Figure 14.

Proposed mechanism of action of investigated combinations (basic scheme adapted from Conn et al. [43]). (A) Impaired effect of glutamate on dysfunctional NMDA receptors located on GABAergic neurons (1), results in decreased GABA release (2), disinhibition of subsequent thalamocortical glutamatergic innervation and overactivation of pyramidal glutamatergic neurons in the cortex (3). (B) M₁ and M₅ receptors may be expressed on GABAergic neurons (4), and thus, their activation by VU0357017 or VU0238429 counteracts NMDA-related impairments (both M₁ and M₅ receptors are linked to Gq protein and thus are excitatory in nature); additionally, the ligands may activate M₁ or M₅ receptors expressed on cholinergic neurons innervating GABAergic interneurons (7). 5-HT_1A receptors are expressed postsynaptically on glutamatergic neurons in the cortex (5). The receptors are linked to Gi proteins; thus, their activation by F15599 inhibits neuronal activity and counteracts the hyperexcitability observed in individuals with schizophrenia. M₄ receptors are expressed presynaptically on glutamatergic terminals; their stimulation by VU0152100 activates Gi protein, which are inhibitory in nature and leads to the inhibition of glutamate release (6).