Acquisition Of Reward Research Articles

Conditioned inhibition of fear and reward in male and female rats

Stimuli in our environment are not always associated with an outcome. Some of these stimuli, depending on how they are presented, may gain inhibitory value or simply be ignored. If experienced in the presence of other cues predictive of appetitive or aversive outcomes, they typically gain inhibitory value and become predictive cues indicating the absence of appetitive or aversive outcomes. In this case, these cues are referred to as conditioned inhibitors. Here, male and female Long Evans rats underwent cue discrimination training where a reward cue was paired with sucrose, a fear cue with footshock, and an inhibitor cue resulted in neither sucrose or footshock. During a subsequent summation test for conditioned inhibition of fear and reward, the inhibitor cue was presented concurrently with the reward and fear cues without any outcome, intermixed with trials of reinforced reward and fear trials. Males showed significant conditioned inhibition of freezing, while females did not, which was not dependent on estrous. Both males and females showed significant conditioned inhibition of reward. During a retardation of fear acquisition test, the inhibitor was paired with footshock and both males and females showed delayed acquisition of fear. During a retardation of reward acquisition test, the inhibitor was paired with sucrose, and females showed delayed acquisition of reward, while males did not. In summary, males and females showed significant reward-fear-inhibitor cue discrimination, conditioned inhibition of reward, and retardation of fear acquisition. The main sex difference, which was not estrous-dependent, was the lack of conditioned inhibition of freezing in females. These data imply that while the inhibitor cue gained some inhibitory value in the females, the strength of this inhibitory value may not have been great enough to effectively downregulate freezing elicited by the fear cue.

Effort cost of harvest affects decisions and movement vigor of marmosets during foraging

Our decisions are guided by how we perceive the value of an option, but this evaluation also affects how we move to acquire that option. Why should economic variables such as reward and effort alter the vigor of our movements? In theory, both the option that we choose and the vigor with which we move contribute to a measure of fitness in which the objective is to maximize rewards minus efforts, divided by time. To explore this idea, we engaged marmosets in a foraging task in which on each trial they decided whether to work by making saccades to visual targets, thus accumulating food, or to harvest by licking what they had earned. We varied the effort cost of harvest by moving the food tube with respect to the mouth. Theory predicted that the subjects should respond to the increased effort costs by choosing to work longer, stockpiling food before commencing harvest, but reduce their movement vigor to conserve energy. Indeed, in response to an increased effort cost of harvest, marmosets extended their work duration, but slowed their movements. These changes in decisions and movements coincided with changes in pupil size. As the effort cost of harvest declined, work duration decreased, the pupils dilated, and the vigor of licks and saccades increased. Thus, when acquisition of reward became effortful, the pupils constricted, the decisions exhibited delayed gratification, and the movements displayed reduced vigor.

Effort cost of harvest affects decisions and movement vigor of marmosets during foraging.

Our decisions are guided by how we perceive the value of an option, but this evaluation also affects how we move to acquire that option. Why should economic variables such as reward and effort alter the vigor of our movements? In theory, both the option that we choose and the vigor with which we move contribute to a measure of fitness in which the objective is to maximize rewards minus efforts, divided by time. To explore this idea, we engaged marmosets in a foraging task in which on each trial they decided whether to work by making saccades to visual targets, thus accumulating food, or to harvest by licking what they had earned. We varied the effort cost of harvest by moving the food tube with respect to the mouth. Theory predicted that the subjects should respond to the increased effort costs by choosing to work longer, stockpiling food before commencing harvest, but reduce their movement vigor to conserve energy. Indeed, in response to an increased effort cost of harvest, marmosets extended their work duration, but slowed their movements. These changes in decisions and movements coincided with changes in pupil size. As the effort cost of harvest declined, work duration decreased, the pupils dilated, and the vigor of licks and saccades increased. Thus, when acquisition of reward became effortful, the pupils constricted, the decisions exhibited delayed gratification, and the movements displayed reduced vigor.

Salmon Calcitonin Attenuates Some Behavioural Responses to Nicotine in Male Mice.

