(A) Hypothesized role of M₄muscarinic receptor activation in rodent models of psychosis.M₄muscarinic receptors.^27,68-70(B) Hypothesized role of M₁muscarinic receptor activation in rodent models of psychosis.^27,70-73 Afferent cholinergic neurons project from the LDT to the medial VTA where they synapse onto DA neurons that project to the striatum. These DA neurons also receive input from glutamatergic pyramidal neurons originating in the PFC that are in turn regulated by parvalbumin-positive GABAergic interneurons. M₄ autoreceptors are expressed presynaptically on the cholinergic projections in the medial VTA. Activation of M₄ autoreceptors reduces cholinergic signaling to the VTA, inhibiting VTA DA release into the striatum and reducing positive psychotic symptoms. M₁ muscarinic receptors are expressed on the parvalbumin-positive GABAergic neurons in the PFC. Activation of these excitatory receptors increases GABA-mediated inhibition of glutamatergic signaling from the PFC to the medial VTA. Decreased glutamate release reduces DA neuron activation in the VTA and DA release in the striatum. ACh, acetylcholine; DA, dopamine; GABA, gamma-aminobutyric acid; Glu, glutamate; LDT, laterodorsal tegmentum; PFC, prefrontal cortex; VTA, ventral tegmental area.