生化学と薬理学: オープンアクセス
オープンアクセス

概要

Nicotine Enhances the Excitability of Gaba Neurons in the Ventral Tegmental Area via Activation of Alpha 7 Nicotinic Receptors on Glutamate Terminals

Devin H Taylor, Poromendro N Burman, Micah D Hansen, Rebecca S Wilcox, Brett R Larsen, Jennifer K Blanchard, Collin B Merrill, Jeffrey G Edwards, Sterling N Sudweeks, Jie Wu MD, Hugo R Arias and Scott C Steffensen

Ventral tegmental area dopamine (DA) and GABA neurons express nicotinic acetylcholine receptor (nAChR) subtypes, whose net activation results in enhancement of DA release in the nucleus accumbens (NAc). This effect decreases after repeated nicotine (NIC) treatment via desensitization. We evaluated the effects of acute NIC on glutamate decarboxylase (GAD67)-positive GABA neurons in the VTA of green fluorescent protein (GFP) knockin (GAD-GFP) mice, and determined the expression of selected nAChR subunits in VTA GABA neurons. In vivo, tachylphylaxis accrued to repeated systemic, but not local administration of NIC. Microelectrophoretic application of NIC and the α7 nAChR partial agonist JN403 markedly enhanced the firing rate of VTA GABA neurons. This activation was suppressed by intraperitoneal administration of the α7 nAChR antagonist methyllycaconitine (MLA, 1 mg/kg), or the glutamate (GLU) NMDA receptor antagonist APV (1 mg/kg), but not by the non-selective non-competitive antagonist mecamylamine (MEC, 1 mg/kg). In patch clamp studies in the slice preparation, the α7 nAChR agonist choline (1-10 mM), in the presence of the muscarinic cholinergic antagonist atropine (50 μM), enhanced sEPSC and mini-EPSC frequency, but not amplitude, which was blocked by MLA (0.5 μM). JN403 (0.1-1 μM) enhanced evoked EPSCs, without affecting membrane currents of VTA GABA neurons. In patch clamp studies in dissociated VTA GABA neurons, choline+atropine failed to induce whole-cell current responses in most cells tested. Single cell RT-qPCR revealed that most GABA neurons did not express α7 nAChRs. Together, this indicates that NIC excites VTA GABA neurons via α7 nAChRs located on GLUergic terminals.