Place Conditioning Procedure Research Articles

Robust aversive effects of trace amine-associated receptor 1 activation in mice.

Drugs that stimulate the trace amine-associated receptor 1 (TAAR1) are under clinical investigation as treatments for several neuropsychiatric disorders. Previous studies in a genetic mouse model of voluntary methamphetamine intake identified TAAR1, expressed by the Taar1 gene, as a critical mediator of aversive methamphetamine effects. Methamphetamine is a TAAR1 agonist, but also has actions at monoamine transporters. Whether exclusive activation of TAAR1 has aversive effects was not known at the time we conducted our studies. Mice were tested for aversive effects of the selective TAAR1 agonist, RO5256390, using taste and place conditioning procedures. Hypothermic and locomotor effects were also examined, based on prior evidence of TAAR1 mediation. Male and female mice of several genetic models were used, including lines selectively bred for high and low methamphetamine drinking, a knock-in line in which a mutant form of Taar1 that codes for a non-functional TAAR1 was replaced by the reference Taar1 allele that codes for functional TAAR1, and their matched control line. RO5256390 had robust aversive, hypothermic and locomotor suppressing effects that were found only in mice with functional TAAR1. Knock-in of the reference Taar1 allele rescued these phenotypes in a genetic model that normally lacks TAAR1 function. Our study provides important data on TAAR1 function in aversive, locomotor, and thermoregulatory effects that are important to consider when developing TAAR1 agonists as therapeutic drugs. Because other drugs can have similar consequences, potential additive effects should be carefully considered as these treatment agents are being developed.

Alcohol-specific transcriptional dynamics of memory reconsolidation and relapse

Relapse, a critical issue in alcohol addiction, can be attenuated by disruption of alcohol-associated memories. Memories are thought to temporarily destabilize upon retrieval during the reconsolidation process. Here, we provide evidence for unique transcriptional dynamics underpinning alcohol memory reconsolidation. Using a mouse place-conditioning procedure, we show that alcohol-memory retrieval increases the mRNA expression of immediate-early genes in the dorsal hippocampus and medial prefrontal cortex, and that alcohol seeking is abolished by post-retrieval non-specific inhibition of gene transcription, or by downregulating ARC expression using antisense-oligodeoxynucleotides. However, since retrieval of memories for a natural reward (sucrose) also increased the same immediate-early gene expression, we explored for alcohol-specific transcriptional changes using RNA-sequencing. We revealed a unique transcriptional fingerprint activated by alcohol memories, as the expression of this set of plasticity-related genes was not altered by sucrose-memory retrieval. Our results suggest that alcohol memories may activate two parallel transcription programs: one is involved in memory reconsolidation in general, and another is specifically activated during alcohol-memory processing.

Δ9-Tetrahydrocannabinol Vapor Exposure Produces Conditioned Place Preference in Male and Female Rats.

Background: The use of place conditioning procedures and drug vapor exposure models can increase our understanding of the rewarding and aversive effects of vaped cannabis products. Currently there are limited data on the conditioned rewarding effects of vaporized Δ9-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis in rats, and no studies to date examining sex differences. Methods: Male and female Sprague-Dawley rats (N=96; 12 per sex/group) underwent place conditioning sessions immediately after exposure to THC or vehicle (propylene glycol [PG]) vapor. Locomotor activity was measured by beam breaks during conditioning sessions. THC vapor-conditioned rats received one of three THC vapor exposure amounts (low: 5 puffs of 100 mg/mL THC, medium: 5 puffs of 200 mg/mL THC, or high: 10 puffs of 200 mg/mL THC) and matched vehicle vapor (PG) exposure on alternate days for 16 daily sessions. A "no THC" control group of vehicle-conditioned rats received only PG vapor exposure each day. After the 8th and 16th conditioning sessions, untreated rats were tested for conditioned place preference (CPP) or aversion (CPA). Next, extinction tests and a THC vapor-primed reinstatement test were conducted. Results: THC vapor produced CPP and locomotor effects in an exposure dependent manner, and some sex differences were observed. Low THC vapor exposure did not produce CPP in males or females. Medium THC vapor exposure produced CPP in males, but not females. High THC vapor exposure produced CPP in both males and females. Medium and high THC vapor exposure amounts produced hyperactivity in female rats, but not male rats. CPP was more resistant to extinction in females than males. THC vapor reexposure (i.e., drug-prime) after extinction did not result in reinstatement of CPP for either sex. Conclusion: This study demonstrates conditioned rewarding effects of THC vapor in both male and female rats and provides evidence for sex differences in amounts of THC vapor that produce CPP and in time to extinction. CPA was not observed at any of the THC vapor exposure amounts tested. These data provide a foundation for future exploration of the conditioned effects of cannabis constituents and extracts using vapor exposure models.

