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Acute and Chronic Nicotinic Interactions with Dopamine Systems and Working Memory Performancea
Abstract
Nicotine has been found to improve memory performance in a variety of tests in rats, monkeys, and humans. Interactions of nicotinic systems with dopamine (DA) systems may be important for this effect. We conducted a series of studies of nicotinic agonist and antagonist interactions with DA systems using rats in a win-shift working memory task in the radial-arm maze. The working memory deficit caused by the nicotinic antagonist mecamylamine was potentiated by the D1/D2 DA antagonist haloperidol and the specific D2 antagonist raclopride. In contrast, the mecamylamine-induced deficit was reversed by co-administration of the D2/D3 agonist quinpirole. Nicotine also has significant interactions with dopamine drugs with regard to working memory performance in the radial-arm maze. The DA agonist pergolide did not by itself improve radial-arm maze memory performance, but when given together with nicotine it produced an elevated dose-dependent increase in choice accuracy. The D1 agonist SKF 38393 significantly impaired radial-arm maze choice accuracy. Nicotine was effective in reversing this deficit. When given together with nicotine, the D2/D3 agonist quinpirole improved RAM choice accuracy relative to either drug alone. Acute local infusion of mecamylamine to the midbrain DA nuclei effectively impairs working memory function in the radial-arm maze. In contrast to acute nicotinic manipulations, considerably less evidence exists that the effects of chronic nicotine administration are influenced by DA systems. This may be an example of the different neural substrates that underlie the memory improvement caused by acute and chronic nicotine.
... The dopaminergic system primarily controls reward processing [52,53] but is also associated with spatial and verbal working memory [54,55] and cognitive flexibility [56]. All these functions are similarly vulnerable to neuronal and connectivity loss with advancing age, particularly loss of functioning of D2 receptors [57] and the dopamine transporter [57,58], in conjunction with modulatory changes from the cholinergic system [59]. Both the cholinergic and dopaminergic systems lose necessary receptor density and connectivity, with aging associated with cognitive changes in performance [60,61]. ...
... Originating in the basal ganglia (nucleus accumbens, ventral tegmental area, substantia nigra, striatum) and heavily enervating the frontal cortices, dopamine availability is involved in attention, decision making, learning, and reward processing [63]. In the context of cognition, dopamine activity is important for reward and decision processing [53,70], visuospatial working memory [55], as well as attention and working memory, with modulation from the cholinergic system as well [59,69]. ...
... Dopamine activity at D2 receptors is associated with memory function, and loss of these receptors with age has been associated with poorer memory functional connectivity between the hippocampus and caudate [74]. The release of dopamine is closely modulated by cholinergic receptors, allowing for fine tuning of working memory [59]. ...
Purpose of review:
As of the year 2016, an estimated 50% of the United States' HIV-Positive population is aged 50 years or older. Due to a combination of increased rates of infection in older adults, and successful anti-retroviral (ART) regimens allowing HIV-positive adults to survive for decades with the disease, we are now faced with a steadily graying HIV-positive population, with only limited knowledge of how the cognitive and physiological effects of aging intersect with those of chronic HIV-infection.
Recent findings:
Age-related changes to mood, cognition, and neurological health may be experienced differently in those living with HIV, and research concerning quality of life, mental health, and cognitive aging needs to account for and explore these factors more carefully in the coming years.
Summary:
This review will explore the topic of cognitive aging with HIV: 1. Central nervous system (CNS) infection of HIV and how the virus affects brain integrity and function; 2. Cognitive and behavioral symptoms of HIV-Associated Neurocognitive Disorders (HAND); 3. Neurobiological theories of Cognitive Aging and how these processes may be exacerbated by HIV-infection; 4: Clinical implications and complications of aging with HIV and factors that may result in poorer cognitive outcomes.
... In the case of acute nicotine administration studies, this compound had a significant positive effect on working memory. Moreover, its effect was reversed by administration of nicotinic antagonists [35]. In his study, Levin et al. concluded as well that chronic nicotine treatment determined an overall reduction in memory. ...
... The most studied complexes that the nicotinic receptors form are the ones with the dopaminergic receptors. During different studies, it was observed that the cholinergic system stimulated the release of dopamine [1,35]. Acetylcholine interacts especially with the D 2 receptors, thus potentiating the effect of nicotine on working memory. ...
Memory development is defined as the ability to encode, store and access new information. Certain neurotransmitters, but most importantly the cholinergic transmission via nicotinic receptors, have been linked not only to memory formation but to attention and other cognitive processes as well. In order to analyse previous literature on this subject a PubMed search was performed and it concluded 63 articles. We determined the overall efficacy and the prevalence of specific tests used. The implication of the cholinergic transmission via nicotinic receptors in memory has been well established over the years. Since the evolvement of technology, the nicotinic receptors have been linked not only to normal cognitive functions, but to the pathophysiology of certain neurodegenerative diseases as well. Due to their important roles in cognition, further studies need to be performed in order to determine their potential therapeutic effects. © 2018, Romanian Society for Pharmaceutical Sciences. All rights reserved.
... In addition, nicotine treatment has been reported to improve WM in animals and humans in maze and n-back tasks. For instance, Levin et al. found that both acute and chronic nicotine treatment significantly improved WM in rats in the radial maze task (Levin and Rose, 1995). We also have shown that subcutaneous injection of 0.2 mg/kg of nicotine improved spatial working memory by activation matrix metalloproteinase 9 (MMP-9) in the hippocampus in rats in the Tmaze task (Shu et al., 2015). ...
Tobacco smoking is a preventable cause of morbidity and mortality throughout the world. Smoking comes in form of absorption of many compounds, among which nicotine is the main psychoactive component of tobacco and its positive and negative reinforcement effects are proposed to be the key mechanism for the initiation and maintenance of smoking. Growing evidence suggests that the cognitive enhancement effects of nicotine may also contribute to the difficulty of quitting smoking, especially in individuals with psychiatric disorders. In this review, we first introduce the beneficial effect of nicotine on cognition including attention, short-term memory and long-term memory. We next summarize the beneficial effect of nicotine on cognition under pathological conditions, including Alzheimer's disease, Parkinson's disease, Schizophrenia, Stress-induced Anxiety, Depression, and drug-induced memory impairment. The possible mechanism underlying nicotine's effect is also explored. Finally, nicotine's detrimental effect on cognition is discussed, including in the prenatal and adolescent periods, and high-dose nicotine- and withdrawal-induced memory impairment is emphasized. Therefore, nicotine serves as both a friend and foe. Nicotine-derived compounds could be a promising strategy to alleviate neurological disease-associated cognitive deficit, however, due to nicotine's detrimental effect, continued educational programs and public awareness campaigns are needed to reduce tobacco use among pregnant women and smoking should be quitted even if it is e-cigarette, especially for the adolescents.
... However, there are a number of studies that have identified an enhancing effect of nicotine on performance on Digit Span (often measured as a total score, adding forwards and backwards spans; e.g. Levin and Rose, 1995;Al-Adawi and Powell, 1997). Again, it may be appropriate to note the low levels of smoking dependence in the current study, and to contrast the results from Al-Adawi and Powell (1997), who found a significant enhancement in Digit Span performance in heavy smokers, and Powell et al (in press), who did not find a significant difference in performance with a sample of smokers comparable to the current sample in terms of dependency. ...
Rationale: Smoking triggers dopamine release, particularly in the mesocorticolimbic dopamine system. Activation of this system has a major overlap with functioning of the frontostriatal circuitry, which has been labelled the 'willed action system'. 'Willed action' describes action that is non-automatic, internally generated, effortful, and involves conscious control. It is implicated in initiation and motivation. There is evidence that abstinence from smoking leads to acute impairments in a range of cognitive and motivational measures, many of which are associated with frontal / frontostriatal functioning. Aims: The current study aimed to investigate the effects of smoking on willed action in 18 brain-injured smokers. Method: A within-subjects cross-over design was utilised, to compare performance after an acute (>2 hours) period of abstinence from smoking with performance after smoking. The test battery included measures of reward responsivity (objective and subjective measures of motivation), initiation (verbal fluency), and working memory. Results: Reward responsivity was enhanced after a cigarette had been smoked compared to the abstinent condition. Additionally, performance on the card sorting task was particularly enhanced after smoking on the first occasion, i.e. when the task was novel. There was no significant enhancement on any other measure. Conclusion: The results suggest that reward responsivity is modulated by acute smoking status, suggesting a specific effect of nicotine on aspects of motivation. Enhancement of performance is particularly seen when the task is novel. These conclusions are partially in concordance with a willed action framework. Implications are discussed with reference to routine neuropsychological assessments, and a possible role for nicotine as a therapeutic agent for enhancing motivation after acquired brain injury.
... The effects of nACh receptors are not transduced through G protein interactions but via ionotrophic ligandgated channels with high permeability to calcium and, as such, are fast-acting. They are involved in the process of learning and memory (Levin and Rose, 1995), antinociception responses (Pert, 1987) and the reinforcement of nicotine use (Benowitz et al., 1989). Acting on glutaminergic cortical projections, the main function of nACh receptors in the thalamus is probably the modulation of attention and sensory gating. ...
Although the neurodegeneration occurring in Alzheimer's disease (AD) affects multiple neurotransmitters, the cholinergic system has received the greatest attention. Acetylcholine (ACh) is fundamental to mnemonic function, assisting in the septal hippocampal pathway and facilitating cortical activation. One of the earliest pathological events in AD is the degeneration of ACh-synthesizing neurons in the subcortical nuclei of the human basal forebrain. Indeed, the loss of cholinergic function in AD is correlated with the density of histopathological markers of AD, the severity of cognitive dysfunction and disease duration. However, the precise mechanism by which the cholinergic system influences cognition, and behaviour, is unknown. Recent preliminary data from functional imaging and ligand-binding studies implicate a dynamic interaction between the nicotinic-muscarinic cholinergic receptor systems. The relatively preserved thalamic nicotinic system, compared with the dysfunctional cortical muscarinic system, may facilitate thalamocortical metabolic excitation in the failing AD brain. Thus, it is hypothesized that thalamic influence within frontal-subcortical circuits is augmented in AD patients who demonstrate a marked improvement to cholinesterase inhibitor therapy. Understanding the cholinergic basis of the cognitive, functional and behavioural deficits in AD, and the differential treatment response to various agents, will ultimately improve patient care and neuropharmacological insights. This paper reviews the current understanding of the cholinergic influence in cognition, behaviour and, as a result, function in AD patients.
... Phamacologicd studies have provided evidence that both D, and DI receptors mediate the etTects of dopamine on leaming and memory. Activation of both D, and D, receptors in the hippocampus and PFC enhances performance in various working memory tasks in rats (Packard and White 1991;White and Viaud 1991;White et ai.. 1993;Levin and Rose 1995) and monkeys Goidman-Rakic 199 1. 1994: Arnsten et al.. 1995). ...
Dopamine receptors are widely expressed throughout the central and peripheral nervous systems and regulate many key functions of the brain. Five dopamine receptors have so far been cloned and classified into two main classes known as D1-like (Dl and D5) and D2-like (D2, D3 and D4) based on similarity in structure, pharmacology and coupling. Primarily because of the lack of receptor subtype-selective ligands, the precise physiological roles of these individual dopamine receptor subtypes remain unclear. The Dl receptor subtype is highly expressed in the striatum, nucleus accumbens and prefrontal cortex, brain regions shown to modulate many functions ranging from locomotion to reward, cognition and emotion. To study the potential in vivo role of the dopamine Dl receptor in the regulation of specific brain functions and drug induced behaviors, we used rnice lacking the functional D1 receptor gene. In these mice, the Dl receptor gene was deleted by means of homologous recombination. Based on the behavioral analysis of Dl receptor-deficient mice, we demonstrate that the D1 receptor is an abundant protein that plays a crucial role in mediating higher brain functions including some aspects of cognition (spatial learning and memory), appetitive motivation (operant responding for sucrose), alcohol seeking behavior and locomotor responses to alcohol and amphetamine. In addition, we have defined, for the first time, a role for the D1 receptor in the normal extinction of conditioned fear responses. However, D1 receptor does not appear to be essential for basal locomotor activity, working memory, sweet-taste preference or acquisition and expression of fear responses. These findings have great importance in furthering the understanding of the role of D1 receptors in brain Functions.
... Auch die positiven Nikotinwirkungen auf Gedächtnisfunktionen werden unter andern mit dem dopaminergen System in Verbindung gebracht (Levin and Rose 1995 (Benowitz 2008). ...
Bei den Wirkungen von Nikotin kommt dem Neurotransmitter Dopamin eine entscheidende Rolle zu. Gleichzeitig werden dopaminerge Medikamente in der Behandlung von periodischen nächtlichen Beinbewegungen (PLMS) angewandt. Dies legt die Vermutung nahe, dass Nikotin einen Einfluss auf das Auftreten von PLMS hat. Bisher liegen nur wenige und widersprüchliche Ergebnisse zu dieser Überlegung vor.
Ziel dieser Arbeit war daher die Untersuchung von PLMS unter akuter und chronischer Nikotinwirkung und ihre Veränderungen im Verlauf des Entzuges. Außerdem wurde der Einfluss von PLMS auf die Schlafqualität untersucht.
In einer placebokontrollierten, doppelblind randomisierten Studie im Paralleldesign wurden 66 gesunde, zwischen 20 und 25 Jahre alte Nichtraucher in vier Verumgruppen (8/16 mg transdermales Nikotinpflaster tagsüber oder nachts) und eine Placebogruppe unterteilt und im Schlaflabor untersucht. Zusätzlich wurden 44 abhängige Raucher zwischen 18 und 50 Jahren zu drei Zeitpunkten (rauchend, akuter Entzug, Follow-up nach 3 Monaten) polysomnographisch untersucht. Als Vergleichsgruppe dienten 44 gesunde, in Alter und Geschlecht entsprechende Nichtraucher.
