The cholinergic mesopontine tegmentum is a relatively neglected nicotinic master modulator of the dopaminergic system: relevance to drugs of abuse and pathology

Abstract

The mammalian mesopontine tegmentum (MPT) contains two cholinergic nuclei, the pedunculopontine tegmental nucleus (PPTg) and the laterodorsal tegmental nucleus (LDTg). These provide the cholinergic innervation of, among other brain areas, the dopaminergic A9 and A10 cell groups. Their axons are thus the source of endogenous acetylcholine (ACh) acting on somato-dendritic acetylcholine receptors in the substantia nigra (SN) and ventral tegmental area (VTA). The anatomy, physiology, functional and pathological implications of these interactions with the nicotinic subtype of acetylcholine receptors (nAChRs) are discussed with a view of the important role of the MPT as a master regulator of nicotinic dopaminergic signalling in the brain, including for nicotine addiction.

Figure 1

(a) A schematic of the mouse brain in sagittal section highlighting the two cholinergic nuclei of the mammalian mesopontine tegmentum (MPT), the pedunculopontine tegmental nucleus (PPTg), filled circle, and laterodorsal tegmental nucleus (LDTg), open circle. (b) The specificity of cholinergic axons from the PPTg, filled circles, is not 100% for the innervation of the substantia nigra (SN), grey-filled circles. The posterior portion of the PPTg, black-filled circle, innervates the ventral tegmental area (VTA). Cholinergic axons from the LDTg, open circles, project exclusively to the VTA. (c) In the blow up, the microcircuit of the VTA and its cholinergic modulation are indicated: dopaminergic (DA) neurons in the centre show rhythmic pacemaker activity that is calcium dependent and controlled through glutamatergic and GABAergic inputs (dark cells). These inputs derive, respectively, from the prefrontal cortex (PFC) or pedunculopontine tegmental nucleus (PPTg), and VTA GABAergic interneurons or projection neurons from the ventral pallidum (VP). The key signal gating the transition from tonic to phasic, burst firing, is the cholinergic input from the tegmentum, PPTg and LDTg (boxed). Note that the glutamatergic afferents contain nicotinic receptors of the α7 subtypes, and are thus also modulated through tegmental acetylcholine (ACh). Additionally, both the DA and γ-aminobutyrate (GABA)ergic neurons in the VTA contain both α7^* and β2^* (boxed) nAChRs.