Acquisition Of Preference Research Articles

Inhibitory effects of forced swim stress and corticosterone on the acquisition but not expression of morphine-induced conditioned place preference: Involvement of glucocorticoid receptor in the basolateral amygdala

Addiction is a common chronic psychiatric disease which represents a global problem and stress has an important role to increase drug addiction and relapse. In the present study, we investigated the effects of physical stress and exogenous corticosterone on the acquisition and expression of morphine-induced conditioned place preference (CPP). Also, we tried to find out the role of glucocorticoid receptors (GRs) of basolateral amygdala (BLA) in this regard. In the CPP paradigm, conditioning score and locomotion activity were recorded by Ethovision software. Male adult rats received forced swim stress (FSS) as a physical stress or corticosterone (10mg/kg; ip) as a dominant stress hormone in rodents, 10min before morphine injection (5mg/kg; sc) during three conditioning days (acquisition) or just prior to CPP test in the post-conditioning day (expression). In FSS procedure, animals were forced to swim for 6min in cylinder filled with water (24–27°C). To evaluate the role of glucocorticoid receptors in the BLA, different doses of mifepristone (RU38486) as a GR antagonist were injected into the BLA (0.3, 3 and 30ng/side) during 3-day conditioning phase before FSS or injection of corticosterone in morphine-CPP paradigm. The results showed that FSS and corticosterone reduce the acquisition but not expression of morphine-induced CPP. Moreover, blockade of GRs in the BLA could diminish the inhibitory effects of FSS or corticosterone on the acquisition of morphine-induced CPP. It seems that stress exerts its effect on reward pathway via glucocorticoid receptors in the BLA.

Involvement of 5-hydroxytryptamine 5-HT3 serotonergic receptors in the acquisition and reinstatement of the conditioned place preference induced by MDMA

Some MDMA (3,4-methylenedioxymethamphetamine) users develop dependence as a result of chronic consumption. The present study evaluated the role of 5-hydroxytryptamine 5-HT3 receptors in the acquisition, expression and reinstatement of the conditioned place preference (CPP) induced by MDMA. Adolescent male mice were conditioned with 10mg/kg of MDMA and then treated with 1 or 3mg/kg of the 5-hydroxytryptamine 5-HT3 antagonist MDL72222 during acquisition of conditioning (experiment 1), before expression of CPP in a post-conditioning test (experiment 2) or before a reinstatement test (experiment 3). MDL72222 was devoid of motivational effects but blocked acquisition of the MDMA-induced CPP. Moreover, following extinction, the low dose of MDL72222 blocked reinstatement of the CPP induced by priming with MDMA. Acute MDMA reduced levels of dihydroxypheylacetic acid (DOPAC) in the striatum and levels of acid 5-hydroxyindoleacetic (5-HIAA) in the cortex. Acute MDMA+MDL72222 also reduced striatal DOPAC. The repeated co-administration of MDMA plus MDL72222 (on PND 32–34–36–38) increased dopamine and decreased DOPAC in the striatum, and increased cortical serotonin and enhanced transporters of dopamine and serotonin. The acute administration (on PND ±55) of MDMA or MDL72222 increased levels of dopamine and reduced those of DOPAC in the striatum and co-administration of MDMA plus MDL72222 increased striatal serotonin. Our results confirm that 5-hydroxytryptamine 5-HT3 receptors are involved in the acquisition of conditioned rewarding effects of MDMA and demonstrate that these receptors are also involved in reinstatement after extinction.

Effects of inactivating the agranular or granular insular cortex on the acquisition of the morphine-induced conditioned place preference and naloxone-precipitated conditioned place aversion in rats

Recent studies have indicated that the insula underlies affective learning. Although affective learning is well-established in the development of opiate addiction, the role of insula in this context remains unclear. To elucidate the organization of opiate-related affective learning within the insular cortex, we reversibly inactivated each of two major subdivisions of the insula in rats and tested the effects of this inactivation on the acquisition of morphine-induced conditioned place preference (CPP) and conditioned place aversion (CPA) induced by naloxone-precipitated acute morphine withdrawal. Results showed that inactivation of the primary interoceptive posterior granular insula (GI), but not that of the high-order anterior agranular insula (AI), disrupted the acquisition of CPP and that both GI and AI inactivation impaired the acquisition of CPA. These data suggest that the insular cortex is involved in positive and negative affective learning related to opiate addiction. In particular, the GI appears to be critical for both forms of affective learning, whereas the AI is crucial for learning associated with negative affects induced by opiate withdrawal.

