Protracted time-dependent increases in cocaine-seeking behavior during cocaine withdrawal in female relative to male rats

Rationale Female rats display higher sensitivity to cocaine relative to males under a variety of conditions. Time-dependent increases in cocaine-seeking behavior (as measured by nonreinforced operant responses) during cocaine withdrawal have been reported in male, but not female, rats. Objectives The present study determines sex and estrous cycle influences on time-dependent changes in cocaine-seeking behavior. Materials and methods Male and female Sprague-Dawley rats were reinforced for “active lever” responses by a cocaine infusion (0.50 mg/kg/infusion, i.v., fixed ratio schedule of reinforcement, FR1) followed by a 20-s time-out when reinforcement was not delivered. Infusions were paired with a light + tone conditioned stimulus. Next, rats underwent cocaine withdrawal for 1, 14, 60, or 180 days before testing cocaine-seeking behavior. Each rat was tested for extinction of operant responding, conditioned-cued reinstatement, and cocaine-primed (10 mg/kg, i.p.) reinstatement. Results Both males and females displayed a time-dependent increase in cocaine-seeking behavior (active lever presses) under extinction of operant responding and conditioned-cued reinstatement conditions after 60 days of cocaine withdrawal. Moreover, cocaine-seeking behavior during extinction of operant responding in females, but not males, remained elevated at 180 days of cocaine withdrawal. Furthermore, females tested during estrus exhibited higher cocaine-seeking behavior under both extinction of operant responding and cocaine-primed reinstatement conditions relative to other rats independent of the duration of cocaine withdrawal. Conclusions The effects of reproductive cycle and withdrawal duration on cocaine-seeking behavior are additive and time-dependent increases in cocaine-seeking behavior are more enduring in females than in male rats.     

Effects of fluoxetine and d-fenfluramine on cocaine-seeking behavior in rats

Rationale. Serotonin (5-HT) systems may play a role in modulating cocaine-seeking behavior. Objectives. The present study examined the effects of acute administration of the 5-HT reuptake inhibitor (SRI) fluoxetine, and the SRI/releaser d-fenfluramine, on reinstatement of extinguished cocaine-seeking behavior elicited by either response-contingent presentations of cocaine-paired cues or cocaine priming. Methods. Separate groups of rats that had been trained to press a lever for a cocaine reinforcer (0.75 mg/kg per 0.1 ml, IV) with a light/tone stimulus complex paired with each infusion underwent daily extinction sessions during which responding had no scheduled consequences (i.e. neither cocaine nor the stimulus complex was available). Subsequently, the effects of fluoxetine (0–10.0 mg/kg, IP) on extinction and cue reinstatement of extinguished cocaine-seeking behavior were examined, as well as the effects of d-fenfluramine (0–3.0 mg/kg, IP) on cue reinstatement. Additionally, dose-dependent effects of fluoxetine (0–10.0 mg/kg, IP) and d-fenfluramine (0–1.0 mg/kg, IP) on cocaine-primed (0–15.0 mg/kg, IP) reinstatement of extinguished cocaine-seeking behavior were examined. Results. Fluoxetine dose-dependently attenuated cocaine-seeking behavior during extinction. Both fluoxetine and d-fenfluramine dose-dependently attenuated cue-reinstated cocaine-seeking behavior. In contrast, neither drug reliably altered cocaine-seeking behavior reinstated by cocaine priming. Conclusions. These findings suggest that 5-HT indirect agonists effectively attenuate cocaine-seeking behavior elicited by cocaine-associated stimuli, but are much less effective in attenuating cocaine-seeking behavior elicited by cocaine priming.     

Influence of individual differences and chronic fluoxetine treatment on cocaine-seeking behavior in rats