Pregestational oxycodone exposure does not impact future maternal care or drug preference in the postpartum mouse.

Females are uniquely sensitive to drugs of abuse at specific points in their reproductive cycle. Females' endogenous opioid system contributes to both reward-related processes and maternally relevant physiological functions, yet less is known about how adolescent opioid exposure impacts females' future behavior, ranging from parental caregiving to opioid preference. The present study explores 2 questions: (a) are there sex differences in response to adolescent oxycodone exposure, spontaneous withdrawal, and oxycodone preference in adulthood, and (b) to what extent does this pregestational opioid exposure alter females' future maternal caregiving behavior? Female and male mice received 12d of oxycodone or saline injections during mid/late adolescence, and drug was then withheld. Some females were then mated and experienced a drug-free pregnancy. Following parturition, females' maternal behavior and motivation were assessed. All mice then underwent a place conditioning procedure to assess the incentive value of oxycodone during adulthood. Mice displayed similar behavioral responses to oxycodone (e.g., sensitization) and patterns of withdrawal behaviors, independent of sex. Mice showed strong group preferences for the oxycodone-paired chamber, and the strength of these preferences did not differ by sex or maternal status. Postpartum females' maternal behavior and motivation were also similar despite adolescent drug history. Together, results did not suggest overt sex differences in response to adolescent oxycodone exposure and that, in females, a range of motivated behaviors may be relatively resilient to such perturbations during adolescence. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Cross-reinstatement of mitragynine and morphine place preference in rats

Kratom is a medicinal plant that exhibits promising results as an opiate substitute. However, there is little information regarding the abuse profile of its main psychoactive constituent, mitragynine (MG), particularly in relapse to drug abuse. Using the place conditioning procedure as a model of relapse, this study aims to evaluate the ability of MG to induce conditioned place preference (CPP) reinstatement in rats. To evaluate the cross-reinstatement effects, MG and morphine were injected to rats that previously extinguished a morphine- or MG-induced CPP. Following a CPP acquisition induced by either MG (10 and 30 mg/kg, i.p.) or morphine (10 mg/kg, i.p.), rats were subjected to repeated CPP extinction sessions. A low dose priming injection of MG or morphine produced a reinstatement of the previously extinguished CPP. In the second experiment of this study, a priming injection of morphine (1, 3 and 10 mg/kg, i.p.) dose-dependently reinstated an MG-induced CPP. Likewise, a priming injection of MG (3, 10 and 30 mg/kg, i.p.) was able to dose-dependently reinstate a morphine-induced CPP. The present study demonstrates a cross-reinstatement effect between MG and morphine, thereby suggesting a similar interaction in their rewarding motivational properties. The findings from this study also suggesting that a priming exposure to kratom and an opioid may cause relapse for a previously abused drug.

Morphine and ethanol pretreatment effects on expression and extinction of ethanol-induced conditioned place preference and aversion in mice.

Opioid receptor antagonists reliably alter the expression or extinction of ethanol's conditioned motivational effects as indexed by the place conditioning procedure, suggesting endogenous opioids are normally involved. These studies examined how exogenous stimulation of opioid receptors alters ethanol's conditioned rewarding and aversive effects. Drugs that either directly (morphine) or indirectly (ethanol) stimulate opioid receptors were tested for their effects on the expression and extinction of ethanol-induced conditioned place preference (CPP) and conditioned place aversion (CPA). Male DBA/2J mice were exposed to unbiased ethanol (2 g/kg) conditioning procedures that produced either CPP (experiments 1-2) or CPA (experiments 3-4). Morphine (0, 2.5, 5, or 10 mg/kg) was injected before three post-conditioning tests in experiments 1 and 3, whereas ethanol (0, 1, 2, or 3 g/kg) was injected before tests in experiments 2 and 4. All groups received vehicle on test 4 to determine whether the drug pretreatments altered the course of extinction. Morphine dose-dependently enhanced CPP expression (experiment 1), but ethanol dose-dependently reduced CPP expression (experiment 2). Test 4 showed no differences between drug-treated mice and mice given vehicle on all tests. Morphine had no effect on expression or extinction of ethanol-induced CPA (experiment 3). The highest ethanol dose (3 g/kg) interfered with CPA expression, but not extinction (experiment 4). Pretreatment drug effects on ethanol CPP and CPA expression were most likely a byproduct of their activity altering effects rather than opioid-receptor mediated modulation of ethanol's conditioned motivational effects. Neither drug affected the course of extinction.