Glycogen synthase kinase-3β in the ventral tegmental area mediates diurnal variations in cocaine-induced conditioned place preference in rats

Cocaine sensitization and reward are reported to be under the influence of diurnal rhythm. However, no previous studies have reported brain areas that play a role as modulators and underlie the mechanism of diurnal variations in cocaine reward. We examined (1) the diurnal rhythm of glycogen synthase kinase-3β (GSK-3β) activity in the suprachiasmatic nucleus (SCN) and reward-related brain areas in naive rats; (2) the effect of day and night on the acquisition of cocaine-induced conditioned place preference (CPP); (3) the influence of cocaine-induced CPP on GSK-3β activity in the SCN and reward-related brain areas; and (4) the effect of the GSK-3β inhibitor SB216763 microinjected bilaterally into the ventral tegmental area (VTA) on cocaine-induced CPP. A significant diurnal rhythm of GSK-3β activity was found in the SCN and reward-related brain areas, with diurnal variations in cocaine-induced CPP. GSK-3β activity in the SCN and reward-related brain areas exhibited marked diurnal variations in rats treated with saline. GSK-3β activity in rats treated with cocaine exhibited distinct diurnal variations only in the prefrontal cortex and VTA. Cocaine decreased the expression of phosphorylated GSK-3β (i.e. increased GSK-3β activity) only in the VTA in rats trained and tested at ZT4 and ZT16. SB216763 microinjected into the VTA bilaterally eliminated the diurnal variations in cocaine-induced CPP, but did not affect the acquisition of cocaine-induced CPP. These findings suggest that the VTA may be a critical area involved in the diurnal variations in cocaine-induced CPP, and GSK-3β may be a regulator of diurnal variations in cocaine-induced CPP.

Roles of levo-tetrahydropalmatine in modulating methamphetamine reward behavior

Levo-tetrahydropalmatine (l-THP), as an alkaloid purified from the traditional Chinese herbal medicine Corydalis and Stephania, has been widely used to produce many traditional Chinese herbal preparations. The effect of l-THP on methamphetamine-induced reward learning still remains unclear although it has been proved to be effective on treating allodynia and drug addiction. This experiment has been designed to examine the effect of l-THP on the acquisition, expression, extinction, and reinstatement of methamphetamine-induced conditioned place preference (CPP) in mice. The results show that methamphetamine (METH) could induce CPP in mice at doses of 0.5mg/kg, 1.0mg/kg and 2.0mg/kg respectively, but l-THP alone could not do so. Meanwhile, l-THP could not induce conditioned place aversion at doses of 1.25mg/kg to 20.0mg/kg in mice, but it could attenuate the acquisition and expression of METH-induced CPP and facilitate the extinction of METH-induced CPP in mice. Besides, l-THP could inhibit the reinstatement of METH-induced CPP at the dose of 10.0mg/kg whether it was given in the extinction training phase or 30min before the reinstatement. These results suggest that l-THP can globally suppress the rewarding properties of METH on all phases of the CPP task and it may have potential effects on the treatment of METH abuse.