RATIONALE: Clinical studies examining the efficacy of the selective serotonin reuptake inhibitor, fluoxetine, in decreasing craving and cocaine use have been inconsistent. OBJECTIVE: To understand better the effects of fluoxetine treatment on incentive motivation for cocaine, the present study assessed the effects of chronic fluoxetine treatment on cocaine-seeking behavior in rats following exposure to a cocaine self-administration environment or a cocaine priming injection. METHODS: Rats were trained to press a lever for a cocaine reinforcer (0.5 mg/kg per 0.1 ml, i.v.) or received yoked administration of saline. They were then withdrawn from this regimen and given 20 daily injections of saline or fluoxetine (3.0 mg/kg, i.p.). Twenty-four hours after the last injection, the rats were placed in the self-administration environment and cocaine-seeking behavior (i.e., non-reinforced lever pressing) was measured for 90 min. Reinstatement of extinguished cocaine-seeking behavior was then measured for 60 min following a saline injection and for 90 min following a cocaine priming injection (15 mg/kg, i.p.). RESULTS: Chronic fluoxetine treatment attenuated cocaine-seeking behavior following exposure to the self-administration environment in most rats (n = 16), but enhanced cocaine-seeking behavior in two rats. Furthermore, the treatment failed to alter cocaine-seeking behavior following a cocaine priming injection. Interestingly, the amount of cocaine intake during self-administration training correlated with cocaine-seeking behavior following the cocaine priming injection. In fact, the priming injection reinstated cocaine-seeking behavior only in rats with high, but not low, cocaine intake based on a median split. CONCLUSIONS: These results suggest that chronic fluoxetine treatment decreases motivation for cocaine when animals are in a cocaine-free state. Furthermore, individual differences in cocaine use are related to individual differences in sensitivity to the incentive motivational effects of cocaine priming.     

The role of dorsal vs ventral striatal pathways in cocaine-seeking behavior after prolonged abstinence in rats

Rationale Recent studies have implicated an important role for the dorsal striatum during craving for cocaine and in cocaine-seeking after abstinence in rats. Objectives We compared the effects of pharmacological inactivation of mesencephalic dopamine (DA) cell body regions and dorsal vs ventral striatal terminal fields in an animal model of relapse after chronic cocaine self-administration. Materials and methods Rats self-administered cocaine for 2 h/day for ten sessions, followed by 2 weeks of abstinence (i.e., no extinction training). Immediately before being returned to the self-administration chamber, we assessed the effects of gamma-aminobutyric acid agonist inhibition of midbrain DA regions (substantia nigra [SN] and ventral tegmental area [VTA]) and striatum (dorsolateral caudate–putamen, nucleus accumbens core, and nucleus accumbens shell) on relapse to cocaine-seeking in the absence of reinforcement. Further testing examined daily extinction responding subsequent to the initial relapse test. Results Inactivation of the dorsal caudate–putamen and midbrain regions attenuated cocaine seeking, while inactivation of the ventral striatum had no such effects. However, subsequent sessions under extinction conditions revealed a rebound in cocaine seeking in animals that had undergone inactivation in all regions except the dorsolateral caudate–putamen. Conclusions The dorsal but not ventral striatum plays a critical role in cocaine seeking immediately after abstinence. These data support the theory that chronic cocaine may shift activity from the ventral to dorsal striatum during drug seeking under certain conditions. While not necessary at the time of relapse, the ventral striatum appears to be involved in processing critical information of the relapse event. An erratum to this article can be found at     

Acamprosate attenuates cocaine- and cue-induced reinstatement of cocaine-seeking behavior in rats

Rationale Previous studies have shown that environmental context can powerfully modulate the induction of psychomotor sensitization to cocaine in the rat. Rats that receive repeated administrations of cocaine in association with environmental novelty exhibit greater psychomotor sensitization than animals that receive the same treatments in their home cages. Objectives The goal of the present study was to investigate whether environmental context can exert its modulatory influence also on cocaine self-administration. Materials and methods Independent groups of rats with intravenous catheters were given the possibility to self-administer different doses of cocaine (0.0, 0.2, 0.4, and 0.8 mg/kg per infusion) under two environmental conditions. Some animals were housed in the self-administration cages (home groups), whereas other rats were transported to the self-administration cages only for the test sessions (novelty groups). Results Environmental “novelty” facilitated the acquisition of cocaine self-administration at the doses of 0.2 and 0.4 mg/kg per infusion. When rats were given access to a higher dose of cocaine (0.8 mg/kg per infusion), there were no significant group differences in drug taking. Environmental context had no effect on the self-administration of the vehicle. Thus, it appears that environmental “novelty” produced a shift to the left in the dose-effect curve for cocaine self-administration. Furthermore, “novelty” enhanced the motivation of the rats to work for cocaine, as indicated by the results of a progressive ratio procedure. Conclusions The present findings demonstrate for the first time that the environment surrounding drug taking can alter both the intake of and motivation for cocaine.     

