Claudia Chauvet

Reversal of cocaine addiction by environmental enrichment

Environmental conditions can dramatically influence the behavioral and neurochemical effects of drugs of abuse. For example, stress increases the reinforcing effects of drugs and plays an important role in determining the vulnerability to develop drug addiction. On the other hand, positive conditions, such as environmental enrichment, can reduce the reinforcing effects of psychostimulants and may provide protection against the development of drug addiction. However, whether environmental enrichment can be used to “treat” drug addiction has not been investigated. In this study, we first exposed mice to drugs and induced addiction-related behaviors and only afterward exposed them to enriched environments. We found that 30 days of environmental enrichment completely eliminates behavioral sensitization and conditioned place preference to cocaine. In addition, housing mice in enriched environments after the development of conditioned place preference prevents cocaine-induced reinstatement of conditioned place preference and reduces activation of the brain circuitry involved in cocaine-induced reinstatement. Altogether, these results demonstrate that environmental enrichment can eliminate already established addiction-related behaviors in mice and suggest that environmental stimulation may be a fundamental factor in facilitating abstinence and preventing relapse to cocaine addiction.

Environmental Enrichment Reduces Cocaine Seeking and Reinstatement Induced by Cues and Stress but Not by Cocaine

Whereas earlier studies have focused on the preventive effects of enriched environments (EE) in drug addiction, in a recent study we suggested that EE can also have ‘curative’ effects. In fact, we found that cocaine addiction-related behaviors can be eliminated by housing cocaine-treated mice in EE during periods of forced abstinence. However, those results were obtained with two simple models of addiction, conditioned place preference (CPP), and behavioral sensitization. In this study, we used intravenous drug self-administration procedures in rats to further investigate the beneficial effects of EE on cocaine addiction in a reinstatement model of relapse. Singly housed rats learned to self-administer cocaine during 10 consecutive daily sessions (0.6 mg/injection, 6 h/day). They were then housed three per cage in either standard environments (SE) or EE and were kept abstinent in the animal facility until testing for extinction and reinstatement. We found that 30 days of EE significantly and consistently reduced cocaine seeking during a 6-h extinction session. In addition, EE significantly reduced cue- and stress-induced reinstatement. Surprisingly, given our earlier results in mice with CPP, EE did not reduce cocaine-induced reinstatement regardless of the level of exposure to cocaine and the duration of the period of abstinence and exposure to EE. Altogether, these results support the hypothesis that EE can reduce cocaine-induced craving and highlight the importance of positive life conditions in facilitating abstinence and preventing relapse to cocaine addiction.

Effects of environmental enrichment on the incubation of cocaine craving

Recent studies have demonstrated that exposure to environmental enrichment (EE) during withdrawal periods reduces the risks of relapse to drug-seeking behavior. In this study, we investigated whether EE could prevent the development of time-dependent increases in cocaine-seeking behavior (incubation of craving). In addition, we investigated whether EE could eliminate already developed incubation and whether the effects of EE would last when enrichment is discontinued. For this, we allowed rats to self-administer cocaine for 10 daily 6 h sessions and measured cocaine-seeking 1, 30 and 60 days after the last self-administration session. In between these tests, rats were kept in forced abstinence and housed either in EE or standard environments (SE). Between day 30 and 60 of withdrawal, half of the rats in each group were maintained in their original environmental condition and the other half was switched to the other environmental condition. We found that exposure to EE prevents development of incubation of cocaine craving and eliminates already developed incubation. In addition, contrary to our expectations, when EE was discontinued, its positive effects on incubation of craving disappeared. These results indicate that EE can reduce cocaine seeking but only temporarily and questions the hypothesis that EE can permanently eliminate the neural consequences of exposure to drugs of abuse. Therefore, stimulating environments could have positive effects on the treatment of cocaine addiction only if they are maintained for long periods of abstinence that encompass the time-frame during which addicts are most vulnerable to relapse.

