Fig 5 - uploaded by Robert Ranaldi
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Histological reconstruction of injection sites adapted from Paxinos and Watson (1986). Black circles for injections in the VTA group; grey circles for injections in the dorsal control group. The numbers to the right of each section indicate the distance posterior to bregma
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We recently found that muscarinic receptor (mAChR) stimulation in the ventral tegmental area (VTA) is involved in the acquisition of a feeding task.
To investigate the involvement of VTA mAChR and nicotinic receptors (nAChR) in the acquisition and performance of a food-rewarded lever-pressing task.
In experiment 1 (N=54), rats were trained under a...
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... of the VTA microinjection sites were localized in the ventromedial portions of the VTA with some injections occurring in the ventrolateral portions (see Figs. 5 and 6). Microinjections aimed at the anatomical control sites were approximately 1.5 to 2.0 mm dorsal to the VTA injection sites (see Fig. 5). The present study tested the hypothesis that VTA ACh neurotransmission is necessary for the acquisition of reward-related operant learning. We found that in animals presented with the opportunity to acquire a food-rewarded operant response, intra-VTA treatment with scopolamine prevented the acquisition of the operant response but not the expression of the same response after it was learned. On the other hand, intra-VTA mecamylamine impaired neither the acquisition nor the expression of the operant response. These data suggest that VTA ACh stimulation of mAChR, but not of nAChR, is necessary for the acquisition of a food-rewarded operant response and that neither is necessary for the expression of the learned operant. We also found that blockade of either muscarinic or nicotinic receptors did not affect BPs for food-rewarded responding under a PR schedule of reinforcement. Given that blockade of VTA nAChR failed to affect the acquisition or expression of responding under a FR schedule of reinforcement, it is not surprising that it had no effect on responding under a PR schedule. These findings suggest that stimulation of nAChR in the VTA is not involved in food reward. However, the finding that blockade of mAChR failed to reduce BPs, interpreted as a failure to reduce food reward, does not necessarily imply that VTA ACh action at muscarinic receptors is not involved in food reward; rather, scopolamine blocked acquisition of FR responding but not expression of FR responding nor expression of PR responding. Thus, only acquisition of operant learning was blocked. One possible explanation is that VTA mAChR stimulation constitutes part of a food reward signal and that this reward signal is present and necessary for the acquisition of operant responding and still present but no longer necessary for the expression of an already acquired operant response. This hypothesis is expanded upon further below. To address the possibility that effects of intra-VTA scopolamine injections on the acquisition of operant responding were due to the drug diffusing to and acting at distal sites, we tested the effects of scopolamine injections 1.5 to 2.0 mm dorsal to the VTA on acquisition of operant responding. Microinjections into the brain are associated with hydraulic pressure that can drive the substance up the cannula tracks toward the pressure sinks of the ventricles (Wise and Hoffman 1992). Once in the ventricular system, the substance can be distributed throughout the brain rapidly and bind to receptors located in distal sites. However, microinjections in the site dorsal to the VTA failed to produce similar behavioral reductions, ruling out the possibility of dorsal diffusion to a distal site of action and supporting the conclusion that the behavioral effects of the intra-VTA microinjections of scopolamine were local. It is unlikely that the present findings were due to scopolamine-induced satiation or motoric effects instead of motivational or learning deficits. During phase III, when animals received either scopolamine or mecamylamine, responding was maintained at the same level as in the previous session, when they did not receive microinjections. Therefore, it is unlikely that initial low levels of responding during phase I were due to scopolamine- induced motoric deficits. Furthermore, if we assume that the time to emit the first lever press represents a measure of exploratory behavior, then scopolamine treatment did not decrease exploratory behavior as all rats, regardless of treatment dose, demonstrated similar latency to begin responding. Finally, when animals were treated with scopolamine before PR sessions, they ate as much as they did when they were treated with vehicle or not treated. Thus, once the task was acquired, all animals demonstrated the capacity to consume the same number of pellets and to press the lever the same number of times under scopolamine treatment as when not. Therefore, satiation and motoric effects can be ruled out. These