Nicotine Potentiation of Excitatory Inputs to Ventral Tegmental Area Dopamine Neurons

Abstract

Drug-induced changes in synaptic strength are hypothesized to contribute to appetitive behavior and addiction. Nicotine, the major addictive substance in tobacco, activates nicotinic receptors (nAChRs) to initiate a series of adaptive changes at the cellular and circuit levels in brain, particularly the ventral tegmental area (VTA). Our lab previously reported that nicotine facilitates induction of long-term potentiation (LTP) in VTA dopamine (DA) neurons by increasing glutamate release via activation of α7 nAChRs on the glutamate terminals, suggesting a critical presynaptic contribution of nicotine in LTP induction. In the present study, we used an in vitro exposure paradigm to study nicotine’s effect on excitatory synaptic strength. Brief exposure of nicotine to brain slices from drug naïve adult rats followed by a period of recovery resulted in an NMDA receptor (NMDAR)-dependent increase of AMPAR/NMDAR ratio in VTA DA neurons, which is consistent with the induction of LTP. These effects are similar to that induced by a single in vivo nicotine injection i.p. The induction of synaptic potentiation required excitation of DA neurons mediated by somatodendritic α4β2 nAChRs, as well as enhancement of NMDAR function via D5 dopamine receptors, also on DA neurons. Nicotine-induced increase of presynaptic glutamate release also contributed to the induction of synaptic plasticity, likely through increased activation of NMDAR. These results identified important receptor systems involved in nicotine-induced long-term changes in excitatory synaptic input to VTA DA neurons. The data also revealed remarkable similarity in the mechanisms underlying synaptic plasticity induced by nicotine and cocaine in the VTA.

α4α6β2* Nicotinic Acetylcholine Receptor Activation on Ventral Tegmental Area Dopamine Neurons Is Sufficient to Stimulate a Depolarizing Conductance and Enhance Surface AMPA Receptor Function

“…6, B and C). Previous studies indicate that DA D1/ D5 receptors in VTA may play a role in altered synaptic plasticity after exposure to drugs of abuse (Gao and Wolf, 2007;Mao et al, 2011). Blockade of DA D1/D5 receptors with SCH23390 (10 mM) did not appear to substantially reduce nicotine-mediated enhancement in AMPA-evoked currents (SCH23390 5 2325.06 44.7 pA; Fig.…”

“…Slices were cut and allowed to recover for 60 minutes, followed by exposure of the slices to 100 nM nicotine (or a control solution containing no nicotine) for 60 minutes similar to previous studies Mao et al, 2011) (Fig. 4A).…”

“…This involves the abused drug causing enhanced excitability of VTA DA neurons and long-term potentiation (LTP) of excitatory inputs to these cells (Ungless et al, 2001;Saal et al, 2003). In particular, nicotine acts through VTA nAChRs on DA neuron somata, as well as presynaptic nAChRs, to depolarize these cells, facilitate N-methyl-D-aspartic acid (NMDA) receptor activation, and enhance glutamate-induced excitatory postsynaptic currents (EPSCs) (Saal et al, 2003;Gao et al, 2010;Jin et al, 2011;Mao et al, 2011). Understanding which proteins-including which nAChR subtypes-mediate these effects could lead to new pharmacotherapy approaches designed to disrupt or reverse the addictive process at the molecular, cellular, or circuit level .…”

Nicotinic Acetylcholine Receptor α7 and β4 Subunits Contribute to Nicotine-Induced Apoptosis in Periodontal Ligament Stem Cells

“…Thus, the present study examined cellular and molecular events of PDLSCs using an experimental model, which can represent tobacco product, nicotine-mediated periodontal disease. Nicotine is a lipophilic molecule of which the effects on neuronal nicotinic acetylcholine receptors (nAChR) have been primarily focused on its physiologic impact within the confines of the nervous system (Mao et al, 2011). However, many studies have recently found neuronal nAChRs to be expressed on many different non-neuronal cell types throughout the body (Chernyavsky et al, 2005;Resende et al, 2008;Wang et al, 2010;Wessler and Kirkpatrick, 2008).…”

Neuroplastic changes in addiction

“…Feduccia et al (2012) in their review added new insights to the function of nicotinic acetylcholine receptors (nAChR) in alcohol and nicotine addiction. The nAChRs are ligand-gated ion channels which are wildly distributed in the brain and play a crucial role in synaptic neurotransmission (Mao et al, 2011). Both alcohol and nicotine are able to activate neuronal nAChRs.…”