Chronic Stimulation of the Tone of Endogenous Anandamide Reduces Cue- and Stress-Induced Relapse in Rats

Background: The endogenous cannabinoid system plays an important role in motivation, stress, and drug abuse. Pharmacologically, the endocannabinoid system can be stimulated by either agonists of CB1 receptors or inhibition of metabolic degradation of endogenous cannabinoids and consequent increases in their brain levels. Methods: Here, we investigated whether chronic administration during a period of withdrawal of the fatty acid amide hydrolase inhibitor URB597, which increases anandamide levels, would decrease the risks of relapse to cocaine seeking. Rats were allowed to self-administer cocaine and then they underwent forced withdrawal for 28 days, during which they were treated with URB597 or vehicle. One day after the last injection, we investigated cocaine seeking in one 6h extinction session and relapse triggered by re-exposure to drug-associated cues or a pharmacological stressor. Results: We found that administration of URB597 significantly decreases cocaine-seeking behavior and cue- and stress-induced relapse.Conclusion: These results suggest that stimulation of the endocannabinoid system could be helpful to prevent relapse to cocaine addiction.

Statins Reduce the Risks of Relapse to Addiction in Rats.

Statins are drugs that have been used for decades in humans for the treatment of hypercholesterolemia. More recently, several lines of evidence demonstrate that statins, in addition to their peripheral effects, produce a wide variety of effects in the brain and may be beneficial in neurological and psychiatric conditions. In this study, we allowed rats to self-administer cocaine for several weeks and, at the end of self-administration training, we treated them with low doses of statins daily for a 21-day period of abstinence. Chronic administration of brain-penetrating statins, simvastatin (1 mg/kg) and atorvastatin (1 mg/kg), reduced cocaine seeking compared with vehicle, whereas administration of pravastatin (2 mg/kg), a statin with low brain penetrability, did not. Importantly, the effects of brain-penetrating statins persisted even after discontinuation of the treatment and were specific for drug seeking because drug taking was not altered by simvastatin treatment. Finally, the effects of simvastatin were found to generalize to another drug of abuse such as nicotine, but not to food reward, and to reinstatement of cocaine seeking induced by stress. These results demonstrate that brain-penetrating statins can reduce risks of relapse to addiction. Given their well-known safety profile in humans, statins could be a novel effective treatment for relapse to cocaine and nicotine addiction and their use could be implemented in clinical settings without major health risks.

C.14 - ANTI-CRAVING EFFECTS OF THE CHOLESTEROL-LOWERING DRUG SIMVASTATIN IN RATS

drug use characterised by a compulsion to take drugs, loss of control over drug use and the emergence of a negative emotional state. Adolescence is a particularly vulnerable period for the development of substance abuse disorders; 9% of adolescents (13–18 years) fulfil the criteria for drug dependence. Risk factors for substance abuse include high levels of impulsivity and alterations in reward regulation. Glutamate plays a key role in facilitating motivational behaviour and control of impulsive behaviours. Glutamatergic innervations coupled to dopaminergic innervations converge on the nucleus accumbens promoting plasticity, allowing drug-related cues to increase in salience and thus, in at-risk individuals, induce hypersensitivity to drug-associated stimuli. As such, reducing glutamatergic signalling in circuits associated with reward processing and impulsive control may serve to attenuate the effects of drugs of abuse in adolescents. To test this we pre-treated adult (7–8 weeks) and juvenile (3 weeks) male C57BL6/j mice with riluzole (2.5, 5, 10 mg/kg or vehicle; i.p.). Riluzole reduces glutamatergic signalling via the activation of synaptic glutamate transporters and blocking sodium channels. 30 min later cocaine (10 mg/kg; i,p.) was administered and locomotor activity was recorded for a subsequent 60 min. Interestingly, riluzole (10 mg/kg) partially attenuated cocaineinduced hyperlocomotion in juvenile mice yet had no effect in adults. This was independent to any sedentary effect as riluzole had no effect on locomotion or motor-coordination. These data suggest juveniles and adults possess differing glutamatergic circuitry responsible for mediating reward processing and impulsive behavioural control. Furthermore, reducing glutamatergic signalling may be a viable therapeutic strategy for treating individuals at risk of developing substance-abuse disorders including certain adolescent populations.