Raucher zeigten im Vergleich zu den Kontrollprobanden zu allen Untersuchungszeitpunkten ein erhöhtes Auftreten von PLMS. Einen Unterschied zwischen nach 3 Monaten abstinenten und rückfälligen Rauchern konnten wir nicht feststellen. Im Verlauf des Entzuges kam es zu keinen wesentlichen Veränderungen der PLMS.
Bei den Nichtrauchern fand sich in der höchsten Nikotindosierung bei nächtlicher Applikation eine signifikant verminderte Anzahl an PLMS im Vergleich zur Placebogruppe. In allen anderen Verumgruppen zeigte sich ebenfalls eine Tendenz zu weniger PLMS.
Obwohl einzelne statistisch signifikante Korrelationen zwischen PLMS und Parametern der Schlafqualität gefunden wurden, scheint es in der Zusammenschau aller Ergebnisse eher unwahrscheinlich, dass PLMS ursächlich die Schlafqualität verschlechtern.
Die erhöhte Anzahl an PLMS bei Rauchern zu allen Untersuchungszeitpunkten entspricht nicht den Erwartungen bei Annahme einer dopaminergen Nikotinwirkung auf die PLMS. Daher sind sicherlich weitere Untersuchungen nötig um mögliche Ursachen der erhöhten Anzahl an PLMS zu identifizieren. Auch der Einfluss der PLMS auf die Schlafqualität sollte weiter geklärt werden.
... Nicotine is named after the tobacco plant Nicotiana tabacum, which in turn is named after the French ambassador in Portugal, Jean Nicot de Villemain, who sent tobacco and seeds to Paris in 1560, and who promoted their medicinal use. The cholinergic modulation of the midbrain dopamine system has been connected to nicotine self-administration in rats and hence is thought to support drug reinforcement [113]. ...
The term neuroenhancement refers to improvement in the cognitive, emotional and motivational functions of healthy individuals through inter alia, the use of drugs. This popular topic attracts attention both from the general public and the scientific community. Our objective is to summarize in a synthetic review the data of randomized placebo-controlled trials that assessed cognitive effects of administration of neuroenhancers in non-sleep-deprived healthy adults compared to placebo. The major outcomes were attention, memory, learning, executive functions, and vigilance/wakefulness. Details on the pharmacological profile, effectiveness and safety for each drug are provided. We classify them according to their recognized major primary mode of action, namely catecholaminergics (methylphenidate, modafinil, amphetamines, tolcapone, pramipexole, guanfacine, antidepressants), cholinergics (nicotine, varenicline, acetylcholine esterase inhibitors, anticholinergics), glutamatergics (ampakines, memantine, Dcycloserine), histaminergics, and non-specified (caffeine, racetams/phosphodiesterase inhibitors and glucocorticoids).
... Most studies employ a young adult population and data from the mid age range is scarce. Nicotine has been shown to be cognitively beneficial in healthy elders (Jones et al., 1992), as well as MCI patients (Newhouse et al., 2012), although rat studies point to attenuated responses to nicotine with age, consequent upon an age-related decrease in nicotinic receptor numbers (Levin and Rose, 1995). Thus, relative to other studies investigating nicotine effects on attentional reorienting in young adults (Thiel and Fink, 2008; Thiel et al., 2005; Vossel et al., 2008), we expected decreased sensitivity to the drug at mid age. ...
Nicotine has been shown to speed attentional reorienting in cued target detection tasks, and work in young adults suggest that individuals carrying the apolipoprotein E (APOE) e4 allele might show greater sensitivity to the cognitive effects of nicotine. The APOE e4 allele is associated with increased risk of Alzheimer's disease (AD), and increased sensitivity to nicotine might reflect early cholinergic differences that relate to an enhanced risk of AD. The aim of this study was to investigate effects of nicotine and APOE on attentional reorienting in mid-age participants. APOE e4 (e4+) were compared to non-APOE e4 (e4-) carriers, and functional magnetic resonance imaging (fMRI) data acquired. Neural data showed that nicotine effects, and the network involved in reorienting, was consistent with studies in young adults. Nicotine improved attentional reorienting at the trend level. Although there were no behavioural effects of genotype, genotype effects were present neurally: e4+ showed decreased extrastriate activation, and enhanced effects of nicotine on reorienting in right middle frontal regions. Drug by genotype interactions were present in hippocampal and anterior cingulate regions. These results are consistent with differential sensitivity to nicotine according to APOE status, possibly reflecting abnormal cholinergic function and accelerated cognitive ageing in mid-age e4+.
... 1992) and their loss has been demonstrated in various neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases (Perry et al. 1995). These receptors are also involved in different CNS functions, for instance, learning and memory (Levin and Rose 1995). It is 185 therefore important to elucidate the exact function of these receptors and their involvement in healthy and pathological conditions. ...
5-[¹²³I]iodo-A-85380, namely 5-iodo-3-(2(S)-azetidinylmethoxy)pyridine, is a new, highly selective radioligand with favourable properties for in vivo imaging of neuronal nicotinic acetylcholine receptors (nAChRs) using single-photon emission computed tomography (SPECT). The aim of this work was to study the identifiability and stability of nAChR parameters in baboon brain using different tracer kinetic modelling strategies with shortened scan durations. Dynamic SPECT imaging studies were performed on two anaesthetised baboons for 3 hours. Kinetic analysis based on 2- and 3-compartment models was used to derive the receptor parameters, including the binding potential (BP) and the volume of distribution (Vd), using the arterial plasma time-activity curves as the input function. Based on the 3-compartment model, Vd was selected as an appropriate outcome measure to assess the parameter stability due to high variability in estimation of BP. Timestability analysis indicated that 90 mins of data collection generated stable outcome measure for 3-compartment model and the use of the 2-compartment model produced outcome measure with a larger bias. Thus, the 3-compartrnent model is the model of choice for analysis of 5-[¹²³I]iodo-A-85380 kinetics and the 2-compartment model is useful only when the data acquisition time is sufficiently long.
... After a baseline is established, a range of nicotine doses is administered, typically via implanted osmotic minipumps, which provide a constant release over several days. Typical results indicate that moderate doses of nicotine (e.g., 5-10 mg/kg per day) are related to modest improvements in the memory task, that is, fewer session-wide repeats, usually approximating an ETR of 7.5 (e.g., Levin, Christopher, Briggs, & Auman, 1996;Levin, Lee, Rose, Reyes, Ellison, Jarvik, & Gritz, 1990;1995;Levin & Torry, 1996; and see Levin, 2002 for a recent review). ...
Emerging evidence suggests that nicotine may enhance short-term memory. Some of this evidence comes from nonhuman primate research using a procedure called delayed matching-to-sample, wherein the monkey is trained to select a comparison stimulus that matches some physical property of a previously presented sample stimulus. Delays between sample stimulus offset and comparison stimuli onset are manipulated and accuracy is measured. The present research attempted to systematically replicate these enhancement effects with pigeons. In addition, the effects of nicotine were assessed under another, more dynamic, memory task called titrating-delay matching-to-sample. In this procedure, the delay between sample offset and comparison onset adjusts as a function of the subject's performance. Correct matches increase the delay, mismatches decrease the delay, and titrated delay values serve as the primary dependent measure. Both studies examined nicotine's effects under acute and chronic administration. Neither provided clear or compelling evidence of memory enhancement following nicotine administration despite reliable and systematic dose-related changes in response latency measures. A modest dose-related effect on accuracy was found, but the magnitude of the effect appears to be directly related to tactics of data analysis involving best-dose analyses of a very circumscribed subset of trial types.
... High dose nicotine infusion of 12 mg kg y1 day y1 causes significant improvement of choice w x accuracy in the radial-arm maze 15-17 which persists for w x several weeks after withdrawal 12 . Lower dose nicotine infusion of 5 mg kg y1 day y1 also causes a significant improvement in radial-arm maze choice accuracy w x 10, 11,13,14,18,19 . However, with the lower dose the improvement does not persist after nicotine withdrawal. ...
Chronic nicotine infusions have been found to significantly improve working memory performance in the radial-arm maze. This effect is blocked by co-infusions of the nicotinic antagonist mecamylamine. Acute nicotine injections also improve working memory performance in the radial-arm maze. This effect is also blocked by mecamylamine co-administration. Recent local infusions studies have demonstrated the importance of the ventral hippocampus for nicotinic involvement in memory. Local infusions of mecamylamine, DHβE or MLA impair working memory performance on the radial-arm maze. The current study was conducted to determine the importance of the ventral hippocampus for the chronic effects of nicotine. Rats were trained on the working memory task in an eight-arm radial maze. After acquisition they underwent either infusions of ibotenic acid lesions or vehicle infusions and received subcutaneous implants of osmotic minipumps that delivered either nicotine at a dose of 5 mg kg−1 day−1 or vehicle in a 2×2 design. The rats then were given 2 days of recovery and were tested on the radial-arm maze three times per week for the next 4 weeks. As seen in previous studies, in the sham lesioned group nicotine infusions caused a significant improvement in choice accuracy. In contrast no nicotine-induced improvement was seen in the rats after ibotenic acid lesions of the ventral hippocampus. The effect of nicotine was blocked even though this lesion did not cause a deficit in performance. Previous work showed that chronic nicotine infusion still caused a significant improvement in working memory performance in the radial-arm maze after knife-cut lesions of the fimbria–fornix carrying the septo-hippocampal cholinergic innervation. Thus it appears that it is the postsynaptic nicotinic receptors in the ventral hippocampus which are critically important for the expression of the chronic nicotine induced working memory improvement.
... Hybridized slides were scanned cytoskeleton-associated protein (ARC) and dendrin in specific brain regions of rats (Schochet et al., 2005(Schochet et al., , 2008Schmitt et al., 2008). Acute nicotine exposure not only increases the activity of dopaminergic neurons and promotes dopamine release (Levin and Rose, 1995), but also enhances dopamine turnover and metabolism (Grenhoff and Svensson, 1988). The administration of a single dose of nicotine enhances the synthesis and release of striatal dynorphin, a component of the circuit promoting negative motivational and affective states, possibly under the regulation of dopamine and glutamate (Isola et al., 2009). ...
Previous human and animal studies demonstrate that acute nicotine exposure has complicated influences on the function of the nervous system, which may lead to long-lasting effects on the behavior and physiology of the subject. To determine the genes and pathways that might account for long-term changes after acute nicotine exposure, a pathway-focused oligoarray specifically designed for drug addiction research was used to assess acute nicotine effect on gene expression in the neuron-like SH-SY5Y cells. Our results showed that 295 genes involved in various biological functions were differentially regulated by 1 h of nicotine treatment. Among these genes, the expression changes of 221 were blocked by mecamylamine, indicating that the majority of nicotine-modulated genes were altered through the nicotinic acetylcholine receptors (nAChRs)-mediated signaling process. We further identified 14 biochemical pathways enriched among the nicotine-modulated genes, among which were those involved in neural development/synaptic plasticity, neuronal survival/death, immune response, or cellular metabolism. In the genes significantly regulated by nicotine but blocked by mecamylamine, 13 enriched pathways were detected. Nine of these pathways were shared with those enriched in the genes regulated by nicotine, including neuronal function-related pathways such as glucocorticoid receptor signaling, p38 MAPK signaling, PI3K/AKT signaling, and PTEN signaling, implying that nAChRs play important roles in the regulation of these biological processes. Together, our results not only provide insights into the mechanism underlying the acute response of neuronal cells to nicotine but also provide clues to how acute nicotine exposure exerts long-term effects on the nervous system.
... SKF 38393 (A.G. Scientific, Institute, San Diego, CA), a partial dopamine D1 receptor family agonist was diluted in saline (0.9%) and administered intraperitoneally in a 10 ml/kg injection volume 10 min prior to testing, with doses based on previous studies [20,62]. Drugs were administered in a cross-over design, with drug treatment on Tuesdays and Fridays, saline on Monday, Wednesday, and Thursday, with a 1-week washout period between drug challenges. ...
Patients with schizophrenia exhibit poor working memory (WM). Although several subcomponents of WM can be measured, evidence suggests the primary subcomponent affected in schizophrenia is span capacity (WMC). Indeed, the NIMH-funded MATRICS initiative recommended assaying the WMC when assessing the efficacy of a putative therapeutic for FDA approval. Although dopamine D1 receptor agonists improve delay-dependent memory in animals, evidence for improvements in WMC due to dopamine D1 receptor activation is limited. In contrast, the dopamine D2-family agonist bromocriptine improves WMC in humans. The radial arm maze (RAM) can be used to assess WMC, although complications due to ceiling effects or strategy confounds have limited its use. We describe a 12-arm RAM protocol designed to assess whether the dopamine D1-family agonist SKF 38393 (0, 1, 3, and 10 mg/kg) or bromocriptine (0, 1, 3, and 10 mg/kg) could improve WMC in C57BL/6N mice (n=12) in cross-over designs. WMC increased and strategy usage decreased with training. The dopamine D1 agonist SKF 38393 had no effect on WMC or long-term memory. Bromocriptine decreased WMC errors, without affecting long-term memory, consistent with human studies. These data confirm that WMC can be measured in mice and reveal drug effects that are consistent with reported effects in humans. Future research is warranted to identify the subtype of the D2-family of receptors responsible for the observed improvement in WMC. Finally, this RAM procedure may prove useful in developing animal models of deficient WMC to further assess putative treatments for the cognitive deficits in schizophrenia.
... Dopamin ist für kognitive Funktionen von Bedeutung. Dopamin-Antagonisten verursachen eine Verschlechterung der Gedächtnisfunktionen, die durch Nikotin verringert werden kann(Levin & Rose 1995). Dabei scheint Nikotin in erster Linie mit dem D1-Rezeptor zu inte-Die Freisetzung von Norepinephrin und Histamin wird durch Nikotin stimuliert. ...