results are in accordance with our previous findings that intra-VTA injections of scopolamine prevent the acquisition of a feeding task. In that study, animals were presented with the opportunity to learn to eat a novel food in a novel environment. Intra-VTA vehicle resulted in the animals acquiring the task within several sessions but intra- VTA scopolamine during the initial sessions prevented the acquisition of the task; when scopolamine treatment was suspended, animals learned the task within several sessions; and when scopolamine treatment was adminis- tered after acquisition, it failed to affect the performance of the eating task (Sharf and Ranaldi 2006). Altogether, these results, in conjunction with the current findings, point to an emerging role of VTA mAChR stimulation as a necessary signal for acquisition of food- related learning. Furthermore, the finding that stimulation of mAChR appears to not be necessary for expression of responding suggests that the relevant function served by VTA mAChR stimulation necessary for acquisition is acquired by another neural mechanism, which then maintains responding. One possibility is that the ability to activate DA cells and cause DA release, a mAChR function which presumably constitutes the mechanism of action for the role of VTA ACh in reward, is acquired by another pathway. Thus, we hypothesize that during the acquisition of food-related operant learning, CSs acquire the ability to activate VTA DA cells. By activating these cells, they could function similarly to food reward itself, that is, they could elicit and reinforce approach (i.e., lever pressing) behavior. The VTA DA cells receive glutamate afferents from the mPFC (Sesack and Pickel 1992; Smith et al. 1996), the amygdala, the bed nucleus of the stria terminalis (Hopkins and Holstege 1978; Phillipson 1979), and the PPN (Charara et al. 1996), which could carry information about CSs. The ACh signal at muscarinic receptors might function as a signal for unconditioned stimuli (USs). So, it is possible that VTA DA cells associate CS and US signals during operant learning. This hypothesis is supported by studies showing that glutamatergic synaptic activity in the VTA is associated with induction of long-term potentiation of the DA neurons (Bonci and Malenka 1999; Overton et al. 1999) and that the VTA is a critical site for synaptic modifications involved in the conditioning of environmental stimuli with drug rewards (Harris et al. 2004). We previously reported that scopolamine treatment reduces BPs under a PR schedule of food reinforcement when the reinforcer magnitude was set to five food pellets (Sharf and Ranaldi 2006). The discrepancy between the present study and the previous one may lie in the differential magnitude of the food reward. Given that food consumption releases ACh in the VTA (Rada et al. 2000), it is reasonable to assume that five pellets cause greater ACh release than one pellet. If this is so, it is conceivable that when food reward is 1 pellet, the amount of ACh released does not contribute appreciably to an already CS-activated reward system. However, when the reward is five pellets, the additional ACh released may make an appreciable contribution. Thus, blockade of mAChR in animals responding for five pellets can possibly eliminate a mAChR-mediated reward contribution while in animals responding for one pellet, there may be no mAChR-mediated contribution to eliminate. This also suggests that scopolamine may affect expression of responding under a FR1 schedule when reward magnitude is five pellets. The possibility of an interaction among scopolamine, reward-magnitude, and reinforcement schedules is interesting and deserves further research consideration. There is an emerging body of evidence linking ACh neurotransmission with reward-related learning. PPN lesions have been shown to prevent the acquisition of conditioned place preference (CPP) to food, opiates, and amphetamine (Bechara and van der Kooy 1989, 1992; Olmstead and Franklin 1993, 1994), but failed to block the CPP effect after conditioning sessions (Bechara and van der Kooy 1989, 1992; Bechara et al. 1992; Nader et al. 1994). PPN lesions have also been shown to disrupt acquisition of a brain-stimulation maintained lever-pressing task; however, responding for self-stimulation was also impaired in animals lesioned after acquisition (Lepore and Franklin 1996). Scopolamine administration into the core region of the NAcc impaired the acquisition and expression of a sucrose-reinforced lever-pressing task (Pratt and Kelley 2004). Altogether, there is an emerging body of literature suggesting that ACh neurotransmission plays a critical role in reward-related ...
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Working memory impairments in the n-back task in schizophrenia have been linked to sustained deficiency in mesocortical dopamine function. More recently, abnormalities in the cholinergic system have also been documented in schizophrenia, with cortical reductions in both nicotinic and muscarinic receptors. While the cholinergic hypothesis of memory...