Segregation of caffeine reward and aversion in the rat nucleus accumbens shell versus core.

Caffeine, the most commonly consumed psychoactive drug in the world, is readily available in dietary sources, including soft drinks, chocolate, tea and coffee. However, little is known about the neural substrates that underlie caffeine's rewarding and aversive properties and what ultimately leads us to seek or avoid caffeine consumption. Using male Wistar rats in a place conditioning procedure, we show that systemic caffeine at a low intraperitoneal dose of 2mg/kg (or 100µM injected directly into the rostral, but not caudal, portion of the ventral tegmental area) produced conditioned place preferences. By contrast, high doses of systemic caffeine at 10 and 30mg/kg produced conditioned place aversions. These aversions were not recapitulated by a caffeine analog restricted to the periphery. Both caffeine reward and aversion were blocked by systemic D1-like receptor antagonism using SCH23390, while systemic D2-like receptor antagonism with eticlopride had smaller effects on caffeine motivation. Most important, we demonstrated that pharmacological blockade of dopamine receptors using α-flupenthixol injected into the nucleus accumbens shell, but not core, blocked caffeine-conditioned place preferences. Conversely, α-flupenthixol injected into the nucleus accumbens core, but not shell, blocked caffeine-conditioned place aversions. Thus, our findings reveal two dopamine-dependent and functionally dissociable mechanisms for processing caffeine motivation, which are segregated between nucleus accumbens subregions. These data provide novel evidence for the roles of the nucleus accumbens subregions in mediating approach and avoidance behaviours for caffeine.

Genetic Relationships Between Ethanol-Induced Conditioned Place Aversion and Other Ethanol Phenotypes in 15 Inbred Mouse Strains.

The genetic relationships between different behaviors used to index the aversive effects of ethanol are unknown. To address this issue, ethanol-induced conditioned place aversion (CPA) was tested in a genetically diverse panel of 15 inbred mouse strains. Mice were exposed to an unbiased place conditioning procedure using ethanol doses of 0, 2, or 4 g/kg; all injections were given immediately after 5-min exposure to distinctive tactile cues. There were dose-dependent effects of ethanol on CPA and on the change in pre-injection activity rates between the first and last conditioning trials. Most strains (80%) developed CPA, demonstrating the generalizability of this behavior. Moreover, genotype had significant effects on CPA magnitude and locomotor activity rates. Strain means from this study and previously published studies were then used to examine genetic correlations. These analyses showed significant genetic correlations between CPA and ethanol intake/preference, conditioned taste aversion, and drug withdrawal (but not blood ethanol concentration or conditioned place preference), supporting the idea of commonality in the genes underlying CPA and each of these behaviors. The overall pattern of findings is consistent with previous data suggesting that genetic differences in sensitivity to ethanol’s aversive effects play a role in determining strain differences in ethanol drinking. The broader implication is that individuals who are more sensitive to the aversive effects of ethanol may be protected from developing the excessive drinking behaviors characteristic of alcohol use disorders.

Clonidine, an α2 adrenergic receptor agonist, disrupts reconsolidation of a cocaine-paired environmental memory.

