Dorsal raphe 5-HT2C receptor and GABA networks regulate anxiety produced by cocaine withdrawal

NEUROPHARMACOLOGY

卷:93

Article

Craige, Caryne P.^1,3  Lewandowski, Stacia³  Kirby, Lynn G.^2,3  Unterwald, Ellen M.^1,3 

[1] Temple Univ, Sch Med, Dept Pharmacol, Philadelphia, PA 19122 USA

[2] Temple Univ, Dept Anat & Cell Biol, Sch Med, Philadelphia, PA 19122 USA

[3] Temple Univ, Ctr Substance Abuse Res, Sch Med, Philadelphia, PA 19122 USA

关键词: Cocaine;    Serotonin;    Anxiety;    Addiction;    GABA;    Electrophysiology;   

DOI  :  10.1016/j.neuropharm.2015.01.021

来源: Elsevier

【 摘 要 】

The serotonin system is intimately linked to both the mediation of anxiety and long-term effects of cocaine, potentially through interaction of inhibitory 5-HT2C receptor and gamma-aminobutyric acid (GABA) networks. This study characterized the function of the dorsal raphe (DR) 5-HT2C receptor and GABA network in anxiety produced by chronic cocaine withdrawal. C57BL/6 mice were injected with saline or cocaine (15 mg/kg) 3 times daily for 10 days, and tested on the elevated plus maze 30 min, 25 h, or 7 days after the last injection. Cocaine-withdrawn mice showed heightened anxiety-like behavior at 25 h of withdrawal, as compared to saline controls. Anxiety-like behavior was not different when mice were tested 30 min or 7 days after the last cocaine injection. Electrophysiology data revealed that serotonin cells from cocaine-withdrawn mice exhibited increased GABA inhibitory postsynaptic currents (IPSCs) in specific DR subregions dependent on withdrawal time (25 h or 7 d), an effect that was absent in cells from non-withdrawn mice (30 min after the last cocaine injection). Increased IPSC activity was restored to baseline levels following bath application of the 5-HT2C receptor antagonist, SB 242084. In a separate cohort of cocaine-injected mice at 25 h of withdrawal, both global and intra-DR blockade of 5-HT2C receptors prior to elevated plus maze testing attenuated anxiety-like behavior. This study demonstrates that DR 5-HT2C receptor blockade prevents anxiety-like behavior produced by cocaine withdrawal, potentially through attenuation of heightened GABA activity, supporting a role for the 5-HT2C receptor in mediating anxiety produced by cocaine withdrawal. (C) 2015 Elsevier Ltd. All rights reserved.

【 授权许可】

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