The behavioural responses to nicotine involve appetite-regulatory hormones; however, the effects of the anorexigenic hormone amylin on reward-related behaviours induced by nicotine remain to be established. Previous studies have shown that the amylinergic pathway regulates behavioural responses to alcohol, amphetamine and cocaine. Here, we evaluated the effects of salmon calcitonin (sCT), an amylin and calcitonin receptor (CTR) agonist, on nicotine-induced locomotor stimulation and sensitisation as well as dopamine release in the nucleus accumbens (NAc) shell. Moreover, we investigated the effects of sCT on the acquisition and expression of nicotine-induced reward in the conditioned place preference (CPP) paradigm. Finally, we performed Western Blot experiments in an attempt to identify the levels of the amylin receptor components CTRa, CTRb, and RAMP1 in reward-related areas of mice responding differently to repeated injections of sCT and nicotine in the locomotor sensitisation test. We found that sCT blocked nicotine’s stimulatory and dopamine-releasing effects and prevented its ability to cause locomotor sensitisation. On the other hand, sCT did not alter nicotine-induced acquisition and expression of CPP. Lastly, sCT-nicotine treated mice from the locomotor sensitisation experiment displayed higher levels of total CTR, i.e. CTRa and CTRb together, in the reward-processing laterodorsal tegmental area (LDTg) of the brain compared to mice treated with vehicle-nicotine. Overall, the present data reveal that activation of CTR or/and amylin receptors attenuates certain nicotine-induced behaviours in male mice, further contributing to the understanding of appetite-regulatory peptides in reward regulation.

The role of intolerance of uncertainty in the acquisition and extinction of reward.

Individuals, who score high in self-reported intolerance of uncertainty (IU), tend to find uncertainty anxiety-provoking. IU has been reliably associated with disrupted threat extinction. However, it is unclear whether IU would be related to disrupted extinction to other arousing stimuli that are not threatening (i.e., rewarding). We addressed this question by conducting a Pavlovian reward conditioning task with acquisition and extinction training phases (n=58). In the Pavlovian reward conditioning task, we recorded liking ratings, skin conductance response (SCR), and corrugator supercilii activity (i.e., brow muscle indicative or negative and positive affect) to learned reward (CS+) and neutral (CS-) cues. Typical patterns of reward acquisition and extinction training were observed for liking ratings. There was evidence for conditioning in SCR during the extinction training phase but not the acquisition training phase. However, no evidence of conditioning in either the acquisition or extinction training phase was observed for the corrugator supercilii. IU was not related to any measures during the acquisition or extinction training phases. Taken together, these results suggest that the current Pavlovian reward conditioning task was not sufficient for eliciting a reliable conditioned reward response, and therefore, further research with optimized reward conditioning designs are required to test whether IU-related deficits occur during the extinction of reward.

Mushroom body output differentiates memory processes and distinct memory-guided behaviors

The mushroom body (MB) of Drosophila melanogaster has multiple functions in controlling memory and behavior.1-9 However, circuit mechanisms that generate this functional diversity are largely unclear. Here, we systematically probed the behavioral contribution of each type of MB output neuron (MBON) by blocking during acquisition, retention, or retrieval of reward or punishment memories. We evaluated the contribution using two conditioned responses: memory-guided odor choice and odor source attraction. Quantitative analysis revealed that these conditioned odor responses are controlled by different sets of MBONs. We found that the valence of memory, rather than the transition of memory steps, has a larger impact on the patterns of required MBONs. Moreover, we found that the glutamatergic MBONs forming recurrent circuits commonly contribute to appetitive memory acquisition, suggesting a pivotal role of this circuit motif for reward processing. Our results provide principles how the MB output circuit processes associative memories of different valence and controls distinct memory-guided behaviors.

Enhancement of alcohol aversion by the nicotinic acetylcholine receptor drug sazetidine-A.

The prevalence of alcohol use disorders (AUDs) has steadily increased in the United States over the last 30 years. Alcohol acts on multiple receptor systems including the nicotinic acetylcholine receptors (nAChRs), which are known to mediate alcohol consumption and reward. We previously reported that the preclinical drug sazetidine-A, a nAChR agonist and desensitizer, reduces alcohol consumption without affecting nicotine consumption in C57BL/6J mice. Here, we found that sazetidine-A enhances the expression of alcohol aversion without affecting the expression or acquisition of conditioned alcohol reward in C57BL/6J mice. Microinjection of sazetidine-A into the ventral midbrain targeting the ventral tegmental area (VTA) reduced binge alcohol consumption, implicating this region in mediating the effects of sazetidine-A. Furthermore, the sazetidine-A-induced reduction in alcohol consumption was mediated by non-α4 containing nAChRs, as sazetidine-A reduced binge alcohol consumption in both α4 knock-out and wild-type mice. Finally, we found that in mice pretreated with sazetidine-A, alcohol induced Fos transcript in Th-, but not Gad2-expressing neurons in the VTA as measured by increased Fos transcript expression. In summary, we find that sazetidine-A enhances the expression of alcohol aversion, which may underlie the reduction in alcohol consumption induced by sazetidine-A. Elucidating the identity of non-α4 nAChRs in alcohol aversion mechanisms will provide a better understanding the complex role of nAChRs in alcohol addiction and potentially reveal novel drug targets to treat AUDs.