Environmental cues can elicit robust cocaine reward memories, contributing to relapse to cocaine abuse. Memories can be manipulated pharmacologically by interfering with reconsolidation after reactivation. Clonidine, an α2 noradrenergic receptor agonist, was tested for its ability to block reconsolidation of cocaine environmental-paired memory. Male Sprague-Dawley rats completed an 8-day cocaine place conditioning procedure to establish a cocaine place preference. Cocaine memory was reactivated by exposure to the cocaine-paired environment in a drug-free state, followed immediately by administration of clonidine (10 or 50 µg/kg) or vehicle. Cocaine place preference was retested 24 h and 1 week later. Clonidine significantly attenuated the previously established cocaine place preference when tested 1 or 7 days later. To investigate the generalizability of this effect to other drug classes, morphine conditioned place preference was tested. Clonidine administration after morphine memory reactivation did not significantly alter the expression of morphine place preference. These results suggest that clonidine can interfere with reconsolidation of cocaine memory and may be a useful approach to reduce relapse.

Predator odor stress blunts alcohol conditioned aversion

Alcohol use disorder is highly co-morbid with traumatic stress disorders in humans, and dually diagnosed individuals cite negative affective symptoms as a primary reason for drinking alcohol. Therefore, it is reasonable to hypothesize that traumatic stress history increases the rewarding properties and/or blunts the aversive properties of alcohol. We used a place conditioning procedure to test the rewarding/aversive properties of alcohol in adult male Wistar rats with or without a traumatic stress (i.e., predator odor exposure) history, and with or without an alcohol drinking history. Because extended amygdala regions have documented roles in stress, reward, and stress-induced changes in reward, we also tested the effect of acute alcohol on CREB phosphorylation (pCREB) and striatal-enriched protein tyrosine phosphatase (STEP) expression in central amygdala (CeA) and bed nucleus of stria terminalis (BNST). Our results show that a moderate alcohol dose (1.0 g/kg) produces conditioned place aversion (CPA) that is blunted by stress history but is not affected by alcohol drinking history, and this effect differed in pair-housed versus single-housed rats. Stress history reduced pCREB expression in BNST of rats with and without an alcohol drinking history. Finally, acute alcohol effects on pCREB and STEP expression in CeA were positively associated with preference for the alcohol-paired chamber. These data suggest that stress history reduces the aversive properties of moderate alcohol doses, and that alcohol aversion is associated with acute alcohol effects on pCREB and STEP expression in the extended amygdala.

Flood-conditioned place aversion as a novel non-pharmacological aversive learning procedure in mice

The place conditioning paradigm is an efficient, widely-used method to study mechanisms that underlie appetitive or aversive learning and memory processes. However, pharmacological agents used to induce conditioned place preference (CPP) or aversion (CPA) can per se interfere with learning and memory processing, hence confounding the results. Therefore, non-pharmacological place conditioning procedures are of high importance. Here, we introduce a novel procedure for induction of CPA in mice, by water flooding. We found that pairing a context with immersion in moderately cold shallow water resulted in aversion and avoidance of that context during a place preference test. Importantly, place aversion emerged only when mice experienced the onset of flood during conditioning training, but not when mice were placed in a compartment pre-filled with water. We also found that warm water was not sufficiently aversive to induce CPA. Moreover, CPA was observed after two or three context-flood pairings but not after one or four pairings, suggesting that moderate conditioning intensity produces optimal CPA expression. Thus, flood-induced CPA is a simple, cheap, and efficient procedure to form and measure place aversion memories in mice, using an ethologically-relevant threat.

An assessment of concurrent cannabidiol and Δ⁹-tetrahydrocannabinol administration in place aversion and taste avoidance conditioning.

Rising interest in medical marijuana has prompted research into its phytocannabinoid constituents, particularly Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD). Coadministration of CBD with THC has been shown to modulate a number of THC's effects, including its negative stimulus properties (e.g., anxiety, paranoia, psychosis) in a clinical setting. The present series of experiments extended these analyses by examining the ability of CBD to impact the aversive effects of THC as assessed in a combined taste and place conditioning procedure. In Experiment 1, male and female Wistar rats were given access to a novel saccharin solution, injected with a vehicle solution CBD (0.075, 0.75 mg/kg), THC (0.75 mg/kg) or several combinations of CBD and THC (1:10 or 1:1 dose ratio), and then placed in a distinct chamber of a place conditioning apparatus. When THC was administered alone, it induced significant place aversions and taste avoidance. At both dose ratios, CBD failed to modulate either effect. There were no sex differences in either assay or at any ratio. A follow-up experiment (Experiment 2) employed identical dose ratios, but a higher dose of THC (7.5 mg/kg) and corresponding CBD doses (0.75, 7.5 mg/kg). Similar to the initial assessment, CBD had no effect on THC-induced place or taste conditioning at either dose ratio. These results may reflect the specific phytocannabinoid dose ratios examined or species differences in cannabinoid action. The current findings further suggest that altering CBD content in medicinal cannabis will likely have minimal effects in terms of tolerability. (PsycINFO Database Record

