Nucleus accumbens shell excitability is decreased by methamphetamine self-administration and increased by 5-HT2C receptor inverse agonism and agonism

• Published in: Neuropharmacology Vol. 89; pp. 113 - 121
• Main Authors: Graves, Steven M., Clark, Mary J., Traynor, John R., Hu, Xiu-Ti, Napier, T. Celeste
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-02-2015
• Subjects: 5-HT2C; Animals; Constitutive activity; Drug Inverse Agonism; Inverse agonist; Male; Methamphetamine; Methamphetamine - administration & dosage; Nucleus accumbens; Nucleus Accumbens - drug effects; Nucleus Accumbens - metabolism; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2C - metabolism; Self Administration; Serotonin; Serotonin 5-HT2 Receptor Agonists - pharmacology; Nucleus accumbens; 5-HT2C; Serotonin; Constitutive activity; Inverse agonist; Methamphetamine; 5-HT(2C)
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2014.09.001

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.
•Methamphetamine self-administration decreased excitability of accumbens shell neurons.•5-HT2C receptor agonism increased accumbens shell excitability.•5-HT2C receptor inverse agonism increased accumbens shell excitability.•5-HT2C receptors in the accumbens engage Gi/o but not Gq proteins.