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.

Off the Beaten Path: Drug Addiction and the Pontine Laterodorsal Tegmentum

“…In addition, while GABAergic inhibitory postsynaptic currents (IPSCs) directed to cholinergic cells were stimulated by nicotine, a larger proportional increase of glutamatergic excitatory postsynaptic currents (EPSCs) was induced by nicotine, presumably via actions of nicotine on nAChRs located on presynaptic glutamate-containing terminals directed onto cholinergic cells. The differential presynaptic actions of nicotine would serve in combination with direct effects to heighten the excitatory action of this drug on cholinergic LDT cells [112]. Use of nAChR subunit-specific antagonists suggested that nAChRs located on cholinergic soma mediating nicotine-induced inward currents were comprised of α 7, β 2, and non- α 7 subunits, agreeing with the mRNA expression study.…”

“…Direct actions could act in concert with indirect actions if, in addition to a postsynaptic localization, nAChRs were present on terminals directed to the postsynaptic cell [111]. Supporting this conclusion and demonstrating presence of functional nAChRs on cholinergic LDT neurons, patch clamp recordings from mouse brain slices combined with immunohistochemistry showed that nicotine has direct excitatory actions on the membrane potential of cholinergic cells, inducing a large inward current sufficient to induce action potential firing [112]. In addition, while GABAergic inhibitory postsynaptic currents (IPSCs) directed to cholinergic cells were stimulated by nicotine, a larger proportional increase of glutamatergic excitatory postsynaptic currents (EPSCs) was induced by nicotine, presumably via actions of nicotine on nAChRs located on presynaptic glutamate-containing terminals directed onto cholinergic cells.…”

Nicotine Persistently Activates Ventral Tegmental Area Dopaminergic Neurons via Nicotinic Acetylcholine Receptors Containing α4 and α6 Subunits

“…One limitation to our study is that it provides little insight into the contribution of nAChR subtypes that are involved in nicotine burst activity because we observe little bursting in DAergic neurons within midbrain slices. This is probably because DAergic neuron bursting in response to concentrations of nicotine achieved by smoking requires other cholinergic and/or noncholinergic inputs that are severed in our slice preparation, and presumably require glutamatergic signaling, which we also block in our experiments Lodge and Grace, 2006;Ishibashi et al, 2009).…”

Response to Transdermal Selegiline Smoking Cessation Therapy and Markers in the 15q24 Chromosomal Region

“…5 However, there is ample evidence that cholinergic input modulates activity in brain dopaminergic nuclei. 15,[27][28][29]51 This may explain why variation at cholinergic loci affects selegiline treatment outcomes in smokers.…”