title: Dorsal raphe 5-HT(2C) receptor and GABA networks regulate anxiety produced by cocaine withdrawal.
abstract: 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 Cocaine-withdrawn mice showed heightened anxiety-like behavior at 25 h of withdrawal, as compared to saline controls.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 Electrophysiology data revealed that serotonin cells from cocaine-withdrawn mice exhibited increased GABA inhibitory postsynaptic currents (IPSCs) in specific DR subregions dependent on withdrawal time (25 h or 7 d), an effect that was absent in cells from non-withdrawn mice (30 min after the last cocaine injection).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.
authors: Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA, USA; Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, USA. Electronic address: caryne.craige@gmail.com.
authors: Caryne P
authors: CP
authors: Craige
authors: Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, USA.
authors: Stacia
authors: S
authors: Lewandowski
authors: Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, PA, USA; Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, USA.
authors: Lynn G
authors: LG
authors: Kirby
authors: Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA, USA; Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, USA.
authors: Ellen M
authors: EM
authors: Unterwald
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001007:Anxiety / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D003042:Cocaine / Q000009:adverse effects*; D004195:Disease Models, Animal; D018765:Dopamine Uptake Inhibitors / Q000009:adverse effects*; D065847:Dorsal Raphe Nucleus / Q000378:metabolism* / Q000473:pathology; D005106:Exploratory Behavior / Q000187:drug effects; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*; D018490:Serotonin Agents / Q000494:pharmacology; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology; D013997:Time Factors; D014365:Tryptophan Hydroxylase / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D018765:Dopamine Uptake Inhibitors; D044405:Receptor, Serotonin, 5-HT2C; D018490:Serotonin Agents; D005680:gamma-Aminobutyric Acid; D014365:Tryptophan Hydroxylase; D003042:Cocaine
keywords: Addiction; Anxiety; Cocaine; Electrophysiology; GABA; Serotonin
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