Die exzitatorische cholinerge Wirkung von Nikotin wird in der Literatur häufig mit einer Veränderung kognitiver Parameter in Verbindung gebracht. Bereits frühe Forschung be-stätigte die Berichte von Rauchern bezüglich der stärkenden Wirkung von Nikotin auf Lernen und Aufmerksamkeit.
Ziel der vorliegenden Arbeit war es, an Nichtrauchern zu demonstrieren, dass sich Niko-tin positiv sowohl auf Aufmerksamkeit als auch auf Lernen und Arbeitsgedächtnis auswirkt.
33 gesunde Nichtraucher zwischen 20 und 25 Jahren wurden gründlich gescreent und in einer placebokontrollierten doppelblind-randomisierten Studie mit Paralleldesign in eine Verum- und eine Placebogruppe unterteilt. Daraufhin erhielten sie entweder ein Nikotin- oder Placebopflaster und absolvierten die Untersuchungen Word Pair Task, Mirror Tracing Task, Zahlennachsprechen/Visuelle Merkspanne, Trail Making Test und die Testbatterie zur Aufmerksamkeitsprüfung. Damit wurden insbesondere die Bereiche Aufmerksamkeit, deklaratives und prozedurales Lernen abgedeckt.
Entsprechend unserer Hypothese fanden wir in den Bereichen deklaratives und proze-durales Lernen und Arbeitsgedächtnis Verbesserungen unter Nikotin. Wir konnten keine Verbesserung der Aufmerksamkeitsleistung nachweisen. Somit war die Verbesserung des Lernens und des Arbeitsgedächtnisses unter Nikotin nicht indirekt über eine gestei-gerte Aufmerksamkeit erklärbar. Vielmehr scheint sich Nikotin unseren Ergebnissen zufolge unabhängig von Aufmerksamkeitsfunktionen wie Vigilanz und geteilte Aufmerk-samkeit direkt auf zentrale Prozesse auszuwirken, die dem Arbeitsgedächtnis zugrundeliegen.
Den Untersuchungsergebnissen kann man entnehmen, dass sicherlich weitere Untersu-chungen mit höheren Nikotindosen und Messung individueller Nikotinspiegel notwendig sind, um die kognitiven Wirkungen von Nikotin genauer zu charakterisieren.
... 'working memory' (Luciana et al., 1992;Levin & Rose, 1995;Curran & Travill, 1997). ...
Thesis (Ph. D.)--University of London, 1998.
The mesolimbic dopamine system which connects with frontal cortex has been implicated in motivation, particularly in mediating REWARD RESPONSIVENESS - the capacity to reach to incentive stimuli with appropriate goal-directed behaviour.
This thesis tests the model that in humans indices of motivation will vary as a function of dopaminergic activity. In contrast to a vast literature in experimental animals, few studies have systematically investigated this model in humans and few well-established measures of motivation exist. One theme of this thesis has therefore been the development and validation of a new objective measure of reward responsiveness (the CARROT) and other observational indices of motivation.
Study One investigated the association between clinical indices of motivation, reward responsiveness, and cognitive function in a group of 54 brain-injured patients. Clinical motivation showed significant correlations with reward responsiveness, and frontal cognitive functions, consistent with the hypothesis that impaired motivation may reflect organic damage to the mesolimbic-cortical circuit.
Study Two with 13 extremely poorly motivated brain-injured patients examined motivation and cognitive functions before and after treatment with a dopamine agonist, bromocriptine. In all 13, improvements in clinical indices of motivation, cognitive function and reward responsiveness were observed at small doses of bromocriptine (<10 mg), consistent with the postulated association between motivation and dopaminergic (DA-ergic) activity. Interestingly, these gains persisted even after the drug was withdrawn.
Study Three was with smokers. Nicotine is postulated to have DA-ergic effects. This naturalistic study examined reward responsiveness and cognitive functions, testing subjects during abstinence and after consumption of a cigarette. After 5-8 hours abstinence, smokers showed very little responsiveness to financial incentive. After smoking a cigarette, their reward responsiveness was greatly enhanced as was their performance on other tests of cognitive function. Non-smokers tested at the same intervals showed no such change. These data are consistent with dopamine activity being elevated by smoking and diminished during abstinence.
The fourth study tested the hypothesis that in healthy subjects a personality dimension - the Behavioural Activation System (BAS) - would predict individual differences in CARROT reward responsiveness. 161 subjects completed self-report scales designed to assess dispositional BAS sensitivity (Carver and White, 1994), and the CARROT. A putatively orthogonal dimension, Anxiety, believed to reflect constitutional differences in the Behavioural Inhibition System (BIS) was also assessed. The results confirmed that, in the presence of rewarding cues, normal subjects achieved greater card-sorting speed. This is consistent with an incentive effect, further supporting the validity of the newly developed assessment tool, the CARROT. Reward responsiveness was significantly greater for male subjects, and for subjects with lower BIS scores. One of the BAS subscales was positively correlated with reward responsiveness, as predicted, but two others were negatively correlated. Detailed analysis suggested that high scorers on these other dimensions sorted close to maximum speeds in baseline trials, thus introducing a ceiling effect into the task.
In summary, the four studies have provided support for the hypothesis that indices of motivation, cognitive functions attributed to mesolimbic-cortical dopamine circuitry, and reward responsiveness, are associated with each other and are influenced in parallel by dopaminergic manipulations.
... Além disso, quando a 6-OHDA foi infundida na parte mais central e medial da SNc alguns animais apresentam comportamento contralateral. (COSTALL et al., 1976;THAL et al., 1979;REDGRAVE e MITCHELL, 1982;HIRSCHHORN et al., 1983;SCHWARTING e HUSTON, 1996;OLDS et al., 2006 (CLARKE, 1995;LEVIN e ROSE, 1995;NISELL et al., 1995;STOLERMAN et al., 1995;DANI e HEINEMANN, 1996;WONNACOTT, 1997;BALFOUR et al., 1998). Interações entre a neurotranmissão dopaminérgica e nicotínica nas vias nigroestriatal e mesolímbica podem ser responsáveis pelos efeitos locomotores observados nestes estudos (CLARKE, 1990;RICHARDSON e TIZABI, 1994;MUSEO e WISE, 1995). ...
Orientador : Claudio da Cunha Co-orientadora : Maria Aparecida B.F. Vidal Dissertação (mestrado) - Universidade Federal do Paraná, Setor de Ciências Biológicas, Programa de Pós-Graduação em Farmacologia. Defesa: Curitiba, 2007 Inclui bibliografia
... For example, clinical studies have demonstrated that nicotine causes a dose-related reversal of haloperidol-induced impairments of memory performance in schizophrenics (Levin et al.,1996). By comparison, working memory deficits caused by the nicotinic antagonist mecamylamine are potentiated by haloperidol (Levin and Rose, 1995). Our data indicate that both typical and atypical antipsychotics inhibit NNR function with potencies in the low micromolar range, as judged by agonist-stimulated ion flux and neurotransmitter release. ...
It has been suggested that the interaction of antipsychotic medications with neuronal nicotinic receptors may increase the cognitive dysfunction associated with schizophrenia and may explain why current therapies only partially address this core feature of the illness. In the present studies we compared the effects of the atypical antipsychotics quetiapine, clozapine and N-desmethylclozapine to those of the typical antipsychotics haloperidol and chlorpromazine on the alpha4beta2 and alpha7 nicotinic receptor subtypes. The binding of [(3)H]-nicotine to rat cortical alpha4beta2 receptors and [(3)H]-methyllycaconitine to rat hippocampal alpha7 receptors was not affected by any of the compounds tested. However, Rb(+) efflux evoked either by nicotine or the selective alpha4beta2 agonist TC-1827 from alpha4beta2 receptors expressed in SH-EP1 cells and nicotine-evoked [(3)H]-dopamine release from rat striatal synaptosomes were non-competitively inhibited by all of the antipsychotics. Similarly, alpha-bungarotoxin-sensitive epibatidine-evoked [(3)H]-norepinephrine release from rat hippocampal slices and acetylcholine-activated currents of alpha7 nicotinic receptors expressed in oocytes were inhibited by haloperidol, chlorpromazine, clozapine and N-desmethylclozapine. The inhibitory effects on nicotinic receptor function produced by the antipsychotics tested occurred at concentrations similar to plasma levels achieved in schizophrenia patients, suggesting that they may lead to clinically relevant effects on cognition.
... In a behavioural study with normal smokers, Wesnes & Warburton (1983) found that a single cigarette administered after a period of tobacco deprivation improved performance on a rapid visual information processing task relative to baseline scores. Levin & Rose (1995) found nicotine to improve performance on tests of working memory; conversely, blockade of nicotinic transmission using antagonists such as mecamylamine has been found to impair working memory, both in humans (Newhouse et al., 1992) and in animals (Arnsten et al., 1994). ...
To investigate the effects of (a) nicotine abstinence and (b) cigarette smoking after abstinence, on reward responsiveness and cognitive functions which are putatively dependent on activity in the dopaminergic system implicated in smoking.
During Ramadhan, Muslim smokers elected to abstain from smoking either for the whole month (RAMQUIT) or during daylight hours (DAYQUIT). These groups, and non-smokers (NOSMOKE), were assessed on two occasions 6 hours apart (TEST1 and TEST2). DAYQUIT participants had abstained for 6 hours at TEST1 and smoked a single cigarette immediately prior to TEST2. RAMQUIT participants had abstained for at least 10 days prior to TEST1 and remained abstinent at TEST2. NOSMOKE and RAMQUIT participants are a small snack prior to TEST2 to control for non-specific consummatory effects.
TEST1 was conducted at the mosque and TEST2 in participants' homes.
All were male; mean age was 26.7 years. Modal cigarette consumption prior to Ramadhan by both the 13 DAYQUIT and the 11 RAMQUIT smokers was 21-30 per day. DAYQUIT subjects rated themselves as more dependent.
The Card Arranging Reward Responsivity Objective Test (CARROT), testing behavioural responsiveness to small financial incentive; digit span, measuring attention; verbal fluency, indexing frontal lobe function; and the two-choice guessing test (2CGT; at TEST1 only), measuring response stereotypy.
At TEST1, compared with non-smokers, both smoking groups showed greater stereotypy (2CG) and lower reward responsiveness (CARROT). DAYQUIT participants improved on all measures after smoking a single cigarette. No marked changes were seen in the other groups.
These data suggest that (i) abstaining smokers have impaired dopaminergic function and (ii) nicotine consumption may boost their dopaminergic activity.
The factors causing schizophrenia are multifaceted, and studies have shown that the disease has heritability. Dopamine hypothesis is one of the pathogenesis hypotheses of schizophrenia. This paper analysed the relationship between genes, dopamine and schizophrenia, and focuses on four important genes associated with schizophrenia. Through analysis, this paper suggests possible ways in which susceptibility genes may cause disease. This paper will lay a foundation for the further study of dopamine in schizophrenia and provide a drug target for the treatment of schizophrenia.
Humans spend the lion's share of their mental life either in their personal past or an anticipated or imagined future. This type of mental state is known as mental time travel. It is perhaps the most sophisticated and fitness-promoting cognition that has evolved in humans and with some reservation in animals. We have proposed that working memory capacity and the complexity of executive functions within working memory might limit the authenticity with which past events are reconstructed and anticipated or imagined future scenarios are constructed. In the present article, we discuss the possibility of a co-evolution between working memory capacity, complexity of executive functions available in the working memory workspace, and mental time travel abilities across species. We further assume that a complex working memory system can be constructed with quite different brains and conclude that the advanced cognitive function of thinking about the past and the future might not be a privilege of the mammalian brain.
[5- 3H]-4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was infused subcutaneously at a daily dose of 7.2 nmol/kg with or without 26 µmol/kg nicotine or cotinine, respectively, over four weeks in male F344 rats. Coadministration of nicotine or cotinine had no effect on the excretion of NNK and its metabolites. However, at the end of the experiment binding of radioactivity to hemoglobin in nicotine- and cotinine-treated rats was reduced by 50% compared to NNK-only treated rats. The inhibition of hemoglobin adduct formation by tobacco alkaloids may explain the lower than expected differences in the adduct levels of tobacco-specific nitrosamines between smokers and nonsmokers as observed in several biomonitoring studies.
Nicotine has been found by many but not all studies to improve and mecamylamine to impair performance on cognitive tasks in humans and experimental animals. In our laboratory, a very reproducible finding has been that chronic infusion of nicotine significantly improves memory performance in a win-shift version of the radial-arm maze. Nicotine attenuates the memory deficits caused by lesions of the fimbria-fornix or the medial basalocortical projection. Chronic co-administration of the nicotinic antagonist mecamylamine eliminates the nicotine effect. Some aspects of the cognitive deficit in Alzheimer’s disease are attenuated by nicotine, suggesting promise for the therapeutic use of nicotine or other nicotinic ligands for cognitive dysfunction.
Nicotine delivery via either cigarette smoking, nicotine injections, or transdermal nicotine patches has been shown in a variety of studies to improve cognitive function including attention, learning, and memory. Nicotine and other nicotinic drugs have been found to improve cognitive function in humans as well as experimental animal subjects (BRIONI et al. 1997; DECKER et al. 1995; LEVIN 1992, 1996; LEVIN and SIMON 1998). Like any drug effect, nicotinic actions on cognitive function are limited and some studies have not found nicotine-induced improvement (for a review, see HEISHMAN et al. 1994). The specific nature of the expression of nicotine-induced cognitive improvement gives insight into the critical neural systems involved. This research is vital for the further development of nicotinic-based therapeutics for cognitive dysfunction.
