Post-Retrieval Extinction Attenuates Cocaine Memories

Recent studies have shown that post-retrieval extinction training attenuates fear and reward-related memories in both humans and rodents. This noninvasive, behavioral approach has the potential to be used in clinical settings to treat maladaptive memories that underlie several psychiatric disorders, including drug addiction. However, few studies to date have used a post-retrieval extinction approach to attenuate addiction-related memories. In the current study, we attempted to disrupt cocaine-related memories by using the post-retrieval extinction paradigm in male Sprague Dawley rats. Results revealed that starting extinction training 1 h after cocaine contextual memory was retrieved significantly attenuated cocaine-primed reinstatement of conditioned place preference (CPP) and relapse of cocaine CPP (drug-free and cocaine-primed) following 30 days of abstinence. However, animals that did not retrieve the contextual cocaine memory before extinction training, or animals that began extinction training 24 h after retrieval (outside of the reconsolidation window), demonstrated normal cocaine CPP. Conversely, animals that received additional CPP conditioning, rather than extinction training, 1 h after reactivation of cocaine memory showed enhanced cocaine CPP compared with animals that did not reactivate the cocaine memory before conditioning. These results reveal that a behavioral manipulation that takes advantage of reconsolidation and extinction of drug memories may be useful in decreasing preference for, and abuse of, cocaine.     

Cannabinoid CB1 receptor antagonist rimonabant disrupts nicotine reward-associated memory in rats

Exposure to cues previously associated with drug intake leads to relapse by activating previously acquired memories. Based on previous findings, in which cannabinoid CB₁ receptors were found to be critically involved in specific aspects of learning and memory, we investigated the role of CB₁ receptors in nicotine reward memory using a rat conditioned place preference (CPP) model. In Experiment 1, rats were trained for CPP with alternating injections of nicotine (0.5 mg/kg, s.c.) and saline to acquire the nicotine-conditioned memory. To examine the effects of rimonabant on the reconsolidation of nicotine reward memory, rats were administered rimonabant (0, 0.3, and 3.0 mg/kg, i.p.) immediately after reexposure to the drug-paired context. In Experiment 2, rats were trained for CPP similarly to Experiment 1. To examine the effects of rimonabant on the reinstatement of nicotine reward memory, rimonabant (0, 0.3, and 3.0 mg/kg, i.p.) was administered before the test of nicotine-induced CPP reinstatement. In Experiment 3, to evaluate whether rimonabant itself produces a reward memory, rats were trained for CPP with alternating injections of different doses of rimonabant (0, 0.3, and 3.0 mg/kg) and saline. Rimonabant at a dose of 3.0 mg/kg significantly disrupted the reconsolidation of nicotine memory and significantly blocked the reinstatement of nicotine-induced CPP. However, rimonabant itself did not produce CPP. These findings provide clear evidence that CB₁ receptors play a role in nicotine reward memory, suggesting that CB₁ receptor antagonists may be a potential target for managing nicotine addiction.     

Food restriction increases acquisition, persistence and drug prime-induced expression of a cocaine-conditioned place preference in rats

Cocaine conditioned place preference (CPP) is more persistent in food-restricted than ad libitum fed rats. This study assessed whether food restriction acts during conditioning and/or expression to increase persistence. In Experiment 1, rats were food-restricted during conditioning with a 7.0 mg/kg (i.p.) dose of cocaine. After the first CPP test, half of the rats were switched to ad libitum feeding for three weeks, half remained on food restriction, and this was followed by CPP testing. Rats tested under the ad libitum feeding condition displayed extinction by the fifth test. Their CPP did not reinstate in response to overnight food deprivation or a cocaine prime. Rats maintained on food restriction displayed a persistent CPP. In Experiment 2, rats were ad libitum fed during conditioning with the 7.0 mg/kg dose. In the first test only a trend toward CPP was displayed. Rats maintained under the ad libitum feeding condition did not display a CPP during subsequent testing and did not respond to a cocaine prime. Rats tested under food-restriction also did not display a CPP, but expressed a CPP following a cocaine prime. In Experiment 3, rats were ad libitum fed during conditioning with a 12.0 mg/kg dose. After the first test, half of the rats were switched to food restriction for three weeks. Rats that were maintained under the ad libitum condition displayed extinction by the fourth test. Their CPP was not reinstated by a cocaine prime. Rats tested under food-restriction displayed a persistent CPP. These results indicate that food restriction lowers the threshold dose for cocaine CPP and interacts with a previously acquired CPP to increase its persistence. In so far as CPP models Pavlovian conditioning that contributes to addiction, these results suggest the importance of diet and the physiology of energy balance as modulatory factors.     