Prior binge-drinking history promotes the positive affective valence of methamphetamine in mice

An alcohol use disorder is a major predisposing factor for methamphetamine (MA) abuse. Further, MA-alcohol co-abuse is a risk factor for treatment discontinuation and non-compliance in MA-dependent individuals. No effective treatment exists for MA addiction, let alone treatments directed at those suffering from MA-alcohol addiction co-morbidity. Thus, it is imperative that we develop high-throughput animal models to study the biobehavioral interactions between MA and alcohol of relevance to the etiology and treatment of co-abuse. To this end, we reported that a history of binge alcohol-drinking [5,10, 20 and 40% (v/v); 2 h/day for 10–14 days] reduces MA reinforcement and intake, but it augments MA-preference and intake when drug availability is behaviorally non-contingent. To reconcile this apparent discrepancy in findings, we employed a comparable 2-week binge-drinking paradigm as that employed in our previous studies followed by place-conditioning procedures (4 pairings of 0.25, 0.5, 1, 2 or 4 mg/kg MA, i.p.). This was meant to determine how a prior binge-drinking history impacts the affective valence of MA and sensitivity to MA-induced psychomotor-activation/sensitization. Prior binge-drinking history blunted spontaneous locomotor activity and shifted the MA dose-place-preference function upwards of water drinking controls. The potentiation of MA-conditioned reward by prior binge-drinking history was independent of any alcohol effects upon the locomotor-activating or –sensitizing effects of MA. Based on these results we propose that the reduced MA reinforcement reported previously by our group likely reflects a compensatory response to an increased sensitivity to MA’s positive subjective effects rather than increased sensitivity to the drug’s psychomotor-activating effects.

Effect of footshock stress on place conditioning produced by Δ9-tetrahydrocannabinol and the fatty acid amide hydrolase (FAAH) inhibitor, URB597, in Sprague-Dawley rats.

Unlike other drugs of abuse, Δ9-tetrahydrocanabinol (THC) is generally aversive in rodent conditioned place preference models, but little is known about how stress may modify THC affective properties. We evaluate the potential of footshock stress to enhance the rewarding effects of THC and the fatty acid amide hydrolase inhibitor, URB597, as it has been shown to enhance their anxiolytic effects. The effect of footshock stress 24h prior to each conditioning trial on the rewarding/aversive effects of THC (1, 0.1, 0.5mg/kg, ip) and URB597 (0.3mg/kg, ip) was evaluated in an unbiased place conditioning procedure in rats. Subsequently, the same stressor was given immediately prior to conditioning with THC (1 and 0.1mg/kg). Locomotor activity was also measured during conditioning. A dose of 1mg/kg THC, but not 0.1-0.5mg/kg, produced a conditioned place aversion (CPA) that was not modified by footshock delivered 24h prior to conditioning trials; however, footshock delivered immediately prior to conditioning trials prevented that CPA. Lower doses of THC and URB597 produced no place conditioning regardless of footshock conditions. A dose of 1mg/kg THC produced locomotor suppression during conditioning trials that was prevented by footshock delivered 24h before and reversed to locomotor activation by footshock delivered immediately before conditioning. Unlike the effect of footshock on THC- and URB597-induced anxiolytic effects, footshock does not promote THC or URB597-induced reward in a conditioned place preference paradigm. However, footshock stress reverses the sedative effects of 1mg/kg THC.

Both nicotine reward and withdrawal are enhanced in a rodent model of diabetes.

