive functions strongly associated with mesocortical DA signaling in the PFC is working memory. Alterations of working memory function, which are similar, if not identical, patterns, caused by pharmacological modulations of DA D1 and D2 receptors have been reported across different vertebrates from rodents (Bushnell and Levin, 1993;Zahrt et al., 1997), non-human primates (Sawaguchi and Goldman-Rakic, 1991;Von Huben et al., 2006), to humans (Muller et al., 1998;Kahkonen et al., 2001;Mehta et al., 2004). This suggests that an evolutionary origin of DA system utilization on cognitive functions is quite old, and have been conserved for a long time in various species. ...
Dopamine (DA) transmission in brain areas such as the prefrontal cortex (PFC) and nucleus accumbens (NAcc) plays important roles in cognitive and affective function. As such, DA deficits have been implicated in a number of psychiatric disorders such as schizophrenia and attention deficit/hyperactivity disorder (ADHD). Accumulating evidence suggests that DA is also involved in social behavior of animals and humans. Although most animals organize and live in social groups, how the DA system functions in such social groups of animals, and its dysfunction causes compromises in the groups has remained less understood. Here we propose that alterations of DA signaling and associated genetic variants and behavioral phenotypes, which have been normally considered as “deficits” in investigation at an individual level, may not necessarily yield disadvantages, but even work advantageously, depending on social contexts in groups. This hypothesis could provide a novel insight into our understanding of the biological mechanisms of psychiatric disorders, and a potential explanation that disadvantageous phenotypes associated with DA deficits in psychiatric disorders have remained in humans through evolution.
... Indeed, the same confound is present in the IGT, and gambling paradigms which have a lower memory load have been developed for clinical use (for example, Rogers et al, 1999). However, systemic administration of D 2 receptors does not alter either working or reference memory (Bushnell and Levin, 1993;Kobayashi et al, 1995), yet eticlopride improves rGT performance. In contrast, peripheral administration of D 2 agonists can impair working memory, yet do not affect short-term reference memory or choice in the rGT (Bushnell and Levin, 1993). ...
... However, systemic administration of D 2 receptors does not alter either working or reference memory (Bushnell and Levin, 1993;Kobayashi et al, 1995), yet eticlopride improves rGT performance. In contrast, peripheral administration of D 2 agonists can impair working memory, yet do not affect short-term reference memory or choice in the rGT (Bushnell and Levin, 1993). Theoretically, the contribution of reference memory to rGT performance could be completely abolished if the location of the different options was altered randomly between sessions. ...
Pathological gambling (PG) is characterized by persistent, maladaptive gambling behavior, which disrupts personal and professional life. Animal models of gambling behavior could make a significant contribution to improving our understanding of the neural and neurochemical basis of gambling, and the treatment of PG. When gambling, failing to win critically results in the loss of resources wagered as well as the absence of additional gain. Here, we have incorporated these concepts into a novel rat gambling task (rGT), based, in part, on the 'Iowa' gambling task (IGT) commonly used clinically to measure gambling-like behavior. Rats choose among four different options to earn as many sugar pellets as possible within 30 min. Each option is associated with the delivery of a different amount of reward, but also with a different probability and duration of punishing time-out periods during which reward cannot be earned. The schedules are designed such that persistent choice of options linked with larger rewards result in fewer pellets earned per unit time. Rats learn to avoid these risky options to maximize their earnings, comparable with the optimal strategy in the IGT. Both d-amphetamine and the 5-HT(1A) receptor agonist, 8-OH-DPAT, impaired task performance. In contrast, the dopamine D(2) receptor antagonist, eticlopride, improved performance, whereas the D(1) receptor antagonist, SCH23390, had no effect. These data suggest that both serotonergic and dopaminergic agents can impair and improve gambling performance, and indicate that the rGT will be a useful tool to study the biological basis of gambling.
... These pharmacological properties of nicotine, especially reinforcing and locomotor effects, have been most strongly linked to the release of dopamine [20]. A number of lines of evidence have suggested that dopaminergic mechanisms also affect learning, and brain dopamine plays a crucial role in memory processes [2,9,32]. For example, the activation of both dopamine D1 and D2 receptors in the prefrontal cortex or hippocampus has been reported to facilitate performance in different working memory tasks in monkeys or rats [2]. ...
... For example, the activation of both dopamine D1 and D2 receptors in the prefrontal cortex or hippocampus has been reported to facilitate performance in different working memory tasks in monkeys or rats [2]. In turn, some results suggest that dopamine D3 receptors exert an inhibitory effect on memory consolidation [9,32]. In addition, it has been reported that the D1 dopamine receptor antagonist SCH 23390, but not the D2 receptor antagonist sulpiride, increases the effects of nicotine on passive avoidance learning. ...
In this study, we investigated the effects of acute administration of nicotine on memory-related behavior in mice using the elevated plus maze test. In this test, the time necessary for mice to move from the open arm to the enclosed arm (i.e., transfer latency) was used as an index of memory. Our results revealed that nicotine (0.035 and 0.175 mg/kg, base, sc) shortened the transfer latency relative to the saline-treated group. Moreover, we investigated the effects of bupropion (10, 20 and 40 mg/kg, ip) and L-type voltage-dependent calcium channel antagonists (nimodipine, flunarizine, verapamil, diltiazem - 5, 10 and 20 mg/kg, ip) on memory-related behavior. At all tested doses, bupropion, did not significantly affect transfer latency. However, flunarizine and verapamil (both at 10 mg/kg) resulted in a slight decrease in transfer latency, whereas nimodipine (10 mg/kg) increased transfer latency. Interestingly, both bupropion (20 mg/kg) and calcium channel blockers (5 mg/kg) attenuated the improvement of memory induced by nicotine. Our findings indicate that the cholinergic nicotinic system may play an important role in memory consolidation, and that neural calcium-dependent mechanisms can be involved in the modulation of memory-related responses induced by nicotine. The results of these studies have revealed neuronal mechanisms that are important for nicotinic modulation of cognition and will be useful for the treatments of human disorders in which cholinergic pathways have been implicated, such as psychiatric disorders and addiction.
... Moreover, it has been shown that, as a result of nicotine administration, the activity of the above-mentioned receptors in the hippocampus area increases [28]. Stimulation of N receptor subtypes, leads to an increase in the frequency and amplitude of mini-discharges, which in turn results in the release of stored Ca 2+ , generating a nerve impulse, and as a result, positively influencing the processes related to remembering of information [24,29]. In turn, a decrease in the density of N receptors within the hippocampus and the amygdala (another structure responsible for the cognitive effects of nicotine) is associated with a significant deterioration of memory [24]. ...
Background: Dysfunction of the cholinergic system is associated with the development of Alzheimer’s disease (AD). One of the new possible strategies for the pharmacological modulation of memory-related problems typical of AD, is connected with the endocannabinoid system (ECS) and the cannabinoid (CB: CB1 and CB2) receptors. Methods: The aim of the study was to determine the influence of the selective CB2 receptor ligands: agonist (JWH 133) and antagonist (AM 630) on different stages of memory and learning in mice, in the context of their interaction with cholinergic pathways. To assess and understand the memory-related effects in mice we used the passive avoidance (PA) test. Results: We revealed that co-administration of non-effective dose of JWH 133 (0.25 mg) or AM 630 (0.25 mg/kg) with the non-effective dose of cholinergic receptor agonist - nicotine (0.05 mg/kg) enhanced cognition in the PA test in mice; however, an acute injection of JWH 133 (0.25 mg/kg) or AM 630 (0.25 mg/kg) had no influence on memory enhancement induced by the effective dose of nicotine (0.1 mg/kg). Co-administration of JWH 133 (0.25 mg) or AM 630 (0.25 mg/kg) with the effective dose of the cholinergic receptor antagonist scopolamine (1 mg/kg) attenuated the scopolamine-induced memory impairment in the PA test in mice. Conclusion: Our experiments have shown that CB2 receptors participate in the modulation of memory-related responses, especially those in which cholinergic pathways are implicated.
... A possible explanation of the prolonged latencies to reach the feeder locations after the treatment with dopamine receptor antagonists could be sedation, changes in motor function, which can complicate interpretation of results (Bushnell and Levin, 1993). Haloperidol at 0.5 mg/kg for example decreased the response rate of pigeons in a delayed-matching-to-sample task but failed to impair accuracy (Poling et al., 1984). ...
We have studied the effects of dopamine antagonists and agonists on Japanese quail behavior in the spatial judgment task. Twenty-four Japanese quail hens were trained in the spatial discrimination task to approach the feeder placed in the rewarded location (Go response, feeder containing mealworms) and to not approach the punished location (No-Go response, empty feeder plus aversive sound). In a subsequent spatial judgment task, the proportion of Go responses as well as approach latencies to rewarded, punished, and three ambiguous locations (near-positive, middle, near-negative, all neither rewarded nor punished) were assessed in 20 quail hens that successfully mastered the discrimination task. In Experiment 1, each bird received five treatments (0.1 and 1.0 mg/kg of dopamine D1 receptor antagonist SCH 23390, 0.05 and 0.5 mg/kg of dopamine D2 receptor antagonist haloperidol, and saline control) in a different order, according to a Latin square design. All drugs were administered intramuscularly 15 min before the spatial judgment test, with 2 days break between the treatments. Both antagonists caused a significant dose-dependent increase in the approach latencies as well as a decrease in the proportion of Go responses. In Experiment 2, with the design analogous to Experiment 1, the hens received again five treatments (1.0 and 10.0 mg/kg of dopamine D1 receptor agonist SKF 38393, 1.0 and 10.0 mg/kg of dopamine D2 receptor agonist bromocriptine, and saline control), applied intramuscularly 2 h before the test. The agonists did not have any significant effect on approach latencies and the proportion of Go responses in the spatial judgment task, as compared to the saline control, except for 10.0 mg/kg SKF 38393, which caused a decrease in the proportion of Go responses. The approach latency and the proportion of Go responses were affected by the cue location in both experiments. Our data suggest that the dopamine D1 and D2 receptor blockade leads to a decrease in the reward expectation and the negative judgment of stimuli. The effect of dopamine receptor activation is less clear. The results reveal that dopamine receptor manipulation alters the evaluation of the reward and punishment in the spatial judgment task.
... Besides this possibility, quinpirole could also disrupt maternal behavior by impairing certain aspects of executive function, such as behavioral organization, attention and working memory, etc. Other studies have shown that D 2 activation often causes perseverative responding, deficit in attention and working memory (Agnoli et al., 2013;Bushnell and Levin, 1993;Herold, 2010;Liu et al., 2008;Pezze et al., 2007;Wang et al., 2004). Under the influence of quinpirole, a mother rat might lose its ability to select and maintain appropriate behavioral responses in the presence of pups. ...
Serotonin 5-HT 2A receptors are expressed throughout the mesolimbic and mesocortical dopamine pathways, and manipulation of this receptor system has a profound impact on dopamine functions and dopamine-mediated behaviors. It is highly likely that 5-HT 2A receptors may also modulate the D 2 -mediated maternal effects. The present study investigated this issue and also explored the possible behavioral mechanisms. We tested the effects of two D 2 drugs (an agonist quinpirole: 0.5, 1.0 mg/kg, and a potent D 2 antagonist haloperidol: 0.05, 0.10 mg/kg, sc) and their combinations with two 5-HT 2A drugs (a selective 5-HT 2A agonist TCB-2: 2.5 mg/kg, and 5-HT 2A antagonist MDL100907, 1.0 mg/kg, sc) on maternal behavior in Sprague-Dawley postpartum females. Individually, TCB-2 (2.5 mg/kg, sc) and quinpirole (0.5 and 1.0 mg/kg, sc) reduced pup preference and disrupted home-cage maternal behavior. In contrast, haloperidol (0.10 mg/kg, sc) only disrupted home-cage maternal behavior, but did not suppress pup preference. MDL100907 (1.0 mg/kg, sc) by itself had no effect on either pup preference or maternal behavior. When administered in combination, pretreatment of TCB-2 did not alter quinpirole's disruption of pup preference and home-cage maternal behavior (possibly due to the floor effect), however, it did enhance haloperidol's disruption of pup retrieval in the home cage. MDL100907 had no effect both quinpirole's and haloperidol's disruption of pup preference and home-cage maternal behavior. Interestingly, haloperidol attenuated TCB-2's disruptive effect on pup preference. These findings suggest that activation of 5-HT 2A receptors tends to enhance D 2 -mediated maternal disruption, whereas blockade of 5-HT 2A receptors is less effective. They also suggest that 5-HT 2A receptors may have a direct effect on maternal behavior independent of their interaction with D 2 receptors. The possible behavioral and neural mechanisms by which 5-HT 2A - and D2-mediated maternal effects and their interaction are discussed.
... Jentsch et al. (1998) reported that prefrontal dopamine utilization was reduced 3 weeks after cessation of sub-chronic PCP treatment. This effect may have contributed to impairments in the novel object recognition task as dopamine activity in the frontal cortex is imperative to working memory tasks and aligns with PAOPA's primarily dopaminergic mechanism of action (Bushnell and Levin, 1993;Jentsch and Roth, 1999;Zhang et al., 2004). In prior investigations, modafinil and lurasidone demonstrated treatment efficacy in the PCP-novel object recognition paradigm, and likewise have demonstrated pro-cognitive therapeutic effects in the clinic (Redrobe et al., 2010;Horiguchi et al., 2011). ...