Lack of neurotensin type 1 receptor facilitates contextual fear memory depending on the memory strength

Neurotensin is known to have antipsychotic-like behavioral and neurochemical effects, but its participation in fear memory has not been fully elucidated. Here, we report that a lack of type 1 neurotensin receptor (Ntsr1) increases the behavioral fear response elicited by weak fear memory. Adult Ntsr1-knockout (KO) mice and their wild-type (WT) littermates were compared in contextual fear conditioning. The mice were exposed twice for 3 min to the context 24 and 48 h after conditioning (first and second exposure, respectively), and freezing response of mice at the exposure was measured to evaluate fear memory. Ntsr1-KO mice showed a higher freezing rate than WT mice at both first and second exposures under the condition where a relatively weak unconditioned stimulus (footshock) was applied and thus elicited a relatively lower freezing rate. The difference in the first exposure between Ntsr1-KO and WT mice disappeared under the condition where a more intense unconditioned stimulus was used. The enhancement of freezing response in Ntsr1-KO mice at second exposure was abolished by propranolol, a β-adrenergic blocker that suppresses fear memory reconsolidation, and suppressed by MK-801, an NMDA receptor antagonist. These results suggest that Ntsr1 plays inhibitory roles in weak fear memory.     

Effects of cannabinoid CB1 receptor antagonist rimonabant in consolidation and reconsolidation of methamphetamine reward memory in mice

Rationale  Previous studies have shown that cannabinoid CB1 receptors play an important role in specific aspects of learning and memory, yet there has been no systematic study focusing on the involvement of cannabinoid CB1 receptors in methamphetamine-related reward memory. Objectives  The purpose of this study was to examine whether rimonabant, a cannabinoid CB1 receptor antagonist, would disrupt the consolidation and reconsolidation of methamphetamine-related reward memory, using conditioned place preference paradigm (CPP). Materials and methods  Separate groups of male Kunming mice were trained to acquire methamphetamine CPP. Vehicle or rimonabant (1 mg/kg or 3 mg/kg, i.p.) was given at different time points: immediately after each CPP training session (consolidation), 30 min before the reactivation of CPP (retrieval), or immediately after the reactivation of CPP (reconsolidation). Methamphetamine CPP was retested 24 h and 1 and 2 weeks after rimonabant administration. Results  Rimonabant at doses of 1 and 3 mg/kg significantly inhibited the consolidation of methamphetamine CPP. Only high-dose rimonabant (3 mg/kg) disrupted the retrieval and reconsolidation of methamphetamine CPP. Rimonabant had no effect on methamphetamine CPP in the absence of methamphetamine CPP reactivation. Conclusions  Our findings suggest that cannabinoid CB1 receptors play a major role in methamphetamine reward memory, and cannabinoid CB1 receptor antagonists may be a potential pharmacotherapy to manage relapse associated with drug-reward-related memory.     