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... mACh-рецепторы VTA опосредуют побудительные мотивационные эффекты награды, в том числе пищевой [33]. Мускарин вызывал деполяризацию нейронов VTA in vitro [97], ACh и агонисты m/nAChR стимулировали активность DA-нейронов in vivo [94] и высвобождение DA в префронтальной коре и NAc [98,99]; тогда как блокада mAChR предотвращала эти эффекты, а также оперантное поведение крыс по получении пищевой награды [100]. ...
Feeding behavior includes both the satisfaction of metabolic nutrient requirements and the hedonic aspects of pleasure. The orexigenic hormone ghrelin increases motivation to food intake. In addition, by modulating the reward system, ghrelin enhances the rewarding properties of non-food stimuli. The dopaminergic mesolimbic system plays a key role in the mechanisms of reward. Ghrelin regulates the activity of this system by acting on several levels of brain organization. The hierarchy of ghrelin-sensitive neural networks, as well as afferent connections and reciprocal interactions between its components, mediating the effect of ghrelin on the process of motivation in metabolic and hedonic type of feeding are considered.
... 48 Intra-VTA administration of mAChR antagonists reduces food intake in food-deprived rats, 48 and, in line with this, intra-VTA treatment with scopolamine, but not mecamylamine, blocks the acquisition of a food-rewarded operant response in rats. 49 Scopolamine also blocks the acquisition of a feeding task involving learning to eat a novel food in a novel environment. Together, these studies suggest a role for VTA mAChRs in both reward-related responses and food-related learning. ...
Despite increased awareness and intensified biomedical research efforts, the prevalence of obesity continues to rise worldwide. This is alarming, because obesity accelerates the progression of several chronic disorders, including type 2 diabetes, cancer and cardiovascular disease. Individuals who experience significant weight loss must combat powerful counter‐regulatory energy homeostatic processes, and, typically, most subjects regain the lost weight. Therefore, decoding the neural mechanisms underlying the regulation of energy homeostasis is necessary for developing breakthroughs in obesity management. It has been known for decades that cholinergic neurotransmission both directly and indirectly modulates energy homeostasis and metabolic health. Despite this insight, the molecular details underlying the modulation remain ill‐defined, and the potential for targeting cholinergic muscarinic receptors for treating metabolic disease is largely uncharted. In this MiniReview, we scrutinize the literature that has formed our knowledge of muscarinic acetylcholine receptors (mAChRs) in energy homeostasis. The role of mAChRs in canonical appetite‐regulating circuits will be discussed as will the more indirect regulation of energy homoeostasis via neurocircuits linked to motivated behaviours and emotional states. Finally, we discuss the therapeutic prospects of targeting mAChRs for the treatment of obesity and type 2 diabetes. This article is protected by copyright. All rights reserved.
... The non-selective nicotinic and muscarinic receptor antagonists mecamylamine and scopolamine, respectively, were dissolved in 0.9% saline. The selection of doses for the mecamylamine (0, 10, and 30 μg) and scopolamine (0, 2.4, and 24 μg) were based on previously published data showing the behavioral effectiveness of these VTA infusion doses (Sharf et al., 2006;Schmidt et al., 2009;Solecki et al., 2013 ;Addy et al., 2015a). Importantly, we previously demonstrated that these behaviorally relevant doses had no effect on general locomotor activity Addy et al., 2015a). ...
... Nevertheless, future behavioral experiments should incorporate multiple behavioral paradigms that can adequately measure negative valence based behaviors in tandem. Another potential limitation of this study is the ability of impaired VTA cholinergic transmission to produce general deficits in reward-related learning and motor activity (Sharf et al., 2006;Galaj et al., 2017). However, data from our laboratory has demonstrated that these doses of mecamyalmine and scopolamine infused in the VTA does not affect general locomotor activity Addy et al., 2015a) Therefore, our results on both cue-induced cocaine seeking and on the EPM appear not to be related to general behavioral deficits as a result of disrupting VTA cholinergic transmission. ...
