Elsevier

Neuroscience

Volume 184, 16 June 2011, Pages 88-96
Neuroscience

Cognitive, Behavioral, and Systems Neuroscience
Research Paper
Brain regions associated with the reversal of cocaine conditioned place preference by environmental enrichment

https://doi.org/10.1016/j.neuroscience.2011.03.068Get rights and content

Abstract

In addition to the known preventive effects of environmental enrichment (EE) on drug addiction, we have recently shown that EE can also have “curative” effects and eliminate addiction-related behaviors in mice and rats. In the present study, using Fos immunohistochemistry, we investigated brain regions involved in the elimination of cocaine conditioned place preference (CPP) produced by a 30-day exposure to EE. A first group of mice was conditioned to cocaine in the CPP apparatus, a second group that served as control received cocaine in a cage different from the CPP apparatus and a third control group received only saline injections. At the end of conditioning, we kept mice abstinent in the animal facility, housing them in standard environments (SE) or EE for 30 days and then we tested them for expression of CPP. SE, but not EE mice, conditioned to cocaine showed long-lasting preferences for the cocaine-paired compartment. Expression of CPP was paralleled by significant increases in the expression of Fos in the anterior cingulate cortex, the lateral caudate putamen, the shell of the nucleus accumbens, the dentate gyrus of the hippocampus, the basolateral and central nuclei of amygdala, the bed nucleus of the stria terminalis, and the ventral tegmental area. In contrast, EE mice showed levels of expression of FOS similar to control groups. These results demonstrate that EE can eliminate context-induced cocaine seeking and that this effect appears associated with a general reduction in the activation of several brain regions implicated in relapse.

Highlights

▶Exposure to EE during a 30-day period of abstinence prevents the expression of cocaine CPP. ▶Only SE conditioned mice show significant induction of Fos expression in several brain areas. ▶The effects of EE are associated with a general inhibition of brain circuitry involved in relapse. ▶Expression of Fos is not found in unconditioned and saline control mice.

Section snippets

Animals

Seventy-two adult male C57/BL6 mice (Elevage Janvier, France), 10–12 weeks old, experimentally naïve at the start of the study, were housed in a temperature- and humidity-controlled room and maintained on a 12 h light/dark cycle with the lights on from 7:00 am–7:00 pm and had ad libitum access to food and water. All experimentation was conducted during the light period. Experiments were carried out in accordance with the European Communities Council Directive of November 24, 1986 (86/609/EEC)

Cocaine seeking behavior in SE and EE mice

As previously shown (Solinas et al., 2008), after 30 days of withdrawal, conditioned SE mice showed significant preferences for the compartment previously associated with cocaine compared to saline-treated mice whereas the preference for cocaine-paired compartment was completely lost in conditioned EE mice (Fig. 3A). As expected, SE and EE saline as well as unconditioned groups showed no CPP. Statistical analysis demonstrated no significant main effect for environment or treatment but a

Discussion

In this study, we have found that the “curative” effects of EE on cocaine seeking behavior are associated with a general inhibition in the activation of the brain neurocircuitry involved in relapse, including cortical, motor, and limbic structures that have previously been shown to be involved in cocaine seeking behavior in rodents (Bossert et al., 2005, Kalivas, 2008, Koob and Le Moal, 2001). In fact, all the regions that were significantly activated in SE mice conditioned to cocaine compared

Acknowledgments

The authors thank N. Thiriet for helpful comments on the manuscript and A. Gaillard for advices on the immunohistochemistry procedures. This work was supported by Centre National de la Recherche Scientifique (CNRS), University of Poitiers, Mission Interministérielle de Lutte contre la Drogue et la Toxicomanie, Région Poitou-Charentes, and the Contrat de Projet Etat Region (CPER) #5. C. Chauvet is a recipient of a PhD fellowship from the French Ministry of Research.

References (65)

  • G. Laviola et al.