Assessing learned associations between conditioned cocaine reward and environmental stimuli in the Wistar Kyoto rat

Clinical studies demonstrate that anxiety disorders increase the risk of substance use disorder. However, few studies have directly assessed anxiety as a vulnerability factor in processing of rewarding stimuli. The Wistar-Kyoto (WKY) rat has been proposed as a model of anxiety vulnerability because it exhibits extreme behavioral inhibition in novel and social environments; yet, it displays paradoxical rapid active avoidance learning that is resistant to extinction. The present study was designed to characterize the acquisition and persistence of cocaine conditioned place preference (CPP) in WKY rats. In the first of a series of three experiments, adult male WKY and Sprague Dawley (SD) rats were given six pairings of cocaine (3, 5, 10, 15 mg/kg) or saline on alternating days. SD rats developed cocaine-induced CPP to each of the four doses of cocaine tested. In contrast, WKY rats demonstrated CPP when conditioned with 3, 5, and 10 mg/kg, but displayed no preference to the 15 mg/kg dose. Next, separate groups of rats were subject to an extended CPP paradigm, which included acquisition, extinction and reinstatement phases. Rats were conditioned with cocaine and saline on alternating days using either a 6/6 (as above) or 4/4 conditioning regimen. Both SD and WKY rats acquired a lasting CPP with the 6/6 conditioning regimen. Results from the 4/4 conditioning regimen show that SD, but not WKY, rats acquired CPP. Preference scores for SD rats during the cocaine primed reinstatement test were significantly different from pretest scores indicating reinstatement of CPP in this group. Paradoxically, WKY rats demonstrated a latent sensitization to the conditioned rewarding effects of cocaine during the drug-primed reinstatement test. Taken together, WKY rats appear to be more sensitive to high doses of cocaine and need more experience with the drug to acquire a preference than SD rats.     

Distal and proximal pre-exposure to ethanol in the place conditioning task: tolerance to aversive effect,sensitization to activating effect,but no change in rewarding effect

RATIONALE: The literature offers many examples of tolerance to ethanol's inhibitory/depressant effects and sensitization to its activating effects. There are also many examples of tolerance to ethanol's aversive effects as measured in the conditioned taste aversion and conditioned place aversion (CPA) procedures. However, there are very few demonstrations of either tolerance or sensitization to ethanol's rewarding or reinforcing effects. OBJECTIVE: The present studies were designed to examine effects of two forms of ethanol pre-exposure (distal or proximal) on ethanol's rewarding and aversive effects as indexed by the place conditioning procedure. METHOD: Male inbred (DBA/2J) mice were exposed to ethanol (2 g/kg IP) in an unbiased place conditioning procedure that normally produces either conditioned place preference (CPP) (ethanol injection before CS exposure) or CPA (ethanol injection after CS exposure). In the distal pre-exposure studies (experiments 1 and 2), mice initially received a series of four ethanol injections (0, 2, or 4 g/kg) in the home cage at 48-h intervals during the week before place conditioning. In the proximal pre-exposure studies (experiments 3-4), mice were injected with ethanol 65 min before (experimental groups) or 65 min after (control groups) each paired ethanol injection on CS+ trials. RESULTS: Distal pre-exposure produced a robust sensitization to ethanol's activating effect, whereas proximal pre-exposure generally reduced the activation normally produced by the paired ethanol injection. Both forms of pre-exposure interfered with CPA, but had no effect on CPP. CONCLUSIONS: These studies suggest that both forms of pre-exposure reduced ethanol's aversive effect, but had no impact on ethanol's rewarding effect. In general, the detrimental effects of pre-exposure on CPA are explained best in terms of a reduction in ethanol's efficacy as an aversive unconditioned stimulus (i.e. tolerance), although explanations based on other types of associative interference are also possible. The failure to affect CPP with pre-exposure treatments that reduced or eliminated CPA suggests that these behaviors are mediated by independent, motivationally opposite effects of ethanol. Moreover, these results indicate dissociation between sensitization to ethanol's locomotor activating effect and changes in its rewarding effect. To the extent that motivational processes measured by CPP and CPA normally contribute to ethanol drinking, the present findings suggest that increases in ethanol intake seen after chronic ethanol exposure are more likely caused by tolerance to ethanol's aversive effect rather than sensitization to its rewarding or reinforcing effect.     