A Claustro-Frontal Dopamine-Driven Circuit Essential For Contextual Association of Reward

The claustrum is a small nucleus, exhibiting vast reciprocal connectivity with cortical, subcortical and midbrain regions. Recent studies, including ours, implicate the claustrum in salience detection and attention. In the current study, we develop an iterative functional investigation of the claustrum, guided by quantitative spatial transcriptional analysis. Using this approach, we identify a circuit involving dopamine-receptor expressing claustral neurons projecting to frontal cortex necessary for context association of reward. We describe the recruitment of the claustral dopamine system by cocaine and its essential role in drug sensitization. Applying chemo- and opto- genetic manipulation of increasingly specified claustral subpopulations, we identify a role for a defined network of claustrum neurons in the acquisition of contextual cocaine reward and de novo context reinforcement. In sum, our results identify a role for a dopamine-driven claustro-frontal neural circuit in the attribution of incentive salience, allocating contextual attention to reward-related cues.

Role of mesolimbic ghrelin in the acquisition of cocaine reward

The present study examined the ability of ghrelin administration into either the ventral tegmental area (VTA) or nucleus accumbens (NAc) to potentiate cocaine-induced conditioned place preference (CPP). Additionally, we examined the impact of co-injection of the ghrelin 1a antagonist JMV 2959 with ghrelin in order to evaluate the potential attenuation of ghrelin’s effects on cocaine-induced CPP. Adult male Sprague-Dawley rats were allowed simultaneous access to either side of the CPP apparatus to establish baseline chamber preferences. The rats were then restricted to either their non-preferred or preferred side over the course of conditioning which lasted for a total of 8 consecutive days. On days in which rats were restricted to their non-preferred side, systemic cocaine (0.5–5.0 mg/kg IP) followed by central ghrelin (300 pmol), or co-administration of ghrelin (300 pmol) with JMV 2959 (10 μg), was administered either into the VTA or NAc immediately prior to the conditioning period. On alternate days rats were treated with vehicle then placed into what was initially determined to be their preferred side. CPP was calculated as the difference in the percentage of total time spent in the treatment-paired compartment during the post-conditioning session and the pre-conditioning session. Our results indicated that ghrelin potentiated cocaine-induced CPP and that this effect was attenuated by JMV 2959. Overall, these findings provide further evidence that mesolimbic ghrelin signaling is indeed critically involved in mediating the rewarding effects of cocaine.

Deficient neural activity subserving decision-making during reward waiting time in intertemporal choice in adult attention-deficit hyperactivity disorder.

Impulsivity, which significantly affects social adaptation, is an important target behavioral characteristic in interventions for attention-deficit hyperactivity disorder (ADHD). Typically, people are willing to wait longer to acquire greater rewards. Impulsivity in ADHD may be associated with brain dysfunction in decision-making involving waiting behavior under such situations. We tested the hypothesis that brain circuitry during a period of waiting (i.e., prior to the acquisition of reward) is altered in adults with ADHD. The participants included 14 medication-free adults with ADHD and 16 healthy controls matched for age, sex, IQ, and handedness. The behavioral task had participants choose between a delayed, larger monetary reward and an immediate, smaller monetary reward, where the reward waiting time actually occurred during functional magnetic resonance imaging measurement. We tested for group differences in the contrast values of blood-oxygen-level dependent signals associated with the length of waiting time, calculated using the parametric modulation method. While the two groups did not differ in the time discounting rate, the delay-sensitive contrast values were significantly lower in the caudate and visual cortex in individuals with ADHD. The higher impulsivity scores were significantly associated with lower delay-sensitive contrast values in the caudate and visual cortex. These results suggest that deficient neural activity affects decision-making involving reward waiting time during intertemporal choice tasks, and provide an explanation for the basis of impulsivity in adult ADHD.

Preventing morphine reinforcement with high-frequency deep brain stimulation of the lateral hypothalamic area.

