Muscarinic Receptors in Brain Stem and Mesopontine Cholinergic Arousal Functions

All five muscarinic receptor subtypes and mRNAs are found widely in the brain stem, with M2 muscarinic receptors most concentrated in the hindbrain. Three cholinergic cell groups, Ch5: pedunculopontine (PPT); Ch6: laterodorsal tegmental (LDT); Ch8: parabigeminal (PBG), are found in the tegmentum. Ch5,6 neurons are activated by arousing and reward-activating stimuli, and inhibited via M2-like autoreceptors. Ch5,6 ascending projections activate many forebrain regions, including thalamus, basal forebrain, and orexin/hypocretin neurons (via M3 receptors) for waking arousal and attention. Ch5,6 activation of dopamine neurons of the ventral tegmental area and substantia nigra (via M5 receptors) increases reward-seeking and energizes motor functions. M5 receptors on dopamine neurons facilitate brain-stimulation reward, opiate rewards and locomotion, and male ultrasonic vocalizations during mating in rodents. Ch5 cholinergic activation of superior colliculus intermediate layers facilitates fast saccades and approach turns, accompanied by nicotinic and muscarinic inhibition of the startle reflex in pons. Ch8 PBG neurons project to the outer layers of the superior colliculus only, where M2 receptors are associated with retinotectal terminals. Ch5,6 descending projections to dorsal pontine reticular formation contribute to M2-dependent REM sleep.