Ten patients with Parkinson's disease were examined using a procedural learning task and Sternberg's declarative short term memory test, under two condition's: on dopaminergic medication producing an optimal motor state, and without medication. The performance in the non-declarative task was improved, while reaction times in the declarative memory test were delayed in medicated subjects. The findings lead to the conclusion that dopaminergic medication can impair declarative short-term memory even in doses producing motor improvement.
Nicotinic acetylcholine receptors have been shown in many studies to be critically involved in memory function. The precise roles these receptors play depend on the receptor subtype, their anatomic localization, their interactions with other parts of the neural systems underlying cognition and the particular domain of cognitive function. Nicotinic agonists can significantly improve learning, memory, and attention. Nicotinic receptors in the hippocampus are innervated by cholinergic projections from the medial septum and diagonal band. Local infusions of either α7 or α4β2 nicotinic antagonists into either the dorsal or ventral hippocampus produce amnestic effects in rats navigating about a radial arm maze. There is cholinergic innervation of nicotinic receptors in other components of the limbic system as well. In the basolateral amygdala and the anterior thalamus, similar amnestic effects of nicotinic α7 and α4β2 antagonists are seen. Interestingly, there are no additive amnestic effects observed in these limbic areas when α7 and α4β2 receptor antagonists are combined. The particular expression patterns of α7 and α4β2 nicotinic receptors in these limbic and cortical areas may explain this nonadditivity, but further research is needed to determine the specific cause of this phenomenon. Nicotinic receptor mechanisms in the limbic system play an important role in cognitive impairment for a variety of neurological disorders, including Alzheimer's disease and schizophrenia. Alzheimer's disease results in a dramatic decrease in hippocampal nicotinic receptor density, affecting α4β2 receptor expression most prominently. In schizophrenia, there are anomalies in α7 nicotinic receptor expression, which seem to be crucial for the cognitive impairment of the disorder. Chronic nicotine exposure, such as seen with tobacco use, results in an increase in nicotinic receptor density in the limbic system. This effect appears to be related to the desensitization of nicotinic receptors seen after agonist application. Open questions remain concerning the role of desensitization versus activation of nicotinic receptors in cognitive improvement.
5-iodo-3-(2(S)-azetidinylmethoxy)pyridine (5-[123I]iodo-A-85380) is a novel radioligand for brain nicotinic acetylcholine receptors (nAChRs), having demonstrated high specific binding to nAChRs and favourable properties for in vivo imaging. The purpose of this study was to evaluate different tracer kinetic modelling strategies for the quantification of regional nAChR binding in baboon brain using dynamic single-photon emission computed tomography (SPECT). Imaging studies were performed on two anaesthetised baboons. The radioligand (397 ± 43 MBq) was infused into the animals over 2 min and dynamic SPECT images were acquired for 3 hr. The plasma input function was determined from arterial blood samples with metabolite correction. The data were analysed using 2- and 3-compartment models. Reliable fits could be obtained with a 3-compartment model which provided significantly improved fitting as compared to the 2-compartment model, despite poor identifiability in some parameters. The 2-compartment model failed to fit the data adequately even though the identifiability of parameters was high. The 3-compartment model described the data well, and with the strategies used to obtain reliable fits, is the model of choice for analysis of 5-[123I]iodo-A-85380 kinetics.
Previous studies have shown that rats subjected to subchronic treatment with nicotine experience changes in COX-2 (a marker of pro-inflammatory systems) and accumulate lipid hydroperoxides (a marker of oxidative stress) in the CNS (CNSMC, 2010; 10:180-206) (hippocampus, frontoparietal cortex and cerebellar cortex). Such changes are specific to each region since each contains different types of neuronal and glial cells with different nicotine receptors. They also differ in animals exposed to a source of oxidative stress, such as D-amphetamine. This paper discusses the changes in other markers of oxidative stress - the isozymes of superoxide dismutase Mn-SOD and Cu/Zn-SOD - in nicotine- and nicotine + D-amphetamine-treated rats. The biochemical and histochemical changes observed were specific to each region (in general very marked in the frontoparietal cortex and the hippocampus but less so in the cerebellar cortex) and each type of neuronal and glial cell. The SODs induced by nicotine may exert a neuroprotective effect via the reduction of oxidative stress. This might be beneficial in the treatment of neurodegenerative diseases. The fact that nicotine did not greatly increase the SODs in the rats treated with D-amphetamine may indicate that the effect of nicotine is partially or totally abolished in situations of oxidative stress. However, since ROS and lipid hydroperoxide levels are also reduced when nicotine is administered to such animals, it could be argued that nicotine is beneficial.
Four halogen-substituted analogues of N-methylepibatidine, a nicotinic acetylcholine receptor (nAChR) ligand, were synthesized. They were (±)-exo-N-methyl-2-(2-halogeno-5-pyridyl)-7-azabicyclo[2.2.1]heptanes, where halogeno = F (1a), Cl (2a), Br (3a), I (4a). (±)-N-Ethylepibatidine (2b) also was synthesized. The compounds 1a, 2a, 3a, and 4a and their corresponding normethyl analogues 1, 2, 3, and 4 inhibited the in vitro binding of [3H]epibatidine to nAChRs to a similar degree, with affinities in the 27−50 pM range. The binding affinity of N-ethylepibatidine (2b), however, was substantially lower. The N-[11C]methyl derivatives of 1, 2, and 3 were synthesized from high-specific radioactivity [11C]methyl iodide using a high-temperature/high-pressure technique. The corresponding radiolabeled compounds [11C]1a, [11C]2a, and [11C]3a were administrated to mice intravenously. The pattern of regional distribution of the three tracers in the mouse brain following intravenous administration matched those of [3H]epibatidine, [3H]norchloroepibatidine, and (±)-exo-2-(2-[18F]fluoro-5-pyridyl)-7-azabicyclo[2.2.1]heptane ([18F]FPH), which are highly specific nAChR probes. The initial brain uptake of the 11C analogues and the acute toxicity of the corresponding authentic nonlabeled compounds appeared to be related to their lipophilicity.
A structural study on two dopamine-based imide derivatives, namely, 2-(3,4-dihydroxyphenethyl)isoindole-1,3-dione (1) and 2,6-bis-[2-(3,4-dihydroxyphenyl)ethyl]pyrrolo [3,4-f]isoindole-1,3,5,7-tetrone (2), and their solvates was carried out. The compound 1 (Z′ = 2) was crystallized through a melt crystallization process, whereas its two solvates (Z′ = 1 of each), containing one water molecule (1a) and the other containing two quinoline molecules (1b) in their crystal lattices, respectively, were obtained through solution crystallization. The reasons for Z′ = 2 arising from symmetry nonequivalent molecules in the unit cell of 1 is attributed to the nonparallel arrangement of two layers of self-assembled molecules in crystal lattice, where one layer has C−H···π and another layer has C═O···π interactions. Four different solvates of compound 2 (Z′ = 0.5 of each), containing two DMF molecules (2a), two DMSO molecules (2b), two pyridine molecules (2c), and six quinoline molecules (2d), were also obtained through solution crystallization of 2 in respective solvents. Solvate 2d has channels in its structure which are formed by interaction of 2 with quinoline molecules through O−H···N and C−H···π interactions. Additional quinoline molecules reside in these channels of approximately (11 × 12) Å dimension. Structural features of all the compounds and their solvates have been studied by single crystal X-ray structures, powder X-ray diffractions (PXRD), thermogravimetric analyses (TGA), and differential scanning calorimetric (DSC) measurements.
The radiochemical synthesis of 2-[18F]fluoro-3-(2(S)-azetidinylmethoxy)pyridine (2-[18F]A-85380, [18F]1) was accomplished by Kryptofix® 222 assisted nucleophilic no-carrier-added [18F]fluorination of 2-iodo-3((1-tert-butoxycarbonyl-2(S)-azetidinyl)methoxy)pyridine, 2 followed by acidic deprotection. The average radiochemical yield was 10% and the average specific radioactivity was 1050 mCi/μmol, calculated at end-of-synthesis (EOS). © 1998 John Wiley & Sons, Ltd.
Smoking is becoming increasingly concentrated in people with co-factors suck as depression, attention deficit-hyperactivity disorder, anxiety disorders, and bulimia/bingeing. These behavioral or cognitive patterns may be adaptive or neutral in the conditions under which toe evolved but maladaptive in environments requiring alertness for extended periods, where a fatty mobilized fight-or-flight response is inappropriate, and where food availability makes lack of an “appestat” a liability. Such conditions are amenable to management by nicotine because of its ability to produce small but reliable adjustments in relevant cognitive and behavioral functions. Moreover, symptomatology may be unmasked or exacerbated by nicotine abstinence, persisting beyond the usual time-course for nicotine withdrawal, which may explain the particular attraction of smoking and the difficulty these individuals experience in quitting without necessarily requiring that they be more nicotine-dependent. The implications are: (1) a better understanding of the evolutionary psychobiology of smoking may promote development of tailored interventions for smokers with co-factors; (2) nicotine may have therapeutic applications for non-smokers with co-factors; (3) because smoking has a fairly high heritability index, and because of evidence of assortative mating, special prevention efforts targeting children of smokers with co-factors, as well as early identification of the co-factor itself, may be needed.
Chronic nicotine administration has been repeatedly shown to facilitate working memory function in rats on the radial-arm maze. The critical neural mechanisms for this effect are still being discovered. The nicotinic nature of the chronic nicotine induced memory improvement is supported by the finding that it is blocked by chronic mecamylamine co-infusion. The hippocampus also appears to be critically important. Hippocampal ibotenic acid lesions block the effect. Within the hippocampus, we have found that the α4β2 nicotinic receptor subtype is involved in memory functioning. Acute ventral hippocampal infusions of the α4β2 nicotinic antagonist dihydro-β-erythroidine (DHβE) significantly decreased working memory performance in the radial-arm maze. The aim of the current study was to determine the importance of α4β2 receptors within the ventral hippocampus for the memory enhancing effects of chronic nicotine treatment. Adult female Sprague–Dawley rats were trained on the 8-arm radial maze and were cannulated bilaterally in the ventral hippocampus. Osmotic minipumps administering chronic nicotine at a rate of 5 mg per kg per day were also implanted in the nicotine treatment rats. Control rats received saline-only minipumps. For a period of 4 weeks after surgery, each rat received bilateral hippocampal infusions of 0, 2, 6 and 18 μg per side of DHβE and tested for memory performance on the radial-arm maze. Radial-arm maze choice accuracy was impaired by acute hippocampal DHβE infusion in a dose-related fashion. This acute hippocampal DHβE-induced choice accuracy impairment was eliminated by chronic systemic nicotine infusion. Chronic nicotine in combination with acute vehicle hippocampal infusion was not seen to alter choice accuracy. Response latency was not found to be altered by acute hippocampal DHβE in the absence of chronic nicotine administration, but it did attenuate the response latency reduction induced by chronic nicotine infusion. Wet dog shakes were not found to be affected by hippocampal DHβE when given without chronic nicotine. Wet dog shakes were significantly increased by chronic nicotine infusion. Intra-hippocampal DHβE significantly potentiated this effect. The results from the current study reinforce the hypothesis that ventral hippocampal α4β2 nicotinic receptors are important for memory function. These receptors may also have a role to play in the development of other aspects of behavior associated with chronic nicotine treatment.
Cigarette smoking during pregnancy has been shown in a variety of studies to be associated with cognitive deficits in the children. Nicotine administration to rats during gestation has been found to cause subtle cognitive effects in the offspring. Some individual differences in cognitive impairment may be related to prenatal nicotine effects on noradrenergic (NE) systems. In the current study, 10 Sprague-Dawley rat dams were infused with approximately 2 mg/kg/day of nicotine ditartrate via osmotic minipumps and 10 control dams were exposed to vehicle-containing minipumps from gestational day (GD) 4–20. Starting on postnatal day (PND) 50, the offspring were tested for T-maze rewarded spatial alternation with intertrial intervals of 0, 10, 20 or 40 s. There was a sex- and delay-dependent effect of prenatal nicotine exposure on T-maze alternation. Nicotine-exposed males showed a significant deficit at the 0 s delay. In radial-arm maze (RAM) acquisition training there were no significant nicotine effects. However, significant nicotine-related effects were seen with subsequent behavioral and pharmacological challenges in the RAM. Changing the RAM testing location to an identical maze in a different room elicited a significant choice accuracy deficit in the prenatal nicotine-exposed rats compared with controls. Acute nicotine challenge did not cause any differential effects in the prenatal nicotine and control groups. During the isoproterenol (β-NE agonist) challenge phase there appeared a significant facilitation of choice accuracy and speeding of response in the prenatal nicotine females but groups which was not seen in the control group. The α-NE agonist phenylpropanolamine caused a significant deficit in control females but not in the females prenatally exposed to nicotine. No differential effects of the α-NE antagonist phenoxybenzamine were seen in the prenatal nicotine and control groups. Throughout RAM testing there was a significant sex effect with males having better choice accuracy than females. These results demonstrate that the persisting cognitive effects of prenatal exposure to 2 mg/kg/day cause subtle effects in cognitive performance which can be elicited with behavioral and pharmacological challenge. These results also support previous studies suggesting the involvement of NE systems in persisting effects of prenatal nicotine exposure.
Spontaneous (novel) object recognition (SOR) is one of the most widely used rodent behavioural tests. The opportunity for rapid data collection has made SOR a popular choice in studies that explore cognitive impairment in rodent models of schizophrenia, and that test the efficacy of drugs intended to reverse these deficits.
We provide an overview of the many recent studies that have used SOR to explore the mnemonic effects of manipulation of the key transmitter systems relevant to schizophrenia-the dopamine, glutamate, GABA, acetylcholine, serotonin and cannabinoid systems-alone or in combination. We also review the use of SOR in studying memory in genetically modified mouse models of schizophrenia, as well as in neurodevelopmental and lesion models. We end by discussing the construct and predictive validity, and translational relevance, of SOR with respect to cognitive impairment in schizophrenia.