Role of test activity in ethanol-induced disruption of place preference expression in mice

Rationale Reduced expression of a drug-induced conditioned place preference (CPP) may reflect a decrease in the drug’s conditioned rewarding effects. However, CPP is also open to disruption by processes unrelated to the underlying motivation. In unpublished studies, we previously observed that ethanol pretreatment before testing disrupted expression of ethanol-induced CPP in DBA/2J mice. We hypothesized that this interference effect was due to large ethanol-induced increases in activity. Objective The present studies were designed to examine the relationship between test activity and expression of ethanol-induced CPP both in the presence and absence of ethanol. To assess the generality of this relationship, we examined these effects both in DBA/2J (which are highly activated by ethanol) and in NZB/B1NJ mice (which show similar CPP, but less ethanol-induced activation). Materials and methods In separate experiments, inbred mice from each strain underwent ethanol (2 g/kg) place conditioning. Saline or ethanol was then administered immediately before the test. Results Ethanol, given immediately before the test, blocked the expression of ethanol CPP in DBA/2J, but not in NZB/B1NJ mice. Moreover, ethanol significantly increased test activity levels in DBA/2J and to a much lesser degree in NZB/B1NJ mice. Correlation analyses showed an inverse phenotypic relationship between preference and test activity, reflecting stronger preferences in less active mice. Conclusions Disruption of ethanol-CPP observed in DBA/2J mice may be a consequence of high ethanol-induced activity levels. More generally, these studies suggest that competing behaviors can affect expression of a drug-induced CPP independent of affecting the conditioned rewarding effects of the drug.     

Acute ethanol administration affects memory reactivation: a look at the neuronal density and apoptosis in the rat hippocampus

This study is an attempt to examine whether administration of ethanol after memory reactivation will modulate expression of memory in rats or not. We further examined whether this administration alters the number of tunnel positive cells in hippocampus.Adult male Wistar rats were trained in a fear conditioning system using two 1 s , 0.6 mA shock with an interval of 180 s. 24 h later the rats were returned to the chamber for reactivation, and then they were injected with ethanol (0.5, 1, 1.5 mg/kg) or saline, ip. Again, one, seven and fourteen days after reactivation, the rats were returned to the context for 5 min. The freezing time (absence of all movements except respiration) was scored in seconds.In the second experiment, after test 1, the animals were anesthetized and a transcardial perfuse with phosphate buffer and paraformaldehyde 4% was conducted. After post-fixation of brains 5-μm sections were stained with cresyl violet.Finally, paraffin-embedded sections of 10 μm were cut out throughout the tissue and each sample was processed with TUNEL. The number of apoptotic cells in a 130 μm-long segment of the hippocampal CA1 and CA3 fields and dentate gyrus was counted.The data demonstrate that ethanol exposure impairs post retrieval processes. Rats receiving ethanol (1.5 mg/kg) showed lower freezing levels during the first test. Moreover, ethanol decreases the density of CA1, CA3 and DG cells and increases the density of apoptotic cells in all regions of hippocampus. Therefore, ethanol exposure impairs reconsolidation of contextual fear conditioning probably via decreasing the density of CA1, CA3 and DG cells.     

NeuroD Modulates Opioid Agonist-Selective Regulation of Adult Neurogenesis and Contextual Memory Extinction