Opposing roles for the ventral prefrontal cortex and the basolateral amygdala on the spontaneous recovery of cocaine-seeking in rats

Rationale The neural circuitry subserving cocaine-seeking after extinction vs abstinence alone requires different constituent brain structures. Spontaneous recovery of cocaine-seeking, a model, which incorporates both extinction and abstinence, depends on an unknown neural circuit. Objectives The present study examined the hypothesis that the spontaneous recovery of cocaine-seeking would require overlapping but distinct neural circuits compared to models that incorporate either extinction or abstinence alone. Material and methods Rats were trained to self-administer cocaine (0.2 mg/inf), then responding on the cocaine-paired lever was extinguished, followed by an additional period of abstinence in the home cage. Finally, rats were returned to the self-administration context for a test of spontaneous recovery (SR TEST). Just before the SR TEST, discrete brain regions were inactivated with a GABA agonist cocktail (1 mM baclofen + 0.1mM muscimol) to determine the relative importance of these brain regions in the spontaneous recovery of cocaine-seeking. Results The inactivation of the ventromedial prefrontal cortex (vPFC) enhanced cocaine-seeking, whereas the inactivation of the basolateral amygdala (BLA) attenuated spontaneous recovery. Inactivation of the nucleus accumbens core (Core) resembled the effects of BLA inactivation, but these results were confounded by an inhibitory effect of the vehicle treatment. Finally, the spontaneous recovery of cocaine-seeking was unaltered by manipulations of the dorsomedial prefrontal cortex (dPFC) and the nucleus accumbens shell (Shell). Conclusions The neural circuitry subserving cocaine-seeking behavior in a spontaneous recovery model requires the BLA and possibly the Core, like extinction models. In addition, this behavior is subject to regulation by vPFC, in a manner functionally opposite to that of the BLA.     

The effects of quipazine and fluoxetine on extinction of a previously-reinforced operant response in rats

Previous studies have shown that treatments that reduce serotonergic neurotransmission lead to enhanced responding during extinction. To evaluate the generality of this effect, the present study examined the effects of the serotonin agonists, quipazine and fluoxetine on responding in extinction. In Experiment 1, 72 rats were trained to lever press on a continuous reinforcement schedule for 5 30-min sessions. Four sessions of extinction followed; 30-min prior to each, 3 groups (n = 16) received quipazine (0, 1.0, 5.0 mg/kg) and 3 groups (n = 8) received fluoxetine (0, 1.0, 5.0 mg/kg). The 5.0 mg/kg dose of quipazine resulted in a significant reduction in responding on day 1; the lower dose of quipazine and both doses of fluoxetine were without significant effect. In Experiment 2, 3 similarly trained groups (n = 8) received either saline or quipazine (5.0 mg/kg) prior to each extinction session; additionally, one quipazine group was injected twice with the 5.0 mg/kg dose in its home cage several days before the beginning of extinction. The results of the drug-naive quipazine group replicated those of that group from Experiment 1 whereas the drug-experienced group showed no significant effect of quipazine in extinction. The results suggested that prior drug experience could modify the effects of quipazine on behaviour. Apart from this drug novelty effect the lack of significant effect of either quipazine or fluoxetine suggested that the effects of manipulations believed to increase and decrease serotonin functioning on responding in extinction may not be symmetrical. These results may be understood with reference to the hypothesis that serotonin plays a role in tuning out or reducing responsiveness to nonreinforced or irrelevant stimuli.     

Neurobehavioral effects of environmental enrichment and drug abuse vulnerability

Environmental enrichment during development produces a host of neurobehavioral effects in preclinical models. Early work demonstrated that enrichment enhances learning of a variety of behavioral tasks in rats and these changes are associated with neural changes in various cortical regions. In addition to promoting superior learning, more recent evidence suggests that environmental enrichment also has a protective effect in reducing drug abuse vulnerability. The current review describes some of the most important environment-dependent neural changes in reward-relevant brain structures and summarizes some of the key findings from the extensive literature showing how enrichment decreases the impact of drugs of abuse. Some critical neural mechanisms that may mediate the behavioral changes are postulated, along with some notes of caution about the limitations of the work cited.     