PAOPA, a potent analog of prolyl-leucyl-glycinamide, has shown therapeutic potential at the preclinical stage for dopaminergic related illnesses, including animal models of schizophrenia, Parkinson’s disease and haloperidol-induced extrapyramidal movement disorders. PAOPA’s unique allosteric mechanism and dopamine D2 receptor specificity provide a unique composition of properties for the development of potential therapeutics for neuropsychiatric illnesses. We sought to investigate PAOPA’s therapeutic prospects across the spectrum of schizophrenia-like symptoms represented in the established phencyclidine-induced rat model of schizophrenia, (5 mg/kg PCP twice daily for 7 days, followed by 7 days of drug withdrawal). PAOPA was assessed for its effect on brain metabolic activity and across a battery of behavioral tests including, hyperlocomotion, social withdrawal, sensorimotor gating, and novel object recognition. PAOPA showed therapeutic efficacy in behavioral paradigms representing the negative (social withdrawal) and cognitive-like (novel object recognition) symptoms of schizophrenia. Interestingly, some behavioral indices associated with the positive symptoms of schizophrenia that were ameliorated in PAOPA’s prior examination in the amphetamine-sensitized model of schizophrenia were not ameliorated in the PCP model; suggesting that the deficits induced by amphetamine and PCP—while phenotypically similar—are mechanistically different and that PAOPA’s effects are restricted to certain mechanisms and systems. These studies provide insight on the potential use of PAOPA for the safe and effective treatment of schizophrenia.
... However, this term had also been used in animal studies. In animal studies, "working memory" was usually distinguished from "reference memory" [34][35][36][37][38][39][40]. In animal studies, "working memory" was defined as a memory system that retains information that is necessary for only one trial, not for subsequent trials, while "reference memory" was considered to be a memory that was useful over many trials and even for an entire experiment that lasted for several weeks or months [22,41]. ...
The prefrontal cortex participates in a variety of higher cognitive functions. The concept of working memory is now widely used to understand prefrontal functions. Neurophysiological studies have revealed that stimulus-selective delay-period activity is a neural correlate of the mechanism for temporarily maintaining information in working memory processes. The central executive, which is the master component of Baddeley's working memory model and is thought to be a function of the prefrontal cortex, controls the performance of other components by allocating a limited capacity of memory resource to each component based on its demand. Recent neurophysiological studies have attempted to reveal how prefrontal neurons achieve the functions of the central executive. For example, the neural mechanisms of memory control have been examined using the interference effect in a dual-task paradigm. It has been shown that this interference effect is caused by the competitive and overloaded recruitment of overlapping neural populations in the prefrontal cortex by two concurrent tasks and that the information-processing capacity of a single neuron is limited to a fixed level, can be flexibly allocated or reallocated between two concurrent tasks based on their needs, and enhances behavioral performance when its allocation to one task is increased. Further, a metamemory task requiring spatial information has been used to understand the neural mechanism for monitoring its own operations, and it has been shown that monitoring the quality of spatial information represented by prefrontal activity is an important factor in the subject's choice and that the strength of spatially selective delay-period activity reflects confidence in decision-making. Although further studies are needed to elucidate how the prefrontal cortex controls memory resource and supervises other systems, some important mechanisms related to the central executive have been identified.
... Blockade of D1-like receptors in PFC disrupts WM (Sawaguchi and Goldman-Rakic, 1991;Arnsten et al., 1994) and the administration of the D1 agonist SFK 38393 in animals is sufficient to rescue the WM defect associated to DA depletion (Arnsten et al., 1994;Mizoguchi et al., 2000). The role of D2 receptors in WM is more controversial given that D2-like receptor antagonists have been reported to impair WM and delaydependent PFC neuronal activity in some studies (Didriksen, 1995;Murphy et al., 1996;Arnsten and Goldman-Rakic, 1998), but not in others (Bushnell and Levin, 1993;Sawaguchi and Goldman-Rakic, 1994;Williams and Goldman-Rakic, 1995;Verma and Moghaddam, 1996;Aultman and Moghaddam, 2001). Recent evidence suggests that D4 receptors, which are detected mainly in the corticolimbic areas, with particularly high levels in PFC (for reviews see Tarazi and Baldessarini, 1999;Oak et al., 2000), are involved in mediating WM in rodents (Zhang et al., 2004a). ...
Dopamine (3,4-dihydroxyphenethylamine, DA) is a neuroendocrine transmitter belonging to the catecholamine and phenethylamine families. DA in the brain plays a critical role in modulating a variety of actions on neuroendocrine and behavioral systems. Pathological change in DA transmission is a key feature of many neurological and psychiatric disorders, such as schizophrenia, Parkinson's disease, Tourette's syndrome, and many others. Theories on the behavioral function of DA in the brain have advanced from the original proposal that DA could mediate the hedonic impact of rewards and motor behavior, to the hypothesis that this system may mediate incentive salience to reward-related stimuli. More recently it has been proposed that DA mediates reinforcement learning. Even if the theoretical debate around DA function continues, the central role of this neurotransmitter as a mediator of memory formation is being widely recognized. Memory has been distinguished, according to a temporal gradient, as: short-term memory, which lasts from seconds to minutes, and long term memory, which lasts from hours to years. The two forms of memory rely on different neural substrates and are affected by different pharmacological manipulations. Long-term memory has been further distinguished into different categories depending on the kind of learning mechanism activated. The multiple memory system theory, in fact, posits that long-term memory can be distinguished into explicit and implicit memories. Explicit memory derives from relational and/or action-outcome learning mechanisms that lead to the formation of mental representation of events, contexts, or instrumental actions. Explicit memory is thought to be dependent upon the activity of regions located in the cortico limbic systems (i.e., hippocampus). Implicit memory is formed through stimulus-response learning and leads to the incremental acquisition of skills and habits, and it is dependent on the activity of sensorimotor systems (i.e., the dorsal striatum). DA modulates the activity of both of these neuronal pathways, and therefore it mediates the formation of different forms of memory. In this chapter we will first describe the characteristics and general functions of the dopaminergic system, including an overview of the pharmacological agents available to modulate it. Then we will discuss the involvement of DA in learning and memory within this theoretical framework. In particular, we will review pre-clinical behavioral pharmacological experiments using DAergic drugs to manipulate DA activity, supporting the role for DA in modulating different forms of memory during the consolidation phase.
... Ellis et al. (Ellis et al., 2005) showed that the simultaneous stimulation of D1R and D2R in dopamine-depleted participants caused impairment of WM. Also several animal studies have shown that the DA system plays an important role for spatial WM (Bushnell and Levin, 1993;Kim and Levin, 1996;Korz and Frey, 2007;Lopes Aguiar et al., 2008;Wilkerson and Levin, 1999;Wisman et al., 2008), mainly via pathways located in the hippocampus as the mid brain neurons innervate the hippocampus (Gasbarri et al., 1997;Verney et al., 1985). White, 1989, 1991) have revealed that the D2R agonist LY 171555 improved spatial WM performance and it was shown that intra-hippocampal injection of the D1R agonist SKF-38393 also improved spatial working memory performance in rats. ...
A series of compounds have been reported to enhance memory via the DA system and herein a heterocyclic compound was tested for working memory (WM) enhancement. 2-(diphenylmethanesulfinylmethyl)-1,3-thiazole (CE-103) was synthesized in a six-step synthesis. Binding of CE-103 to the dopamine (DAT), serotonin (SERT) and norepinephrine (NET) transporters and dopamine reuptake inhibition was tested as well as blood brain permeation and a screen for GPCR targets. 60 male Sprague Dawley rats were divided into six groups: CE-103 treated 1-10 mg/kg body weight, trained (TDI) and yoked (YDI) and vehicle treated, trained (TVI) and yoked (YVI) rats. Daily single intraperitoneal injections for a period of 10 days were administered and rats were tested in a radial arm maze (RAM). Hippocampi were taken six hours following the last day of training and complexes containing the unphosphorylated or phosphorylated dopamine transporter (DAT) and complexes containing the D1-3 dopamine receptor subunits were determined. CE-103 was binding to the DAT but insignificantly to SERT or NET and dopamine reuptake was blocked specifically (IC50 =14.73 μM). From day eight the compound was decreasing WM errors in the RAM significantly at both doses tested as compared to the vehicle controls. In the trained CE-103-treated group levels of the complex containing the phosphorylated dopamine transporter (pDAT) as well as D1R were decreased while levels of complexes containing D2R and D3R were significantly increased. CE-103 was shown to enhance spatial WM and DA reuptake inhibition with subsequent modulation of D1-3 receptors is proposed as a possible mechanism of action.
... A more plausible explanation for the quinpirole-induced change in active/inactive selection is that rats were less able to retain information from the active-lever light during periods when no information was present. In support of this hypothesis, there is limited evidence from previous studies that quinpirole disrupts spatial working memory [53]. It is possible that quinpirole reduced memory of, or memory confidence for, the spatial location of the active lever, once the observing light has extinguished and this might be one of the mechanisms driving 39 increased observing in quinpirole-treated rats. ...
Excessive checking is a common, debilitating symptom of obsessive-compulsive disorder (OCD). In an established rodent model of OCD checking behaviour, quinpirole (dopamine D2/3-receptor agonist) increased checking in open-field tests, indicating dopaminergic modulation of checking-like behaviours.
We designed a novel operant paradigm for rats (observing response task (ORT)) to further examine cognitive processes underpinning checking behaviour and clarify how and why checking develops. We investigated i) how quinpirole increases checking, ii) dependence of these effects on D2/3 receptor function (following treatment with D2/3 receptor antagonist sulpiride) and iii) effects of reward uncertainty.
In the ORT, rats pressed an ‘observing’ lever for information about the location of an ‘active’ lever that provided food reinforcement. High- and low-checkers (defined from baseline observing) received quinpirole (0.5 mg/kg, 10 treatments) or vehicle. Parametric task manipulations assessed observing/checking under increasing task demands relating to reinforcement uncertainty (variable response requirement and active-lever location switching). Treatment with sulpiride further probed the pharmacological basis of long-term behavioural changes.
Quinpirole selectively increased checking, both functional observing lever presses (OLPs) and non-functional extra OLPs (EOLPs). The increase in OLPs and EOLPs was long-lasting, without further quinpirole administration. Quinpirole did not affect the immediate ability to use information from checking. Vehicle and quinpirole-treated rats (VEH and QNP respectively) were selectively sensitive to different forms of uncertainty. Sulpiride reduced non-functional EOLPs in QNP rats but had no effect on functional OLPs. These data have implications for treatment of compulsive checking in OCD, particularly for serotonin-reuptake-inhibitor treatment-refractory cases, where supplementation with dopamine receptor antagonists may be beneficial.
... Another reasonable hypothesis for the deficient suppression observed could be the interference of SCH 23390 on memory retention, hindering retrieval of the association that was learned during the conditioning phase. Although working and reference memory do not appear to be affected by systemic SCH 23390 treatment in rats (Bushnell and Levin, 1993), other studies point to mnemonic impairment caused by dopamine D 1 receptor antagonism. Arnsten et al. (1994) showed that systemic SCH 23390 administration impaired memory performance in young monkeys in a delayed response task, whereas agonist-induced improvements were blocked by this drug. ...
... The differential effects of SCH23390 (inhibitory) and raclopride (no effect) on the STFP are in agreement with D1 and D2 receptors having opposing roles in appetitive conditioning (Eyny and Horvitz, 2003) and in line with results showing a role for the D1 (Beninger and Miller, 1998; Smith-Roe and Kelley, 2000; Azzara et al, 2001; Baldwin et al, 2002; Eyny and Horvitz, 2003; Touzani et al, 2008) but not D2 (Bushnell and Levin, 1993) receptor in appetitive learning in non-social learning paradigms. D2-type receptors can act in direct antagonism to the D1-type receptors in learning mechanisms, with D1 activating and D2 inhibiting the regulatory DA and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32; Calabresi et al, 2000; Otani et al, 2003; Calabresi et al, 2007; Nishi et al, 1997; Svenningsson et al, 2004) in glutamate-dependent long-term potentiation of synapses (Nishi et al, 1997; Otani et al, 2003; Svenningsson et al, 2004; Lemon and Manahan-Vaughan, 2006). ...