It is presently unclear whether diabetic rats experience greater rewarding effects of nicotine and/or negative affective states produced by nicotine withdrawal. The present study utilized a rodent model of diabetes to examine the rewarding effects of nicotine and negative affective states and physical signs produced by withdrawal. Separate groups of rats received systemic administration of either vehicle or streptozotocin (STZ), which destroys insulin-producing beta cells in the pancreas and elevates glucose levels. Place conditioning procedures were utilized to compare the rewarding effects of nicotine (conditioned place preference; CPP) and negative affective states produced by withdrawal (conditioned place aversion; CPA) in vehicle- and STZ-treated rats. CPA and physical signs of withdrawal were compared after administration of the nicotinic receptor antagonist mecamylamine to precipitate withdrawal in nicotine-dependent rats. A subsequent study utilized elevated plus maze (EPM) procedures to compare anxiety-like behavior produced by nicotine withdrawal in vehicle- and STZ-treated rats. STZ-treated rats displayed greater rewarding effects of nicotine and a larger magnitude of aversive effects and physical signs produced by withdrawal as compared to vehicle-treated controls. STZ-treated rats also displayed higher levels of anxiety-like behavior on the EPM during nicotine withdrawal as compared to controls. The finding that both nicotine reward and withdrawal are enhanced in a rodent model of diabetes implies that the strong behavioral effects of nicotine promote tobacco use in persons with metabolic disorders, such as diabetes.

Nicotine Enhances Footshock- and Lithium Chloride-Conditioned Place Avoidance in Male Rats.

Numerous studies have shown that nicotine (NIC) can enhance the reinforcing effects of non-NIC stimuli through a nonassociative mechanism. To date, it is unclear whether NIC reinforcement enhancement serves to increase behaviors motivated by rewarding stimuli only, or whether NIC potentiates behavior motivated by all stimuli, regardless of valence. The current study used a place conditioning procedure to examine whether acute NIC injection modulates avoidance of an environment previously associated with an aversive stimulus. Separate groups of rats underwent place conditioning using either lithium chloride (125mg/kg/ml, i.p.) or footshock (0.75 mA) as the aversive stimulus. Other rats served as nonconditioned controls. The magnitude of place avoidance was assessed after acute NIC (0.1 or 0.4mg/kg/ml, s.c.) or saline. Rats avoided chambers previously paired with either lithium chloride or footshock, and conditioned place avoidance was significantly enhanced by NIC pre-treatment. These results demonstrate that the ability of NIC to enhance motivated behavior extends to behaviors elicited by aversive stimuli, evidence that NIC affects behavior motivated by a broader range of stimuli than previously appreciated. The current study examined whether the reinforcement enhancement properties of NIC apply to aversive stimuli by testing NIC enhancement of conditioned place avoidance in rats. The results demonstrate that NIC enhances the motivational impact of these distinct aversive stimuli, providing novel evidence that NIC affects behavior motivated by a broader range of stimuli than has previously been demonstrated.

A role for sigma receptors in stimulant self-administration and addiction.

Sigma-1 receptors (σ1Rs) are structurally unique intracellular proteins that function as chaperones. σ1Rs translocate from the mitochondria-associated membrane to other subcellular compartments, and can influence a host of targets, including ion channels, G-protein-coupled receptors, lipids, and other signaling proteins. Drugs binding to σRs can induce or block the actions of σRs. Studies indicate that stimulant self-administration induces the reinforcing effects of σR agonists, because of dopamine transporter actions. Once established, the reinforcing effects of σR agonists are independent of dopaminergic mechanisms traditionally thought to be critical to the reinforcing effects of stimulants. Self-administered doses of σR agonists do not increase dopamine concentrations in the nucleus accumbens shell, a transmitter and brain region considered important for the reinforcing effects of abused drugs. However, self-administration of σR agonists is blocked by σR antagonists. Several effects of stimulants have been blocked by σR antagonists, including the reinforcing effects, assessed by a place-conditioning procedure. However, the self-administration of stimulants is largely unaffected by σR antagonists, indicating fundamental differences in the mechanisms underlying these two procedures used to assess the reinforcing effects. When σR antagonists are administered in combination with dopamine uptake inhibitors, an effective and specific blockade of stimulant self-administration is obtained. Actions of stimulant drugs related to their abuse induce unique changes in σR activity and the changes induced potentially create redundant and, once established, independent reinforcement pathways. Concomitant targeting of both dopaminergic pathways and σR proteins produces a selective antagonism of stimulant self-administration, suggesting new avenues for combination chemotherapies to specifically combat stimulant abuse.

Effects of Chronic Stress on Alcohol Reward- and Anxiety-Related Behavior in High- and Low-Alcohol Preferring Mice.