Influence of sex and estrous cyclicity on conditioned cue-induced reinstatement of cocaine-seeking behavior in rats

Rationale Sex differences have been reported in physiological and behavioral responses to cocaine, but it is unclear whether sex differences exist in conditioned-cued relapse to cocaine seeking after prolonged abstinence. Furthermore, the role of estrous cyclicity in conditioned-cued relapse has not been investigated.Objective We assessed the influence of sex and estrous cyclicity on conditioned-cued reinstatement of drug-seeking behavior in Sprague–Dawley rats.Methods Rats were trained to self-administer intravenous cocaine (unconditioned stimulus, US; 0.25, 0.4, 0.5, 0.6, or 1.0 mg/kg per infusion) paired with light+tone conditioned stimuli (CSs) and were subsequently tested for the ability of the CSs to reinstate extinguished cocaine seeking (i.e., nonreinforced lever responding).Results Females exhibited more responding on the cocaine-paired lever during self-administration and extinction than males. Subsequently, males exhibited equally robust conditioned-cued reinstatement of extinguished drug-seeking behavior independent of cocaine training dose. Males and females trained on 0.4–0.6 mg/kg cocaine reinstated to a similar extent. However, females trained on the lowest dose (0.25 mg/kg) exhibited less reinstatement than males, and the source of this effect was the absence of reinstatement in estrous females. In addition, independent of estrous state, females trained on the highest dose (1.0 mg/kg) exhibited less reinstatement than males.Conclusions While males and females are equally responsive to cocaine-paired CSs when the conditions for CS–US association are optimal, females appear to attribute less motivational significance to the CS when it presumably acquires weaker motivational salience because of (a) a low cocaine dose or (b) weaker CS–US contiguity due to the prolonged effects of a high cocaine dose.     

Effects of environmental enrichment on nicotine-induced sensitization and cross-sensitization to d-amphetamine in rats

Introduction

Research indicates that adolescent nicotine exposure may predispose individuals to use other psychostimulants later in adulthood, offering support for the incentive-sensitization theory of addiction. Preclinical studies testing the incentive-sensitization theory show that repeated nicotine exposure in adolescent rats can lead to an increased sensitivity to the motor stimulant effects of nicotine and other psychostimulants in adulthood. Although previous nicotine exposure can increase sensitivity to stimulant drugs, rats raised in enriched conditions (EC) show, decreased sensitivity to psychostimulant drugs compared to rats raised in isolation conditions (IC).

Methods

We examined whether nicotine sensitization or cross-sensitization to d-amphetamine induced by adolescent nicotine exposure is altered by exposure to environmental enrichment. Adolescent EC and IC male rats received subcutaneous (s.c.) injections of saline or 0.4 mg/kg of nicotine once daily for seven days. Thirty-five days following the last nicotine injection EC and IC animals were challenged with saline, nicotine (0.2 or 0.4 mg/kg) or d-amphetamine (0.5 or 1.0 mg/kg).

Results

EC rats failed to show nicotine sensitization at either nicotine dose tested while IC rats showed nicotine sensitization following the 0.4 mg/kg nicotine dose. EC rats also failed to show nicotine-induced cross-sensitization to the 0.5 mg/kg dose of d-amphetamine while IC rats displayed cross-sensitization. However, EC rats did exhibit nicotine-induced cross-sensitization to the 1.0 mg/kg dose of d-amphetamine.

Conclusion

These findings indicate that environmental enrichment can alter the ability of adolescent nicotine exposure to induce sensitization and cross-sensitization in adulthood and may be used as a protectant factor against adolescent nicotine exposure.     

Adolescent environmental enrichment prevents the emergence of schizophrenia-like abnormalities in a neurodevelopmental model of schizophrenia

