title: Nucleus accumbens shell excitability is decreased by methamphetamine self-administration and increased by 5-HT2C receptor inverse agonism and agonism.
abstract: Methamphetamine profoundly increases brain monoamines and is a widely abused psychostimulant. The effects of methamphetamine self-administration on neuron function are not known for the nucleus accumbens, a brain region involved in addictive behaviors, including drug-seeking. One therapeutic target showing preclinical promise at attenuating psychostimulant-seeking is 5-HT2C receptors; however, the effects of 5-HT2C receptor ligands on neuronal physiology are unclear. 5-HT2C receptor agonism decreases psychostimulant-mediated behaviors, and the putative 5-HT2C receptor inverse agonist, SB 206553, attenuates methamphetamine-seeking in rats. To ascertain the effects of methamphetamine, and 5-HT2C receptor inverse agonism and agonism, on neuronal function in the nucleus accumbens, we evaluated methamphetamine, SB 206553, and the 5-HT2C receptor agonist and Ro 60-0175, on neuronal excitability within the accumbens shell subregion using whole-cell current-clamp recordings in forebrain slices ex vivo. We reveal that methamphetamine self-administration decreased generation of evoked action potentials. In contrast, SB 206553 and Ro 60-0175 increased evoked spiking, effects that were prevented by the 5-HT2C receptor antagonist, SB 242084. We also assessed signaling mechanisms engaged by 5-HT2C receptors, and determined that accumbal 5-HT2C receptors stimulated Gq, but not Gi/o. These findings demonstrate that methamphetamine-induced decreases in excitability of neurons within the nucleus accumbens shell were abrogated by both 5-HT2C inverse agonism and agonism, and this effect likely involved activation of Gq-mediated signaling pathways.
authors.affiliation: Department of Pharmacology, Center for Compulsive Behavior and Addiction, Rush University Medical Center, 1735 W Harrison St, Cohn Research Building Chicago, IL 60612, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Graves
authors.affiliation: Department of Pharmacology, Substance Abuse Research Center University of Michigan, 1150 W Medical Center Drive, Medical Science Research Building III Ann Arbor, MI 48109, USA.
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Clark
authors.affiliation: Department of Pharmacology, Substance Abuse Research Center University of Michigan, 1150 W Medical Center Drive, Medical Science Research Building III Ann Arbor, MI 48109, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Traynor
authors.affiliation: Department of Pharmacology, Center for Compulsive Behavior and Addiction, Rush University Medical Center, 1735 W Harrison St, Cohn Research Building Chicago, IL 60612, USA.
authors.forename: Xiu-Ti
authors.initials: XT
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, Center for Compulsive Behavior and Addiction, Rush University Medical Center, 1735 W Harrison St, Cohn Research Building Chicago, IL 60612, USA; Department of Psychiatry, Rush University Medical Center, 2150 W Harrison St Chicago, IL 60612, USA. Electronic address: Celeste_Napier@rush.edu.
authors.forename: T Celeste
authors.initials: TC
authors.lastname: Napier
mesh_terms: D000818:Animals; D054314:Drug Inverse Agonism; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*; D012646:Self Administration; D058826:Serotonin 5-HT2 Receptor Agonists / Q000494:pharmacology*
chemical_list: D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists; D008694:Methamphetamine
keywords: 5-HT(2C); Constitutive activity; Inverse agonist; Methamphetamine; Nucleus accumbens; Serotonin