Postweaning maternal food provisioning in a bat with a complex hunting strategy

Adult animals of many taxa exhibit extended parental care by transferring food to inexperienced offspring, thus allocating nutritional and sometimes even informational benefits such as the acquisition of adult dietary preferences and foraging skills. In bats, postweaning food provisioning is severely understudied, despite the taxon's diverse and complex foraging strategies. The Neotropical common big-eared bat, Micronycteris microtis, preys on relatively large insects gleaned from vegetation, finding its silent and motionless prey by echolocation. The demands of this cognitively challenging hunting strategy make M. microtis a likely candidate for maternal postweaning food provisioning. We studied five free-living mother–pup pairs in their night roost using infrared video recordings. Each mother exclusively fed her own pup and mother–pup recognition was mutual. Provisioned pups were volant and had started their own hunting attempts. Weaned pups were provisioned for 5 subsequent months with a variety of insects, reflecting the adult diet. Mothers transferred over 50% of their prey to pups. Maternal prey transfers declined as pups matured, whereas the pups' own prey captures increased. During prey transfers, aggressive behaviour between mothers and pups was rare. We argue that postweaning maternal food provisioning might yield two informational benefits for M. microtis pups. First, learning how to handle large and well-defended prey is mandatory for inexperienced pups and could be practised with prey items provided by their mothers. Second, acoustically characteristic echo images of prey items could be gained during mother–pup prey transfers, probably facilitating the successful acquisition of M. microtis's complex hunting strategy.

Acetylcholinesterase inhibitors attenuate the acquisition and reinstatement of morphine-induced conditioned place preference

Acetylcholinesterase inhibitors attenuate the acquisition and reinstatement of morphine-induced conditioned place preference

Region-specific expression of brain-derived neurotrophic factor splice variants in morphine conditioned place preference in mice

It is well established that brain-derived neurotrophic factor (BDNF) plays a pivotal role in brain plasticity-related processes, such as learning, memory and drug addiction. However, changes in expression of BDNF splice variants after acquisition, extinction and reinstatement of cue-elicited morphine seeking behavior have not yet been investigated. Real-time PCR was used to assess BDNF splice variants (I, II, IV and VI) in various brain regions during acquisition, extinction and reinstatement of morphine-conditioned place preference (CPP) in mice. Repeated morphine injections (10mg/kg, i.p.) increased expression of BDNF splice variants II, IV and VI in the hippocampus, caudate putamen (CPu) and nucleus accumbens (NAcc). Levels of BDNF splice variants decreased after extinction training and continued to decrease during reinstatement induced by a morphine priming injection (10mg/kg, i.p.). However, after reinstatement induced by exposure to 6min of forced swimming (FS), expression of BDNF splice variants II, IV and VI was increased in the hippocampus, CPu, NAcc and prefrontal cortex (PFC). After reinstatement induced by 40min of restraint, expression of BDNF splice variants was increased in PFC. These results show that exposure to either morphine or acute stress can induce reinstatement of drug-seeking, but expression of BDNF splice variants is differentially affected by chronic morphine and acute stress. Furthermore, BDNF splice variants II, IV and VI may play a role in learning and memory for morphine addiction in the hippocampus, CPu and NAcc.

HDAC3 Is a Negative Regulator of Cocaine-Context-Associated Memory Formation

Cocaine-induced neuroplasticity mediated by histone acetylating and deacetylating enzymes may contribute to addiction-like behaviors. For example, overexpression of histone deacetylases (HDACs) 4 or 5 in the nucleus accumbens suppresses cocaine-induced conditioned place preference (CPP) acquisition in mice. HDAC4 and HDAC5 are known to interact with HDAC3, but the role of HDAC3 in cocaine-induced behaviors has never been examined. In this study, we address the hypothesis that HDAC3 is a negative regulator of cocaine-context-associated memory formation in mice. We examined the role of HDAC3 during the conditioning phase of CPP, when the mouse has the opportunity to form an associative memory between the cocaine-paired context and the subjective effects of cocaine. To address this hypothesis, Hdac3(flox/flox) and Hdac3(+/+) mice (generated from a C57BL/6 background) were infused into the nucleus accumbens with adeno-associated virus expressing Cre recombinase to create focal, homozygous Hdac3 deletions. Hdac3(flox/flox) mice exhibit significantly enhanced CPP acquisition, which is correlated with increased gene expression during the consolidation phase of acquisition. Increased gene expression of c-Fos and Nr4a2 is correlated with decreased HDAC3 occupancy and increased histone H4 lysine 8 acetylation at their promoters. The results from this study demonstrate that HDAC3 negatively regulates cocaine-induced CPP acquisition.