In the present study, we investigated whether exposure to an enriched environment (EE) during adolescence might affect the behavioural dysfunction (sensorimotor gating deficit, memory and social interaction impairments) and neurochemical changes (GAD67 expression, histone methylation) induced by methylazoxymethanol (MAM) in the MAM-E17 rat model of schizophrenia. EE was introduced for 7 days in early adolescence (days 23–29), and behavioural and biochemical studies were performed on adult rats at postnatal day 70. The results showed that exposure to EE prevented the development of adult behavioural deficits induced by prenatal MAM administration. EE also prevented the decrease in GAD67 mRNA and protein levels induced by MAM in the medial prefrontal cortex (mPFC). Moreover, EE inhibited the reductions in the amount of Gad1 bound to H3K4me3 and in the total H3K4me3 protein level induced by prenatal MAM administration in the adult mPFC. However, there was no effect of EE on behaviour or levels of the various neurochemical markers in adult rats prenatally treated with vehicle. Thus, these results indicate that EE exposure during early adolescence may inhibit the development of schizophrenia related symptoms through epigenetic mechanisms that regulate the expression of genes (e.g., Gad1) that are impaired in schizophrenia.     

Reinstatement of nicotine-seeking behavior by drug-associated stimuli after extinction in rats

Rationale Smoking-related environmental stimuli have been implicated as an important factor in triggering relapse in abstinent tobacco smokers, and recent evidence indicates that drug-associated stimuli can reinstate nicotine-seeking in rats. However, there is little investigation on the factors that contribute to the latter effect. Objective This study examined whether a nicotine-associated visual stimulus (VS) can reinstate nicotine-seeking after extinction in a response-reinstatement model of relapse, and whether the behavioral effects of the VS are sensitive to pharmacological blockade of nicotinic neurotransmission. It also determined whether active lever reassignment after food training influences nicotine self-administration and the VS-induced reinstatement. Methods Male Sprague–Dawley rats were trained to self-administer nicotine (0.03 mg/kg/infusion, IV) and associate a VS with each nicotine infusion in 30 daily 1-h sessions. Half of the animals received nicotine infusions for responding at the same lever that previously delivered food; for the other half, infusions resulted from pressing the previously inactive lever during food training. Then, the nicotine-maintained response was extinguished by saline substitution and withholding the VS. One day after rats reached extinction criterion, the reinstatement tests were conducted where the VS was response-contingent represented without further delivery of nicotine. In pharmacological tests, a nicotinic antagonist, mecamylamine, was subcutaneously administered 30 min before reinstatement sessions. Results Presentation of the nicotine-associated VS significantly reinstated responding at the previously drug-reinforced lever and pretreatment with mecamylamine effectively attenuated the response-reinstating effect of the VS. Additionally, animals showed similar profiles of nicotine-taking and nicotine-seeking behavior regardless of reassignment of the active lever after food training. Conclusions Nicotine self-administration and the VS-induced reinstatement of nicotine-seeking do not result from a lever bias due to prior experience for food reinforcement. Significantly, these results suggest that environmental stimuli associated with nicotine self-administration can effectively elicit nicotine-seeking behavior in abstinent subjects, that this effect is blocked by nicotine antagonism, and that the present procedures may be useful for studying neurobiological mechanisms of nicotine-seeking behavior and relapse.     

Different patterns of pharmacological reinstatement of cocaine-seeking behavior between Fischer 344 and Lewis rats

Rationale Fischer 344 (F344) and Lewis (LEW) rats differ in cocaine self-administration behaviors. Whether or not these inbred strains of rats differ in pharmacological reinstatement of cocaine-seeking behavior is unknown.Objectives The purpose of the present study was to determine if inbred strains of rats demonstrate differences in alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) and cocaine-induced reinstatement of previously extinguished cocaine-seeking behavior.Methods F344 and LEW rats received indwelling jugular catheters, bilateral guide cannula aimed at the nucleus accumbens core, and were trained to lever press for 0.5 mg/kg intravenous cocaine during 2-h self-administration sessions. Following 14 sessions, rats underwent extinction sessions, where previously reinforced lever pressing resulted in no programmed consequences. Just prior to beginning extinction session 7, rats received an intracranial infusion of saline. Lever pressing was not reinforced. During subsequent extinction sessions, rats received AMPA injections (0.2, 0.4, or 0.6 nM). Dosing order was determined by a within-subject Latin square design. At least two extinction sessions separated each AMPA session. Rats then underwent cocaine-induced reinstatement test sessions (lever pressing was not reinforced). Rats received passive intravenous cocaine (0.0, 0.5, 1.0, or 2.0 mg/kg) after being placed in the experimental chamber. At least two extinction sessions separated each cocaine-prime session, and subjects were tested at each dose according to a within-subjects Latin square design.Results LEW rats demonstrated blunted maximal responding to AMPA-induced reinstatement and heightened sensitivity to cocaine-induced reinstatement compared with F344 rats.Conclusions This study demonstrates that inbred strains differ in pharmacological reinstatement of cocaine-seeking behavior.     