Deep brain stimulation (DBS) has been proposed as a promising intervention for patients with treatment-refractory substance use disorder. Here, we investigated if high-frequency DBS in the lateral hypothalamic area (LHA) could affect drug-induced reinforcement. Rats were bilaterally implanted with bipolar stimulation electrodes in the LHA and trained to the morphine conditioned place preference. DBS (monophasic square pulses, 130Hz, 100-microsecond pulse duration and 150μA) was applied during the morphine-pairing trials (30minutes daily for 4days) or drug-free postconditioning test (15minutes) to determine its effect on the acquisition or expression of morphine reward, respectively. LHA DBS during morphine-conditioning trials blocked subsequent preference for the drug-associated context. In contrast, DBS in the postconditioning phase failed to inhibit expression of morphine-induced conditioned place preference. These results were further controlled by ruling out significant changes by DBS in physical performance and anxiety-like behavior as measured by an open field test and by precluding anhedonia-like behavior as measured by sucrose consumption test. Our results suggest that LHA DBS can prevent development of morphine reward without diminishing the motivation for naturally rewarding stimuli. Therefore, the LHA could be a potential target for research in the field of DBS-based treatment of intractable substance use disorder. Further studies will be necessary to assess the translatability of these findings to the clinic.

The role of the vasopressin system and dopamine D1 receptors in the effects of social housing condition on morphine reward

BackgroundThe association with opioid-abusing individuals or even the perception of opioid abuse by peers are risk factors for the initiation and escalation of abuse. Similarly, we demonstrated that morphine-treated animals housed with only morphine-treated animals (referred to as morphine only) acquire morphine conditioned place-preference (CPP) more readily than morphine-treated animals housed with drug-naïve animals (referred to as morphine cage-mates). However, the molecular mechanisms underlying these effects are still elusive. MethodsMice received repeated morphine or saline while housed as saline only, morphine only, or cage-mates. Then, they were examined for the expression levels of D1 dopamine receptor (D1DR), D2 dopamine receptor (D2DR), dopamine transporter (DAT), oxytocin, and Arginine-vasopressin (AVP) in the striatum using qPCR. Additionally, we examined the effects of the AVP-V1b receptor antagonist, SSR149415, on the acquisition of morphine conditioned place-preference (CPP). ResultsIncreased striatal expression of D1DR and AVP was observed in morphine only animals, but not morphine cage-mates. No significant effects were observed on the striatal expression of D2DR, DAT, or oxytocin. Antagonizing the AVP-V1b receptors decreased the acquisition of morphine CPP in the morphine only mice, but did not alter the acquisition of morphine CPP in the morphine cage-mate mice. ConclusionsHousing with drug-naïve animals protects against the increase in striatal expression of D1DR and AVP elicited by morphine exposure. Moreover, our studies suggest that the protective effect of housing with drug-naïve animals on the acquisition of morphine reward might be, at least partially, mediated by AVP.

Role of orexin receptors in the ventral tegmental area on acquisition and expression of morphine-induced conditioned place preference in the rats

The orexins are hypothalamic neuropeptides and their role in reward processing and drug addiction has been demonstrated. The extent of involvement of each orexin receptor in the acquisition and expression of conditioned place preference (CPP) for morphine is still a matter of controversy. We investigated the functional differences between orexin-1 and -2 receptor blockade in the ventral tegmental area (VTA) on the acquisition and expression of morphine CPP. A total of 86 adult male Wistar rats weighing 250±30g (age 7–8weeks) received intra-VTA microinjection of either SB334867 (0.1, 1 and 10nM), a selective orexin-1 receptor (OX1R) antagonist, or TCS-OX2-29 (1, 5 and 25nM), a selective orexin-2 receptor (OX2R) antagonist. To measure the acquisition, the animals received each antagonist (SB334867 or TCS-OX2-29) 5min prior to subcutaneous injection of morphine (5mg/kg) during the conditioning phase. To measure the CPP expression, the animals received each antagonist on the post-conditioning phase. The CPP conditioning score was recorded by Ethovision software. Data showed that intra-VTA microinjection of OX1-R antagonist significantly attenuated morphine CPP acquisition, during the conditioning phase, and expression, during the post-conditioning phase. Intra-VTA microinjection of OX2-R antagonist also significantly attenuated morphine CPP acquisition and expression in the mentioned phases. Our results showed the orexin role in learning and memory and indicate that orexin receptors (OX1R and OX2R) function in the VTA is essential for both acquisition and expression of morphine reward in rats in the CPP model.

