Selective action of acute systemic clozapine on acetylcholine release in the rat prefrontal cortex by reference to the nucleus accumbens and striatum.

The effects of i.p. clozapine [0 (n = 6), 5 (n = 5), 10 (n = 5), 20 (n = 9) and 40 (n = 5) mg/kg] on acetylcholine (ACh) release in the prefrontal cortex (PFC), nucleus accumbens (NAC) and striatum (STR) were studied by simultaneous triple microdialysis in freely moving rats. Clozapine dose-responsively increased extracellular ACh in the studied areas. The effect was larger in the PFC. Comparisons of the slopes of the regression equations showed differences between the effects in PFC and nucleus accumbens (t = 4.29; df = 56; P < .001) and PFC and STR (t = 4.56), but not between nucleus accumbens and STR. These differential actions were not artifacts of the simultaneous perfusion because clozapine (20 mg/kg) increased ACh levels during single microdialysis of the PFC (353 +/- 72%; n = 5) or STR (168 +/- 24%; n = 5), in the same proportion as the respective increases in those areas during the simultaneous triple microdialysis (PFC = 330 +/- 41%; STR = 144 +/- 18%; n = 9). Local infusion of tetrodotoxin (10 microM) reduced ACh in the areas studied to about 30% of the mean baselines, confirming the neuronal origin of this neurotransmitter. Extrapolation of these results to humans suggests that adequate levels of cholinergic activity in the PFC are required for mental health, and that a similar ACh release in the human PFC by clozapine could be therapeutic. The low impact on striatal ACh could explain the lack of extrapyramidal symptoms by clozapine.