Perturbation of the dopamine or glutamate systems can generate robust and reliable impairment in SOR. Impaired performance is also seen following antagonism of the muscarinic acetylcholine system, or exposure to cannabinoid agonists. Cognitive enhancement has been reported using alpha7-nicotinic acetylcholine receptor agonists and 5-HT(6) antagonists. Among non-pharmacological models, neonatal ventral hippocampal lesions and maternal immune activation can impair SOR, while mixed results have been obtained with mice carrying mutations in schizophrenia risk-associated genes, including neuregulin and COMT.
While SOR is not without its limitations, the task represents a useful method for studying manipulations with relevance to cognitive impairment in schizophrenia, as well as the interactions between them.
Abstinence from smoking has been associated with acute impairments of performance in a number of tasks associated with incentive motivation and executive functioning in non-injured participants. The current study aimed to investigate the effects of smoking on various cognitive and motivational measures in 18 brain injured smokers, thus generalising previous findings from non-injured participants. A within-subjects cross-over design was utilised, to compare performance after an acute period of abstinence from smoking with performance after smoking. The test battery included measures of reward responsivity (a card-sorting task providing a behavioural index of incentive motivation), verbal fluency, and working memory. Reward responsivity was enhanced after a cigarette had been smoked compared to when abstinent. Performance on the card sorting task was particularly enhanced when the task was novel. There was no significant enhancement on any other measure. It was concluded that smoking has a direct effect on responsiveness to incentive, which we have found elsewhere to be closely related to motivation in therapy. Implications for clinical neuropsychological assessment and treatment are discussed.
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.
The cholinergic system has long been linked to cognitive processes. Two main classes of acetylcholine (ACh) receptors exist in the human brain, namely muscarinic and nicotinic receptors, of which several subtypes occur.
This review seeks to provide an overview of previous findings on the influence of cholinergic receptor manipulations on cognition in animals and humans, with particular emphasis on the role of selected cholinergic receptor subtypes. Furthermore, the involvement of these receptor subtypes in the regulation of emotion and brain electrical activity as measured by electroencephalography (EEG) shall be addressed since these domains are considered to be important modulators of cognitive functioning.
In regard to cognition, the muscarinic receptor subtypes have been implicated mainly in memory functions, but have also been linked to attentional processes. The nicotinic α7 receptor subtype is involved in working memory, whereas the α4β2* subtype has been linked to tests of attention. Both muscarinic and nicotinic cholinergic mechanisms play a role in modulating brain electrical activity. Nicotinic receptors have been strongly associated with the modulation of depression and anxiety.
Cholinergic receptor manipulations have an effect on cognition, emotion, and brain electrical activity as measured by EEG. Changes in cognition can result from direct cholinergic receptor manipulation or from cholinergically induced changes in vigilance or affective state.
Nicotine/nicotine agonists or allosteric modulators of nicotine receptors have been suggested as the most important therapeutic agents in the prevention and clinical control of cognitive impairment which characterize neuropsychiatric and neurodegenerative disorders such as schizophrenia, attention deficit/hyperactivity disorder and Alzheimer's disease. Both clinical studies and animal experiments support the important role of the nicotinic systems in learning, different kind of memory and cognition. For development of nicotinic treatments we have a well characterized lead compound, nicotine. However, the neural nicotinic mechanisms underlying cognitive functions are not well known because the side effects of nicotine overdose have hindered the development of this therapeutical line. The new development of non-toxic, brain specific nicotine drugs need a full knowledge of these mechanism and a reevaluation of the nicotine effects. This review aims to analyze the different kind of effects of nicotine on the Central Nervous System (CNS), especially on the cortex and hippocampus. Nicotine effects are, theoretically and/or practically, of variable character depending on daily dose and time of treatment; on the subtype and density of the different nicotinic receptors existing in the distinct brain regions; on the processes of desensitization and tolerance of nicotinic receptors and on other neuronal factors. Nicotine produces the above mentioned activation of the cognitive functions acting directly or indirectly on cortical neurons. In some experiments, high doses of nicotine can impair memory. This substance induces increases in the glycolytic pathway and Krebs cycle of neurons, as well as brain blood flow. Nicotine also produces an increase in NGF immunoreactivity in frontoparietal cortex. All these neuronal changes may cause different positive effects such as neuroprotection, neuroplasticity and better performance of synaptic circuits. The benefit of other neuronal changes can be matter of discussion such as some modifications in synaptic transmission, the COX-2 increase in frontoparietal cortex and hippocampus or the changes in the antioxidant systems. Finally, other neuronal changes can be of negative effect such as the induction of apoptosis and oxidative stress (DNA damage, ROS and lipid peroxide increase). All these described effects explain both the beneficial and neurotoxic consequences of the activation of the nicotinic receptors. The diversity and variability of the nicotinic effects should take into account when nicotine agonists will be used as a possible cognitive treatment.
Nicotinic drugs have been proposed as putative drugs to treat Parkinson's disease (PD). In this study, we investigated whether nicotine can sensitize parkinsonian animals to the effect of dopaminergic drugs. Testing this hypothesis is important because nicotine has been shown to present neuroprotective and acute symptomatic effects on PD, but few studies have addressed the question of whether it may induce long-lasting effects on dopamine neurotransmission. We tested this hypothesis in the 6-hydroxydopamine (6-OHDA) rat model of PD. A pretreatment of these rats with 0.1-1.0 mg/kg nicotine induced a dose-dependent sensitization of the turning behavior when the animals were challenged with the dopamine receptor agonist apomorphine 24 h later. In agreement with previous studies, while apomorphine induced contraversive turns, nicotine, as well as amphetamine, induced ipsiversive turns in the 6-OHDA rats. This result suggests that, like amphetamine, nicotine induces turning behavior by promoting release of dopamine in the non-lesioned striatum of the rats. However, it is unlikely that the release of dopamine may also explain the nicotine-induced sensitization of turning behavior. First, the dopamine amount that could be released in the lesioned hemi-striatum by the nicotine pretreatment was minimum-less than 3%, as detected by HPLC-EC. Second, a pretreatment with amphetamine did not induce this behavioral sensitization. A pretreatment with apomorphine-induced sensitization, but it was minimal when compared to that induced by nicotine. Therefore, it is unlikely that the sensitization of the turning behavior induced by nicotine was consequent of the release of dopamine. However, the expression of such sensitization seems to depend on the activation of dopaminergic receptors, since it was seen when the nicotine-sensitized animals were challenged with apomorphine, but not with a second nicotine challenge. These findings are relevant for PD drug therapy since they suggest that the doses of dopaminergic drugs used to treat PD could be reduced if a nicotinic drug were co-administered.
Acute and chronic nicotine administration has been repeatedly been found in our laboratory to improve working memory performance of normal adult rats in the radial-arm maze. The current study was conducted to determine if acute or chronic nicotine administration would improve working memory performance in aged rats. Sixteen young adult (3-7 months) and 32 aged (24-28 months) male Sprague-Dawley rats were trained on an eight-arm radial maze. A significant age-related choice deficit was seen during the 21 sessions of training. After training, half of the rats in each age group were implanted with nicotine-containing osmotic minipumps and the other half implanted with vehicle-containing pumps. Consistent with previous work, the young adult rats given chronic nicotine (approximately 5 mg/kg per day as measured as nicotine base) showed a significant improvement in working memory performance. In contrast, the aged rats did not show a significant effect of this dose of chronic nicotine. After a 2 week withdrawal period the remaining rats underwent a series of acute drug challenges with nicotinic and muscarinic agonists and antagonists as well as the dopaminergic antagonist haloperidol. Mecamylamine and haloperidol impaired the memory performance of the young adult rats, whereas the aged rats showed no effect. In contrast, scopolamine impaired performance of both young adult and aged rats in a similar manner. Both pilocarpine and nicotine improved the memory performance of the aged rats, but did not improve the young adult rats, possibly due to a ceiling effect on performance. During the cholinergic agonist drug phase, the aged rats which had previously been given chronic nicotine infusions showed better performance than those which had not. The resistance of the aged rats to chronic nicotine-induced working memory improvements and acute mecamylamine-induced working memory deficits may have resulted from the decline in nicotinic receptors seen with aging. Chronic co-administration of the nicotinic antagonist mecamylamine in a previous study was found to abolish the chronic nicotine-induced working memory improvement. The aged rats were resistant to haloperidol-induced deficits which may have resulted from the decrease in dopaminergic receptors seen with aging. Interestingly, acute cholinergic agonists including nicotine did improve working memory performance in the aged rats and previous chronic nicotine infusion was beneficial during the period of acute cholinergic agonist challenge. This suggests that nicotinic treatment may be of use for treating age associated memory impairments but that special dosing regimens may be required.
Several lines of evidence suggest that nicotine may be useful in treating the symptoms of Attention-Deficit/Hyperactivity Disorder (ADHD). The current study was an acute, placebo-controlled double-blind experiment to determine whether nicotine might be useful as an alternative treatment of adults with ADHD symptomatology. Six smokers and 11 nonsmokers who were outpatient referrals for ADHD were diagnosed by DSM-IV criteria. Measures of treatment effect included the Clinical Global Impressions (CGI) scale, Hopkins' symptom check list (SCL-90-R), the Profile of Mood States (POMS), Conners' computerized Continuous Performance Test (CPT), the Stroop test, and an interval-timing task. The smokers underwent overnight deprivation from smoking and were given a 21 mg/day nicotine skin patch for 4.5 h during a morning session. The nonsmokers were given a 7 mg/day nicotine skin patch for 4.5 h during a morning session. Active and placebo patches were given in a counter-balanced order approximately 1 week apart. Nicotine caused a significant overall nicotine-induced improvement on the CGI. This effect was significant when only the nonsmokers were considered, which indicated that it was not due merely to withdrawal relief. Nicotine caused significantly increased vigor as measured by the POMS test. Nicotine caused an overall significant reduction in reaction time (RT) on the CPT, as well as, with the smokers, a significant reduction in another index of inattention, variability in reaction time over trial blocks. Nicotine improved accuracy of time estimation and lowered variability of time-estimation response curves. Because improvements occurred among nonsmokers, the nicotine effect appears not to be merely a relief of withdrawal symptoms. It is concluded that nicotine deserves further clinical trials with ADHD.
Chronic nicotine infusion has been found in a series of studies in our laboratory to significantly improve choice accuracy of rats in the eight-arm radial maze. The current study was designed to compare the effects of chronic nicotine infusion on working and reference memory in a 16-arm radial maze. Nicotine was administered to female Sprague-Dawley rats at approximately 5 mg/kg per day SC via osmotic minipumps. Controls received saline infusions. Chronic nicotine infusion significantly lowered the number of working memory errors compared to controls, whereas the number of reference memory errors was not significantly affected. The modest nicotine-induced reduction in working memory errors was seen as a main effect over the 4 weeks of infusion, but the clearest effect was seen in weeks 3-4 of nicotine administration. For the 2 weeks after withdrawal, the nicotine effect was no longer evident. Acute D1 challenges were given with the D1 agonist dihydrexidine (0, 0.25, 0.5 and 1 mg/kg) and the D1 antagonist SCH 23390 (0, 0.005, 0.015 and 0.05 micrograms/kg) during weeks 3-4 of chronic nicotine administration and weeks 1-2 after withdrawal from nicotine. Dihydrexidine caused a modest dose-related increase in reference memory errors but not working memory errors in the nicotine-treated, but not the control rats. The D1 antagonist SCH 23390 caused a modest though significant decrease in reference memory errors but not working memory errors in the control, but not the nicotine-treated rats. The behavioral specificity of chronic nicotine infusion was demonstrated with selective improvement in working memory function. Pharmacological interactions were seen with chronic nicotine treatment increasing responsivity to D1 agonist and decreasing responsivity to a D1 antagonist with regard to reference memory. The mechanisms of this interaction are still undiscovered.
Smoking is becoming increasingly concentrated in people with co-factors such as depression, attention deficit-hyperactivity disorder, anxiety disorders, and bulimia/bingeing. These behavioral or cognitive patterns may be adaptive or neutral in the conditions under which we evolved but maladaptive in environments requiring alertness for extended periods, where a fully mobilized fight-or-flight response is inappropriate, and where food availability makes lack of an "appestat" a liability. Such conditions are amenable to management by nicotine because of its ability to produce small but reliable adjustments in relevant cognitive and behavioral functions. Moreover, symptomatology may be unmasked or exacerbated by nicotine abstinence, persisting beyond the usual time-course for nicotine withdrawal, which may explain the particular attraction of smoking and the difficulty these individuals experience in quitting without necessarily requiring that they be more nicotine-dependent. The implications are: (1) a better understanding of the evolutionary psychobiology of smoking may promote development of tailored interventions for smokers with co-factors; (2) nicotine may have therapeutic applications for non-smokers with co-factors; (3) because smoking has a fairly high heritability index, and because of evidence of assortative mating, special prevention efforts targeting children of smokers with co-factors, as well as early identification of the co-factor itself, may be needed.