Drug relapse after periods of abstinence is a common feature of substance abuse. Moreover, anxiety and other mood disorders are often co-morbid with substance abuse. Cholinergic receptors in the ventral tegmental area (VTA) are known to mediate drug-seeking and anxiety-related behavior in rodent models. However, it is unclear if overlapping VTA cholinergic mechanisms mediate drug relapse and anxiety-related behaviors associated with drug abstinence. We examined the effects of VTA cholinergic receptor blockade on cue-induced cocaine seeking and anxiety during cocaine abstinence. Male Sprague-Dawley rats were trained to self-administer intravenous cocaine (~0.5 mg/kg/infusion, FR1 schedule) for 10 days, followed by 14 days of forced abstinence. VTA infusion of the non-selective nicotinic acetylcholine receptor antagonist mecamylamine (0, 10, and 30 μg/side) or the non-selective muscarinic receptor antagonist scopolamine (0, 2.4 and 24 μg /side) significantly decreased cue-induced cocaine seeking. In cocaine naïve rats, VTA mecamylamine or scopolamine also led to dose-dependent increases in open arm time in the elevated plus maze (EPM). In contrast, rats that received I.V. cocaine, compared to received I.V. saline rats, displayed an anxiogenic response on day 14 of abstinence as reflected by decreased open arm time in the EPM. Furthermore, low doses of VTA mecamylamine (10 μg /side) or scopolamine (2.4 μg /side), that did not alter EPM behavior in cocaine naive rats, were sufficient to reverse the anxiogenic effects of cocaine abstinence. Together, these data point to an overlapping role of VTA cholinergic mechanisms to regulate relapse and mood disorder-related responses during cocaine abstinence.
... Concerning subtype specific VTA AChR mechanisms, we previously found that VTA mAChR blockade reversed the pro-depressive effects of VTA physostigmine in the FST [2]. Several studies had previously demonstrated a role of VTA mAChRs in multiple behaviors, including feeding behavior [30,31], conditioned reinforcement [39] and cue-induced drug-seeking [32,42]. However, our previous FST investigation was the first to suggest a role for VTA mAChR mechanisms in stress-related behavior. ...
Cholinergic and dopaminergic mechanisms within the mesolimbic dopamine system are suggested to play a role in the manifestation of depression and anxiety-related disorders. However, despite the fact that cholinergic mechanisms in the ventral tegmental area (VTA) highly regulate dopamine activity, the role of VTA cholinergic mechanisms in depression-related behaviors is relatively unknown. Here we sought to determine whether enhancing cholinergic tone in the VTA would alter depression and anxiety-related behavior in the forced swim test (FST), elevated plus maze (EPM) and sucrose preference test (SPT). Adult Sprague Dawley male rats received VTA infusion of the acetylcholinesterase inhibitor, physostigmine (0, 1, 2 μg/side), immediately prior to the FST, EPM, or SPT. Physostigmine administration increased immobility time in the FST, decreased time spent on open arms in the EPM, and decreased sucrose preference. In a separate cohort of rats, we also examined whether activation of VTA muscarinic receptors was sufficient to alter behavior in the FST and EPM. Similar to physostigmine, VTA infusion of the muscarinic receptor agonist, pilocarpine (0, 3, 30 μg/side), increased immobility time in the FST and decreased time spent on open arms in the EPM. These data suggest that enhanced VTA cholinergic tone promotes pro-depressive and anxiogenic-like effects and demonstrate that specific activation of VTA muscarinic receptors is also sufficient to induce pro-depressive and anxiogenic responses. Together, these findings reveal a novel role of VTA cholinergic, and specifically muscarinic receptor, mechanisms in mediating responses to stress and anxiety.
... For example, acetylcholine is considered to be a satiety signal when secreted within the nucleus accumbens, and its imbalanced release in this area may be linked with food addiction withdrawal symptoms [214]. In general, acetylcholine alters the reward system-related food intake using muscarinic receptors [215][216][217][218]. Importantly, both the muscarinic (scopolamine) and nicotinic (mecamylamine) antagonists, when injected peripherally to rats, were able to disrupt the incentive motivation to obtain food reward [219,220], indicating that systemically administered pharmaceuticals impinging on the cholinergic system might be used to modify the rewarding value of food. ...
