Dopamine‐Acetylcholine Interactions in the Modulation of Glutamate Release

Schizophrenia is a neurological disease whose precise anatomic substrate and cellu- lar mechanisms are largely unknown. Internally generated voices and auditory hal- lucinations are among the recurrent symptoms characteristic of schizophrenia, suggestive of an impaired function of the temporal lobes.1,2 Several neurotransmit- ters appear to be involved in the pathophysiology of schizophrenia, including dopamine,3 acetylcholine,4 and glutamate.5 The "dopamine hypothesis," supported by pharmacological and clinical studies, proposes that an excess of dopamine or dopamine sensitivity might be associated with the disease.3 Acetylcholine, secreted by a complex of nuclei in the basal forebrain, is an important regulator of cerebral functions such as learning and memory, sleep and wake cycles, and attention.6 Among its cellular effects, acetylcholine binds to muscarinic receptors depressing the release of glutamate, the main excitatory neurotransmitter in the brain. Muscar- inic reduction of glutamate release has been observed in many brain areas including the amygdala,7 the hypothalamus,8 basal ganglia,9 and visual cortex.10 These data suggest that the reduction of glutamate release is a general mechanism for limiting other potent excitatory effects of acetylcholine such as blockage of K+ channels11 and potentiation of NMDAR-mediated currents.12 Both dopamine and acetylcholine act on complex cascades involving multiple intracellular pathways potentially inter- acting with each other. We considered the possibility that dopamine affects the ca- pability of acetylcholine to depress glutamate release in the temporal cortex. Using patch-clamp recording in a thin slice preparation, we measured pharmacologically isolated AMPAR-mediated currents from visually identified pyramidal cells of layer II/III. We evoked monosynaptic glutamatergic currents (EPSCs) stimulating the