Nicotinic acetylcholine (ACh) and dopamine (DA) receptor activation has been found to be important for working memory. The regional distribution of these receptors in the brain has been well characterized. However, the relationship of the region-specific nicotinic ACh and DA binding density to memory performance has not been well assessed. In the current studies the relationship of receptor binding and memory function was examined. Receptor binding and memory performance were assessed in rats in three types of conditions: 1) chronic nicotine and mecamylamine vs. vehicle infusion; 2) lesions of the fimbria-fornix or medial basalocortical projection vs. sham lesions; and 3) 2-year-old aged rats vs. 3-month-old young adult rats. Nicotinic ACh receptors were labeled by [3H]N-methyl-carbamylcholine ([3H]MCC), D1 receptors by [3H]SCH 23390, and D2 receptors by [125I]iodosulpiride. Working memory was assessed using the radial-arm maze and T-maze delayed spatial alternation tasks. Chronic nicotine infusion substantially increased nicotinic receptor binding in a variety of brain areas and significantly improved working memory performance in the radial-arm maze. However, nicotinic receptor binding did not correlate well with memory performance. The nicotinic antagonist mecamylamine did not block nicotine-induced increased nicotinic binding, but it did block nicotine-induced memory improvement. Aged rats relative to young adults showed both a decrease in nicotinic binding and impaired memory performance. However, chronic effects of nicotine on nicotinic receptor binding and memory performance did not correlate in the aged rats. Nicotine also increased nicotinic receptor binding in the aged rats in brain areas except for the VTA, but did not improve memory performance. Lesions of the medial basalocortical projection or the fimbria-fornix did not cause significant changes in nicotinic binding in their target fields, but they did cause significant deficits in memory performance. Finally, there were no significant correlations of nicotinic binding in any brain region and memory performance. DA receptor binding was not altered by chronic nicotine or mecamylamine infusion, fimbria-fornix lesions, medial basalocortical lesions, or in aged rats. However, DA receptor binding did correlate with memory performance. There was a positive correlation of T-maze accuracy and D1 receptor binding in the frontal cortex and a negative correlation of T-maze accuracy and D1 receptor binding in the VTA and dentate gyrus. In contrast, a positive correlation was seen between radial-arm maze accuracy and D1 receptor binding in the VTA. Radial-arm maze accuracy was positively correlated with D2 receptor binding in the striatum and dentate gyrus. There are significant relationships between the extent of DA receptor binding and working memory, but relationship between nicotinic ACh receptor binding density and memory is weak.
Advances in our understanding of the structure, function and distribution of nicotinic acetylcholine receptors in the CNS have provided the impetus for new studies examining the role(s) that these receptors and associated processes may play in CNS functions. Further motivation has come from the realisation that such receptors must be involved in the maintenance of cigarette smoking, and from clues provided by studies of degenerative neurological diseases such as Alzheimer's disease and Parkinson's disease, in which the loss of nicotinic receptors has been described. Ongoing investigations of the molecular substructure of central nicotinic receptors and their pharmacology have begun to open up new possibilities for novel CNS therapeutics with nicotinic agents. Exploiting these possibilities will require understanding of the role(s) that these receptor systems play in human cognitive, behavioural, motor and sensory functioning. Clues from careful studies of human cognition are beginning to emerge and will provide direction for studies of potentially therapeutic novel nicotinic agents. Despite the promising results of acute studies, few long term studies with nicotine or nicotinic drugs have been performed in dementing disorders. Thus there is uncertainty as to whether long term nicotinic treatment will provide sustained cognitive benefit. It is even more uncertain whether such cognitive benefit will have a significant clinical impact on patients and their families. To maximise the potential benefit of long term treatment with nicotinic agonists (or other cholinergic drugs), we suggest that drug treatment should be combined with cognitive rehabilitation strategies. This will enable patients and/or their families to focus on the particular cognitive domains that may be improved.
Mesolimbocortical dopamine plays a role in learning and memory. The specific receptor subtypes mediating the effects of dopamine, however, are still unknown. Dopamine D2, D3 and D4 receptors are expressed in the hippocampus and dopamine D3 receptors are present in the septal area, suggesting that these receptor subtypes can contribute to the behavioral effects of dopamine D2-like receptor agonists. We now investigated the role of dopamine D2 and D3 receptors in learning and memory by using the transient amnesia induced by scopolamine in the passive avoidance test as experimental model. The data strongly suggest that both dopamine D2 and D3 receptors mediate the effects of dopamine on the integrative function of learning and memory. In particular, we show that the non-selective dopamine agonist apomorphine prevents the scopolamine-induced disruption of consolidation of the previously acquired passive avoidance behavior. This effect is mediated by receptors belonging to the dopamine D2 family since it was antagonized by (-)-sulpiride and mimicked by quinpirole. Nafadotride, a relatively selective antagonist for dopamine D3 receptors, antagonized scopolamine-induced memory disruption and potentiated the facilitatory effect of quinpirole. Taken together, these results suggest that the effects of dopamine on memory consolidation are the result of a balance between dopamine D2 receptor-mediated facilitation and dopamine D3 receptor-mediated inhibition, and that dopamine D2 and D3 receptors play opposite roles in the control of the mechanisms leading to memory consolidation.
The diverse physiological actions of dopamine are mediated by at least five distinct G protein-coupled receptor subtypes. Two D1-like receptor subtypes (D1 and D5) couple to the G protein Gs and activate adenylyl cyclase. The other receptor subtypes belong to the D2-like subfamily (D2, D3, and D4) and are prototypic of G protein-coupled receptors that inhibit adenylyl cyclase and activate K+ channels. The genes for the D1 and D5 receptors are intronless, but pseudogenes of the D5 exist. The D2 and D3 receptors vary in certain tissues and species as a result of alternative splicing, and the human D4 receptor gene exhibits extensive polymorphic variation. In the central nervous system, dopamine receptors are widely expressed because they are involved in the control of locomotion, cognition, emotion, and affect as well as neuroendocrine secretion. In the periphery, dopamine receptors are present more prominently in kidney, vasculature, and pituitary, where they affect mainly sodium homeostasis, vascular tone, and hormone secretion. Numerous genetic linkage analysis studies have failed so far to reveal unequivocal evidence for the involvement of one of these receptors in the etiology of various central nervous system disorders. However, targeted deletion of several of these dopamine receptor genes in mice should provide valuable information about their physiological functions.
The in vivo brain regional distribution of 2-[18F]fluoro-A-85380, a novel tracer for positron emission tomographic (PET) studies, followed the regional densities of brain nAChRs reported in the literature. Evidence of binding to nAChRs and high specificity of the binding in vivo was demonstrated by inhibition with nAChR selective ligands as well as with unlabeled 2-fluoro-A-85380. A preliminary toxicology study of the 2-fluoro-A-85380 showed a relatively low biological effect. 2-[18F]Fluoro-A-85380 holds promise as a useful radiotracer for imaging of nAChRs with PET.
In rats, the effects of an intracerebroventricular (ICV) nicotinic agonist nicotine (NIC), the nicotinic antagonist mecamylamine (MEC), and combinations of NIC + MEC were assessed in a radial-arm maze (RAM). In experiment 1, exploratory behavior was assessed in untrained rats (N = 13). The rats received 4 μg, 8.65 nmol NIC (NIC 4), 200 μg, 0.98 μmol MEC (MEC), and saline (SAL) ICV infusions. NIC 4 caused a significant increase in choice distribution compared to SAL (P < 0.025). In experiment 2, rats (N = 10) were trained to perform a working memory task for food reinforcement in the RAM. ICV doses of SAL, NIC 4, NIC 8, MEC, MECNIC 4, and MECNIC 8 were administered after completion of the training period. MEC caused a significant deficit in choice accuracy when compared to SAL (P < 0.025). This deficit was reversed when NIC 8 was coadministered with MEC (P < 0.05). There were no significant effects on choice latency for either study. The effects of ICV NIC and MEC on RAM performance are generally similar to their systemic effects in that NIC improves and MEC impairs choice accuracy. The reversal of the MEC-induced choice deficit by ICV NIC administration has not been reported with systemic administration. ICV MEC induces a choice accuracy deficit without increasing choice latency. This has not been seen with systemic MEC administration. The current result implies that the MEC-induced choice accuracy deficit did not result from MEC-induced sedation. The data indicate that previously reported changes in choice accuracy from peripherally administered NIC and MEC result from their central effects. © 1994 Wiley-Liss, Inc.
Performance on the radial-arm maze depends on the integrity of both cholinergic and dopaminergic systems. We have previously found that administration of either the nicotinic-cholinergic antagonist, mecamylamine, or the muscarinic-cholinergic antagonist, scopolamine, impairs choice accuracy in the radial-arm maze. Co-administration of the dopaminergic antagonist, haloperidol, ameliorated the performance deficit caused by scopolamine but exacerbated the deficit caused by mecamylamine. Furthermore, antagonism of the effect of scopolamine is due specifically to blockade of D1 receptors. In the present experiment behaviorally subthreshold doses of mecamylamine and the D2 antagonist raclopride impaired maze performance when administered together. No interactive effects were observed between mecamylamine and the D1 antagonist SCH 23390. Although several of the drug treatments studied significantly increased choice latency, an index of motor behavior, there was no perfect relationship between choice accuracy and choice latency. These data indicate that nicotinic-cholinergic and muscarinic-cholinergic systems interact selectively and differentially with D1 and D2 dopaminergic systems.
The ability of nicotinic receptor blockers, mecamylamine and pempidine, to antagonize the changes in striatal dopamine (DA) metabolism induced by repeated nicotine administration was studied. The contents of DA and its metabolites 3-methoxytyramine (3-MT), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured. Mice kept at 20–22°C were given nicotine, 3 mg/kg, s.c., four times, at 30 min intervals, and sacrificed 20 min after the last dose. Hexamethonium, 10 mg/kg, i.p., was administered at 30 min before the first nicotine dose in order to prevent the peripheral effects of nicotine. Mecamylamine, 0.6 or 10 mg/kg, i.p., and pempidine, 0.6 or 20 mg/kg, i.p., were given at 60 min before sacrifice.
Mecamylamine and pempidine decreased clearly the striatal 3-MT content, which suggests that the nigrostriatal dopaminergic neurons are physiologically controlled by a stimulatory nicotinic mechanism. The repeatedly administered nicotine caused deep hypothermia, and increased the striatal DOPAC content but decreased the 3-MT and HVA contents. The small dose of mecamylamine, which was the only dose found to effectively antagonize the nicotine-induced hypothermia, antagonized the decrease of HVA content. The large but not the small doses of mecamylamine and pempidine antagonized the nicotine-induced increase of DOPAC content but none of the doses studied antagonized the decrease of 3-MT content. Thus it seems that nicotine decreases the 3-MT content by a mechanism distinct from the mechanism mediating the increase of the DOPAC content. The decreased 3-MT content most probably results from desensitization of nicotinic cholinergic receptors (nAChR) and following decrease of cholinergic regulation of nigrostriatal dopaminergic neurons. The changed conformation of nAChR explains the inability of mecamylamine and pempidine to antagonize the nicotine-induced decrease of 3-MT content.
It is clear that disruption of cholinergic systems can cause impairments of cognitive function (Bartus et al., 1987). For example, the muscarinic cholinergic antagonist scopolamine has been found by numerous studies to impair working memory performance (Levin, 1988). A wide variety of experiments have also shown that nicotinic cholinergic antagonists impair learning (Chiappeta and Jarvik, 1969; Diltz and Berry, 1967; Oliverio, 1966; Sansone et al., 1990) and memory function (Decker and Majchrzak, 1992; Dougherty et al., 1981; Elrod and Buccafusco, 1988, 1991; Flood et al., 1981; Hodges et al., 1991; Levin et al., 1987a, 1989a,b; Levin and Rose, 1990; McGurk et al., 1989a; Osborne et al., 1991; Riekkinen et al., 1990) and that muscarinic and nicotinic receptors have important interactions (Levin et al., 1989b, 1990b; Riekkinen et al., 1990) (see also Levin and Russell, this volume). However, it has also become increasingly clear that cholinergic systems do not function in isolation; they have important interactions with other transmitter systems in the neural bases of cognitive function (Decker and McGaugh, 1991; Levin et al., 1990a).
: Nicotinic cholinergic receptor binding sites labeled by [3H]acetylcholine were measured in the cerebral cortices, thalami, striata, and hypothalami of rats lesioned by intraventricular injection of either 6-hydroxydopamine or 5,7-dihydroxytryptamine. In addition, [3H]acetylcholine binding sites were measured in the cerebral cortices of rats lesioned by injection of ibotenic acid into the nucleus basalis magnocellularis. [3H]Acetylcholine binding was significantly decreased in the striata and hypothalami of both 6-hydroxydopamine-and 5,7-dihydroxytryptamine-lesioned rats. There was no change in binding in the cortex or thalamus by either lesion. Ibotenic acid lesions of the nucleus basalis magnocellularis, which projects cholinergic axons to the cortex, did not alter [3H]acetylcholine binding. These results provide evidence for a presynaptic location of nicotinic cholinergic binding sites on catecholamine and serotonin axons in the striatum and hypothalamus.
Acute and chronic nicotine treatment has been found to improve learning and memory function in a variety of tasks. In several studies we have found that chronic nicotine infusion improves working memory performance. Replicating these results, the current study showed that chronic nicotine treatment (12 mg/kg/day) significantly improved working memory performance in the radial-arm maze. The nicotine effect did not diminish during the 2 weeks following withdrawal. The nicotine-induced improvement was eliminated when the nicotinic antagonist mecamylamine (3 mg/kg/day) was given concurrently, suggesting that the nicotine effect was mediated via actions on the nicotinic receptor. Surprisingly, when this chronic dose of mecamylamine was given alone, it caused a transient improvement in choice accuracy during the first week of administration. This improvement subsequently became attenuated and was not evident at all by the third and fourth weeks of administration.
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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.
Pharmacological blockade of either nicotinic or muscarinic cholinergic receptors has been found to impair choice accuracy in the radial-arm maze. Simultaneous blockade of both of these receptor types causes an additive impairment. However, despite these common effects, nicotinic and muscarinic receptors have been found to have differential involvement with dopamine receptors. The cognitive impairment caused by the muscarinic antagonist scopolamine is reversed by the D1 antagonist SCH 23390 but is unaffected by the D2 antagonist raclopride. In contrast, the cognitive impairment caused by the nicotinic antagonist mecamylamine is unaffected by SCH 23390 but is is potentiated by raclopride. In the current study, the D2 agonist LY 171555 was found to be effective in reversing the radial-arm maze choice accuracy impairment caused by mecamylamine. In contrast, the D1 agonist SKF 38393 was not found to be effective. Thus, we have found selective dopaminergic D1 and D2 treatments which counteract the adverse cognitive effects of their nicotinic or muscarinic blockade. A combination of these treatments may be useful in treating the cognitive effects of generalized cholinergic underactivation.