The neurobiological bases of social learning, by which an animal can 'exploit the expertise of others' and avoid the disadvantages of individual learning, are only partially understood. We examined the involvement of the dopaminergic system in social learning by administering a dopamine D1-type receptor antagonist, SCH23390 (0.01, 0.05, and 0.1 mg/kg), or a D2-type receptor antagonist, raclopride (0.1, 0.3, and 0.6 mg/kg), to adult female mice prior to socially learning a food preference. We found that while SCH23390 dose-dependently inhibited social learning without affecting feeding behavior or the ability of mice to discriminate between differently flavored diets, raclopride had the opposite effects, inhibiting feeding but leaving social learning unaffected. We showed that food odor, alone or in a social context, was insufficient to induce a food preference, proving the specifically social nature of this paradigm. The estrous cycle also affected social learning, with mice in proestrus expressing the socially acquired food preference longer than estrous and diestrous mice. This suggests gonadal hormone involvement, which is consistent with known estrogenic regulation of female social behavior and estrogen receptor involvement in social learning. Furthermore, a detailed ethological analysis of the social interactions during which social learning occurs showed raclopride- and estrous phase-induced changes in agonistic behavior, which were not directly related to effects on social learning. Overall, these results suggest a differential involvement of the D1-type and D2-type receptors in the regulation of social learning, feeding, and agonistic behaviors that are likely mediated by different underlying states.
... It has been approved for the symptomatic treatment of mild-to-advanced Parkinson's disease (PD) in the USA, Canada, Israel, and the European Union (for review, see Guay, 2006 ). The inhibition of MAO- B reduces the breakdown of various monoamine neurotransmitters that are important in learning and memory processes (Bushnell and Levin, 1993; Arnsten et al., 1998; Lidow et al., 1998). Earlier studies have shown that central dopaminergic and cholinergic functions were significantly enhanced after rasagiline treatment (Lamensdorf et al., 1996; Speiser et al., 1998b ). ...
The effect of rasagiline on learning and memory in Lister-Hooded rats was investigated in this study. Two cognitive tests were used: a 24-h temporal deficit novel object recognition test and a modified water maze task. Rasagiline (0.3 and 1 mg/kg) was administered subcutaneously 15 min before the cognitive tests. In a novel object recognition test, rasagiline treatment enhanced object recognition memory. A small effect was observed with 0.3 mg/kg rasagiline; at 1 mg/kg, rasagiline-treated animals spent twice as much time exploring the novel object. On the water maze test, the use of an on-demand platform allowed adjustment of the difficulty of this spatial learning task. This enabled the detection of a small positive effect of rasagiline (1 mg/kg) on spatial learning, which was not observed in earlier reports. For the first time, our study has showed the procognitive effect of rasagiline in young healthy rats. On the basis of these findings, a monoamine oxidase-B inhibitor would seem to be a potential symptomatic treatment for cognitive impairments affecting patients with neurodegenerative disorders.
... Specifically, stress-induced working memory impairment arises in part from high levels of catecholamine release, stimulating dopamine (DA) D1 receptors (Murphy et al. 1996), which in turn activate the cAMP (Vijayraghavan et al. 2007) intracellular signaling cascade. Accordingly, intra-PFC infusions of a D1 agonist produce working memory impairment (Bushnell and Levin 1993; Birnbaum et al. 1999), while D1 receptor antagonists, as well as cAMP inhibitors, have been shown to reverse stress-related working memory impairments when infused into the PFC (Arnsten 2007). It has further been shown that stimulation of the norepinephrine (NE) alpha-2a receptor can protect working memory during stress, likely through its inhibition of the cAMP signaling pathway (Birnbaum et al. 2000). ...
Understanding effects of estrogen on the medial prefrontal cortex (PFC) may help to elucidate the increased prevalence of depression and post-traumatic stress disorder in women of ovarian cycling age. Estrogen replacement in ovariectomized (OVX) young rats amplifies the detrimental effects of stress on working memory (a PFC-mediated task), but the mechanisms by which this occurs have yet to be identified. In male rats, stimulation of norepinephrine alpha-2 adrenoceptors protects working memory from stress-induced impairments. However, this effect has not been studied in females, and has not been examined for sensitivity to estrogen. The current study asked whether OVX females with estrogen replacement (OVX+Est) and without replacement (OVX+Veh) responded differently to stimulation of alpha-2 adrenoceptors after administration of the benzodiazepine inverse agonist FG7142, a pharmacological stressor. The alpha-2 agonist, guanfacine, protected working memory from the impairing effects of FG7142 in OVX+Veh, but not in OVX+Est rats. Western Blot analysis for alpha-2 receptors was performed on PFC tissue from each group, but no changes in expression were found, indicating that the behavioral effects observed were likely not due to changes in receptor expression. These findings point to possible mechanisms by which estrogen may enhance the stress response, and hold implications for the gender discrepancy in the prevalence of stress-related mental illness.
... All these peptides showed significant cognition enhancing properties that could imply a causal relationship between the stimulation of central dopamine neurotransmission and learning. The more so that the most at these peptides affected also the metabolism of dopamine in brain (Sirnonnet et al. 1981, Sumners and Philips 1983, Braszko et al. 1991) which, as already mentioned, is basic for the cognitive processes (Packard and White 1989, 1991, Sawaguchi and Goldman-Rakic 1991, McGurk et al. 1992, Bushnell and Levin 1993). The angiotensin fragments which did not contain complete Ang I1 (3-7) amino acid sequence like Ang I1 (3-5) and Ang I1 (3-6) (Wlasienko et al. 1989) or Ang I1 (1-6) and Ang I1 (2-6) (Holy et al. 1994) were inactive at both, intensifying stereotype behaviour and enhancing memory. ...
In this study I attempted to assess, in rats, the role of AT1 and AT2 angiotensin receptor subtypes in the phenomenon of improved learning and memory after an intracerebroventricular (icv) injection of angiotensin II (Ang II) and Ang II (3-7). Selective AT1 (losartan, 1 mg) or AT2 (CGP 42112 A, 2 micrograms) receptor antagonist was dissolved in 2 microliters of saline and given to the left cerebral ventricle 5 min before 1 nmol Ang II or Ang II (3-7) injected in the same volume of saline to the right ventricle. Consequently, there were 9 experimental groups which underwent 3 memory oriented and 3 auxiliary tests. Ang II and Ang II (3-7) significantly improved retention of the passive avoidance and recognition memory. These effects were abolished by losartan or CGP 42112 A. Better, after Ang II and Ang II (3-7), acquisition of conditioned avoidance responses was unchanged by losartan and abolished by CGP 42112 A. None of the treatments significantly changed rats motor behaviour in open field. Losartan as well as CGP 42112 A abolished significant enhancement of apomorphine (1 mg/kg, i.p.) stereotypy caused by Ang II and Ang II (3-7). The results suggest considerable involvement of AT1 and AT2 angiotensin receptors in the cognitive enhancement produced by angiotensins.
... For example, post training administration of quinpirole (D 2 agonist) and D-amphetamine (catecholaminergic agonist) has been found to improve performance in various types of tasks (see [96]). Others have reported an impairment of short-term memory in a delayed response task after administration of o-amphetamine [21]. This deficit appeared to be related to the D 2 and D 3 receptor subtypes. ...
The cholinergic hypothesis claims that the decline in cognitive functions in dementia is predominantly related to a decrease in cholinergic neurotransmission. This hypothesis has led to great interest in the putative involvement of the cholinergic neurotransmission in learning and memory processes. This review aims to assess the data of studies in which the role of acetylcholine (ACh) in cognitive functions was investigated. For this purpose, studies from three different fields of research, namely: (1) behavioral pharmacology (effects of drugs on behavior); (2) behavioral neuroscience (effects of brain lesions on behavior); and (3) dementia, are discussed separately. The experimental tools that have been used in pharmacological studies may appear to be inadequate to enable conclusions to be drawn about the involvement of ACh in learning and memory processes. Especially, the use of scopolamine as a pharmacological tool is criticized. In the field of behavioral neuroscience a highly specific cholinergic toxin has been developed. It appears that the greater and more specific the cholinergic damage, the fewer effects can be observed at the behavioral level. The correlation between the decrease in cholinergic markers and the cognitive decline in dementia may not be as clearcut as has been assumed. The involvement of other neurotransmitter systems in cognitive functions is briefly discussed. Taking into account the results of the different fields of research, the notion that ACh plays a pivotal role in learning and memory processes seems to be overstated. Even when the role of other neurotransmitter systems in learning and memory is taken into consideration, it is unlikely that ACh has a specific role in these processes. On basis of the available data, ACh seems to be more specifically involved in attentional processes than in learning and memory processes.
The prefrontal cortex plays important roles in a variety of higher cognitive functions, such as thinking, reasoning, planning, and decision-making (Goldman-Rakic 1987; Miller 2000; Miller and Cohen 2001; Fuster 2008; Funahashi 2015). Neural mechanisms for the prefrontal cortex to operate these functions have been extensively examined using human subjects and animals. Especially, studies using nonhuman primates have contributed significantly to understanding prefrontal functions and their neural mechanisms. Since Jacobsen (1936) first reported that monkeys having bilateral lesions in the prefrontal cortex exhibited severe and long-lasting impairments of delayed-response performances, the delayed-response task has been one of the important behavioral tasks to examine prefrontal functions using animal models. Since the monkey is required to retain the baited position during the delay period to correctly perform the delayed-response task, delayed-response deficits had been thought to be caused by an impairment of short-term storage of spatial information. Subsequently, not only the tasks requiring short-term storage of spatial information but also behavioral tasks requiring the storage of non-spatial information were shown to be impaired by bilateral lesions of the prefrontal cortex. Therefore, an important function of the prefrontal cortex was thought to be the short-term storage of various information. Although behavioral studies repeatedly exhibited delayed-response deficits in monkeys having prefrontal lesions, no agreement regarding the cause of delayed-response deficits had been reached among researchers. Some researchers concluded that delayed-response deficits were caused by an impairment of short-term memory. However, other researchers concluded that these deficits were caused by an increase in susceptibility to interference stimuli or difficulty to use kinesthetic information. In addition, the disagreement regarding behavioral deficits after prefrontal lesions was also present between animal studies and human clinical studies. Especially, human patients having damages in the prefrontal cortex did not exhibit delayed-response deficits and exhibit any impairment in memory functions.
Early postnatal development in rodents is sensitive to neurotoxic effects of the environmental contaminant, methylmercury. While juvenile and adolescent exposure also produce long-term impairments in behavior, the outcome of neonatal exposure is less understood. Neural development during the neonatal period in rodents is akin to that seen in humans during the third trimester of pregnancy but methylmercury exposure occurring during the neonatal period has not been modeled, partly because breast milk is a poor source of bioavailable methylmercury. To examine this developmental period, male Long-Evans rats were exposed to 0, 80, or 350 µg/kg/day methylmercuric chloride from postnatal days 1 to 10, the rodent neonatal period. As adults, behavioral flexibility, attention, memory, and expression of the dopamine transporter in these rats was assessed. Rats exhibited changes in behavioral flexibility assessed in a spatial discrimination reversal procedure. Those rats exposed to the highest dose of methylmercury displayed subtly altered patterns of perseveration compared to control animals. During acquisition of the attention/memory procedure, rats exposed to this dose also had slower acquisition, and achieved lower overall accuracy during training, compared to controls despite neither attention nor memory being affected once the task was acquired. Finally, dopamine transporter expression in the striatum, prefrontal cortex, and hippocampus was unchanged in these adult rats. The results of this study replicate the trend of findings seen with exposure during gestation or during adolescence.
Gestational exposure to methylmercury disrupts dopamine-mediated behavior and produces heightened sensitivity to monoamine agonists later in life. This has been reported and replicated following both pre- and post-natal exposure. Impacts of methylmercury when exposure occurs during the sensitive period of adolescence, a key period of dopaminergic development, remain underexplored. There have been variable results thus far in studies investigating links between adolescent exposure to methylmercury and alterations in executive function and altered sensitivity to monoamine agonists. The current study was designed to investigate adolescent exposure by exposing male mice to 0, 0.3, or 3 ppm methylmercury during adolescence and training them in a hybrid task to assess two executive functions, attention and memory, in adulthood. Behavior in these animals was probed with a range of doses of the dopamine agonist, d-amphetamine, and the norepinephrine agonist, desipramine. Attention and memory in these mice were sensitive to disruption by d-amphetamine and interacted with methylmercury exposure. Choice latencies were also longer in the MeHg-exposed mice. Desipramine did not affect behavior in these animals nor did it interact with methylmercury. It is concluded that methylmercury-related inhibition of behavior observed in this study were differentially sensitive to acute disruption in dopamine, but not norepinephrine, neurotransmission.
A series of compounds have been shown to enhance cognitive function via the dopaminergic system and indeed the search for more active and less toxic compounds is continuing. It was therefore the aim of the study to synthetise and test a novel heterocyclic compound for cognitive enhancement in a paradigm for working memory. Specific and effective dopamine re-uptake inhibition DAT (IC50 = 4,1 ± 0,8 μM) made us test this compound in a radial arm maze (RAM) in the rat.
CE-125 (4-((benzhydrylsulfinyl)methyl)-2-cyclopropylthiazole), was tested for dopamine (DAT), serotonin and norepinephrine re-uptake inhibition by a well-established system. The working memory index (WMI) was evaluated in male Sprague Dawley rats that were intraperitoneally injected with CE-125 (1 or 10 mg/kg body weight). In order to evaluate basic neurotoxicity, the open field, elevated plus maze, rota rod studies and the forced swim test were carried out. Frontal cortex was taken at the last day of the RAM test and dopamine receptors D1R and D2R, DAT and phosphorylated DAT protein levels were determined.