Addictive drugs, including opioids, modulate adult neurogenesis. In order to delineate the probable implications of neurogenesis on contextual memory associated with addiction, we investigated opioid agonist-selective regulation of neurogenic differentiation 1 (NeuroD) activities under the conditioned place preference (CPP) paradigm. Training mice with equivalent doses of morphine and fentanyl produced different CPP extinction rates without measurable differences in the CPP acquisition rate or magnitude. Fentanyl-induced CPP required much longer time for extinction than morphine-induced CPP. We observed a parallel decrease in NeuroD activities and neurogenesis after morphine-induced CPP, but not after fentanyl-induced CPP. Increasing NeuroD activities with NeuroD-lentivirus (nd-vir) injection at the dentate gyrus before CPP training reversed morphine-induced decreases in NeuroD activities and neurogenesis, and prolonged the time required for extinction of morphine-induced CPP. On the other hand, decreasing NeuroD activities via injection of miRNA-190-virus (190-vir) reversed the fentanyl effect on NeuroD and neurogenesis and shortened the time required for extinction of fentanyl-induced CPP. Another contextual memory task, the Morris Water Maze (MWM), was affected similarly by alteration of NeuroD activities. The reduction in NeuroD activities either by morphine treatment or 190-vir injection decreased MWM task retention, while the increase in NeuroD activities by nd-vir prolonged MWM task retention. Thus, by controlling NeuroD activities, opioid agonists differentially regulate adult neurogenesis and subsequent contextual memory retention. Such drug-related memory regulation could have implications in eventual context-associated relapse.     

Persistent expression of methamphetamine-induced CTA in periadolescent rats

It is well documented that the transition from periadolescence to adulthood produces profound changes in motivated behavior, and furthermore, attenuates the aversive experience of abused drugs. Little is known, however, about adolescent memory for the conditioned aversive effects of abused drugs following retention intervals that span this developmental transition. The present experiment investigated methamphetamine-induced conditioned taste aversion (CTA) in periadolescent rats to determine if the magnitude of conditioning was altered following retention intervals that extend to adulthood. Rats consumed saccharin (0.1%, w/v) and were immediately injected with saline or methamphetamine (3.0 mg/kg) either once (PND 40) or three times (PND 38-40), and memory was assessed one or 50 days later on post natal days 41 or 90, respectively. Rats exhibited robust methamphetamine-induced CTA one and 50 days after conditioning, and the strength of responding did not change as a function of retention interval, regardless if animals were trained with one or three saccharin-methamphetamine pairings. These findings indicate that the expression of memory for the aversive effects of methamphetamine was resistant to degradation throughout the developmental period of periadolescence to adulthood.     

Nicotine-induced conditioned place preference in adolescent rats

A number of clinical reports have noted that women are more vulnerable to tobacco abuse than men, and adolescent females are especially vulnerable to nicotine addiction. Conditioned place preference (CPP) is a widely used technique for determining the rewarding effects of drugs with abuse potential in animal models. Several studies have reported that nicotine was ineffective in eliciting CPP in rats; while others have observed conditioned place aversion (CPA) rather than preference for nicotine. One recent investigation established CPP in adolescent female rats, however at a reasonably high dose; while a second reported dose dependence of nicotine-induced CPP in male but not female rats. The present study was designed to determine the lowest dose necessary to induce CPP to nicotine in adolescent female rats. Nicotine-induced CPP was obtained at a subcutaneous dose of 0.03 mg/kg (salt content) using a biased conditioning paradigm. Higher doses produced aversion and lower doses provided no rewarding or aversive effects. CPP persisted for at least 3 weeks following conditioning in the absence of further nicotine treatment. In contrast with results from adolescent human females and males, age-matched male rats also evidenced CPP at this very low dose of nicotine. These results indicate that even a low dose of nicotine is reinforcing and addicting in both adolescent male and female rats and brings into question the suggestion that nicotine induces greater addicting capacity in adolescent girls than boys.     

Effects of deletion of <Emphasis Type="Italic">gria1</Emphasis> or <Emphasis Type="Italic">gria2</Emphasis> genes encoding glutamatergic AMPA-receptor subunits on place preference conditioning in mice