Potentiation of rewarding properties of morphine by concurrent chemical stimulation of lateral hypothalamus in rats

Orexinergic projections from the lateral hypothalamus (LH) have an important role in acquisition of morphine conditioned place preference (CPP). However, little is known about the functional interaction between orexinergic and opioidergic systems in the reward circuitry in the rats. In the present study, we investigated the effects of different doses of carbachol, for chemical stimulation of LH, on rewarding properties of morphine in the rats. 132 adult male albino Wistar rats weighing 220–320g were unilaterally implanted by a cannula into the LH. The CPP paradigm was done; conditioning score and locomotor activity were recorded by Ethovision software. In this paradigm, we used different doses of carbachol (31.25, 62.5, 125 and 250nmol/0.5μl saline), as a cholinergic agonist, in the LH. In the next set of experiment, we concurrently administered the ineffective doses of carbachol (31.25 and 62.5nmol) and morphine (1mg/kg; a dose that produced no appreciable effect when given alone) during 3-day conditioning (Acquisition) and post-conditioning (Expression) phases. Our results showed that unilateral intra-LH administration of both ineffective doses of carbachol during conditioning phase significantly (P<0.01) potentiated the development of CPP by morphine (1mg/kg). However, in the expression experiments, only dose of 62.5nmol/rat carbachol could induce morphine-CPP (P<0.05). Our findings suggest that a chemical stimulation of LH in sub-threshold condition could potentiate rewarding properties of morphine through mechanisms involved in alteration of dopamine release or morphine sensitization at the level of nucleus accumbens and/or ventral tegmental area by orexin receptors in the rats.

The Receptor Guanylyl Cyclase Type D (GC-D) Ligand Uroguanylin Promotes the Acquisition of Food Preferences in Mice

Rodents rely on olfactory stimuli to communicate information between conspecifics that is critical for health and survival. For example, rodents that detect a food odor simultaneously with the social odor carbon disulfide (CS(2)) will acquire a preference for that food. Disruption of the chemosensory transduction cascade in CS(2-)sensitive olfactory sensory neurons (OSNs) that express the receptor guanylyl cyclase type D (GC-D; GC-D+ OSNs) will prevent mice from acquiring these preferences. GC-D+ OSNs also respond to the natriuretic peptide uroguanylin, which is excreted into urine and feces. We analyzed if uroguanylin could also act as a social stimulus to promote the acquisition of food preferences. We found that feces of mice that had eaten odored food, but not unodored food, promoted a strong preference for that food in mice exposed to the feces. Olfactory exploration of uroguanylin presented with a food odor similarly produced a preference that was absent when mice were exposed to the food odor alone. Finally, the acquisition of this preference was dependent on GC-D+ OSNs, as mice lacking GC-D (Gucy2d(-)(/-) mice) showed no preference for the demonstrated food. Together with our previous findings, these results demonstrate that the diverse activators of GC-D+ OSNs elicit a common behavioral result and suggest that this specialized olfactory subsystem acts as a labeled line for a type of associative olfactory learning.

Withania somnifera prevents acquisition and expression of morphine-elicited conditioned place preference

Previous studies have reported that some of the central effects of morphine are counteracted by the administration of the methanolic extract of the root of Indian ginseng, Withania somnifera Dunal (WSE). The present study sought to determine whether WSE affects acquisition and expression of morphine-elicited conditioned place preference (CPP) in CD-1 mice. In CPP acquisition experiments, WSE (0, 25, 50, and 100 mg/kg) was administered, during conditioning, 30 min before morphine (10 mg/kg), whereas in expression experiments, WSE (0, 25, 50, and 100 mg/kg) was administered 30 min before the postconditioning test. The results demonstrate (i) that WSE was devoid of motivational properties; (ii) that WSE (100 mg/kg) was devoid of effects on spontaneous and morphine-stimulated motor activity and on spatial memory; and (iii) that WSE (50 and 100 mg/kg) significantly prevented the acquisition and expression of CPP. Further, to characterize the receptor(s) involved in these effects, we studied, by receptor-binding assay, the affinity of WSE for µ-opioid and γ-aminobutyric acid B receptors. These experiments revealed a higher affinity of WSE for γ-aminobutyric acid B than for µ-opioid receptors. Overall, these results point to WSE as an interesting alternative tool, worthy of further investigation, to study opiate addiction.