    Effects of enriched environment on animal models of neurodegenerative diseases and psychiatric disorders

    Neurobiol Dis

    (2008)
  • L. Lu et al.

    Effect of environmental stressors on opiate and psychostimulant reinforcement, reinstatement and discrimination in rats: a review

    Neurosci Biobehav Rev

    (2003)
  • L. Lu et al.

    Systemic and central amygdala injections of the mGluR(2/3) agonist LY379268 attenuate the expression of incubation of cocaine craving

    Biol Psychiatry

    (2007)
  • W.J. Lynch et al.

    Aerobic exercise attenuates reinstatement of cocaine-seeking behavior and associated neuroadaptations in the prefrontal cortex

    Biol Psychiatry

    (2010)
  • J. Nithianantharajah et al.

    The neurobiology of brain and cognitive reserve: mental and physical activity as modulators of brain disorders

    Prog Neurobiol

    (2009)
  • P.V. Piazza et al.

    The role of stress in drug self-administration

    Trends Pharmacol Sci

    (1998)
  • D.J. Rohsenow et al.

    Urge-specific and lifestyle coping strategies of cocaine abusers: relationships to treatment outcomes

    Drug Alcohol Depend

    (2005)
  • M. Solinas et al.

    Prevention and treatment of drug addiction by environmental enrichment

    Prog Neurobiol

    (2010)
  • K.J. Thiel et al.

    Environmental living conditions introduced during forced abstinence alter cocaine-seeking behavior and Fos protein expression

    Neuroscience

    (2010)
  • N. Thiriet et al.

    Environmental enrichment during adolescence regulates gene expression in the striatum of mice

    Brain Res

    (2008)
  • Z. Xu et al.

    Effects of enriched environment on morphine-induced reward in mice

    Exp Neurol

    (2007)
  • A.R. Zavala et al.

    Fos and glutamate AMPA receptor subunit coexpression associated with cue-elicited cocaine-seeking behavior in abstinent rats

    Neuroscience

    (2007)
  • A.T. Alleweireldt et al.

    Effects of SCH-23390 infused into the amygdala or adjacent cortex and basal ganglia on cocaine seeking and self-administration in rats

    Neuropsychopharmacology

    (2006)
  • E. Bezard et al.

    Enriched environment confers resistance to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and cocaine: involvement of dopamine transporter and trophic factors

    J Neurosci

    (2003)
  • D.M. Buffalari et al.

    Inactivation of the bed nucleus of the stria terminalis in an animal model of relapse: effects on conditioned cue-induced reinstatement and its enhancement by yohimbine

    Psychopharmacology (Berl)

    (2010)
  • C. Chauvet et al.

    Environmental enrichment reduces cocaine seeking and reinstatement induced by cues and stress but not by cocaine

    Neuropsychopharmacology

    (2009)
  • A.R. Childress et al.

    Limbic activation during cue-induced cocaine craving

    Am J Psychiatry

    (1999)
  • R. Ciccocioppo et al.

    Cocaine-predictive stimulus induces drug-seeking behavior and neural activation in limbic brain regions after multiple months of abstinence: reversal by D(1) antagonists

    Proc Natl Acad Sci U S A

    (2001)
  • H.S. Crombag et al.

    ReviewContext-induced relapse to drug seeking: a review

    Philos Trans R Soc Lond B Biol Sci

    (2008)
  • J.S. de Olmos et al.

    The concepts of the ventral striatopallidal system and extended amygdala

    Ann N Y Acad Sci

    (1999)
  • P. Di Ciano et al.

    Direct interactions between the basolateral amygdala and nucleus accumbens core underlie cocaine-seeking behavior by rats

    J Neurosci

    (2004)
  • P. Di Ciano et al.

    Differential effects of nucleus accumbens core, shell, or dorsal striatal inactivations on the persistence, reacquisition, or reinstatement of responding for a drug-paired conditioned reinforcer

    Neuropsychopharmacology

    (2008)
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