Rationale The conditioned place preference (CPP) paradigm has been used as a measure of the rewarding effects of a number of stimuli. Critically, this classical conditioning procedure requires the formation of associations between a rewarding stimulus and environmental cues, and the ability of these cues to direct subsequent behaviour.Objectives The purpose of the current experiments was to examine the role of glutamatergic transmission via subunit-specific populations of -amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors in the formation of stimulus–reward associations involving contextual stimuli.Methods We investigated the ability of cocaine and food to induce a CPP in mice lacking either the GluR1 or GluR2 subunits of the AMPA receptor [gria1 or gria2 knockout (KO) mice]. In separate experiments, food pellets or cocaine (5–20 mg/kg IP) were paired with one compartment of the CPP apparatus, while no-food or vehicle was paired with an alternative compartment.Results Following conditioning, gria1 KOs displayed a significant preference for the food or cocaine-paired compartment, and did not differ from wild-type (WT) controls. However, gria2 knockouts displayed a preference for a cocaine-paired compartment, but not a food-paired compartment, indicating a specific deficit in place preference conditioning to food.Conclusions These results obtained using knockout mice indicate that GluR2-containing AMPA receptors may be critical for learning about contextual stimuli relevant to food rewards, but not drug rewards. When the results are considered in relation to our previous findings with gria1 and gria2 knockout mice, they also raise questions about the CPP paradigm representing a model of conditioned reward over a conditioned approach interpretation. However, it would be important to confirm these findings with alternative approaches, should selective ligands become available.     

Neurobehavioral development of CD-1 mice after combined gestational and postnatal exposure to ozone

 Outbred CD-1 mice were exposed continuously to ozone (O₃, 0.6 ppm) from 6 days prior to the formation of breeding pairs to the time of weaning of the offspring on postnatal day 22 (PND 22) or to PND 26. One half of the mice in each of eight O₃ and eight control litters were subjected on PND 24 to a 20-min open-field test after IP treatment by either saline or scopolamine (2 mg/kg). The remaining mice (those exposed until PND 26) were subjected on PNDs 28–31 to a conditioned place preference (CPP) test, using a short schedule with a single IP injection on PND 29 of either d-amphetamine (3.3 mg/kg) or saline. Subsequently, the saline mice of the open-field experiment were used on PND 59 for an activity test in one of the CPP apparatus compartments after IP treatment by either d-amphetamine (same dose) or saline. In addition, the saline mice of the CPP experiment underwent a multi-trial, step-through passive avoidance (PA) acquisition test on PND 59 or 60, followed 24 h later by a single-trial retention test. In the absence of effects on reproductive performance (proportion of successful pregnancies, litter size, offspring viability, and sex ratio), O₃ offspring showed a long-lasting reduction in body weight without modification of sex differences. Ozone effects on neurobehavioral development were not large and quite selective, including: attenuation of the sex differences in several responses (rearing and sniffing in the open-field, activity in the final CPP test session); a change in response choices in the final CPP test, in the absence of a main effect on conditioning; a reduction of grooming in the activity test on PND 29; and impairment of PA acquisition limited to the initial period of training. Received: 3 November 1994/Accepted: 30 January 1995     

The CB1 inverse agonist AM251, but not the CB1 antagonist AM4113, enhances retention of contextual fear conditioning in rats

The effects of CB1 antagonist/inverse agonists on the acquisition and consolidation of conditioned fear remain uncertain. Recent studies suggest that the CB1 antagonist/inverse agonist AM251 affects acquisition or consolidation of both contextual and discretely cued fear memories. AM251 is frequently referred to as a CB1 antagonist; however in vitro signal transduction assays indicate that this drug also elicits inverse agonist activity at CB1 receptors. The present studies were undertaken to compare the effects of AM251 on conditioned fear with those produced by AM4113, a novel CB1 antagonist with minimal inverse agonist activity. All drugs were administered prior to conditioning. In retention tests conducted two weeks after conditioning, both AM251 (4.0 mg/kg) and AM4113 (6.0 mg/kg)-treated animals exhibited reduced freezing during a conditioned tone cue played within a novel context. In contextual fear retention tests, animals previously treated with 4.0 or 8.0 mg/kg AM251 exhibited enhanced freezing. By contrast, no dose of AM4113 had any significant effect on contextual fear memory, which is consistent with the lower signal transduction activity of AM4113 at CB1 receptors compared to AM251. These results suggest that CB1 neutral antagonists may be less likely than CB1 inverse agonists to facilitate the acquisition or consolidation of contextual fear that may contribute to some clinical disorders.     