Excessive intake of food, especially palatable and energy-dense carbohydrates and fats, is largely responsible for the growing incidence of obesity worldwide. Although there are a number of candidate antiobesity drugs, only a few of them have been proven able to inhibit appetite for palatable foods without the concurrent reduction in regular food consumption. In this review, we discuss the interrelationships between homeostatic and hedonic food intake control mechanisms in promoting overeating with palatable foods and assess the potential usefulness of systemically administered pharmaceuticals that impinge on the endogenous cannabinoid, opioid, aminergic, cholinergic, and peptidergic systems in the modification of food preference behavior. Also, certain dietary supplements with the potency to reduce specifically palatable food intake are presented. Based on human and animal studies, we indicate the most promising therapies and agents that influence the effectiveness of appetite-modifying drugs. It should be stressed, however, that most of the data included in our review come from preclinical studies; therefore, further investigations aimed at confirming the effectiveness and safety of the aforementioned medications in the treatment of obese humans are necessary.
... With respect to cholinergic mechanisms, previous evidence suggests a role of the VTA AChRs in mediating primary reward. Specifically, VTA acetylcholine levels rise during eating and drinking (Rada et al., 2000) while VTA infusion of mAChR antagonists, but not nAChR antagonists, decrease feeding behavior (Yeomans et al., 1993;Sharf et al., 2006b). Furthermore, pharmacological activation of VTA AChRs leads to the development of a conditioned place preference (Yeomans and Baptista, 1997;Ikemoto and Wise, 2002) and is sufficient to produce self-administration behavior (Ikemoto and Wise, 2002), suggesting an important role of VTA AChRs in primary reward processing. ...
Stimuli paired with rewards acquire reinforcing properties to promote reward-seeking behavior. Previous work supports the role of ventral tegmental area (VTA) nicotinic acetylcholine receptors (nAChRs) in mediating conditioned reinforcement elicited by drug-associated cues. However, it is not known whether these cholinergic mechanisms are specific to drug-associated cues or whether VTA cholinergic mechanisms also underlie the ability of cues paired with natural rewards to act as conditioned reinforcers. Burst firing of VTA dopamine (DA) neurons and the subsequent phasic DA release in the nucleus accumbens (NAc) plays an important role in cue-mediated behavior and in the ability of cues to acquire reinforcing properties. In the VTA, both AChRs and N-methyl-d-aspartate receptors (NMDARs) regulate DA burst firing and phasic DA release. Here, we tested the role of VTA nAChRs, muscarinic AChRs (mAChRs), and NMDARs in the conditioned reinforcement elicited by a food-associated, natural reward cue. Subjects received 10 consecutive days of Pavlovian conditioning training where lever extension served as a predictive cue for food availability. On day 11, rats received bilateral VTA infusion of saline, AP-5 (0.1 or 1 μg), mecamylamine (MEC: 3 or 30 μg) or scopolamine (SCOP: 3 or 66.7 μg) immediately prior to the conditioned reinforcement test. During the test, nosepoking into the active (conditioned reinforced, CR) noseport produced a lever cue while nosepoking on the inactive (non-conditioned reinforced, NCR) noseport had no consequence. AP-5 robustly attenuated conditioned reinforcement and blocked discrimination between CR and NCR noseports at the 1-μg dose. MEC infusion decreased responding for both CR and NCR while 66.7-μg SCOP disrupted the subject’s ability to discriminate between CR and NCR. Together, our data suggest that VTA NMDARs and mAChRs, but not nAChRs, play a role in the ability of natural reward-associated cues to act as conditioned reinforcers.
... However, the role of VTA AChR mechanisms in cueinduced food-seeking behavior is largely unknown. To date, examinations of VTA cholinergic receptor mechanisms for food reward have mainly focused on free feeding behavior and operant learning [12,13]. In the current study, we sought to determine whether VTA nAChR and mAChR mechanisms mediate cue-induced sucrose-seeking. ...