The effect of nicotine and total alkaloids extracted from cigarette smoke on avoidance behavior in rats under extinction procedure

The effect of nicotine and total alkaloids extracted from smoke on the avoidance behavior of rats under extinction procedure has been measured in an experiment extended over a period of three months. There was no significant difference between the two substances, with both inhibiting the extinction of avoidance response to approximately the same degree. Significance against the control was achieved with all treatments, the effect being significantly greater with the dose of 0.2 mg/kg than with the two doses of 0.1 or 0.05 mg/kg.This study was made possible through the help of a research grant from the Swiss Association of Cigarette Manufacturers.     

The investigation of neonatal MK-801 administration and physical environmental enrichment on emotional and cognitive functions in adult Balb/c mice

N-methyl-d-aspartate (NMDA) receptors play an important role in brain maturation and developmental processes. It is known that growing up in an enriched environment has effects on emotional and cognitive performance. In our study, we evaluated the effects of physically enriched environment on the emotional and cognitive functions of the adult brain in the setting of previous NMDA receptor hypoactivity during the critical developmental period of the nervous system. In this study, NMDA receptor blockade was induced 5-10 days postnatally (PD5-10) using MK-801 in mice Balb/c (twice a day 0.25 mg/kg, for 5 days, intraperitoneal). MK-801 was given to developing mice living in a standard (SE) and an enrichment environment (EE) and once the animals reached adulthood, emotional behaviors were evaluated using an open field test (OF) and an elevated plus maze (EPM) test whereas cognitive processes were evaluated using the Morris water-maze (MWM). The EE group showed decreased locomotor activity (p < 0.05) in the OF and increased exploratory behaviour (p < 0.01) and decreased fear of heights/anxiety-like behaviour (p < 0.05) in the EPM test. The EE had positive effects on spatial learning in the MWM (p < 0.05). Blockade of the NMDA receptor increased the fear of height (p < 0.05), decreased exploratory behaviour and locomotor activity (p < 0.001). Also, it led to decreased spatial learning (p < 0.05). The decreases in spatial learning and exploratory behaviours and the increase in fear of heights/anxiety-like behaviour with NMDA receptor blockade was not reversed by EE. NMDA receptor blockade during the critical period of development led to deterioration in the emotional and cognitive processes during adulthood. An enriched environmental did not reverse the deleterious effects of the NMDA receptor blockade on emotional and cognitive functions.     

Escalation of i.v. cocaine self-administration and reinstatement of cocaine-seeking behavior in rats bred for high and low saccharin intake

Rationale Rats selectively bred for high saccharin (HiS) intake consume more alcohol, acquire intravenous (i.v.) cocaine self-administration more rapidly, and show more dysregulated patterns of cocaine self-administration than their low saccharin-consuming (LoS) counterparts.Objectives The purpose of the present study was to determine whether HiS and LoS rats also differ in the escalation, maintenance, extinction, and reinstatement of i.v. cocaine self-administration.Materials and methods Two experiments were conducted in separate groups of rats. In the first experiment, HiS and LoS female rats were allowed to self-administer cocaine [0.4 mg/kg; fixed ratio (FR) 1] under short (ShA, 2 h per day) or long (LgA, 12 h per day) access conditions for 21 days. Session lengths were subsequently equated (2 h), and FR1-maintained cocaine self-administration was examined. In the second experiment, additional groups of HiS and LoS female rats were given access to cocaine (0.4 mg/kg; FR 1) self-administration during 2-h sessions for 10 days. Subsequently, saline was substituted for cocaine, and responding was extinguished. After a 14-day extinction period, saline- and cocaine-[5, 10, and 15 mg/kg, intraperitoneal (i.p.)] induced reinstatement of drug-seeking behavior was measured.Results HiS LgA rats escalated their cocaine intake more rapidly than LoS rats, and during the 2 h sessions after escalation cocaine self-administration was significantly higher in HiS LgA rats, compared to LoS LgA rats. HiS rats responded on the cocaine-paired lever more than LoS rats during maintenance, extinction, and cocaine-(15 mg/kg) induced reinstatement.Conclusions These results suggest that HiS and LoS rats have distinct drug-seeking and drug-taking profiles. The HiS and LoS rats differ along a wide range of behavioral dimensions and represent an important model to study the interactions of excessive intake of dietary substances and vulnerability to drug abuse.     