On the 10th day both doses were increasing the WMI as compared to the vehicle-treated group. In both, trained and treated groups, D1R levels were significantly reduced while D2R levels were unchanged. DAT levels were comparable between all groups while phosphorylated DAT levels were increased in the trained group treated with 1 mg/kg body weight. CE-125 as a probably non-neurotoxic compound and specific reuptake inhibitor was shown to increase performance (WMI) and modulation of the dopaminergic system is proposed as a possible mechanism of action.
In this study, cortical receptor complex levels were determined in fetal Down syndrome (DS, trisomy 21) brain. Frontal cortices were obtained from individuals with DS (19th-22nd week of gestation) and controls. Membrane proteins were extracted, assayed on blue native gels and immunoblotted with brain receptor antibodies. Levels of a D1R-containing complex were markedly decreased in male and female cortices of DS individuals. Females with DS had significant reductions of nicotinic acetylcholine receptors α4 and α7, NMDA receptor GluN1 and AMPA receptor GluA1- and GluA3-containing receptor complexes. Levels of other brain receptor complexes (5-hydroxytryptamine 1A, GluA2 and GluR4 receptor-containing complexes) were comparable between the groups of females. Levels of GluA2- and GluA3-containing complexes were significantly increased in males. Decreased levels of D1R complexes in both sexes, along with the significant reduction of α4, α7-containing receptor complexes observed in females, may explain the brain deficits and impaired cognition observed in DS.
Nicotine has been found to improve memory performance in a variety of tests including the radial-arm maze. Nicotine may have effects mediated by promoting the release of dopamine. The present study was conducted to determine the interactions of nicotine with D1 and D2 agonists. Rats were acutely administered nicotine, the D1 agonist SKF 38393, and D2/D3 agonist quinpirole, and nicotine together with each of these agonists. Nicotine significantly improved choice accuracy in the radial-arm maze. The D1 agonist SKF 38393 significantly impaired choice accuracy. Nicotine was effective in reversing this effect. The D2/D3 agonist quinpirole showed a trend toward potentiating the improvement in choice accuracy caused by 0.2 mg/kg (0.43 μmol/kg) of nicotine. These data show that, as with the nicotinic antagonist mecamylamine, there are significant interactions of dopamine systems with nicotine effects. © 1994 Wiley-Liss, Inc.
Substantial evidence supports the claim that neurocognitive deficits, rather than positive or negative symptoms, are the core features of schizophrenia that are the most effective predictors of the psychosocial functioning of patients. Unfortunately, these cognitive processes are only minimally affected by even ‘next generation’ antipsychotic treatments, indicating that they represent an important unmet need. Despite the centrality of cognitive impairments to the psychopathology of schizophrenia, the development of animal models of clinically-relevant neurocognitive processes, with the possible exception of working memory, has lagged far behind the development of animal models for negative or positive symptoms. Here, I will outline progress to date towards validating animal models of cognitive dysfunction in schizophrenia. I will also propose how models may be better implemented to facilitate the generation of data that is as meaningful as possible for clinical neuroscience and treatment research. In this way, pre-clinical neuroscience may be able to make even more practical and relevant contributions to schizophrenia research and treatment development.
Evidence suggests that acute exposure to (+/-)3,4-methylenedioxymethamphetamine (MDMA) produces qualitatively similar effects on recognition task performance as other stimulant-type drugs. The current study examined whether there was a similar neurochemical basis to these memory effects by examining the effects of a D1 receptor antagonist (SCH23390) and D2 antagonist (eticlopride) on MDMA- or cocaine-induced impairments in delayed matching-to-sample performance in rats. At low doses it was shown that eticlopride was ineffective in antagonizing either MDMA or cocaine's effects, and at higher doses exacerbated their effects. In contrast, the D1 receptor antagonist SCH23390 was only able to significantly attenuate the disruption caused by MDMA, but not cocaine's effects. Therefore, although present evidence suggests that the effect of acute MDMA on memory-task performance may be related to its effects at D1 receptor sites, there may be differences between MDMA and cocaine in the precise neurochemical pathways involved despite their having similar cognitive effects.
It is well established that learning and memory are complex processes involving and recruiting different brain modulatory neurotransmitter systems. Considerable evidence points to the involvement of dopamine in various aspects of cognition, and interest has been focused on investigating the clinical relevance of dopamine systems to age-related cognitive decline and manifestations of cognitive impairment in schizophrenia, Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases. In the past decade or so, in spite of the molecular cloning of the five dopamine receptor subtypes, their specific roles in brain function remained inconclusive due to the lack of completely selective ligands that could distinguish between the members of the D1-like and D2-like dopamine receptor families. One of the most important advances in the field of dopamine research has been the generation of mutant mouse models permitting evaluation of the dopaminergic system using gene targeting technologies. These mouse models represent an important approach to explore the functional roles of closely related receptor subtypes. In this review, we present and discuss evidence on the role of dopamine receptors in different aspects of learning and memory at the cellular, molecular and behavioral levels. We compare evidence using conventional pharmacological, lesion or electrophysiological studies with results from mice with targeted deletions of different subtypes of dopamine receptor genes. We particularly focus on dopamine D1 and D2 receptors in an effort to delineate their specific roles in various aspects of cognitive function. We provide strong evidence, from our own recent work as well as others, that dopamine is part of the network that plays a very important role in cognitive function, and that although multiple dopamine receptor subtypes contribute to different aspects of learning and memory, the D1 receptor seems to play a more prominent role in mediating plasticity and specific aspects of cognitive function, including spatial learning and memory processes, reversal learning, extinction learning, and incentive learning.
D1-receptor antagonism is known to impair rodent memory but also inhibits spontaneous exploration of stimuli to be remembered. Hypo-exploration could contribute to impaired memory by influencing event processing. In order to explore this effect, the D1 receptor antagonist, SCH23390, was administered to rats via routes that either did or did not affect spontaneous exploration: systemic or prelimbic administration, respectively. Effects were tested in spatial and non-spatial memory tasks selected for their requirements for self-initiated exploration of stimuli to be remembered in order to examine the effects on memory: cross-maze and object recognition task. Systemic administration reduced spatial exploration in cross-maze as well as in an open field test, and also reduced object exploration. Spatial (hippocampus-dependent) short-term memory was inhibited in the cross-maze and non-spatial short-term object retention was also impaired. In contrast to these systemic effects, bilateral injections of SCH23390 into the prelimbic cortices altered neither spatial nor object exploration, but did inhibit short-term memory in both cross-maze and object recognition task. Therefore, the inhibiting effects of SCH23390 on both spatial and non-spatial memory were not mediated indirectly via reduced exploration of stimuli to be remembered, but through antagonism of a prelimbic D1-R function that is directly involved in memory formation. Finally, a cooperative regulation of spatial exploration between D1-R and mGlu5 was indicated by a synergistic effect of the antagonists SCH23390 and MPEP.
Working memory impairment is a core symptom of schizophrenia, but no existing treatment remediates this deficit. Inconsistent conceptualizations and few reliable translational measures are major hindrances to understanding the neurobiology of this aspect of cognition. Using comparable task designs may help bridge clinical and preclinical research efforts.
A novel rodent procedure was designed to translate the n-back working memory task used in schizophrenic patients.
Rats were trained in five-lever operant chambers to recall either the last (one-back) or penultimate (two-back) lever from random sequences of lever presentations of variable lengths. Psychotomimetic doses of amphetamine, dizocilpine maleate (MK801), and (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) were tested for disruption of accuracy, and cognitive-enhancing doses of amphetamine, nicotine, and (+/-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride (SKF38393 hydrochloride) were examined for improvements in performance.
High doses of amphetamine (0.8 and 1.6 mg/kg) significantly reduced accuracy while increasing total trials; 0.1 mg/kg MK801 and 2.0 mg/kg DOI also reduced accuracy, but the latter concurrently impaired responding. At the lowest dose (0.2 mg/kg), amphetamine increased total trials and rewards without affecting accuracy; 1.0 mg/kg nicotine reduced accuracy without affecting total trials, whereas 10.0 mg/kg SKF38393 had the opposite effect.
Although the possibility for mediating behaviors may exist, the rodent n-back task provides a clinically relevant model of working memory. Amphetamine and MK801 produced selective impairments without disrupting responding. The cognitive enhancers did not improve working memory, but low doses of amphetamine improved response efficiency. This novel procedure may be useful for examining cognitive deficits and their potential reversal in animal models of schizophrenia.
In order to clarify the interactions between monoaminergic and cholinergic systems in working and reference memory functions, the effects of administration of the alpha, beta-adrenergic, D1-, D2-dopaminergic or serotonergic receptor antagonist together with the muscarinic receptor antagonist scopolamine on this behavior were examined using a three-panel runway task. Both in working and reference memory tasks, the number of errors (attempts to pass through two incorrect panels of the three panel-gates at four choice points) was significantly increased by 0.32 mg/kg scopolamine, but not by the doses up to 0.18 mg/kg. The beta-adrenergic antagonist propranolol at 10 mg/kg had no effect on the number of working memory errors. Combined administration of 10 mg/kg propranolol and scopolamine at 0.1 and 0.18 mg/kg significantly increased the number of working memory errors. However, in a reference memory task, propranolol at 10 mg/kg did not affect the number of errors, whether administered alone or together with 0.1 mg/kg scopolamine. Other monoaminergic receptor antagonists, including the alpha-adrenergic antagonist phentolamine (3.2 and 10 mg/kg), D1-antagonist SCH23390 (0.032 and 0.056 mg/kg). D2-antagonist sulpiride (100 mg/kg) and serotonin antagonist cinanserin (10 and 32 mg/kg) had no significant effect on working or reference memory errors, whether they were administered independently or in combination with scopolamine at 0.1 mg/kg. These results suggest that beta-adrenergic/muscarinic interactions play an important role in mediating processes involved in working memory performance of rats.
Dopamine has been implicated in the cognitive process of working memory but the cellular basis of its action has yet to be revealed. By combining iontophoretic analysis of dopamine receptors with single-cell recording during behaviour, we found that D1 antagonists can selectively potentiate the 'memory fields' of prefrontal neurons which subserve working memory. The precision shown for D1 receptor modulation of mnemonic processing indicates a direct gating of selective excitatory synaptic inputs to prefrontal neurons during cognition.
Two catechol O-methyltransferase inhibitors, peripherally acting entacapone and also centrally acting tolcapone, were tested regarding their capacity to influence learning and memory in adult intact rats. Tolcapone was also studied in rats treated with scopolamine, in adult rats lesioned in the nuclei basalis magnocellularis, and in aged rats. Spatial working memory performance (radial-arm maze) of intact rats was facilitated following pretraining i.p. administration of tolcapone (10 mg/kg). Entacapone was ineffective at doses of 10 and 30 mg/kg. Senescent poor performers improved their accomplishment in the spatial memory task (linear-arm maze) under the influence of tolcapone. Scopolamine (1 mg/kg) impaired working memory performance. Bilateral lesions in the nucleus basalis magnocellularis reduced choline acetyltransferase activity in the frontal cortex by 26% and retarded the learning rate of spatial place task. Tolcapone was not able to counteract the performance deficits in these models. It is concluded that tolcapone can either slightly improve or impair the memory functions depending on task specific elements and performance factors.
Profound latent learning and memory deficits with increased monoamine levels in the brain following concussive brain injury (CBI) have been documented in our previous work. The purpose of the present study was to determine the role of dopamine (DA) receptor subtypes in the memory deficits associated with CBI. Profound latent learning and memory impairments were observed in the vehicle-treated CBI mice. SCH-23390 administered 15 min post-injury had no significant effects on the impairments of latent learning and memory in the CBI mice. Sulpiride significantly improved the impairments of latent learning and memory in a dose-dependent manner, indicating that activation of dopaminergic neuronal function is involved in the CBI-induced amnesia. Interestingly, co-administration of sulpiride and SCH-23390, at doses which alone has no significant effect, significantly ameliorated the impairments of latent learning and memory. These results strongly suggested that D1 and D2 receptor subtypes are synergistically involved in the dysfunction of learning and memory associated with CBI.
The effects of new selective catechol-O-methyltransferase (COMT) inhibitors entacapone (mainly peripheral effect) and tolcapone (acting also in the brain) on normal and impaired cognitive functions were studied in aversively motivated inhibitory avoidance using a single-trial passive avoidance paradigm in young adult rats. Passive avoidance retention latency was shortened by either scopolamine (1.0 mg/kg) or bilateral lesions to nucleus basalis magnocellularis (NBM) caused by infusions of ethylcholine aziridinium (AF64A). Entacapone (30 mg/kg) administered once before training or before the retention test, 24 h after training, prevented the effect of scopolamine but did not alter extinction in these rats. However, entacapone (30 mg/kg) prolonged lag time when given during the extinction process to intact rats after training. Tolcapone administered once before training (10 mg/kg) counteracted the effect of scopolamine. It prolonged retention latency of the intact rats when given after training (10 mg/kg). Tolcapone (3 mg/kg) also prolonged lag time when given during extinction to rats bearing NBM lesions. The effect of scopolamine on extinction and retrieval was not prevented by tolcapone. Only entacapone improved memory storage. Collectively, the present results indicate that COMT inhibitors prolong retention latencies in a single-trial passive avoidance test assessed at several memory phases.