Nicotine has been found in a variety of studies to improve performance in memory tasks. This study was conducted to determine if chronic nicotine administration is useful in counteracting the working memory deficits seen after lesions of the fimbria or the medial basalocortical projection. Rats were trained to asymptotic performance on a working memory version of the radial-arm maze. Then, they were given knife cut lesions of the fimbria or the medial basalocortical projection or underwent sham surgeries. At the time of surgery, rats in each treatment group were implanted with either nicotine-containing or placebo glass and Silastic pellets. Rats with fimbria or basalocortical lesions showed a significant decline in working memory performance. Chronic nicotine significantly improved choice accuracy in both lesioned and unlesioned rats. Nicotine treatment restored performance of the lesioned rats to control levels. These data show that in addition to improving memory performance in normal rats, nicotine can counteract lesion-induced memory impairments. Nicotine also may be useful for treatment of disease-related memory impairments such as seen in Alzheimer's disease.
Muscarinic acetylcholine (ACh) systems have long been known to be necessary for accurate performance in cognitive tests. Nicotinic ACh systems have been shown to be involved as well. However, there is only a limited amount of information concerning the interactions of these two branches of the ACh transmitter system. The current study was conducted to investigate the improvement in choice accuracy caused by muscarinic and nicotinic agonists and how it is affected by antagonists of these systems. Adult female Sprague-Dawley strain rats (N = 11) were trained on a working memory task in an 8-arm radial maze. Acute injections of the muscarinic and nicotinic agonists, pilocarpine (PILO, 1.0 mg/kg) and nicotine (NIC, 0.2 mg/kg), were made alone or in combination with the muscarinic and nicotinic antagonists, scopolamine (SCOP, 0.1 mg/kg) and mecamylamine (MEC, 10 mg/kg). NIC administration caused a significant improvement in choice accuracy compared with saline (p<0.01) and PILO caused a marginally significant improvement in choice accuracy (p<0.06). The combination of these nicotinic and muscarinic agonists did not cause an additive improvement. However, the improvement caused by either agonist was reversed by both nicotinic or muscarinic antagonists. This reversal was more complete for NIC than PILO despite the fact that NIC caused a greater improvement than PILO. These results suggest that muscarinic and nicotinic components of the ACh system, which are both important for cognitive function, interact in important ways. These interactions may be critical to consider when devising treatments for cognitive dysfunction associated with cholinergic hypofunction such as with Alzheimer's disease.
Rats were tested for choice accuracy in an eight-arm radial maze during and after chronic administration of nicotine via subcutaneously implanted glass and Silastic capsules. Nicotine administration significantly improved choice accuracy relative to controls. The effect gradually became apparent over the first 2 weeks of exposure and persisted through the third week. Surprisingly, the significant facilitation of the nicotine-treated rats relative to controls continued for 2 weeks after the end of nicotine administration. No effects of nicotine were seen on choice latency or the strategy to make adjacent arm entries.
Choice accuracy performance in the radial-arm maze is dependent upon the integrity of both the nicotinic and muscarinic cholinergic receptors. Pharmacological blockade of either of these subtypes of cholinergic receptors with mecamylamine or scopolamine impairs choice accuracy in the radial-arm maze. We have previously demonstrated that the performance deficit caused by muscarinic blockade is exacerbated in at least an additive fashion by coadministration of the nicotinic antagonist, mecamylamine. In the present study, it was found that mecamylamine and scopolamine act together in a greater than additive fashion in disrupting radial-arm maze choice accuracy. When doses of these drugs which do not by themselves cause significant impairments in choice accuracy are given together, they induce a pronounced impairment. Previous results have shown that the adverse effects of nicotinic blockade could be reversed by the dopaminergic D2 agonist LY 171555. In this study, this drug was found to attenuate the cognitive impairment caused by combined nicotinic and muscarinic blockade. On the other hand, the dopaminergic D1 antagonist SCH 23390 which has previously been shown to reverse the adverse effects of muscarinic blockade was not found in this study to attenuate the impairment of combined nicotinic and muscarinic blockade. Since combined nicotinic and muscarinic blockade approximates generalized cholinergic underactivation, treatments like LY 171555, which attenuate the adverse effects of this combined blockade, may be useful in treating syndromes like Alzheimer's disease, which are characterized by generalized cholinergic loss.
The effects of the nicotinic cholinoceptor blocking drug, mecamylamine (alone or in combination with morphine or haloperidol) were investigated on the striatal homovanillic acid (HVA) concentration and on the α‐methyl‐ p ‐tyrosine (AMPT)‐induced depletion of striatal or mesolimbic dopamine content in the brain of rats.
Mecamylamine (2 mg/kg) alone did not alter the striatal HVA concentration, but it reduced the probenecid‐induced accumulation of HVA. Mecamylamine pretreatment reduced the morphine‐and haloperidol‐induced elevation of striatal HVA concentration. Hexamethonium did not alter the striatal HVA concentration when given alone or in probenecid‐ or morphine‐treated rats, whereas pempidine (8 mg/kg) clearly reduced the probenecid‐induced accumulation of HVA in the striatum.
Mecamylamine (2 and 8 mg/kg) slowed the rate of AMPT‐induced depletion of dopamine from the striatum and mesolimbic area both in the brain of control rats and of rats treated with morphine or haloperidol.
Mecamylamine slightly prolonged the cataleptic effect of morphine.
The results indicate that mecamylamine inhibits the release of dopamine both from the striatal and mesolimbic dopaminergic neurones.
Nicotinic acetylcholine receptors have been found to be important for maintaining optimal performance on a variety of cognitive tasks. In humans, nicotine-induced improvement of rapid information processing is particularly well documented. In experimental animals nicotine has been found to improve learning and memory on a variety of tasks, while the nicotinic antagonist mecamylamine has been found to impair memory performance. Nicotine has been found to be effective in attenuating memory deficits resulting from lesions of the septohippocampal pathway or aging in experimental animals. Nicotinic receptors are decreased in the cortex of patients with Alzheimer's disease. Preliminary studies have found that some aspects of the cognitive deficit in Alzheimer's disease can be attenuated by nicotine. Nicotine may prove to be useful therapeutic treatment for this and other types of dementia.
Pharmacological studies have shown that both cholinergic and dopaminergic transmitter systems are crucial for optimal choice accuracy in the radial-arm maze and that these systems interact in a complex fashion. Lesion studies have provided evidence that the basal nuclear complex of the forebrain, the origin of cholinergic projections to the cerebral mantle, may be critical for the cholinergic modulation of learning and memory. We have shown that knife-cut lesions of the medial cholinergic pathway significantly impair radial-arm maze choice accuracy performance. The current study examined the effectiveness of D1 and D2 ligands in counteracting this lesion-induced deficit. The adverse effects of medial cholinergic pathway lesions were diminished or reversed by daily treatment with a D1 agonist (SKF 38393), a D2 agonist (LY 171555) or a D1 antagonist (SCH 23390), but were not affected by treatment with a D2 antagonist (raclopride). The three beneficial treatments have previously been found to attenuate the adverse effects of nictonic or muscarinic blockade on choice accuracy performance in the radial-arm maze. The finding that these dopaminergic drugs ameliorate the memory deficit caused by lesions involving the cholinergic medial pathway suggests the importance of interactions between cholinergic and dopaminergic systems in radial-arm maze performance. These results may provide leads for the development of novel therapeutic approaches for treating human disorders thought to result from cholinergic hypofunction.
Nicotine has been found in a variety of species and behavioral paradigms to improve memory performance. The beneficial effect of nicotine has been seen after both acute and chronic administration. Interestingly, improved performance has been seen 24 h after acute injection and for at least 2 weeks after chronic administration. However, it is not clear from previous studies whether the persistence of the improved performance represents a true carryover of the drug effect or is due to the behavioral experience while under nicotine's effect. The current study was conducted to determine whether the facilitating effect of nicotine on learning and memory performance could be seen after withdrawal even if there was no behavioral training during the period of chronic nicotine administration. Rats were administered nicotine chronically for 3 weeks but were not tested during that time. Starting 1 week after withdrawal they were trained on a working memory paradigm in an eight-arm radial maze. The nicotine-treated rats started out at control-like levels of performance, but showed significantly faster learning as detected by three different measures of choice accuracy. By the final phase of testing the control subjects had caught up with the nicotine-treated rats. After the acquisition phase, acute challenges with the nicotinic and muscarinic antagonists, mecamylamine and scopolamine, did not elicit any differential effects in the nicotine-treated and control groups. The current study demonstrated that nicotine-induced cognitive facilitation persists for at least 4 weeks after withdrawal and does not depend upon behavioral test experience under the influence of the drug. The mechanism for this persisting effect is not currently understood.(ABSTRACT TRUNCATED AT 250 WORDS)
Nicotine acts on many transmitter systems in different parts of the brain to promote transmitter release, and these modulatory actions may underlie some of the psychopharmacological and behavioral effects of nicotine. Nicotine provoked the release of [3H]dopamine from synaptosomes isolated from rat striata and preincubated with radiolabelled transmitter. Nicotine-evoked release was concentration-dependent over the range 10-8 to 10-3 M, and the half maximal response was observed with 3.8 μM nicotine. The presynaptic nicotinic receptor on dopaminergic nerve terminals and [3H]nicotine binding sites may be equivalent. There are moderate numbers of [3H]nicotine binding sites in the rat striatum compared with low levels of α-[125I]bungarotoxin binding sites. Nicotinic modulation of transmitter release from hippocampal synaptosomes is discussed. From the data available concerning the presynaptic modulation of transmitter release by nicotine and other agonists, a model is proposed to account this phenomenon.
The behavioral and physiological effects of repeated nicotine administration are complex; sedation and hypothermia are present early but become attenuated while locomotor activity increases. Maximal blood levels and behavioral changes occur within 10 min of s.c. injection. We examined the effects of 10 nicotine injections (0.8 mg/kg) in 14 days on the levels of brain amines following challenge with either saline or nicotine on the 15th day. Dopamine, DOPAC, HVA, 3-methoxytyramine, norepinephrine, 5-hydroxytyramine, and 5-HIAA were measured in the frontal cortex, olfactory tubercle, nucleus accumbens, caudate-putamen, substantia nigra and ventral tegmental area. Ten minutes after nicotine was given to rats that had previously received only saline the levels of dopamine and its metabolite DOPAC indicated an increase in dopamine turnover in the nucleus accumbens. Of the areas examined the accumbens was the most sensitive to nicotine, with few significant amine changes in other regions. Twenty-four hours after the last nicotine injection the levels of dopamine and its metabolites indicated a sustained decrease in dopamine turnover in the accumbens induced by repeated administration. Following repeated nicotine a nicotine challenge still induced an acute increase in dopamine turnover in the accumbens, but the response was less than in animals not previously given nicotine. The results confirm earlier studies indicating that the accumbens is a major site of nicotine action.
Accurate performance on the radial-arm maze is dependent upon the integrity of nicotinic-cholinergic, muscarinic-cholinergic, and dopaminergic systems. Pharmacological blockade of these systems with mecamylamine, scopolamine, or haloperidol impairs choice accuracy in the maze. We have previously demonstrated that the performance deficit caused by muscarinic blockade is enhanced by coadministration of the nicotinic antagonist, mecamylamine, and is diminished by coadministration of the dopamine antagonist, haloperidol. In the present study, it was found that the choice accuracy deficit produced by nicotinic blockade is enhanced, not antagonized, by coadministration of haloperidol. Thus, although both nicotinic and muscarinic cholinergic systems are involved in radial-arm maze performance and antagonists of these receptors are additive in the deficits they cause, nicotinic and muscarinic interactions with dopaminergic systems are opposite in nature.
Lesions of cholinergic neurons have been found by many investigators to impair choice accuracy in the radial arm maze. Because muscarinic receptor blockers, such as scopolamine, have also repeatedly been found to impair choice accuracy in the radial-arm maze, it has generally been thought that the critical effect of cholinergic lesions is the deafferentation of muscarinic receptors. The possible involvement of nicotinic receptors in the cholinergic bases of cognitive performance in the radial-arm maze has not been as well investigated. The present study examined the effects of the blockade of nicotinic receptors on performance of female Sprague-Dawley rats in the radial-arm maze. Acute administration of the the nicotinic receptor blocker, mecamylamine (10 mg/kg) was found to significantly impair radial-arm maze choice accuracy. This dose also caused a significant increase in response latency in the maze. The effect on choice behavior but not locomotor speed seemed to be due to the central effects of mecamylamine, because administration of the peripheral nicotine receptor blocker, hexamethonium (20 mg/kg), did not impair choice accuracy, even though it did increase response latency to a similar degree as the 10-mg/kg dose of mecamylamine. Lower doses of mecamylamine (2.5 and 5 mg/kg) did not impair choice accuracy. These results indicate that central nicotinic as well as muscarinic cholinergic receptors are involved with cognitive functioning.
Acetylcholine (ACh) systems have been found to be crucial for the maintenance of accurate cognitive performance. A great variety of studies have shown that the muscarinic ACh receptor blocker scopolamine impairs choice accuracy in the radial-arm maze. Recently, it has been found that the nicotinic ACh receptor blocker mecamylamine also impairs radial-arm maze choice accuracy. In the present study, we investigated the effects of combined administration of these two ACh blockers. Scopolamine (0.15 mg/kg) and mecamylamine (10 mg/kg) each moderately impaired choice accuracy. Combined treatment with scopolamine and mecamylamine significantly decreased choice accuracy relative to either drug alone. This combination treatment lowered choice accuracy to chance levels. These data show that nicotinic and muscarinic blockade have at least additive effects in producing an anterograde memory deficit. Concurrent blockade of these two components of ACh systems may provide a better animal model of cognitive impairments due to the loss of cholinergic neurons, such as Alzheimer's disease.
