Both
muscarinic and
nicotinic receptors are implicated in cognition. We have previously suggested that stimulation of the
muscarinic M1 receptor has a beneficial effect on cognition, based upon evidence that the
muscarinic M1 receptor agonist of
N-desmethylclozapine, the major metabolite of
clozapine, may contribute to the ability of
clozapine to improve some domains of cognition in
schizophrenia. Present study examined the effectiveness of a new
muscarinic M1 receptor agonist, 4-[3-(4-butylpiperidin-1-yl)-propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one (
AC260584), to increase the release of
acetylcholine and
dopamine in the rat medial prefrontal cortex and hippocampus. Using microdialysis in awake, freely moving rats,
AC260584, 3 and 10, but not 1 mg/kg (s.c.), significantly increased
dopamine release in the medial prefrontal cortex and hippocampus. However, only the high dose of
AC260584, 10 mg/kg (s.c.), significantly increased
acetylcholine release in these regions. Moreover, the increases in
acetylcholine release produced by
AC260584, 10 mg/kg, were attenuated by the
muscarinic M1 receptor antagonist
telenzepine (3 mg/kg, s.c.) but not by the
5-HT1A receptor antagonist N-[2-(4-2-methoxyphenyl)-1-piperazinyl]-N-(2-pyridyl) cyclohexanecarboxamide (WAY100635, 0.2 mg/kg, s.c.). However, the increase in
dopamine release produced by 10 mg/kg
AC260584 was blocked by both
telenzepine and WAY100635. In addition, pretreatment with the atypical
antipsychotic drug risperidone (0.1 mg/kg, s.c.) potentiated
AC260584 (1.0 mg/kg, s.c.)-induced
acetylcholine and
dopamine release in the medial prefrontal cortex. These findings suggest that the
muscarinic M1 receptor agonist property of
AC260584 contributes to its enhancement of cortical
acetylcholine and
dopamine efflux. Therefore,
AC260584, as well as other
muscarinic M1 receptor agonists, may be a valuable target for the development of drugs which can improve the cognitive deficits in
schizophrenia and perhaps other neuropsychiatric disorders, as well.