Although the reinforcing properties of food are reduced in the presence of dopamine antagonist drugs, controversy exists about the relative roles of D1 vs D2 receptor subtypes in the actions of these drugs. The current experiment compared the effects of raclopride (a selective D2 receptor antagonist) and SCH 39166 (a selective D1 receptor antagonist) in the response-reinstating effects of food reinforcement. Hungry rats were trained to run a straight-alley for food reinforcement during single daily trials. The operant was then extinguished during consecutive daily non-reinforced trials. Subjects were then injected with one of four doses of raclopride (0.0, 1.0, 0.5, and 0.25 mg/kg, i.p.) or SCH 39166 (0.0, 1.0, 0.5, and 0.1 mg/kg i.p.) 30 min prior to a single reinforced treatment trial. Twenty-four h later, a test trial was conducted in an unbaited runway. The single reinforced trial in the midst of extinction was observed to reinstate operant runway performance. Raclopride, but not SCH 39166, dose-dependently attenuated this reinstatement. Motor control groups ruled out the possibility that these results were due to differential residual motor effects of the drugs. Results suggest that D2, but not D1, dopamine receptors, are involved in the response-reinstating properties of food reinforcement.
Much evidence has indicated that a disturbance in dopamine neurotransmission following mild to moderate traumatic brain injury is involved in the development of post traumatic memory deficits. In the present study we examined the effects of a dopamine receptor agonist and some antagonists on latent learning and memory deficits associated with a concussive traumatic brain injury in mice. Anaesthetized animals were subjected to mild traumatic brain injury by dropping a weight onto the head, and a single-dose injection of apomorphine (0.3-3.0 mg/kg) or haloperidol (0.3-3.0 mg/kg) was made i.p. 15 min after the trauma. One week later, a water-finding task consisting of an acquisition trial, a retention test and a retest was employed to assess learning and memory functions. Mice that had received a traumatic brain injury were impaired in task performance, with prolonged latencies for finding and drinking in the retention test and retest. Administration of haloperidol but not of apomorphine significantly shortened the prolonged latency in both of the tests, indicating that antagonism of dopamine receptors is beneficial for the recovery of post traumatic memory deficits. In order to evaluate which receptor subtype plays the major role in this model, we examined the effects of SCH-23390 (0.03-0.3 mg/kg), a D1 receptor antagonist, and sulpiride (3.0-30 mg/kg), a D2 receptor antagonist, in the same experimental paradigm. The results showed that administration of sulpiride but not of SCH-23390 significantly improved the deficits in task performance, indicating that D2 receptors are the major site of action. However, combined treatment with SCH-23390 (0.03-0.3 mg/kg) and sulpiride (3.0 mg/kg) at doses that had no effect when the antagonists were given alone exerted a significant additive effect in improving these deficits, indicating that interaction between D1 and D2 receptors is involved in these processes. The present results suggest that a dopaminergic mechanism contributes to the memory dysfunction associated with traumatic brain injury.
Dopamine (DA) within the prefrontal cortex (PFC) plays an important role in modulating the short-term retention of information during working memory tasks. In contrast, little is known about the role of DA in modulating other executive aspects of working memory such as the use of short-term memory to guide action. The present study examined the effects of D1 and D2 receptor blockade in the PFC on foraging by rats on a radial arm maze under two task conditions: (1) a delayed task in which spatial information acquired during a training phase was used 30 min later to guide prospective responses, and (2) a nondelayed task that was identical to the test phase of the delayed task but lacked a training phase, thereby depriving rats of previous information about the location of food on the maze. In experiment 1, microinjections of the D1 antagonist SCH-23390 (0.05, 0.5, or 5 microg/µl), but not the D2 antagonist sulpiride (0.05, 0.5, or 5 microg/microl), into the prelimbic region of the PFC before the test phase disrupted performance of the delayed task without affecting response latencies. In contrast, neither drug affected performance of the nondelayed task. In the present study, we also investigated the role of D1 receptors in modulating activity in hippocampal-PFC circuits during delayed responding. Unilateral injections of SCH-23390 into the PFC in the hemisphere contralateral to a microinjection of lidocaine into the hippocampus severely disrupted performance of the delayed task. Thus, the ability to use previously acquired spatial information to guide responding 30 min later on a radial arm maze requires D1 receptor activation in the PFC and D1 receptor modulation of hippocampal inputs to the PFC. These data suggest that D1 receptors in the PFC are involved in working memory processes other than just the short-term active retention of information and also provide direct evidence for DA modulation of limbic-PFC circuits during behavior.
In the first part of three overviews on recognition memory in the rat, we discussed the tasks employed to study recognition memory. In the second part, we discussed the neuroanatomical systems thought to be of importance for the mediation of recognition memory in the rat. In particular, we delineated two parallel-distributed neuronal networks, one that is essential for the processing of non-spatial/item recognition memory processes and incorporates the cortical association areas such as TE1, TE2 and TE3, the rhinal cortices, the mediodorsal thalamic nucleus and prefrontal cortical areas (Network 1), the other comprising of the hippocampus, mamillary bodies, anterior thalamic nuclei and medial prefrontal areas (Network 2), suggested to be pivotal for the processing of spatial recognition memory. The next step will progress to the level of the neurotransmitters thought to be involved. Current data suggest that the majority of drugs have non-specific, i.e. delay-independent effects in tasks measuring recognition memory. This may be due to attentional, motivational or motoric changes. Alternatively, delay-independent effects may result from altered acquisition/encoding rather than from altered retention. Furthermore, the neurotransmitter systems affected by these drugs could be important as modulators rather than as mediators of recognition memory per se. It could, of course, also be the case that systemic treatment induces non-specific effects which overshadow any specific, delay-dependent, effect. This possibility receives support from lesion experiments (for example, of the septohippocampal cholinergic system) or studies employing local intracerebral infusion techniques. However, it is evident that those delay-dependent effects are relatively subtle and more readily seen in delayed response paradigms, which tax spatial recognition memory. One interpretation of these results could be that some neurotransmitter systems are more involved in spatial than in item recognition memory processes. However, performance in delayed response tasks can be aided by mediating strategies. Drugs or lesions can alter those strategies, which could equally explain some of the (delay-dependent) drug effects on delayed responding. Thus, it is evident that neither of the neurotransmitter systems reviewed (glutamate, GABA, acetylcholine, serotonin, dopamine and noradrenaline) can be viewed as being directly and exclusively concerned with storage/retention. Rather, our model of recognition memory suggests that information about previously encountered items is differentially processed by distinct neural networks and is not mediated by a single neurotransmitter type.
The specific dopamine uptake inhibitor, GBR 12783 was tested on the retention performance of a one-trial passive avoidance test. For a moderate electric shock intensity, GBR 12783 (10 mg/kg), injected before acquisition session, improved retention performance. Scopolamine (0.125-0.5 mg/kg) completely blocked the promnesic effect of GBR 12783. Moreover, GBR 12783 increased hippocampal acetylcholine release in vivo. These data suggest that the promnesic effect of GBR 12783 is mediated by an increase in the septo-hippocampal cholinergic transmission.
Male Wistar rats were trained, in two-lever operant chambers, to press one lever (L5) after the presentation of a conditioned stimulus (a light) for 5 s (CS5) or the other lever (L20) after a conditioned stimulus for 20 s (CS20). Various drugs were administered before experimental sessions, during which CS5, CS20 and a stimulus of the intermediate duration of 12 s (CS12) were randomly presented. Rats pretreated with vehicle made approximately 50% of presses on L5 after the presentation of CS12. Atropine, diazepam, desipramine, clomipramine and moderate doses of haloperidol or of scopolamine increased the percentage of responses made on L5 after the presentation of CS20 and/or CS12. These effects could be due to a reduction of the speed of an internal clock. High doses of either haloperidol or scopolamine decreased the percentage of correct responses, an effect that was interpreted as a disruption of temporal discrimination. Nicotine and d-amphetamine decreased the percentage of responses made on L5 after the presentation of CS5 and/or CS12, an effect that could reflect an acceleration in the speed of the internal clock. Physostigmine, buspirone, mianserin and piracetam did not consistently alter performance, suggesting that these drugs do not affect timing processes.
The present study was designed to examine the effects of haloperidol (0.03, 0.1 mg/kg, intraperitoneal (i.p.)) and d-amphetamine (0.3, 1.0 mg/kg, i.p.) in a cone field task in which spatial working and reference memory (WM and RM, respectively) were assessed simultaneously. The apparatus is a large open field in which 16 cones are placed with four cones baited by placing a food reward in the top. After food-deprived rats had acquired this task they showed a high level of performance, that is avoided visits to non-baited cones (RM) and made few revisits to baited cones (WM). Haloperidol had a greater negative effect on RM than on WM performance, but also decreased the number of food rewards collected. On the other hand, the high dose of d-amphetamine induced a clear WM performance deficit, whereas RM performance was only marginally affected. The present study suggests that spatial discrimination performance can be dissociated using the measures RM and WM in the present task. Further, the deficits induced by haloperidol and d-amphetamine may not be specifically related with impaired mnemonic functions.
It has been well established that the presentation of a single reinforced trial in the midst of extinction results in a reinstatement of the previously reinforced operant response. In previous experiments, we have shown that systemically applied raclopride (a selective dopamine D2 receptor antagonist) dose dependently blocked the response-reinstating properties of food reinforcement, while SCH39166 (a selective dopamine D1 receptor antagonist) did not (11). The current experiments investigated the possible role of the nucleus accumbens in these actions of raclopride. In the first of two experiments, hungry rats were trained to traverse a straight runway for food reinforcement, a response that was then weakened through a series of extinction trials. On a single treatment trial, subjects were infused with one of three doses of intraaccumbens raclopride (0.0, 2.5, or 5.0 microg/0.5 microl/side) just prior to a reinforced trial. Twenty-four hours later, a single test trial was run in an unbaited runway. The results demonstrate that the prior day's reinforced trial produced a reinstatement of operant runway performance that was unaltered by intraaccumbens applications of raclopride. Two days later, the same animals were tested in a second experiment investigating the effects of intraaccumbens raclopride on amphetamine-induced locomotion. Subjects were pretreated with 1.0 mg/kg s.c. amphetamine prior to a 90-min locomotor activity session. The following day, subjects were again pretreated with amphetamine, but this time with a challenge dose of raclopride. Results demonstrate that the same raclopride doses that produced no effect in the response-reinstating experiment produced, in the same rats, a dose-dependent attenuation in amphetamine-induced locomotion. These data suggest that dopamine D2 receptors in the nucleus accumbens may not, in and of themselves, be necessary for the response-reinstating effects of food reinforcement.
The effects of two selective CCK(B) agonists, BC 264 and BC 197, on memory processes were investigated in rats using a recently developed two-trial recognition memory task. Control animals showed recognition memory after a 2 but not a 6 h time interval between the two trials, thus allowing a memory impairing (2 h) or improving (6 h) effect of pharmacological treatments to be measured. Drugs were injected i.p. before the second trial (retrieval phase). This experimental procedure was first studied with scopolamine and DL-amphetamine, for which a significant deficit after a 2 h interval or improvement after a 6 h interval of performance was observed, respectively. The CCK(B) agonist, BC 264, was ineffective after a 2 h time interval, whereas the dose of 0.3 microg/kg significantly enhanced performance after a 6 h inter-trial interval. In contrast, BC 197 (30 microg/kg) produced a significant disruption of performance after a 2 h inter-trial interval but was without effect after a 6 h time interval. The effects of the two CCK(B) agonists were abolished by pretreatment with a selective CCK(B) antagonist, L365,260 but not by a selective CCK(A) antagonist, L364,718. The present results suggest that CCK(B) receptors display functional heterogeneity and that CCK(B) agonists like BC 264 could offer a new perspective for the treatment of attentional and/or memory deficits.
Extracellular levels of dopamine are increased in response to systemic administration of cocaine in several brain areas including the nucleus accumbens and medial prefrontal cortex. While the cocaine-induced increase in extracellular dopamine levels in the nucleus accumbens is augmented after repeated daily cocaine, the response of extracellular dopamine levels in the medial prefrontal cortex is attenuated. Since dopamine in the medial prefrontal cortex has an inhibitory effect on nucleus accumbens dopamine levels and locomotor activity, the role of medial prefrontal cortex dopamine tolerance in the expression of sensitized locomotor behavior was further examined by injection of d-amphetamine sulfate into the prelimbic portion of the medial prefrontal cortex just prior to cocaine challenge in cocaine-sensitized rats. Male Sprague–Dawley rats were non-handled (naive) or injected with either saline (1 ml/kg, i.p.) or cocaine (15 mg/kg, i.p.) for five consecutive days. After a seven to 12 day withdrawal period, rats were microinjected with either saline or various doses of amphetamine into primarily the prelimbic region of the medial prefrontal cortex followed by systemic injection of saline or cocaine. In naive rats, intra-medial prefrontal cortex amphetamine produced a trend toward decreased locomotor responding to cocaine challenge while no effect of amphetamine was evident in daily saline pretreated rats. Daily cocaine pretreated rats that received saline in the medial prefrontal cortex demonstrated a sensitized locomotor response compared to their daily saline pretreated counterparts. This sensitization was blocked by a low dose of amphetamine (0.175 μg/side) in the medial prefrontal cortex, an effect which disappeared in animals administered higher amphetamine doses.