Opiate exposure state controls dopamine D3 receptor and cdk5/calcineurin signaling in the basolateral amygdala during reward and withdrawal aversion memory formation

The dopamine (DA) D3 receptor (D3R) is highly expressed in the basolateral nucleus of the amygdala (BLA), a neural region critical for processing opiate-related reward and withdrawal aversion-related memories. Functionally, D3R transmission is linked to downstream Cdk5 and calcineurin signaling, both of which regulate D3R activity states and play critical roles in memory-related synaptic plasticity. Previous evidence links D3R transmission to opiate-related memory processing, however little is known regarding how chronic opiate exposure may alter D3R-dependent memory mechanisms. Using conditioned place preference (CPP) and withdrawal aversion (conditioned place aversion; CPA) procedures in rats, combined with molecular analyses of BLA protein expression, we examined the effects of chronic opiate exposure on the functional role of intra-BLA D3R transmission during the acquisition of opiate reward or withdrawal aversion memories. Remarkably, we report that the state of opiate exposure during behavioural conditioning (opiate-naïve/non-dependent vs. chronically exposed and in withdrawal) controlled the functional role of intra-BLA D3R transmission during the acquisition of both opiate reward memories and withdrawal-aversion associative memories. Thus, whereas intra-BLA D3R blockade had no effect on opiate reward memory formation in the non-dependent state, blockade of intra-BLA D3R transmission prevented the formation of opiate reward and withdrawal aversion memory in the chronically exposed state. This switch in the functional role of D3R transmission corresponded to significant increases in Cdk5 phosphorylation and total expression levels of calcineurin, and a corresponding decrease in intra-BLA D3R expression. Inhibition of either intra-BLA Cdk5 or calcineurin reversed these effects, switching intra-BLA associative memory formation back to a D3R-independent mechanism.

Developmental changes in associative learning behavior in male rats

To identify the developmental point of onset of learning and memory function under an operant task, performance of young rats was examined on postnatal days (PDs) 16, 19, 22, 25 and 28, and then compared with that of adult rats (PD60). Each group of Long-Evans male rats with difference days of age was assigned to a series of fixed ratio (FR) operant tasks, in which the number of lever-pressing was required for acquisition of food reward. FR rate started from 1, changed into 2, and finished with 20. Each session conducted once a day, 7 sessions per week, lasted 30 min. Response rate (the number of lever-pressing per minute) and the number of session until animal acquired the learning acquisition criterion were measured. In FR20 learning task, performance of animals at PD32 showed the same shape as those of adult rats, showing an increase of response rate and a decrease of the number of sessions. The results indicated that memory and learning function of rats required for FR20 task might be matured at PD32. Results in the present study implied that the higher brain function used for the operant FR tasks mainly depended on the hippocampal development.

102. Enriched maternal care decreases opioid self-administration in adulthood and alters neuroimmune signaling in the nucleus accumbens

Despite decades of progress, the biological mechanisms underlying addiction are unknown. Glia, including astrocytes and microglia, profoundly influence neuronal function and may play a critical role in the development of drug addiction. Previously, we have shown that a neonatal handling procedure (which promotes enriched maternal care) reduces glial activation to an acute morphine challenge and prevents reinstatement of morphine conditioned place preference; likewise, similar results were obtained by pharmacological manipulation of glia within the nucleus accumbens (NAc). Here, we investigated the effects of opioid self-administration on central immune signaling within the NAc and its modulation by early-life experience. Male rat pups were handled (15 min/day) from postnatal day (P) 2 to P20 or left undisturbed. In adulthood, all rats were tested for self-administration of intravenous remifentanil (a short-acting opioid) in daily 1 h sessions for 2 weeks. Brains were then collected to examine persistent alterations in glial activation. Neonatal handling reduced acquisition of remifentanil; this effect was specific for opioids, as acquisition of food reward was unaffected. Remifentanil self-administration substantially increased glial antigen expression (Iba1 and GFAP) and proinflammatory gene expression in NAc, including the innate immune receptor TLR4. However, only handled rats showed increased expression of the anti-inflammatory cytokine IL-10. These data establish neural–glial interactions in the NAc as an essential component of self-motivated drug acquisition that can be altered by early-life environmental conditions.

