Selective antagonism at dopamine D3 receptors enhances monoaminergic and cholinergic neurotransmission in the ratanterior cingulate cortex

Abstract

Recent neuroanatomical and functional investigations focusing on dopamine (DA) D3 receptors have suggested a potential role of this receptor in psychiatric diseases such as schizophrenia and drug dependence. In line with the key role of the prefrontalcortex inpsychiatric disorders, the present study aimed at assessing the effects of the acute systemic administration of the selective DA D3receptor antagonist SB-277011-A on thein vivoextracellular levels of monoamines (DA, norepinephrine (NE), and serotonin (5-HT))and acetylcholine (ACh) in the anterior cingulate subregion of the medial prefrontalcortex. Thein vivoneurochemicalprofile of SB-277011-A (10 mg/kg, i.p.) in the anterior cingulate cortex was compared with both typical and a typical antipsychotics including clozapine(10mg/kg, s.c.), olanzapine (10 mg/kg, s.c.), sulpiride (10mg/kg, s.c.), and haloperidol(0.5 mg/kg, s.c.). The acute administration of SB-277011-A, clozapine, and olanzapine produced a significant increase in extracellular levels of DA, NE, and ACh without affecting levels of5-HT. Sulpiride also significantly increased extracellular DA, but with a delayed onset over SB-277011-A, clozapine, and olanzapine. Incontrast, haloperidolfailed to alter any of the three monoamines and ACh in the anterior cingulate cortex. These findings add to agrowing body of evidence suggesting a differentiation between typical and a typical antipsychotic drugs (APDs) in the anterior cingulatecortex and a role of DA D3receptors in desired antipsychotic drug profile. Similar to their effects on DA and NE, SB-277011-A, clozapine, and olanzapine increased extracellular levels of ACh, whereas haloperidolandsulpiride did not alter ACh. The results obtainedin the present study provide evidence of the important role of DA D3receptors in the effect of pharmacotherapeutic agents that areused for the treatment of psychiatric disorders such as schizophrenia and drug dependence. © 2003 American College of Neuropsychopharmacology.