Effects of the atypical neuroleptic clozapine on micturition parameters in anesthetized rats

Clozapine, an atypical antipsychotic, has resulted in a number of reports of urinary disturbances in the clinical literature. We examined the effects of clozapine on urodynamic parameters in the anesthetized rat and compared the effects to those of the typical antipsychotic haloperidol and the selective D2 and D4 antagonists, raclopride and L-745,870, respectively. Clozapine abolished high-frequency oscillations (HFO) during the expulsion phase, and profoundly altered a number of other parameters (e.g., intercontraction interval and resting pressure). Clozapine did not affect the peak contraction pressure during cystometrograms but displayed peripheral inhibition of bladder contractions elicited by electrical stimulation of the pelvic nerve (possibly mediated via clozapine's anti-muscarinic effects). Haloperidol had less potent effects than clozapine since it reduced the amplitude of HFO to 25% of control and also affected several other parameters but without peripheral bladder inhibition. Raclopride only resulted in a modest decrease (approximately 70% of control) in the HFO and no alteration in other parameters. L-745,870 was effective only at highest dose tested suggesting that it might not be acting selectively at D4 receptors. Therefore, we propose that clozapine primarily interferes with the function of the external urethral sphincter. These effects can only be partly explained through antagonism of D2 receptors. Since both clozapine and haloperidol have interactions with other transmitter systems beside dopamine, we suggest that central antagonism of D2 receptors, coupled to central antagonism of another receptor system and peripheral muscarinic receptor blockade, may account for clozapine's potent effects on micturition.