Nicotinic Activation of Laterodorsal Tegmental Neurons: Implications for Addiction to Nicotine

Abstract

Identifying the neurological mechanisms underlying nicotine reinforcement is a healthcare imperative if society is to effectively combat tobacco addiction. The majority of studies of the neurobiology of addiction have focused on dopamine (DA)-containing neurons of the ventral tegmental area (VTA). However, recent data suggests that neurons of the laterodorsal tegmental (LDT) nucleus which sends cholinergic, GABAergic- and glutamatergic-containing projections to DA-containing neurons of the VTA are critical to gating normal functioning of this nucleus. The actions of nicotine on LDT neurons are unknown. We addressed this issue by examination of nicotinic effects on identified cholinergic and non-cholinergic LDT neurons using whole-cell patch clamp and Ca2+ imaging methods in brain slices from mice (P12-P45). Nicotine applied via puffer pipette or bath superfusion elicited membrane depolarization that often induced firing and TTX-resistant inward currents. Nicotine also enhanced sensitivity to injected current; and, baseline changes in intracellular calcium were elicited in the dendrites of some cholinergic LDT cells. Additionally, activity-dependent calcium transients were increased, suggesting that nicotine exposure sufficient to induce firing may lead to enhancement of levels of intracellular calcium. Nicotine also had strong actions on glutamate and GABA-releasing presynaptic terminals since it greatly increased the frequency of miniature EPSCs and IPSCs to both cholinergic and non-cholinergic neurons. Utilization of nAChR subunit antagonists revealed that presynaptic, inhibitory terminals on cholinergic neurons were activated by receptors containing α7, β2 and non-α7 subunits; whereas, presynaptic glutamatergic terminals were activated by nAChRs comprised of non-α7 subunits. We also found that direct nicotinic actions on cholinergic LDT neurons were mediated by receptors containing α7, β2 and non-α7 subunits. These findings lead us to suggest that nicotine exposure from smoking will enhance both the excitability and synaptic modulation of cholinergic and non-cholinergic LDT neurons and increase their signature neurotransmitter outflow to target regions including the VTA. This may reinforce the direct actions of this drug within reward circuitry and contribute to encoding stimulus saliency.