The study examined the effects of modulation of dopamine D2 receptors-mediated neurotransmission in the rat's prefrontal cortex (PFC) on storage and executive components of working memory. Rats were trained on delayed (delay interval, 3 s) and non-delayed choice in a U-maze. The prominence of proactive interference was evaluated by sorting errors in a current trial on the basis of animal reactions in a preceding trial. The erroneous runs to the same arm of the maze as in the previous trial were identified as the repetitions (RE) and the erroneous runs to the other arm in comparison with the previous trial were classified as alternations (AE). The bilateral microinfusion of D2 agonists PPHT (0.004 microg, 0.04 microg, 0.4 microg/1 microl) into medial wall of the PFC produced a dose-dependent increase in the error rate of the delayed-response task and did not influence non-delayed choice. In delay condition PPHT enhanced the perseverative tendencies (the rate of RE was significantly higher than the rate of AE), in non-delayed choice the erroneous performance was mainly represented by AE. In contrast, the infusion of D2-receptor antagonist sulpiride (0.03 microg, 0.3 microg, 3 microg/1 microl) increased the accuracy of delayed choice and changed the mode of intertrial dependence-rats made significantly more AE than RE. The results are discussed in terms of the involvement of D2 receptor dependent transmission of the PFC in different cognitive processes related to the delayed performance in U-maze (within-trial short-term storage of information versus dynamic control of between-trials working memory processing).
Body-weight maintenance is required in a variety of behavioral and physiological studies. A PC-based animal-weighing system
is described; it features automated data collection and allows for accurate control of body weight in test animals via manipulation
of food intake. Major system components are a PC XT-compatible computer, Lotus 1-2-3 and National Instruments Measure software,
and a digital electronic balance. The system is controlled by Lotus macros, which present menus to the user. Menus provide
for the basic operations of the system, including establishing new data files, collecting weight data, printing, and transferring
files to a laboratory minicomputer. The optional weight-maintenance algorithm calculates the amount of food necessary to maintain
target body weights. Some important aspects of this algorithm, including maintenance-feeding and gain parameters, can be manipulated
to reduce weight oscillation in test animals or to accommodate the maintenance of body weight of different animal species.
The system facilitates acquisition and recording of weight data, minimizes the frequency of error, and reduces variability
both within and across animals when body-weight maintenance is required.
A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. The D3 receptor is localized to limbic areas of the brain, which are associated with cognitive, emotional and endocrine functions. It seems to mediate some of the effects of antipsychotic drugs and drugs used against Parkinson's disease, that were previously thought to interact only with D2 receptors.
The term “stimulus control” derives from operant conditioning experiments in which stimuli are said to “control” responding if changes in the stimuli are associated with changes in the accuracy or rate of responding. The “degree” or “level” of stimulus control in these experiments is defined by the extent of the covariation between stimulus changes and response changes. The most commonly used measure of stimulus control is response accuracy.
In a series of radial-arm maze experiments to investigate the behavioral functions of the hippocampal system in rats, both the type of stimulus to be remembered (extramaze stimuli with a constant topological relationship or intramaze stimuli with a changing topological relationship) and the type of memory procedure (working memory procedure or reference memory procedure) were manipulated independently. Results provide no support for spatial or cognitive mapping ideas of hippocampal function; a deficit was found in nonspatial versions of the maze, and a dissociation of performance was found in a spatial version. Thus, the important dimension for predicting the effects of hippocampal damage was the type of memory required and not the type of stimulus to be remembered. Peer commentary by 38 researchers and the author's reply are appended. (7 p ref) (PsycINFO Database Record (c) 2012 APA, all rights reserved)
A model of working and reference memory in rats is described, based on a discrete-trial operant procedure with concurrent components of spatial matching (for working memory) and nonspatial discrimination (for reference memory). On each trial in the matching component, rats received food for pressing one of two retractable levers after a delay if that lever had been presented in the prior sample phase of the trial. On each trial in the discrimination component, food was delivered if the rat pressed a lever illuminated by a cue light after the delay interval. The model was tested with scopolamine (0.10 to 0.56 mg/kg, ip), which reduced matching accuracy in a dose-related manner. Linear slope and intercept estimates of retention gradients showed that intercepts declined and slopes remained unchanged with increasing scopolamine dose. In contrast, scopolamine had no significant effect on nonspatial discrimination accuracy, indicating a relative insensitivity of reference memory to cholinergic blockade. Because the matching component involved spatial cues and the discrimination component did not, a second group of rats was trained to discriminate between the spatial locations of two levers, to compare the effects of scopolamine on spatial and nonspatial discriminations. Scopolamine at the same doses caused a small, consistent decrease in spatial discrimination accuracy, suggesting that spatial discrimination was more sensitive to disruption by scopolamine than was nonspatial discrimination. The combined delayed matching-to-position/nonspatial discrimination procedure appears to provide a useful technique for characterizing mnemonic effects of drugs and toxicants in rats.
(C) Lippincott-Raven Publishers.
Both acetylcholinergic (ACh) and dopaminergic (DA) systems have been found to be crucial for the maintenance of accurate cognitive performance. In a series of studies examining those aspects of cognitive function revealed by the radial-arm maze, we have found that these two neurotransmitter systems interact in a complex fashion. Choice accuracy deficits in the radial-arm maze can be induced by blockade of either muscarinic- or nicotinic-ACh receptors. The choice accuracy deficit induced by blockade of muscarinic receptors with scopolamine can be reversed by the DA receptor blocker, haloperidol. The specific DA D1 blocker SCH 23390 also has this effect, whereas the specific D2 blocker raclopride does not, implying that it is D1 blockade that is critical for reversing the scopolamine effect. On the other hand, the choice accuracy deficit induced by nicotinic blockade with mecamylamine is potentiated by haloperidol. This effect is also seen with the D2 antagonist raclopride, but not with the D1 antagonist SCH 23390, implying that it is the D2 receptor which is important for the potentiation of the mecamylamine effect. The relevance of the D2 receptor for nicotinic actions on cognitive function is emphasized by the finding that the selective D2 agonist LY 171555 reverses the choice accuracy deficit caused by mecamylamine. Nicotinic and muscarinic blockade are synergistic in the deficit they produce. Antagonist doses subthreshold when given alone produce a pronounced impairment when given together. This latter deficit can be reversed by the D2 agonist LY 171555. These studies have outlined the complex nature of ACh—DA interactions with regard to cognitive function. Possible neural circuits for these interactions are discussed. The effectiveness of these selective DA treatments in reversing cognitive deficits due to ACh underactivation suggests a novel approach to treating cognitive dysfunction in syndromes such as Alzheimer's disease.
Rats were trained to obtain food pellets from the end of each arm of an eight-arm radial maze. Baseline performance was characterized by very few entries into arms from which the food pellet had already been obtained. In Experiment 1, neither d-amphetamine (0.1−3.0 mg/kg) nor pentobarbital (1.0−10.0 mg/kg) affected choice accuracy, although the rate of arm-entry increased after d-amphetamine and decreased after pentobarbital. Scopolamine (0.1−1.0 mg/kg), on the other hand, reduced both accuracy and the rate of arm entry. In a second experiment, the effects of scopolamine were replicated using a between-subjects design. Methylscopolamine (0.17, 1.0 mg/kg) was found to have little effect on performance. Multiple response criteria were also compared in the second experiment. Scopolamine was found to affect runs farther out the arm differently than it affected abbreviated arm entrances. A post-trial feeding test was also included to evaluate changes in reinforcer effectiveness, and showed that food continued to be a reinforcer after both scopolamine and methylscopolamine.
Evidence on the central mechanisms mediating amphetamine-induced anorexia, locomotion, and stereotypy is reviewed, with the findings suggesting the following conclusions. The central mediation of amphetamine's anorexic effect involves both dopaminergic (nigrostriatal system) and noradrenergic (lateral hypothalamus and ascending noradrenergic pathways) processes, with amygdala-hypothalamic connections and cortical sites serving a possible addition role in such an effect of the drug. The central mediation of amphetamine's locomotor-stimulating effect involves both dopaminergic (nigrostriatal and mesolimbic systems) and noradrenergic (ascending noradrenergic pathways as well as their hypothalamic and cortical projections) processes. While the role of amygdala sites in amphetamine-induced locomotion is unclear, additional central processes exert inhibitory influences on the mediation of such an effect of the drug. The central mediation of amphetamine's stereotypical effect involves a rather exclusive role of the dopaminergic nigrostriatal system, although such mediational principles are influenced by additional inhibitory processes. Finally, evidence on the overlap and dissociation of central processes associated with these behavioral effects of the drug is discussed and the importance of such principles to amphetamine studies briefly indicated.
Rats were trained on place or cue spatial navigation tasks in a swimming pool and then given the neuroleptic, alpha-flupentixol. Initial experiments showed that regardless of testing schedule, including blocks of trials given concurrently or separated by 7 or 30 days, drugged rats showed a trial-by-trial decay in latency and accuracy of responding although they continued to swim. The rate of decay increased with increases in drug dosage. Further experiments showed that: 1) Performance decay was specifically related to conditioned components of the test environment. Animals required to swim in a different test, or to struggle, showed less decay than rats exposed to the test platform only or required to perform all aspects of the task. 2) Decay was not due to nonspecific effects of neuroleptic treatment because rats injected and replaced in their home cage, and then subsequently reinjected and tested performed like rats treated and tested for the first time. 3) A trial-dependent decay of performance was also obtained in hippocampectomized and decorticate rats, suggesting that at least part of the major action of the drug is on subcortical systems. The results are discussed with respect to hypotheses of neuroleptic action and with respect to their possible relevance to experience-dependent changes in animal analogues of Parkinson's disease. Finally, it is suggested that behavior may be organized in subsystems, which when active, become selectively sensitive to neuroleptics.
The effects of chlorprothixene (4, 6, 8, and 10 mg/kg), haloperidol (0.13,0.25,0.38, and 0.5 mg/kg), and trifluoperazine (0.5, 1, 2, and 3 mg/kg) were examined in pigeons responding under a delayed-matching-to-sample procedure in which delays of 0.5-, 1-, 2-, 4-, and 8-sec duration were arranged during each experimental session. Both chlorprothixene and trifluoperazine typically reduced accuracy (percent correct responses); the magnitude of this effect was generally largest at the longest delay values, Chlorprothixene was associated with an increased rate of responding to the sample stimulus in two of three subjects, whereas trifluoperazine almost always decreased response rate, Haloperidol at high doses decreased response rate, but failed to consistently impair accuracy at any dose or delay value.
The discovery that the brain contains neurons utilizing dopamine (DA) as their transmitter has led to studies of the behavioral function of these neurons. Changes in overall level of activity of DA neurons appear to produce parallel changes in locomotor activity. Additionally, DA neurons seem to mediate in part the effects of biologically significant (reinforcing) stimuli on learning. One way in which reinforcing stimuli produce learning is to increase the incentive motivational (response-eliciting) properties of neutral stimuli associated with them; also, reinforcing stimuli maintain the incentive motivational properties of previously conditioned incentive stimuli. Normal DA functioning appears to be required for the establishment and maintenance of incentive learning in naive animals. Previous incentive learning in trained animals can influence behavior for a time even when the function of DA neurons is disrupted; however, with continued testing in the absence of normal DA functioning, previously established conditioned incentive stimuli cease to influence behavior. From these observations and recent physiological, anatomical and biochemical studies of DA systems it is suggested that the biological substrate of DA-mediated incentive learning is a heterosynaptic facilitation of muscarinic cholinergic synapses. This model has important clinical implications since it has been suggested that DA hyperfunctioning underlies the development of schizophrenia.
To assess the possible involvement of the monoaminergic neurotransmitters norepinephrine, dopamine and serotonin in the maintenance of spatial working memory rats were treated with antagonists 0 or 2 hr after completing the first 4 choices in an 8 arm maze. Haloperidol (0.25–1 mg/kg), when administered 2 hr after Choice 4, produced a small but consistent impairment in performance on retention tests given 5 hr after the first 4 choices. This deficit closely resembled natural forgetting in terms of the type of errors committed. By contrast, haloperidol in the same doses given 0 hr after Choice 4 or 3 hr before the first 4 choices did not affect retention. Likewise treatment with propranolol (10–20 mg/kg), phentolamine (5–20 mg/kg) or methysergide (5–15 mg/kg) did not impair spatial memory, regardless of when these drugs were injected within the session. Evidently dopaminergic neuronal systems are important in the maintenance of normal spatial working memory.
