Cholinergic axon terminals in the ventral tegmental area target a subpopulation of neurons expressing low levels of the dopamine transporter

Abstract

Cholinergic activation of dopaminergic neurons in the ventral tegmental area (VTA) is thought to play a major role in cognitive functions and reward. These dopaminergic neurons differentially project to cortical and limbic forebrain regions, where their terminals differ in levels of expression of the plasmalemmal dopamine transporter (DAT). This transporter selectively identifies dopaminergic neurons, whereas the vesicular acetylcholine transporter (VAchT) is present only in the neurons that store and release acetylcholine. We examined immunogold labeling for DAT and immunoperoxidase localization of VAchT antipeptide antisera in single sections of the rat VTA to determine whether dopaminergic somata and dendrites in this region differ in their levels of expression of DAT and/or input from cholinergic terminals. VAchT immunoreactivity was prominently localized to membranes of small synaptic vesicles in unmyelinated axons and axon terminals. VAchT‐immunoreactive terminals formed almost exclusively asymmetric synapses with dendrites. Of 159 dendrites that were identified as cholinergic targets, 35% contained plasmalemmal DAT, and 65% were without detectable DAT immunoreactivity. The DAT‐immunoreactive dendrites postsynaptic to VAchT‐labeled terminals contained less than half the density of gold particles as seen in other dendrites receiving input only from unlabeled terminals. These results suggest selective targeting of cholinergic afferents in the VTA to non‐dopaminergic neurons and a subpopulation of dopaminergic neurons that have a limited capacity for plasmalemmal reuptake of dopamine, a characteristic of those that project to the frontal cortex. J. Comp. Neurol. 410:197–210, 1999. © 1999 Wiley‐Liss, Inc.

Cellular and synaptic mechanisms of nicotine addiction

“…Cholinergic projections to the VTA come from brain stem nuclei, the pedunculopontine tegmental nucleus (PPTg) and the lateral dorsal tegmental nucleus (LDTg). Ultrastructural analyses have shown that cholinergic boutons within the VTA contact postsynaptic structures with low levels of dopamine transporter expression (Garzón et al, 1999). Numerous other neurotransmitters and neuromodulators influence the activity of the VTA, including serotonin, norepinephrine, endogenous opioids, and others (Tzschentke, 2001).…”

“…Desensitization not only prevents further activation of nAChRs by nicotine, it also precludes the contribution of those nAChRs to endogenous cholinergic signaling. Cholinergic inputs to VTA from the laterodorsal and the pedunculopontine tegmental nuclei (Oakman et al, 1995) selectively target non-DA neurons and a subset of DA neurons (Garzón et al, 1999). VTA DA neurons are only sparsely targeted by cholinergic projections.…”

“…One interpretation of this data is that endogenous ACh transmission in the VTA activates the DA system. However, physiologic experiments indicate very sparse cholinergic inputs to VTA DA neurons (Fiorillo and Williams, 2000), while ultrastructural analyses of cholinergic projections to the VTA found that only a very small proportion of cholinergic terminals make contact on DA neurons (Garzón et al, 1999). The vast majority of the cholinergic neurons in the laterodorsal tegmental and the pedunculopontine nuclei project to GABA neurons in the VTA (Garzón et al, 1999).…”

“…However, physiologic experiments indicate very sparse cholinergic inputs to VTA DA neurons (Fiorillo and Williams, 2000), while ultrastructural analyses of cholinergic projections to the VTA found that only a very small proportion of cholinergic terminals make contact on DA neurons (Garzón et al, 1999). The vast majority of the cholinergic neurons in the laterodorsal tegmental and the pedunculopontine nuclei project to GABA neurons in the VTA (Garzón et al, 1999). Therefore, the in vivo application of the cholinesterase inhibitor in the VTA by Blaha et al (1996), which was maintained for several hours, may induce increased DA levels in the NAcc by disinhibition of VTA DA neurons due to nAChR desensitization on GABA neurons.…”

Double target concept for smoking cessation

“…Nicotine also activates then desensitizes α4β2-nAChRs on both DA and GABAergic neurons [9] . Since cholinergic innervations in GABAergic neurons have much higher density than that in DA neurons [11] , the nicotineinduced α4β2-nAChR desensitization (after brief activation) mainly decreases GABA release onto DA neurons, and consequently increases DA neuronal activity. It has been proposed that nicotine-induced desensitization is at least one of the major mechanisms for nicotine addiction [12][13][14] .…”