Effects of puromycin on memory for shuttle box extinction in goldfish and barpress extinction in rats

Five experiments were conducted to investigated the generality of puromycin's reported effect on disruption on memory of a recently learned task. The first experiment replicated previous work on acquisition to determine the effectiveness of the procedures used. The second investigated the role of puromycin's low pH in memory disruption. The third experiment used short training and extinction sessions to determine if puromycin retarded retention of extinction. The fourth experiment used longer training and extinction sessions and multiple and delayed injections of puromycin, and the fifth experiment attempted to extend puromycin's effect on avoidance extinction to extinction produced in an appetitive operant task. Puromycin disrupted retention of extinction of both shuttle box avoidance in fish and barpressing in rats. The role of puromycin's pH was negligible.     

Effects of TRH on acquisition and extinction of shuttlebox-avoidance behavior in Fischer344 rats

Thyrotropin-releasing hormone (TRH) was injected intraperitoneally into male Fischer₃₄₄ rats in doses ranging between 1 mg/kg and 20 mg/kg to assess the effects on the acquisition and extinction of shuttlebox-avoidance behavior. Administration of 20 mg/kg TRH resulted in a rapid acquisition of avoidance behavior in early training trials. This enhancement did not involve changes in the occurence of anticipatory responses to an inevitable shock but was correlated with an increase of concurrent intertrial-responses. Thus, the behavioral changes observed would be a reflection of TRH-induced changes on motor activity. TRH treatment did not alter the resistance to extinction of the avoidance response. This finding is corroborated by the fact that rats given the TRH treatment withheld the well-learned response to a warning signal, when this response was selectively punished after initial acquisition stage.     

Impairment of endocannabinoids activity in the dorsolateral striatum delays extinction of behavior in a procedural memory task in rats

The dorsolateral striatum (DLS) has been implicated in the learning of habits and procedural memories. Extinction of this kind of memories has been poorly studied. The DLS expresses high levels of the cannabinergic receptor one (CB1), and, lately, it has been suggested that the activation of CB1 in this structure is indispensable for long-term depression (LTD) development. We performed experiments in a T-maze and evaluated the effects of intrastriatal and intrahipocampal administration of the CB1 antagonist AM251 on extinction and on c-Fos expression. We also administered anandamide to evaluate if an artificial increase of endocannabinoids facilitates extinction. Our results indicate clearly a dose-response blockade of extinction induced by AM251 injected into the striatum but a facilitation of extinction when administered into the hippocampus. Anandamide did not induce any observable changes. AM251 effects were accompanied by an increase in c-Fos immunoreactivity in the DLS and its decrease in the hippocampal region, suggesting that the activation of CB1 in the striatum is necessary for the extinction of procedural memories. These findings could be important in some neurological conditions, such as obsessive-compulsive disorder in which striatal activity seems to be abnormal.     

The inhibition of histone deacetylases reduces the reinstatement of cocaine-seeking behavior in rats

Drug addiction is a chronic brain disease characterized by a persistent risk of relapse, even after a long period of abstinence. A current hypothesis states that relapse results from lasting neuroadaptations that are induced in response to repeated drug administration. The adaptations require gene expression, some of which being under the control of stable epigenetic regulations. We have previously demonstrated that pretreatment with histone deacetylase (HDAC) inhibitors reduces the cocaine reinforcing properties as well as the motivation of rats for cocaine. We show here that the same HDAC inhibitors, trichostatin A and phenylbutyrate, significantly reduced the cocaine-seeking behavior induced by the combination of a cocaine injection together with the exposure to a light cue previously associated with cocaine taking. Reinstatement of drug-seeking behavior was carried out after a 3-week withdrawal period, which came after ten daily sessions of cocaine intravenous self-administration. Our results suggest that pharmacological treatment aimed at modulating epigenetic regulation, and particularly treatment that would inhibit HDAC activity, could reduce the risk of relapse, a major drawback in the treatment of drug addiction.