... Importantly, these Scop findings are not likely due to nonspecific motor effects, as we have previously demonstrated that VTA infusion of 24 μg Scop does not alter general locomotor activity [16]. Previous work also demonstrated that VTA Scop infusion does not alter operant responding in a progressive ratio task in rats that have already undergone operant acquisition training [13]. Thus, we propose that our observed effects of VTA mAChR blockade are likely specific to cue-induced sucroseseeking and would not be observed in a non-extinction session. ...
... We also observed a cholinergic receptor dissociation, where mAChR blockade, but not nAChR blockade, attenuated cue-induced sucrose-seeking. This dissociation is similar to what was previously demonstrated in an operant task where mAChR, but not nAChR, blockade prevented the learning of operant responding for food [13]. Our findings, together with previous work, suggest that VTA mAChR, and not nAChR, mechanisms play a role in the learning of operant food-related tasks and in the expression of cue-mediated food seeking behavior. ...
The mesolimbic dopamine (DA) system is known to play a role in cue-mediated reward-seeking for natural rewards and drugs of abuse. Specifically, cholinergic and glutamatergic receptors in the ventral tegmental area (VTA) have been shown to regulate cue-induced drug-seeking. However, the potential role of these VTA receptors in regulating cue-induced reward seeking for natural rewards is unknown. Here, we examined whether blockade of VTA acetylcholine receptors (AChRs) and N-methyl-D-aspartate receptors (NMDARs) would alter cue-induced sucrose seeking in male Sprague-Dawley rats. Subjects underwent 10 days of sucrose self-administration training (fixed ratio 1 schedule) followed by 7 days of forced abstinence. On withdrawal day 7, rats received bilateral VTA infusion of vehicle, the muscarinic AChR antagonist scopolamine (2.4 or 24μg/side), the nicotinic AChR antagonist mecamylamine (3 or 30μg/side), or the NMDAR antagonist AP-5 (0.1 or 1μg/side) immediately prior to examination of cue-induced sucrose-seeking. Scopolamine infusion led to robust attenuation, but did not completely block, sucrose-seeking behavior. In contrast, VTA administration of mecamylamine or AP-5 did not alter cue-induced sucrose-seeking. Together, the data suggest that VTA muscarinic AChRs, but not nicotinic AChRs nor NMDARs, facilitate the ability of food-associated cues to drive seeking behavior for a food reward.
Copyright © 2015. Published by Elsevier B.V.
... For instance, acetylcholinedepleting striatal lesions have been shown to disrupt appetitive, but spare aversive, learning (Kitabatake et al, 2003). Furthermore, both scopolamine (Sharf et al, 2006;Pratt and Kelley, 2004;Tikhonravov et al, 1997) and mecamylamine (Levin et al, 2000) tend to suppress foodreinforced lever pressing. Although such findings implicate both muscarinic and nicotinic receptors in instrumental performance, they provide little information about the nature of their contributions. ...
Reward-seeking actions can be guided by external cues that signal reward availability. For instance, when confronted with a stimulus that signals sugar, rats will prefer an action that produces sugar over a second action that produces grain pellets. Action selection is also sensitive to changes in the incentive value of potential rewards. Thus, rats that have been prefed a large meal of sucrose will prefer a grain-seeking action to a sucrose-seeking action. The current study investigated the dependence of these different aspects of action selection on cholinergic transmission. Hungry rats were given differential training with two unique stimulus-outcome (S1-O1 and S2-O2) and action-outcome (A1-O1 and A2-O2) contingencies during separate training phases. Rats were then given a series of Pavlovian-to-instrumental transfer tests, an assay of cue-triggered responding. Prior to each test, rats were injected with scopolamine (0, 0.03, or 0.1 mg/kg, i.p.), a muscarinic receptor antagonist, or mecamylamine (0, 0.75, or 2.25 mg/kg, i.p.), a nicotinic receptor antagonist. Whereas the reward-paired cues were capable of biasing action selection when rats were tested off-drug, both anticholinergic treatments were effective in disrupting this effect. During a subsequent round of outcome devaluation testing - used to assess the sensitivity of action selection to a change in reward value-we found no effect of either scopolamine or mecamylamine. These results reveal that cholinergic signaling at both muscarinic and nicotinic receptors mediates action selection based on Pavlovian reward expectations, but is not critical for flexibly selecting actions using current reward values.Neuropsychopharmacology accepted article preview online, 27 December 2013. doi:10.1038/npp.2013.348.