Pharmacological and biochemical criteria can be used to separate those dopamine receptors which are linked to the enzyme adenylyl cyclase and those which are not. As an example of the location of different dopamine receptors within a tissue, it is of interest to examine the striatum, the most extensively studied dopaminergic brain region. We are able to identify dopamine receptors at five sites within the nigro-striatal axis. The dopamine receptors at three of these sites are not associated with adenylyl cyclase (and therefore would be designated D-2 dopamine receptors in our classification); at two of the sites, the dopamine receptors are linked to adenylyl cyclase (and therefore would be designated D-1 dopamine receptors). In the striatum there are: (1) presynaptic receptors which control tyrosine hydroxylase and are unassociated with an adenylyl cyclase; (2) postsynaptic receptors responding to ergot antagonists in vivo, also unrelated to an adenylyl cyclase; and (3) postsynaptic receptors closely associated with an adenylyl cyclase. Furthermore, in the substantia nigra there are: (4) presynaptic dopamine receptors (which are associated with adenylyl cyclase); and (5) autoreceptors (unassociated with adenylyl cyclase). From current knowledge, it is not possible to construct a theoretical framework ascribing a function, in terms of motor control, to any of these various dopaminergic mechanisms.
Central dopaminergic transmission has been implicated in memory processes. The present experiments examined the effects of several direct acting dopaminergic agents on performance of a delayed-non-match-to-sample radial arm maze task. Preadministration of apomorphine (D1-D2 agonist; 0.25, 0.5, and 1.0 mg/kg), quinpirole (D2 agonist; 0.1 mg/kg), or SKF38393 (D1 agonist; 3 mg/kg) increased the latency of choices but did not affect any index of accuracy with a 1 h retention interval. Post-training administration of quinpirole (0.1, 0.2, 1.0, and 2.0 mg/kg), SKF38393 (0.3, 3.0, and 6.0 mg/kg), sulpiride (D2 antagonist; 3, 10, and 30 mg/kg), or SCH23390 (D1 antagonist; 0.01, 0.1, and 1.0 mg/kg) also did not affect accuracy, although quinpirole produced a dose-dependent increase in the latency of choices, assessed 10 h post-treatment. For comparison, pretraining and post-training administration of the benzodiazepine chlordiazepoxide (1, 3, 5 mg/kg) was also tested and produced dose-dependent impairments in mnemonic performance at either a 1 or 4 h retention interval. The effects of chlordiazepoxide are consistent with evidence indicating that GABAergic agents can influence memory processes. In contrast, the present findings indicate that (peripheral administration of dopaminergic agents IS) not sufficient to alter the mnemonic processes required for accurate performance of this DNMTS-RAM task.
Pharmacological blockade of muscarinic cholinergic (ACh) receptors has been found to impair choice accuracy in a variety of tasks including the radial-arm maze. The cognitive impairment caused by the muscarinic antagonist scopolamine is reversed by the dopaminergic (DA) antagonist haloperidol as well as the selective D1 antagonist SCH 23390. In the current study, interactions were studied between scopolamine and selective agonists of D1 (SCH 38393) and D2 (quinpirole) receptors. Surprisingly, the D1 agonist SKF 38393 was found to significantly alleviate the scopolamine-induced choice accuracy deficit. In contrast, the D2 agonist quinpirole was not found to significantly alter the effects of scopolamine on choice accuracy but did have supra-additive effects of increasing choice latency. Both the D1 agonist SKF 38393 and the D1 antagonist SCH 23390 have been found to reverse the choice accuracy deficit caused by scopolamine and the deficit resulting from lesions of the medial projection from the basal forebrain to the cortex. Possible mechanisms for these effects are discussed.
Since quinpirole (or LY171555) has a high affinity for dopamine D2 receptors, and since the high-affinity state of D2 appears to be the functional state of D2, we prepared [3H]quinpirole to investigate its suitability for labelling the high-affinity state of the D2 receptor. The dissociation constant of [3H]quinpirole binding to canine striatum homogenate was 3.9 nM in the absence of NaCl and 6.8 nM in the presence of NaCl. Only 50% of the total binding was specifically displaced by 10 microM S-sulpiride. The data are consistent with the conclusion that much or most of the [3H]quinpirole binds to the high-affinity state of the D2 receptor, since dopamine D2 agonists and antagonists were the most potent in inhibiting the binding of this ligand, because the density of binding sites was 8-9 pmol/g, about half that for [3H]spiperone, and because the density was reduced by 70% in the presence of guanylylimidodiphosphate. Since quinpirole has a reported Ki value of 5.1 nM for dopamine D3 receptors, similar to the quinpirole Ki value of 4.8 nM for the high-affinity state of the dopamine D2 receptor, it appears that [3H]quinpirole with its Kd of 3.9-6.8 nM could label both these two dopamine receptors. However, since the spiperone and haloperidol Ki values against [3H]quinpirole were the same as their values at dopamine D2 receptors rather than dopamine D3 receptors, it appears that [3H]quinpirole predominantly labels dopamine D2 receptors in the canine striatum. The guanine nucleotide-insensitive component of [3H]quinpirole binding (about 30%) may be to dopamine D3 receptors.
The prefrontal cortex is involved in the cognitive process of working memory. Local injections of SCH23390 and SCH39166, selective
antagonists of the D1 dopamine receptor, into the prefrontal cortex of rhesus monkeys induced errors and increased latency
in performance on an oculomotor task that required memory-guided saccades. The deficit was dose-dependent and sensitive to
the duration of the delay period. These D1 antagonists had no effect on performance in a control task requiring visually guided
saccades, indicating that sensory and motor functions were unaltered. Thus, D1 dopamine receptors play a selective role in
the mnemonic, predictive functions of the primate prefrontal cortex.
Behavioral effects of organophosphates (OPs) typically decrease with repeated exposure, despite persistence of OP-induced inhibition of acetylcholinesterase (AChE) and downregulation of muscarinic acetylcholine (ACh) receptors. To characterize this tolerance phenomenon, rats were trained to perform an appetitive operant task which allowed daily quantification of working memory (accuracy of delayed matching-to-position), reference memory (accuracy of visual discrimination) and motor function (choice response latencies and inter-response times during delay). Daily s.c. injections of 0.2 mg/kg of diisopropylfluorophosphate (DFP) caused no visible cholinergic signs, did not affect body weight or visual discrimination, but progressively impaired matching accuracy and lengthened response latencies and interresponse times. These effects recovered in seven of eight treated rats after termination of DFP treatment. Resumption of daily DFP at 0.1 mg/kg caused smaller impairments of both matching accuracy and response latency. After 21 injections of 0.2 mg/kg/day of DFP, rats were subsensitive to the hypothermia induced by acute oxotremorine (0.2 mg/kg i.p.), as expected after OP-induced downregulation of muscarinic ACh receptors. Evidence for supersensitivity to scopolamine (0.03 and 0.056 mg/kg i.p.) in DFP-treated rats was mixed, with additive effects predominating on both the cognitive and motor aspects of the task. After 18 days of 0.1 mg/kg of DFP, AChE was inhibited 50 to 75% and muscarinic ACh receptor density was reduced 15 to 20% in hippocampus and frontal cortex. Progressive declines in AChE activity in hippocampus and frontal cortex across 15 daily doses with DFP at 0.1 and 0.2 mg/kg were observed in other rats; quinuclidinyl benzilate binding was significantly reduced in hippocampus after 15 doses at both levels of DFP. These results indicate that animals showing a definitive sign of tolerance to OP administration (subsensitivity to a cholinergic agonist) were also functionally impaired on both the mnemonic and motoric demands of a working memory task. The nature of this impairment suggests further that it results from compensatory changes in the central nervous system, e.g., muscarinic receptor downregulation, considered to produce "tolerance" to OPs in exposed animals.
Nine structurally related 1-phenyl-1H-3-benzazepine derivatives and two thienopyridines were tested for agonist and antagonist properties at the adenylate cyclase-coupled D1 dopamine receptor in homogenates of the striatum of the rat. The benzazepines SK&F 77434 and SK&F 82958, both of which contain a catechol ring, were agonists; the intrinsic activity of SK&F 77434 was similar to that of SK&F 38393, whereas SK&F 82958 was a full agonist. The remaining benzazepines inhibited the stimulation of adenylate cyclase by dopamine. Antagonist potency depended on the nature of the substituent at position 7 of the benzazepine molecule, 7-halogen compounds being the most potent. The Ki values, obtained from analysis of the antagonism of dopamine-stimulated adenylate cyclase, were significantly correlated with the Ki values for displacement of D1 ligands in binding experiments. Furthermore, antagonist activity of the resolved racemic benzazepine SK&F 83566 resided almost exclusively in the R-enantiomer. The thienopyridine derivatives SK&F 89641 and SK&F 89145 were partial agonists with greater efficacies than SK&F 38393.
Dopaminergic neurotransmission has been implicated in reward-related learning. With the advent of pharmacological agents that are relatively specific for D1 and D2 dopamine receptors, it has become possible to assess the role of these receptor subtypes in this form of learning. Antagonist studies have shown that either D1 or D2 receptor blockers produced extinction-like effects on operant responding for food, water or brain stimulation reward and in drug self-administration paradigms. They also blocked place preference learning based on amphetamine. Agonist studies showed that D2, but not D1 agonists were self-administered, produced place preferences and enhanced responding for conditioned reward. It may be that the dopaminergic signal at the D1 receptor is important for the establishment and maintenance of reward-related learning. From this point of view the effects of D1 antagonists can be understood. D2 antagonists may produce extinction-like effects because they lead to increased dopamine release and, therefore, indirectly mask the dopamine signal at the D1 receptor. D1 agonists may fail to produce reward effects because they, unlike D2 agonists, directly mask the dopaminergic signal at the D1 receptor.
The study of behaviors induced by centrally acting dopaminergic agents is a classical means of investigating the pharmacology of the dopamine system and the pathophysiology of human neuropsychiatric diseases for which these behaviors serve as animal models. Observation and quantification of stereotypic and nonstereotypic behaviors has been a standard research protocol since the earliest work on the central activity of amphetamine and related agents (Randrup and Munkvad, 1967; Kelly and Iversen, 1975). Quantification of rotational behavior in lesioned rats (Ungerstedt and Arbuthnott, 1970) has more recently become an established means of investigating the activity of dopaminergic agents within the CNS. The compartmentalization of dopamine receptors on the basis of their ability to stimulate (D1 receptors) or not stimulate (D2 receptors) adenylate cyclase (Kebabian and Calne, 1979) and the introduction of agents selective for these receptor subtypes have provided the means with which to extend the classical behavioral observations and to utilize these techniques to more comprehensively characterize the pharmacology of the central dopamine system.
Rats trained to run through an 8-arm radial maze for food reinforcement were injected with a broad range of doses of the dopamine D-2 receptor agonist, LY 171555. Deficits were detected by the choice measures of entries to repeat and arms entered in the first eight choices. There was a dose-related increase in latency to finish the maze even though there was no significant increase in the number of choices needed to finish the maze.
The similarity in the pattern of responding produced by extinction and dopamine (DA) receptor blockers has led to the suggestion that DA neurons may participate in the usual effects of reward on behaviour. The purpose of the present study was to evaluate the effect of receptor-subtype specific DA antagonists on food-rewarded operant responding. Rats were trained to lever press for food on a variable interval 30-s schedule. They then received one of the following treatments prior to testing on the next 5 days: saline, nonreinforcement, the DA receptor blocker pimozide (0.5 or 1.0 mg/kg), the D1 receptor blocker SCH 23390 (0.01, 0.05, 0.1 mg/kg), and the D2 receptor blocker metoclopramide (1.0, 5.0, 10.0 mg/kg). Nonreinforcement resulted in both intra- and intersession declines in responding. The drugs produced dose-dependent decreases in overall responding. Additionally, both doses of pimozide and the higher doses of SCH 23390 and metoclopramide altered intrasession patterns of responding when compared to saline, with their greatest effect being in the latter portion of the session. Intersession declines were seen with the highest doses of SCH 23390 and metoclopramide and control studies showed that these declines could not be attributed to a buildup of the drug with repeated dosing. It was concluded that both D1 and D2 receptors participate in the control of behaviour by reward.
Separate groups of rats of three ages (6 month, 15 month or 24 month) were trained in a two-lever operant chamber on one of two versions of a paired-trial delayed response task involving either matching or non-matching of the choice response to a sample lever. The older rats were unimpaired in learning either version of the task during initial training with no (0 s) delay between the sample and choice responses. However, when variable 0-24 s delay intervals were introduced, the 24-month group was impaired on acquisition of the delayed non-matching task, and both the 15- and 24-month groups were impaired on acquisition of the delayed matching task compared to the 6-month group. Deficits in the older groups in asymptotic performance were attributable to an impairment at longer delay intervals whilst maintaining near perfect performance at the shorter delay intervals, suggesting a selective short-term memory impairment. The delay-dependent deficits of the older groups were not ameliorated by the muscarinic agonist arecoline or the cholinesterase inhibitor physostigmine, and so failed to corroborate a cholinergic interpretation of the observed age-related impairment in short-term memory.