Preclinical Evaluation of Reconsolidation Blockade by Clonidine as a Potential Novel Treatment for Posttraumatic Stress Disorder

Exposure to traumatic events can lead to posttraumatic stress disorder (PTSD). Current PTSD treatments typically only produce partial improvement. Hence, there is a need for preclinical research to identify new candidate drugs and to develop novel therapeutic approaches. Animal studies have indicated that fear memories can be weakened by blocking restabilization after retrieval, a process known as reconsolidation. Furthermore, evidence suggests that there are important alterations of the noradrenergic system in PTSD, and hence it may be of interest to study drugs that target this pathway. Here, we investigated the efficacy of clonidine, an α₂-adrenoreceptor agonist, to block reconsolidation in an animal model of persistent traumatic memories. Using an auditory fear conditioning paradigm in rats, we tested the efficacy of clonidine to weaken fear memory retention when administered systemically after retrieval. We evaluated dosage, number of treatments, and specificity in reconsolidation blockade. We found that postretrieval administration of clonidine disrupts fear-related memories in a dose-dependent manner and that two treatments are sufficient for maximal memory impairment. Furthermore, we determined that this effect is long lasting and specific to reconsolidation processes as shown by the selectivity to affect reactivated memories and the absence of spontaneous recovery and of postreactivation short-term memory impairment. Our results demonstrate the efficacy of systemic administration of clonidine following retrieval to persistently disrupt fear memory retention through reconsolidation blockade. This study provides important preclinical parameters for future therapeutic strategies involving clonidine to block reconsolidation as a novel treatment for PTSD symptoms.     

5-HT induces temporomandibular joint nociception in rats through the local release of inflammatory mediators and activation of local β adrenoceptors

Objectives

The present studies assessed the effects of adolescent and adult ethanol exposure on the rewarding effects of cocaine as measured with the conditioned place preference procedure.

Methods

Male rats were exposed to intraperitoneal (IP) injections of ethanol or vehicle for 10 days [postnatal days (PNDs) 30-39 or PNDs 70-79; 2 mg/kg]. Place preference conditioning began on PND 65 or PND 105, respectively, and consisted of a baseline test followed by four conditioning cycles with either 0, 5, 10 or 20 mg/kg cocaine. Following the fourth conditioning cycle a final preference test was performed. Changes in time on the drug-paired side between the baseline and final test were analyzed.

Results

Animals exposed to vehicle (during adolescence or adulthood) showed a significant place preference at 20 mg/kg cocaine. Animals exposed to ethanol (during adolescence or adulthood) showed a significant place preference at 10 mg/kg cocaine.

Conclusions

Exposure to ethanol (adolescents or adults) sensitized the rewarding effects of cocaine. This may indicate an increase in the abuse liability of cocaine following a history of ethanol exposure.     

GABAA receptors modulate ethanol-induced conditioned place preference and taste aversion in mice