... In the VTA, extracellular concentrations of ACh increase during eating, drinking and self-stimulation of the lateral hypothalamus [27]. In addition, injections of muscarinic ACh receptor (mAChR) antagonists in the VTA reduce eating both in our laboratory [22,28,29] and others [27] and reduce approach and consummatory responses for food [30]. In vivo [31] and in vitro [32] studies show that stimulation of mAChRs in the VTA depolarizes presumed DA neurons and releases DA in terminal regions of the mesocorticolimbic system [33,34]. ...
... The current study suggests that conditioned approach occurs through signal activation of DA cells, at the level of the cell bodies, in the VTA. We proposed this signal is glutamatergic in nature [6,22,28]. If this is true then one would expect reduced responding maintained by reward-associated stimuli and reduced dopamine release in the mesolimbic DA terminal regions after blockade of glutamate signaling in the VTA and in fact this is what Sombers et al. found [42]. ...
Neutral stimuli associated with unconditioned stimuli (USs) acquire the ability to act as conditioned stimuli (CSs), which can elicit behaviors similar to the US with which they are associated. The neural mechanisms by which this occurs are not fully known. We have previously proposed a model stipulating CSs function as such because they acquire the capacity to activate dopamine (DA) neurons at the level of the ventral tegmental area (VTA). In the present experiments we hypothesized that a food-associated CS (light), which demonstrably functions as such by eliciting conditioned responses (CRs), comes to acquire the capacity to activate VTA DA neurons. In Experiment 1, rats were allowed to eat or not eat food (food being the US). In Experiment 2, rats were trained to retrieve food pellets after light presentations (the CS) and then tested for the expression of the food checking response (the CR) with only CS presentations. In Experiment 1, eating food (exposure to the US) caused a significantly greater number of VTA DA (TH-labeled) cells to express c-Fos than not eating. In Experiment 2, CS (light) presentations caused a significant amount of conditioned approach and a significantly greater number of VTA TH-labeled (DA) cells to express c-Fos. These findings support our model stipulating that conditioned approach learning occurs when CSs acquire the capacity to cause conditioned activation of VTA DA neurons.
... These regions of the brain are thought to be involved in reward or motivation [28,38,42,545556. Since the VTA is the site of origin of the mesocorticolimbic DA system and is critical for synaptic plasticity underlying reward-related learning [57], we examined expression of TH in this region. ...
The reciprocal interaction of pups and cocaine on reward effects in rodent mothers is known. However,it remains unclear whether such effects are apparent in father-offspring bonding. The mandarin vole (Microtus mandarinus) is a monogamous rodent with a high level of paternal care. We investigated the reinforcing properties of pups on vole fathers using a conditioned place preference paradigm across the postpartum period and looked for interactions and differences between the reinforcing effects of pups and cocaine. We also measured neuronal Fos and tyrosine hydroxylase (TH) expression underlying the preferences of fathers for pups or cocaine. Our data showed that fathers developed strong preferences for pups at various times (postnatal day 5–9, 13–17 and 19–23) without cocaine conditioning. Fathers showed a reduced preference for pups following simultaneous conditioning with cocaine. Although they preferred cocaine over postnatal day (PND) 5–9 pups, this preference was not detected for PND 13–17 pups. Fathers preferring cocaine exhibited an increase in Fos-immunoreactive neurons in the accumbens,medial nucleus of the amygdala, cingulate cortex, medial preoptic area and ventral tegmental area and had more TH-IR neurons in the ventral tegmental area compared to fathers preferring PND 5–9 pups. These results showed that similar to cocaine, mandarin vole pups elicit significant reward value to their fathers, but that paternal motivation is impaired by cocaine. A preference for cocaine over pups arose from the release of more dopamine and activation of a greater number of neurons within specific reward-associated neuronal subsets.