Agmatine attenuates acquisition but not the expression of ethanol conditioned place preference in mice

The present study investigated the effect of agmatine on acquisition and expression of ethanol conditioned place preference (CPP) and its modulation by imidazoline agents. Swiss albino mice were treated intraperitoneally with saline or agmatine (20-40 mg/kg) before injection of ethanol (1.25 mg/kg) during conditioning days or on a test day (20-120 mg/kg), to observe the effect on acquisition or expression of CPP, respectively. Agmatine inhibited the acquisition but not the expression of ethanol CPP. Furthermore, both the I₁ receptor antagonist, efaroxan (9 mg/kg) and the I₂ receptor antagonist, BU224 (5 mg/kg) attenuated the agmatine-induced inhibition of the ethanol CPP acquisition. In contrast, the I₂ receptor agonist, 2-BFI (5 mg/kg) and I₁ receptor agonist, moxonidine (0.4 mg/kg) alone, or a combination of their subeffective doses, significantly attenuated the effect of agmatine (20 mg/kg) on acquisition of ethanol CPP. Agmatine or imidazoline agents alone produced neither place preference nor aversion, and at the doses used in the present study did not affect locomotor activity. Thus, agmatine attenuates the acquisition of ethanol CPP at least in part by imidazoline (I₁ or I₂) receptors. In future studies, agmatine or agents acting at the imidazoline receptors could be explored for their therapeutic potential in ethanol dependence.

Streptozotocin-induced diabetes affects the development and maintenance of morphine reward in rats

Diabetes mellitus is a chronic illness that has been associated with the decrease of insulin in type I diabetes. Insulin has an impact not only on the direct control of food intake and plasma glucose levels, but also on brain pathways associated with reward. It affects brain reward pathways through regulation of the dopamine (DA) transporter (DAT). Moreover, it has been found to affect the ability of drugs that target the DA system. In the present study, the effects of streptozotocin (STZ)-induced diabetes on the acquisition (development) and maintenance of morphine-induced conditioned place preference (CPP) were investigated in rats. Forty adult male Albino Wistar rats were used in these experiments. For induction of diabetes, STZ was administered at a dose of 60mg/kg. After seven days, the CPP paradigm was done; conditioning score and locomotor activity were recorded by Ethovision software. The results showed that diabetes significantly increased the magnitude of conditioning scores, acquisition of morphine-induced CPP in compared to naive animals (P<0.05). Moreover, in the diabetic group, there were significant differences among conditioning scores in the post-conditioning phase and the last four days (7th–10th), but these differences elongated up to 10 days after the CPP protocol while the extinction period was eight days in the naive group. Our findings indicated that the magnitude and maintenance of morphine rewarding properties have been changed in STZ-induced diabetic animals. It seems that a level of insulin and their receptors are involved in the development and maintenance of morphine-induced CPP in the rats.

Role of intra-accumbal cannabinoid CB1 receptors in the potentiation, acquisition and expression of morphine-induced conditioned place preference

Recent studies demonstrate a functional interaction between opioid and endogenous cannabinoid system. These two systems possess similar pharmacological effects on drug addiction and reward. The present study was designed to investigate the role of intra-accumbal cannabinoid CB1 receptors in the acquisition and expression of morphine-induced conditioned place preference (CPP). Two-hundred forty eight adult male albino Wistar rats were used in these experiments. Using a 3-day schedule of conditioning, it was found that subcutaneous administration of morphine (0.2–10mg/kg) induced CPP at the doses of 5 and 10mg/kg. Solely intra-accumbal administration of WIN55,212-2 (1, 2 and 4mmol/0.5μl DMSO) as CB1 receptor agonist could induce CPP. Also, our results showed that ineffective dose of WIN55,212-2 (1mmol) when administered before the ineffective dose of morphine (2mg/kg) could induce the CPP and potentiate the rewarding effect of morphine. On the other hand, intra-accumbal injection of the cannabinoid CB1 receptor antagonist AM251 (90μmol/0.5μl DMSO) alone induced a significant conditioned place aversion. Moreover, intra-NAc injection of AM251 (45 and 90μmol/0.5μl DMSO) inhibited morphine-induced CPP. Interestingly, injection of WIN55,212-2 (1, 2 and 4mmol) or AM251 (15, 45 and 90μmol) into the NAc had no effect on the expression of morphine (5mg/kg)-induced CPP. These observations provide evidence that cannabinoid CB1 receptors in the NAc are involved in development of reward-related behaviors and they can potentiate the rewarding effects of morphine. It seems that these receptors can affect the reward modulatory system at the level of nucleus accumbens in rats.