Using a sensitive perfusion system we have studied the nicotine-induced release of [3H]dopamine ([( 3H]DA) from striatal synaptosomes. Nicotine-evoked release was concentration dependent with an EC50 of 3.8 microM. The response to 1 microM nicotine was comparable to that to 16 mM K+; 10 microM veratridine evoked a larger response. All three stimuli were Ca2+ dependent but only the response to veratridine was blocked by tetrodotoxin. Repetitive stimulations by 1 microM (-)-nicotine (100 microliters) at 30-min intervals resulted in similar levels of [3H]DA release; higher concentrations of (-)-nicotine resulted in an attenuation of the response particularly following the third stimulation. This may reflect desensitisation or tachyphylaxis of the presynaptic nicotinic receptor. The action of nicotine was markedly stereoselective: a 100-fold higher concentration of (+)-nicotine was necessary to evoke the same level of response as 1 microM (-)-nicotine. It is proposed that these presynaptic nicotinic receptors on striatal terminals are equivalent to high-affinity nicotine binding sites described in mammalian brain.
An apparent inverse relationship between smoking and Parkinson's disease prompted an investigation of the effect of chronic nicotine administration on dopaminergic and serotonergic receptors in rat brain. Nicotine, 0.8 mg/kg, was injected once daily, five times per week, for 6 weeks. In nucleus accumbens the Kd for [3H]domperidone was increased 2-4-fold, and the Bmax was increased 1.5-2-fold. No changes were observed in the binding of [3H]domperidone in caudate-putamen or in that of [3H]ketanserin in frontal cortex. It is concluded that chronic nicotine administration may have a suppressant effect on central nervous system release of dopamine that in pre-parkinsonian persons causes an aversion to the effects of smoking.
The effect of intravenous (i.v.) nicotine on the single unit activity of midbrain dopamine (DA) neurons was studied in rats under either local or general anesthesia. Nicotine (50-500 micrograms/kg) produced a dose-related increase in the firing rate of nigral pars compacta DA cells (A9), up to 25% above baseline, irrespective of the preparation. The same range of doses was more than three times as effective on ventral tegmental area DA cells (A10) in rats paralyzed and given a local anesthetic. By contrast, the majority of these cells were temporarily depressed in deeply anesthetized animals. All of the above effects were reversed and prevented by i.v. mecamylamine suggesting the involvement of nicotine cholinergic receptors. Moreover, after nicotine-induced stimulation, low doses of i.v. apomorphine inhibited the firing rate similar to controls indicating that dopamine receptors are not directly involved in the nicotinic action. The results suggest that acute nicotine shares with other drugs of abuse the characteristic of being more effective in stimulating A10 than A9 neurons.
The effects of systemic administration of nicotine or the nicotinic antagonist mecamylamine on the midbrain dopamine (DA) systems of the rat were studied with single cell recording techniques. Dopamine cells of the zona compacta, substantia nigra (ZC-SN) and the ventral tegmental area (VTA) were identified by their characteristic action potentials, antidromic stimulation methodology and conventional histological procedures. Firing rates as well as firing patterns were determined from computer-generated interspike interval histograms describing burst-firing in relation to single-spike firing. A larger proportion of burst-firing DA cells was found in the VTA when compared with the ZC-SN area. (-)-Nicotine bitartrate (0.5 mg kg-1 i.p.) not only increased the firing rate of ZC-SN neurons but also the amount of burst firing of the ZC-SN neurons and VTA neurons, respectively. Mecamylamine HCl (4.0 mg kg-1 i.p.) decreased the firing rate of VTA cells which, in principle, indicates a tonic nicotinic input in this area. The increase in firing rate of central DA neurons following nicotine administration was found to be associated with increased bursting of the burst firing cells whereas, in contrast, the non-bursting neurons did not respond with burst-firing. Generally, the correlation between nicotine induced changes in firing rate and in burst-firing activity, respectively, was found to be low for midbrain DA neurons. These observations, in conjunction with the previous demonstration of nicotinic receptors in these areas, indicate the existence of a nicotinic input, specifically regulating the firing pattern of these central DA cells. This neuromodulatory effect of nicotine may be significant for its behavioural stimulant action.(ABSTRACT TRUNCATED AT 250 WORDS)
Extracellular recordings of single unit activity were made in the substantia nigra (SN) of chloral hydrate‐anaesthetized rats.
Dopaminergic neurones of the pars compacta (SNC) were stimulated by (—)‐nicotine bitartrate (1.0 mg k ⁻¹ ) given subcutaneously (s.c.). This action was prevented by the secondary amine mecamylamine HCl (2.0 mg kg ⁻¹ i.v.) but not by a ganglion‐blocking dose of the bisquaternary compound chlorisondamine Cl (0.1 mg kg ⁻¹ i.v.). Mecamylamine reduced the spontaneous activity of dopaminergic neurones.
Nicotine, when administered intravenously (2–128 μg kg ⁻¹ cumulative dose), also stimulated dopamine cells and this action was dose‐related.
Nicotine, administered intravenously, (2–128 μg kg ⁻¹ cumulative dose) markedly excited non‐dopamine cells in the pars reticulata (SNR) in a dose‐related manner. In rats pretreated with chlorisondamine (0.1 mg kg ⁻¹ i.v.), nicotine induced a small excitatory or depressant action, but the marked excitation was not seen. Mecamylamine (2 mg kg ⁻¹ i.v.) completely prevented the actions of nicotine.
The results are consistent with a direct excitatory action of nicotine on dopaminergic neurones of the substantia nigra pars compacta. The pronounced excitatory action of systemically administered nicotine on non‐dopamine cells of the pars reticulata appears to be of peripheral origin.
Rats received unilateral injections of 6-hydroxydopamine into the medial forebrain bundle, resulting in an ipsilateral loss of striatal dopamine and of dopaminergic perikarya. A concomitant reduction of displaceable tritiated nicotine binding was observed autoradiographically in the ipsilateral substantia nigra, ventral tegmental area, striatum, nucleus accumbens, and olfactory tubercle. Thus, nicotine receptors appear to be located on nigrostriatal and mesolimbic dopaminergic neurons at the level of perikarya and terminals.
The autoradiographic visualisation of 90%-specific tritiated nicotine binding to slide-mounted sections of rat brain is reported. Tritiated nicotine bound with high affinity (nanomolar Kd) and was selectively displaced by nicotinic agonists (e.g. L-nicotine approximately ACh greater than D-nicotine). The strikingly discrete distribution pattern obtained deviates from that of alpha-bungarotoxin, and suggests several possible roles for nicotinic transmission in the brain.
In rats anaesthetized with urethane, firing of neurones of the substantia nigra zona compacta was accelerated after subcutaneous or iontophoretic administration of nicotine or after iontophoretic application of acetylcholine. The excitation was prevented by iontophoretic application of dihydro-beta-erythroidine, but not by atropine. The units were identified by antidromic stimulation as neurones of the nigrostriatal system; their activity was depressed by iontophoretically applied dopamine (DA). Under the same conditions of anaesthesia, a subcutaneous injection of nicotine produced an increase in DA turnover and in homovanillic acid levels in the striatum. The effect of nicotine on striatal DA turnover was comparable to that of electrical stimulation of the nigrostriatal pathway at the average frequency seen in the firing of zona compacta neurones after systemic administration of nicotine. These observations corroborate the idea that nicotine exerts an excitatory action at the level of nigral DA nerve cells. Observations made after electrical stimulation or haloperidol under urethane anaesthesia and after nicotine in unanaesthetized rats suggest that the relatively modest effect of nicotine on striatal DA turnover is due mainly to the short duration of drug action rather than to effects of the anaesthetic on DA metabolism.
Nicotine has been found to improve memory performance in a variety of tests, including the radial-arm maze. This improvement, together with the consistent finding of a decline in cortical nicotinic receptor concentration in Alzheimer's patients, has fueled the search for novel nicotinic ligands with therapeutic potential. In the current studies, a series of nicotinic compounds was tested for effects on working memory performance in the radial-arm maze. One of the three compounds tested, DMAE II (dimethylaminoethanol cyclohexyl carboxylate fumurate), produced significant improvements in working memory performance. In the first experiment, this drug produced a biphasic dose-response curve with improved performance at the 20-mg/kg dose but not at 10 or 40 mg/kg. In a second round of DMAE II administration, the same rats showed a significant improvement with the 40-mg/kg dose. In the second experiment, a new set of rats also showed a biphasic dose-response to DMAE II. The 20-mg/kg dose caused a significant improvement whereas the 40-mg/kg dose did not. Interactions of DMAE II with nicotine and mecamylamine were also studied. Nicotine (0.2 mg/kg) by itself caused a significant improvement in working memory performance. No additive effects of DMAE II with nicotine were seen. In fact, some attenuation of response was seen with the combination. Choice accuracy data for mecamylamine could not be analyzed because of excessive sedation and nonresponding. These studies show that, like nicotine, the nicotinic ligand DMAE II causes an improvement in radial-arm mace choice accuracy. The lack of additivity with nicotine may have been to the partial agonist effects of DMAE II.
The nicotinic antagonist mecamylamine has been found to impair working memory performance in the radial-arm maze (RAM) after s.c. or i.c.v. administration. Mecamylamine has important interactions with dopaminergic (DA) systems. Mecamylamine-induced memory deficits in the RAM are potentiated by the D2 antagonist raclopride and reversed by the D2 agonist quinpirole. The nicotinic agonist nicotine has been found to improve working memory performance in the RAM after s.c. or i.c.v. administration. Nicotine-induced memory improvement in the RAM is potentiated by the D2 agonist quinpirole. The midbrain DA nuclei, the substantia nigra (SN) and the ventral tegmental area (VTA) have relatively dense concentrations of nicotinic receptors which may be critical sites of action for mecamylamine and nicotine. In the current study, the effects of mecamylamine (1, 3.3 and 10 micrograms/side) infusions into the SN (n = 12) and VTA (n = 13) on working memory in the radial-arm maze were examined in adult female Sprague-Dawley rats. The 10-micrograms/side dose of mecamylamine significantly impaired radial-arm maze working memory performance when infused into either the SN or VTA. No significant effects of mecamylamine on response latency were seen. The nicotinic agonists cytisine (0.1, 0.33 and 1.0 microgram/side) and nicotine (0.3, 1.0 and 3.3 micrograms/side) were administered in a counterbalanced order. The high dose of cytisine (1 microgram/side) nearly caused a significant deficit in choice accuracy. Nicotine slightly depressed choice accuracy but not significantly in this study. The interaction of nicotine and mecamylamine was then studied. A dose of 1.0 microgram/side of nicotine caused a significant decrease in choice accuracy. Interestingly, this was significantly reversed by a 3.3-micrograms/side dose of mecamylamine.(ABSTRACT TRUNCATED AT 250 WORDS)
Chronic nicotine administration in rats has been previously found to improve choice accuracy performance of rats in the radial-arm maze. A nicotine-induced choice accuracy improvement was also seen in the current study. Rats were trained to asymptotic levels of choice accuracy performance on a working memory paradigm in an 8-arm radial maze. During and after 3 weeks of chronic nicotine treatment, rats were tested for sensitivity to acute doses of the nicotinic and muscarinic receptor antagonists, mecamylamine and scopolamine. During the first week of administration, nicotine-treated rats were supersensitive to the sedation caused by mecamylamine. This suggests that nicotine may not have been acting as a simple nicotinic agonist, since in this case, the opposite effect, an attenuated effect of mecamylamine in the nicotine-treated group, would have been expected. Three to 4 weeks after withdrawal from chronic nicotine administration, the treated rats were more sensitive to the choice accuracy deficits caused by the muscarinic blocker scopolamine (0.16mg/kg) and the nicotinic blocker mecamylamine (10mg/kg). This supersensitivity may have been due to a lasting change caused by chronic nicotine in the cholinergic bases of memory function.
(C) Lippincott-Raven Publishers.
Acute and chronic nicotine treatment has been found to improve learning and memory function in a variety of tasks. In several studies we have found that chronic nicotine infusion improves working memory performance. Replicating these results, the current study showed that chronic nicotine treatment (12mg/kg/day) significantly improved working memory performance in the radial-arm maze. The nicotine effect did not diminish during the 2 weeks following withdrawal. The nicotine-induced improvement was eliminated when the nicotinic antagonist mecamylamine (3mg/kg/day) was given concurrently, suggesting that the nicotine effect was mediated via actions on the nicotinic receptor. Surprisingly, when this chronic dose of mecamylamine was given alone, it caused a transient improvement in choice accuracy during the first week of administration. This improvement subsequently became attenuated and was not evident at all by the third and fourth weeks of administration.
Interactive effects of nicotinic and rnuscarinic agonists with the dopaminergic agonist pergolide on rats in the radial-arm maze Intracerebroven-tricular nicotine and mecamylamine alter radial-arm maze performance in rats
- E D Levin
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Preferential stimulation of ventral tegmental area dopaminergic neurons by nicotine
- G Meru
- K P V Yoon
- G L Boi
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- Westfall
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Preferential stimulation of ventral tegmental area dopaminergic neurons by nicotine
- Meru
Nicotinic effects on the firing pattern of midbrain dopamine neurons
- Grenhoff
Interactive effects of nicotinic and muscarinic agonists with the dopaminergic agonist pergolide on rats in the radial-arm maze
- E D Levin
Chronic nicotinic stimulation and blockade effects on working memory
- Ievin E. D.