  Rationale: GABA_A receptor antagonists have been shown to reduce ethanol self-administration and ethanol-induced conditioned taste aversion (CTA) in rats, suggesting a role for the GABA_A receptor in modulating ethanol’s motivational effects. Objectives: The present experiments examined the effects of the GABA_A receptor antagonists, bicuculline and picrotoxin, on the acquisition of ethanol-induced conditioned place preference (CPP) and CTA in male DBA/2J mice. Methods: Mice in the CPP experiments received four pairings of ethanol (2 g/kg) with a distinctive floor stimulus for a 5-min conditioning session (CS+ sessions). During CS+ sessions, mice also received bicuculline (0, 1.0, 3.0, or 5.0 mg/kg) or picrotoxin (2.0 mg/kg) before an injection of ethanol. On intervening days (CS– sessions), the pretreatment injection was always vehicle followed by saline injections that were paired with a different floor type. For the preference test, all mice received saline injections and were placed on a half grid and half hole floor for a 60-min session. For the CTA experiments, mice were adapted to a 2-h per day water restriction regimen followed by five conditioning trials every 48 h. During conditioning trials, subjects received an injection of vehicle, bicuculline (0.5 and 2.0 mg/kg), or picrotoxin (0.75 and 2.5 mg/kg) before injection of 2 g/kg ethanol or saline following 1-h access to a saccharin solution. Results: Both picrotoxin and the lowest dose of bicuculline (1.0 mg/kg) significantly increased the magnitude of CPP relative to vehicle-treated controls. Picrotoxin alone did not produce place conditioning. Ethanol-stimulated locomotor activity was significantly reduced during conditioning trials with picrotoxin and the higher doses of bicuculline (3.0 and 5.0 mg/kg). Bicuculline did not alter ethanol-induced CTA; however, picrotoxin dose-dependently increased the magnitude of ethanol-induced CTA. Bicuculline and picrotoxin did not produce CTA when administered alone. Conclusions: Overall, these results suggest that blockade of GABA_A receptors with bicuculline and picrotoxin enhances ethanol’s motivational effects in the CPP paradigm; however, only picrotoxin enhances ethanol’s motivational effects in the CTA paradigm. Received: 12 September 1998 / Final version: 21 December 1998     

Stress-induced reinstatement of amphetamine-conditioned place preference and changes in tyrosine hydroxylase in the nucleus accumbens in adolescent rats

Drug abuse among humans often begins during adolescence. Exposure to psychostimulants during this age period may have long-term consequences which can render the organism more susceptible to drug abuse and relapse later in life. It has been demonstrated that exposure to stress can promote relapse to drug use even after long periods of withdrawal. The reinstatement of conditioned place preference (CPP) is a useful animal model for studying relapse. In humans and animals, changes in tyrosine hydroxylase (TH) have been related to drug addiction. Our study examined whether amphetamine-induced CPP during adolescence could be reinstated by exposure to stress 1 (adolescence) and 30 (adulthood) days after the extinction test. We also investigated TH levels following the reinstatement of CPP. Our results showed that amphetamine-induced CPP during adolescence can be reinstated by stress exposure 1 day (P42, end of adolescence) but not 30 days after extinction (P71, adulthood). Moreover the reinstatement of AMPH-induced CPP by stress exposure occurred in the presence of decreased TH in the nucleus accumbens. In conclusion, our data add new evidence that neuroadaptations on TH may mediate relapse to drug-seeking behavior induced by stress within adolescence.     

Effects of oxytocin on methamphetamine-induced conditioned place preference and the possible role of glutamatergic neurotransmission in the medial prefrontal cortex of mice in reinstatement

Accumulating evidence has shown the neuroactive properties of oxytocin (OT), a neurohypophyseal neuropeptide, and its ability to reduce the abuse potential of drugs. The present study investigated the effects of OT on the conditioned place preference (CPP) induced by methamphetamine (MAP, 2.0 mg/kg, i.p.) in mice and the possible role of glutamatergic neurotransmission in the reinstatement of CPP. The results showed that OT (0.1, 0.5, 2.5 μg, i.c.v.) significantly inhibited the acquisition and facilitated the extinction of MAP-induced CPP and abolished the reinstatement of CPP induced by restraint stress. This effect of OT could be attenuated by atosiban (Ato, 2.0 μg, i.c.v.), a selective OT-receptor antagonist. OT failed to block the expression and the reinstatement of CPP induced by MAP challenge. Extracellular glutamate (Glu) levels in the medial prefrontal cortex (mPFC) were determined using microdialysis coupled to a high-performance liquid chromatography (HPLC) with a fluorescence detection system. The results indicated that OT markedly inhibited extracellular Glu levels induced by restraint stress in CPP mice, but not those induced by MAP priming. Ato also attenuated the effects of OT on the changes in Glu levels. Therefore, these findings suggest that OT inhibits drug reward-related behaviors induced by MAP via the OT receptor, and OT blocks the reinstatement of CPP, at least partially, by interfering with the glutamatergic system in the mPFC.