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

Abstract

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.

Acute Ethanol Inhibits Dopamine Release in the Nucleus Accumbens via α6 Nicotinic Acetylcholine Receptors

“…These channels can exist in either homomeric or heteromeric form, with the a7 subunit composing the most common homomeric nAChR in the CNS, and pentameric mixtures of a (a2-a10) and b (b2-b4) subunits, with a4b2*-nAChRs as the most common heteromeric CNS receptor (Taylor et al, 2013a). Although nAChRs are of a wide variety in the VTA (Wooltorton et al, 2003), heteromeric a6*-nAChRs are highly expressed in the mesolimbic DA system (Champtiaux et al, 2003;Yang et al, 2009bYang et al, , 2011 and a6 is the primary a subunit that plays a prominent role in DA release (Quik et al, 2011), and they are predominantly expressed in catecholaminergic systems (Brunzell, 2012).…”