The effect of scopolamine on remembering was examined in a delayed conditional discrimination procedure with rats. Remembering was quantified by a negative exponential function fitted to estimates of discriminability derived from a signal detection type of analysis. This function had two parameters: a measure of initial discriminability of the sample stimuli in the absence of a memory requirement (at zero delay) and a measure of rate of forgetting. Eight rats were trained on an auditory delayed conditional discrimination task until they were showing stable performance. Each rat then received doses of 0, 0.005, 0.014, 0.042, 0.125 and 0.375 mg/kg scopolamine IP in a saline vehicle. There was a highly significant, largely linear, decrease in initial discriminability. This was obvious even at the lowest dose of scopolamine. Poorer memory, as demonstrated by an increase in b, was only apparent at the highest dose. Significant changes in per cent of correct responses were also only obtained at higher doses. These results show that initial discriminability and rate of forgetting are pharmacologically as well as theoretically independent. They suggest that the measure of initial discriminability used here is a particularly sensitive measure of at least some types of cholinergic dysfunction; and they also suggest that effects of scopolamine in other working memory tasks could be more a result of changed stimulus processing than of impairment of memorial processes.
Working memory was modeled in rats using a delayed response task with spatial location as the discriminative cue. Rats received food for pressing 1 of 2 retractable levers in the choice phase of a trial if that lever had been presented in the prior sample phase of that trial. When delays of 0-20 sec were imposed between sample and choice, choice accuracy declined with increasing delay. With short intertrial intervals (ITIs), choice accuracy decreased more at long delays than at short delays, showing that interference from previous trials impaired memory but not discrimination. Rats emitted overt mediating responses during delay by pressing the levers in the retracted position. However, the frequency of delay presses was low (less than 2/trial in all rats) and neither their frequency nor accuracy was related to choice accuracy. Resetting the delay interval for each delay press did not significantly alter choice response accuracy. Trimethyltin (TMT), 7 mg/kg IV, reduced the choice accuracy of one rat to chance levels at all delays; two other rats were affected transiently. TMT reduced choice accuracy during weeks 1 and 4 postinjection, with significant effects on the linear slope and intercept of the mean retention gradient during week 4. TMT did not affect responses to the retracted levers during delays. TMT treatment also elevated levels of glial fibrillary acidic protein (GFAP) in the CNS, measured 4 weeks after treatment. Hippocampal GFAP correlated highly with the reduction in choice accuracy during week 1 (r = -.903) and week 4 (r = -.797) postTMT.(ABSTRACT TRUNCATED AT 250 WORDS)
p-Xylene is a ubiquitous solvent and chemical precursor used in industry, gasoline, and household products. While the population at risk for exposure is thus quite large, little is known about its neurobehavioral effects. To evaluate the possibility that p-xylene affects cognitive behavior, male Long-Evans hooded rats inhaled p-xylene at concentrations of 0 or 1600 ppm, 4 hr per day for 1 to 5 days, and were evaluated after exposure on two learning tasks and a test of motor activity. Autoshaping was carried out across 5 successive days with p-xylene exposure in the morning followed by testing in the afternoon. For this test, the retraction of a single response lever on a variable-time 35-sec schedule was followed by delivery of a food pellet. When the force required to depress the lever was low (0.10 N), response acquisition was faster in animals having inhaled 1600 ppm p-xylene than in air-exposed controls. When the force was increased to 0.20 N, however, p-xylene-exposed rats acquired the response no faster than controls. In contrast, inhaled p-xylene at 1600 ppm suppressed response rates in an automaintained reversal learning paradigm without affecting reversal rate. Studies of motor activity showed that while vertically-directed activity was unaffected by p-xylene, horizontally-directed activity was increased by about 30% for the first 15 min of each daily 25-min test.(ABSTRACT TRUNCATED AT 250 WORDS)
A comparison of the effects of scopolamine and physostigmine on working memory and reference memory in White Carneaux pigeons was undertaken. In Experiment 1, the pigeons received injections of scopolamine hydrobromide (0.03 mg/kg), or saline. Scopolamine hydrobromide had greater disruptive effects on working memory trials than on reference memory trials, and the centrally active form of scopolamine disrupted working memory trial accuracy more than the peripherally active form. The differential sensitivity of accuracy on working memory trials to disruption by central cholinergic blockade was obtained even though the discrimination required on reference memory trials was more difficult. In Experiment 2, the pigeons received injections of scopolamine hydrobromide (0.015 mg/kg), physostigmine (0.075 mg/kg) both scopolamine and physostigmine, or saline. Physostigmine given with scopolamine was able to reverse the scopolamine-induced reduction of accuracy on working memory trials. In neither study did scopolamine promote accelerated forgetting as the delay interval was increased. These results indicate that manipulation of central cholinergic neurotransmitter systems influences working memory processes in the pigeon, but these effects occur without alterations in the ability of the birds to actively maintain information during the retention interval.
The interaction of SCH 23390 with central serotonin 5-HT2 receptors was studied in vivo on [3H]spiperone binding and in vitro on [3H]ketanserin binding. SCH 23390 inhibited [3H]spiperone binding in rat frontal cortex with an ID50 of 1.5 mg/kg i.p., thus being equipotent to the two 5-HT2 antagonists cinanserin and methysergide. In vitro, SCH 23390 competed with [3H]ketanserin with an IC50 of 30 nM. These data indicate that SCH 23390 also binds with high affinity to 5-HT2 receptors in rat brain.
Previous studies have shown that dopamine antagonists such as haloperidol, pimozide and metoclopramide will produce gradually increasing decrements of operant and avoidance responding. The present study was carried out to investigate whether the dopamine D1 blocking agent, SCH 23390, would exert a similar effect. In the first experiment, SCH 23390 produced a dose-related (0.03-0.1 mg/kg) reduction in responding maintained by an FR 10 schedule of food reinforcement. However, the compound gave rise to similar reductions of response rate throughout the 15 min session. In a second experiment, higher doses of SCH 23390 (0.1-1.0 mg/kg) disrupted one-way avoidance performance in a shuttle-box. Again, there was no within-session decline in responding after administration of SCH 23390 although injection of a dose of 0.4 mg/kg of haloperidol produced a greater response deficit during the second half of the session. During 4 daily administrations of 0.3 mg/kg of SCH 23390 the degree to which avoidance responding was disrupted neither increased nor decreased. SCH 23390 disrupts operant bar pressing and one-way avoidance responding but its actions in these behavioral tests are not identical to the effects of typical neuroleptics such as haloperidol.
Rats were examined for the development of adverse motor and cognitive effects during and after 24 weeks of chronic haloperidol (HAL) administration using an 8-arm maze and a computerized apparatus for measuring spontaneous oral movements. In the maze, HAL caused a significant decline in choice accuracy only during the first week of administration, whereas it caused a significant decline in locomotor speed throughout drug administration. There were no effects of HAL on maze behavior after withdrawal. Haloperidol reduced the number of mouth movements during drug administration, but after withdrawal there was a significant increase. This replicated a previous finding from our lab. The oral movements which did occur in the HAL-treated rats were slower than normal. The timing of the HAL-induced cognitive dysfunction was similar to the Parkinson-like disorder shown by patients given chronic neuroleptics, whereas the timing of the increase in oral movements after the withdrawal of HAL was more related to the appearance of tardive dyskinesia. There was evidence in both tests of a persisting sedation during chronic neuroleptic administration.
To provide a more specific test of memory impairments following lesions to central cholinergic systems, rats were trained on an operant delayed matching task. Ibotenic acid lesions of the nucleus basalis produced a disruption of performance at all delay intervals (a parallel downward shift in the delay-performance curve). By contrast, fimbria-fornix transections had no effects at short delays, but produced a progressively greater impairment as the delays lengthened (an increased downward slope of the delay-performance curve). Scopolamine produced a dose-dependent disruption of performance, apparent at the shortest delays but greater at longer delays, that was similar to the two lesion deficits combined, whereas physostigmine induced a mild but significant enhancement of performance. The results support the hypothesis that disruption of hippocampal circuitries, including cholinergic afferents via the fimbria-fornix, produces short-term or working memory impairments, whereas disruption of the cortical cholinergic system implicates more stable long-term aspects of task performance. Peripherally administered cholinergic drugs produce both types of effect and thus may influence both systems.
Experiments in which the treatments are composed of a series of doses of a compound and a zero dose control are often used in animal toxicity studies. A test procedure is proposed to assess trends in the response variable. The notion of a no-statistical-significance-of-trend (NOSTASOT) dose is introduced, and questions of multiplicity of statistical tests in this context are addressed.
Amphetamine induces a behavioral syndrome in mammals that includes a variety of repetitive behaviors. An integral component of this syndrome in humans is the presence of a thought disturbance not unlike that manifest in idiopathic paranoid schizophrenia. The consistent pattern of behavioral changes produced by amphetamine across species, when considered in light of the psychosis it elicits in humans, has suggested to many that these drug-induced changes in animals may provide a model of the endogenous psychosis in humans. Amphetamine-induced changes in open-field behavior in the rat have been the most widely studied in attempts to formulate a model for investigating the neurobiological mechanisms underlying amphetamine psychosis and paranoid schizophrenia in humans and for testing the therapeutic efficacy of new antipsychotic drugs. The procedures used to assess the behavioral response to amphetamine, however, typically include rating scales or automated recordings that by their very nature ignore those components of the behavioral response that may be most critical for developing a viable animal model of the naturally occurring psychosis. Further, open-field behavior is often recorded during arbitrarily selected intervals without consideration for the multiphasic nature of the entire amphetamine response. We discuss how incomplete descriptive analyses of the amphetamine behavioral response in rats has led to confusion in the literature and describe behavioral research that is paradigmatic of the work we believe is most likely to eventuate in significant progress in the field.
To assess the effects of amphetamine on working and reference memory rats were trained on a 12-arm radial maze with six arms baited and six arms unbaited until stable performance was achieved. Administration of 2.0 mg/kg d-amphetamine sulfate increased both working and reference memory errors, but only if a 5-min delay was imposed after three successful choices. With no delay this dose had no reliable effect on either working or reference memory. Lower doses (0.5 or 1.0 mg/kg) were ineffective even when a delay was imposed during the test. We suggest that amphetamine heightens arousal, which disrupts accurate retention when the rat's attention to the relevant cues is interrupted, as during a brief delay. Alternative explanations are discussed.
The effect of physostigmine (0.2 mg/kg), scopolamine (0.1 mg/kg), d,l-amphetamine (1 mg/kg), apomorphine (0.05 mg/kg), and piracetam (100 mg/kg) on working memory was examined in 12 rats that were highly overtrained in the radial maze. In experiment 1, drugs administered 10 min before the trial did not worsen performance of rats in the 12-arm maze. In experiment 2, insertion of a 5-min delay between the sixth and seventh choices increased the number of errors over choices 7-12. Performance was unaffected by pretreatment with physostigmine or apomorphine, but was significantly impaired by scopolamine, amphetamine, and piracetam. In experiment 3, performed in a 24-arm maze, the number of errors and trial duration increased, but performance was not decreased by amphetamine or piracetam. It is concluded that the uninterrupted radial maze task is relatively resistant to pharmacological disruption, but that scopolamine, amphetamine, and piracetam enhance the effect of stimuli interfering with the storage of spatial information over delays.
d-Amphetamine injections produce a dose-dependent disruption of performance within a discrete delayed alternation and a spatial delayed matching-to-sample task. Since d-amphetamine in the doses used had no deleterious effects on discrimination performance (no delay condition), it is suggested that d-amphetamine disrupts neuronal activity representing short-term memory. The data provide support for an independence model of short- and long-term memory.
A model of working and reference memory in rats is described, based on a discrete-trial operant procedure with concurrent components of spatial matching (for working memory) and nonspatial discrimination (for reference memory). On each trial in the matching component, rats received food for pressing one of two retractable levers after a delay if that lever had been presented in the prior sample phase of the trial. On each trial in the discrimination component, food was delivered if the rat pressed a lever illuminated by a cue light after the delay interval. The model was tested with scopolamine (0.10 to 0.56 mg/kg, ip), which reduced matching accuracy in a dose-related manner. Linear slope and intercept estimates of retention gradients showed that intercepts declined and slopes remained unchanged with increasing scopolamine dose. In contrast, scopolamine had no significant effect on nonspatial discrimination accuracy, indicating a relative insensitivity of reference memory to cholinergic blockade. Because the matching component involved spatial cues and the discrimination component did not, a second group of rats was trained to discriminate between the spatial locations of two levers, to compare the effects of scopolamine on spatial and nonspatial discriminations. Scopolamine at the same doses caused a small, consistent decrease in spatial discrimination accuracy, suggesting that spatial discrimination was more sensitive to disruption by scopolamine than was nonspatial discrimination. The combined delayed matching-to-position/nonspatial discrimination procedure appears to provide a useful technique for characterizing mnemonic effects of drugs and toxicants in rats.
Agonist and antagonist properties of benzazepine and thie-nopyridine derivatives at the Dm dopamine receptor
- O Boyle
- K Giatanopoulos
- D E Brenner
- M Waddington
O'Boyle, K.; Giatanopoulos, D. E.; Brenner, M.; Waddington, J. L. Agonist and antagonist properties of benzazepine and thie-nopyridine derivatives at the Dm dopamine receptor. Neurophar-macology 28:401-405; 1989.
The role of dopamine in locomotor activity and learning
- Beninger