Involvement of CB1 receptors in the ventral tegmental area in the potentiation of morphine rewarding properties in acquisition but not expression in the conditioned place preference model

The ventral tegmental area (VTA) is a critical part of the brain reward system and has been engaged in mediating rewarding actions. CB1 receptors are one of the receptors that mediate the actions of cannabinoids and endocannabinoids in the central nervous system. Our aim was to determine the potentiating effects of CB1 receptors within the VTA in the acquisition and expression of morphine conditioned place preference (CPP). Stereotaxic surgery was performed bilaterally on each rat to administrate WIN55,212-2 (1, 2 and 4mmol/0.3μl DMSO) as CB1 receptor agonist and AM251 (15, 45 and 90mmol/0.3μl DMSO) as CB1 receptor antagonist. A three-compartment apparatus was used for the CPP test. The results showed that two doses of WIN55,212-2 (2 and 4mmol) potentiates the rewarding effects of ineffective dose of morphine (2mg/kg). We did not see any significant difference between any other doses of WIN55,212-2 and vehicle in the group which received the effective dose of morphine (5mg/kg). Additionally, conditioning scores decreased significantly with the highest administrated dose of AM251 (90mmol) compared to the vehicle group. We did not observe any significant differences in the experiments for CPP expression by WIN55,212-2 or AM251. It seems that the cannabinoid and opioid systems are in interaction with each other and affect dopaminergic and/or non-dopaminergic neurons in the VTA. Blockade of CB1 receptors may increase GABA release, resulting in the reduction of dopamine output followed by a decrease in the acquisition of morphine-induced CPP in rats.

Effects of CCK-8 on the reinstatement of morphine-induced CPP and expression of behavioral sensitization in rats

Cholecystokinin octapeptide (CCK-8), a neuropeptide, plays an important role in morphine dependence and several addictive behaviors. We have previously reported that CCK-8 attenuates the acquisition of morphine-induced conditioned place preference (CPP), but the possible functions of CCK-8 on drug relapse remain unclear. Here we evaluated the effects of CCK-8 on the reinstatement of extinguished morphine-induced CPP and behavioral sensitization. A single injection of 0.1 and 1μg CCK-8 (i.c.v.) significantly attenuated both drug- (morphine) and stress- (foot shock) primed reinstatement of CPP and reduced the escalated locomotor activity in reinstatement tests. Additionally, CCK-8 blocked the expression of morphine-induced behavioral sensitization. However, administration of CCK-8 (0.01, 0.1 and 1μg) alone to morphine-pretreated rats could not trigger reinstatement of CPP and had no significant effect on threshold sensitivity to foot shock. In conclusion, our study identifies a distinct inhibitory effect of CCK-8 on the reinstatement of drug-seeking behavior and provides a potential application to the medication of drug relapse.

The histone deacetylase inhibitor sodium butyrate modulates acquisition and extinction of cocaine-induced conditioned place preference

