Abstract
Previous studies have reported intravenous cocaine self-administration behavior in several strains of mice with the exception of BALB/cByJ, a strain considered a mouse model of high emotional reactivity. The present experiments further investigated acquisition of self-administration in BALB/cByJ mice using a low dose and a habituation session. Following evidence of an initial drug-seeking behavior, we observed a progressive decline of intravenous self-administration. Pretreatment with diazepam (0.5 mg/kg, IP), reinstated cocaine-maintained responding. To test the hypothesis that injections directly into a reward-relevant brain region might support consistent cocaine-seeking behavior, BALB/cByJ mice implanted in the nucleus accumbens (NAc) or the caudate-putamen nucleus (CPu) were trained to discriminate between the arm enabling a microinjection of cocaine (30 pmol/50 nl or 150 pmol/50 nl) and the neutral arm of a Y-maze. Only NAc subjects exhibited a spatial discrimination toward the cocaine-reinforced arm and the D2 antagonist, sulpiride (50 mg/kg, IP) eliminated intra-NAc cocaine self-administration. However, after several days of cocaine self-injection, animals developed an approach/avoidance-like behavior between the start box and the reinforced arm. This behavior was suppressed by systemic diazepam (1 mg/kg, IP) pretreatment. We conclude that: (1) medio-ventral NAc is involved both in the rewarding (via a D2 dopaminergic mechanism) and aversive effects of cocaine in mice; and (2) anxiolytic pretreatment (diazepam) indirectly enhanced the reinforcing properties of cocaine in BALB/cByJ, suggesting that emotionality can act as a protective mechanism against stimulant abuse.
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Acknowledgements
We thank Drs. A. Contarino, R. Picetti, A. Roberts, and M. Taffe for their helpful comments on a earlier version of the manuscript; M. Arends for skillful editorial assistance, and L. Decorte, T. Lafon, B. Lintz, D. Panzeri, and I. Polis for excellent technical assistance. This investigation was supported by the CNRS (UMR 5807) and Grant DA 10191(LHG). This is publication 12605-NP from The Scripps Research Institute.
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David, V., Gold, L., Koob, G. et al. Anxiogenic-Like Effects Limit Rewarding Effects of Cocaine in BALB/cByJ Mice. Neuropsychopharmacol 24, 300–318 (2001). https://doi.org/10.1016/S0893-133X(00)00205-0
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