Differential Nicotinic Modulation of Glutamatergic and GABAergic VTA Microcircuits

Abstract Ventral tegmental area (VTA) neurons receive glutamatergic and/or GABAergic input from other local neurons within the VTA. Nicotinic acetylcholine receptor (nAChR) activity is capable of modulating such intra-VTA transmission, but the mechanisms are unclear. Here, we isolated monosynaptic glutamate or GABA transmission from mouse medial VTA (mVTA) to lateral VTA (latVTA) using pharmacology and optogenetics, and we studied nicotine’s ability to modulate these modes of transmission. Nicotine’s action on mVTA to latVTA glutamate transmission was bidirectional; nicotine enhanced glutamate release in half of the recorded latVTA cells and inhibited release in the other half. Nicotine-mediated reduction in glutamate release was reversed by blockade of GABAA receptors. This, coupled with expression data demonstrating co-expression of vesicular glutamate transporter 2 (vGluT2) and glutamate decarboxylase 2 (Gad2) in mVTA neurons, suggests that nicotine is able to stimulate GABA co-release from mVTA vGluT2+ neurons. Nicotine had an altogether different effect on mVTA to latVTA GABA release from Gad2+ cells; nicotine suppressed GABA release from mVTA Gad2+ terminals in nearly all cells tested. Together, these data uncover a complex system of local circuitry in the VTA that is modulated by nAChR activity. These actions of nicotine, which occurred at concentrations of nicotine found in the artificial cerebrospinal fluid of cigarette smokers, may play a role in the reward system’s adaptive response to repeated nicotine exposure. Significance Statement This study uncovers novel aspects of nAChR neuropharmacology and VTA neurobiology that have implications for understanding nicotine dependence mechanisms. Nicotine must interact with receptors and circuits in VTA to cause dependence, and this study advances our understanding of specific nicotine-sensitive circuits that reside within this brain area. Identifying these novel nicotine-sensitive systems could provide new/additional mechanisms for targeting with smoking cessation drugs or therapeutics. Our results also add new details to the conceptual framework associated with reward circuit wiring, which could lead to an improved mechanistic understanding of natural reward processing.