Vigor of Movements and the Cost of Time in Decision Making

If we assume that the purpose of a movement is to acquire a rewarding state, the duration of the movement carries a cost because it delays acquisition of reward. For some people, passage of time carries a greater cost, as evidenced by how long they are willing to wait for a rewarding outcome. These steep discounters are considered impulsive. Is there a relationship between cost of time in decision making and cost of time in control of movements? Our theory predicts that people who are more impulsive should in general move faster than subjects who are less impulsive. To test our idea, we considered elementary voluntary movements: saccades of the eye. We found that in humans, saccadic vigor, assessed using velocity as a function of amplitude, was as much as 50% greater in one subject than another; that is, some people consistently moved their eyes with high vigor. We measured the cost of time in a decision-making task in which the same subjects were given a choice between smaller odds of success immediately and better odds if they waited. We measured how long they were willing to wait to obtain the better odds and how much they increased their wait period after they failed. We found that people that exhibited greater vigor in their movements tended to have a steep temporal discount function, as evidenced by their waiting patterns in the decision-making task. The cost of time may be shared between decision making and motor control.

Reward Contexts Extend Dopamine Signals to Unrewarded Stimuli

SummaryBasic tenets of sensory processing emphasize the importance of accurate identification and discrimination of environmental objects [1]. Although this principle holds also for reward, the crucial acquisition of reward for survival would be aided by the capacity to detect objects whose rewarding properties may not be immediately apparent. Animal learning theory conceptualizes how unrewarded stimuli induce behavioral reactions in rewarded contexts due to pseudoconditioning and higher-order context conditioning [2, 3, 4, 5, 6]. We hypothesized that the underlying mechanisms may involve context-sensitive reward neurons. We studied short-latency activations of dopamine neurons to unrewarded, physically salient stimuli while systematically changing reward context. Dopamine neurons showed substantial activations to unrewarded stimuli and their conditioned stimuli in highly rewarded contexts. The activations decreased and often disappeared entirely with stepwise separation from rewarded contexts. The influence of reward context suggests that dopamine neurons respond to real and potential reward. The influence of reward context is compatible with the reward nature of phasic dopamine responses. The responses may facilitate rapid, default initiation of behavioral reactions in environments usually containing reward. Agents would encounter more and miss less reward, resulting in survival advantage and enhanced evolutionary fitness.

Medial prefrontal cortex inactivation attenuates the diurnal rhythm in amphetamine reward

Psychostimulant reward, as assessed via the conditioned place preference (CPP) paradigm, exhibits a daily rhythm with peaks in the late dark and early light periods, and a nadir near the light-to-dark transition. While this diurnal rhythm is correlated with neural activity in several corticolimbic structures, the brain regions mediating this behavioral rhythm remain unknown. Here, we examine the role of the ventral medial prefrontal cortex (mPFC). The effects of excitotoxic mPFC lesions on daily rhythms in amphetamine CPP were examined at previously observed peak (zeitgeber time [ZT] 23) and nadir times (ZT11). mPFC lesions encompassing the prelimbic and infralimbic subregions increased the CPP for amphetamine at the nadir time, thereby eliminating the daily rhythm in amphetamine reward. To examine the effects of transient mPFC inactivation, rats received intra-mPFC infusions of GABA receptor agonists during the acquisition or expression phases of CPP testing. Inactivation of the ventral mPFC at either of these phases also eliminated the daily rhythm in amphetamine-induced CPP via an increase in drug-paired chamber dwell time at the baseline nadir. Together, these results indicate that the ventral mPFC plays a critical role in mediating the diurnal rhythm in amphetamine CPP during both the acquisition and expression of learned reward–context associations. Moreover, as the loss of rhythmicity occurs via an increase at the nadir point, these results suggest that excitatory output from the ventral mPFC normally inhibits context-elicited reward seeking prior to the light-to-dark transition.

Cocaine self-administration in rats lacking a functional trpc4 gene

The canonical transient receptor potential (TRPC) family of Ca 2+ permeable, non-selective cation channels is abundantly expressed throughout the brain, and plays a pivotal role in modulating cellular excitability. Unlike other TRPC channels, TRPC4 subtype expression in the adult rodent brain is restricted to a network of structures that receive dopaminergic innervation, suggesting an association with motivation- and reward-related behaviors. We hypothesized that these channels may play a critical role in dopamine-dependent drug-seeking behaviors. Here, we gathered data testing trpc4 knockout (KO) rats and wild-type (WT) littermates in the acquisition of a natural sucrose reward (10 days), and cocaine self-administration (13 days) at 0.5 mg/kg/infusion. Rats lacking the trpc4 gene ( trpc4-KO) learned to lever press for sucrose to a similar degree as their WT controls. However, when they were switched to cocaine, the trpc4-KO rats had substantially reduced cocaine-paired lever pressing compared to WT controls. No obvious group differences in inactive lever pressing were observed, for any time, during cocaine self-administration.