Stress exposure (SE) during adolescence is associated with an increased risk for the development of alcohol use disorders (AUDs). Past research has shown that SE during adolescence increases voluntary alcohol consumption in mice during adulthood; however, little is known about the positive or negative motivational aspects of this relationship. High-alcohol preferring (HAP2) and low-alcohol preferring (LAP2) male mice were exposed to stress during adolescence, stress during adulthood, or no stress. After a 30-day interim, subjects were exposed to alcohol-induced place and footshock-induced fear conditioning procedures to measure stress-induced behavioral alterations during adulthood. SE during adolescence did not increase the magnitude of alcohol-induced conditioned place preference (CPP), as hypothesized, but increased the magnitude of conditioned fear, as measured by fear-potentiated startle (FPS), in HAP2 subjects only. Regardless of stress treatment group, LAP2 subjects showed greater alcohol-induced CPP expression than HAP2 mice. HAP2 mice also showed greater FPS than LAP2 mice, as previously shown. These results in mice, taken together with past research, suggest that mice exposed to stress during adolescence do not increase alcohol consumption during adulthood because of a greater sensitivity to the rewarding effects of alcohol, as measured via place conditioning. These results in mice also suggest that humans exposed to stress during adolescence may be more susceptible to developing anxiety during adulthood. The findings may be particularly relevant for humans with a familial history of AUDs.

Nicotine enhances the expression of a sucrose or cocaine conditioned place preference in adult male rats

Nicotine has been shown to enhance the motivational properties of non-nicotine stimuli. This reinforcement-enhancing property of nicotine has the potential to promote the use of other illicit substances as well as maladaptive patterns of food intake. Therefore, the current study aimed to examine whether nicotine enhances preference for contexts paired with cocaine or sucrose utilizing a place conditioning procedure. Separate groups of adult male rats were administered sucrose or cocaine in one of two compartments of a standard CPP chamber on four consecutive days. Preference was then assessed following no injection, a single subcutaneous (s.c.) injection of nicotine, and a s.c. saline injection. The animals preferred the chamber paired with either sucrose or cocaine, as evident from an increased time spent in the paired chamber compared to baseline. Nicotine further increased the time spent in the sucrose- or cocaine-paired chamber, consistent with a reinforcement-enhancement effect. Previous results demonstrate an interaction between nicotine and intake of other drugs or food. The present findings provide an additional mechanism that may underlie these effects and which may have implications for drug dependence and obesity.

NMDA receptor blockade in the prelimbic cortex activates the mesolimbic system and dopamine-dependent opiate reward signaling.

N-Methyl-D-aspartate (NMDA) receptors in the medial prefrontal cortex (mPFC) are involved in opiate reward processing and modulate sub-cortical dopamine (DA) activity. NMDA receptor blockade in the prelimbic (PLC) division of the mPFC strongly potentiates the rewarding behavioural properties of normally sub-reward threshold doses of opiates. However, the possible functional interactions between cortical NMDA and sub-cortical DAergic motivational neural pathways underlying these effects are not understood. This study examines how NMDA receptor modulation in the PLC influences opiate reward processing via interactions with sub-cortical DAergic transmission. We further examined whether direct intra-PLC NMDA receptor modulation may activate DA-dependent opiate reward signaling via interactions with the ventral tegmental area (VTA). Using an unbiased place conditioning procedure (CPP) in rats, we performed bilateral intra-PLC microinfusions of the competitive NMDA receptor antagonist, (2R)-amino-5-phosphonovaleric acid (AP-5), prior to behavioural morphine place conditioning and challenged the rewarding effects of morphine with DA receptor blockade. We next examined the effects of intra-PLC NMDA receptor blockade on the spontaneous activity patterns of presumptive VTA DA or GABAergic neurons, using single-unit, extracellular in vivo neuronal recordings. We show that intra-PLC NMDA receptor blockade strongly activates sub-cortical DA neurons within the VTA while inhibiting presumptive non-DA GABAergic neurons. Behaviourally, NMDA receptor blockade activates a DA-dependent opiate reward system, as pharmacological blockade of DA transmission blocked morphine reward only in the presence of intra-PLC NMDA receptor antagonism. These findings demonstrate a cortical NMDA-mediated mechanism controlling mesolimbic DAergic modulation of opiate reward processing.