Despite decades of research on treatments for cocaine dependence, relapse rates following many behavioral and drug-based therapies remain high. This may be in part because cocaine-associated cues and contexts can invoke powerful drug cravings years after quitting. Recent studies suggest that drugs that promote cognitive function can enhance the formation of memories involving cocaine and other substances. One target of these drugs is facilitating histone acetylation to promote learning by increasing gene transcription that supports memory formation. Here, we investigate the effects of the histone deacetylase (HDAC) inhibitor sodium butyrate (NaBut) on cocaine-induced conditioned place preference (CPP) in C57BL/6 mice. After establishing a graded dose–response curve (2, 5, & 20mg/kg) for cocaine-induced CPP, we examined the effects of different doses of NaBut (0, 0.3, 0.6, & 1.2g/kg) on conditioning, extinction, and post-extinction reconditioning of CPP. A high dose of NaBut (1.2g/kg) enhanced initial acquisition of cocaine CPP, but there were no effects of NaBut on reconditioning of extinguished CPP. Effects of NaBut on extinction were more complex, with a low-dose (0.3g/kg) facilitating extinction and a high dose (1.2g/kg) weakening extinction evident by preference at a retention test. These findings suggest that HDAC inhibition may have dose dependent effects on different components of cocaine CPP, with implications for (1) involvement of histone acetylation in context-drug learning, (2) interpretation of acute and chronic drug effects, and (3) the targeting of different types of learning in therapeutic application of HDAC inhibitors.

Metabotropic Glutamate Receptor I (mGluR1) Antagonism Impairs Cocaine-Induced Conditioned Place Preference via Inhibition of Protein Synthesis

Antagonism of group I metabotropic glutamate receptors (mGluR1 and mGluR5) reduces behavioral effects of drugs of abuse, including cocaine. However, the underlying mechanisms remain poorly understood. Activation of mGluR5 increases protein synthesis at synapses. Although mGluR5-induced excessive protein synthesis has been implicated in the pathology of fragile X syndrome, it remains unknown whether group I mGluR-mediated protein synthesis is involved in any behavioral effects of drugs of abuse. We report that group I mGluR agonist DHPG induced more pronounced initial depression of inhibitory postsynaptic currents (IPSCs) followed by modest long-term depression (I-LTD) in dopamine neurons of rat ventral tegmental area (VTA) through the activation of mGluR1. The early component of DHPG-induced depression of IPSCs was mediated by the cannabinoid CB1 receptors, while DHPG-induced I-LTD was dependent on protein synthesis. Western blotting analysis indicates that mGluR1 was coupled to extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin (mTOR) signaling pathways to increase translation. We also show that cocaine conditioning activated translation machinery in the VTA via an mGluR1-dependent mechanism. Furthermore, intra-VTA microinjections of mGluR1 antagonist JNJ16259685 and protein synthesis inhibitor cycloheximide significantly attenuated or blocked the acquisition of cocaine-induced conditioned place preference (CPP) and activation of translation elongation factors. Taken together, these results suggest that mGluR1 antagonism inhibits de novo protein synthesis; this effect may block the formation of cocaine-cue associations and thus provide a mechanism for the reduction in CPP to cocaine.

Assessing Anxiety and Reward-Related Behaviors Following Alcohol Administration or Chronic Stress

Dysregulation of stress- and reward-related neurocircuitry that results from experience with alcohol or chronic stress may underlie vulnerability to initiate or relapse to alcohol use. Related changes in behaviors associated with such dysregulation may provide insight into factors that increase or decrease vulnerability to alcohol dependence in humans. In the present study, anxiety-like behavior and the acquisition of conditioned place preference were assessed in male Wistar rats with differing histories of exposure to stress or alcohol two weeks following the termination of treatment. Thus, time spent on the open arms of the elevated plus maze as well as the number of days required to acquire alcohol-based place conditioning were evaluated in control animals vs. those with a history of exposure to chronic unpredictable stress, experimenter-administered intragastric alcohol, or selfadministered alcohol liquid diet. Exposure to chronic unpredictable stress decreased open arm exploration on the elevated plus maze while no difference in open arm exploration was observed between the control group and alcohol-administration groups. However, animals with a history of intragastric ethanol administration or chronic unpredictable stress acquired alcohol-based placed conditioning after 3 alcohol-context pairings while control animals and animals with a history of alcohol self-administration required 4 alcohol-context pairings to acquire a significant preference for the alcohol-paired compartment. Results reveal that 1) a history of alcohol contributes to the acquisition of conditioned place preference but is dependent on the administration regimen and 2) chronic unpredictable stress enhances the acquisition of alcohol-based conditioned place preference and produces anxiogenic performance. These findings suggest overlap in the neuroadaptive changes that result from chronic exposure to alcohol or stress which may contribute to vulnerability to alcohol use.