Clozapine increases cutaneous blood flow and reduces sympathetic cutaneous vasomotor alerting responses (SCVARs) in rats: comparison with effects of haloperidol.

RATIONALE

Clozapine inhibits sympathetic outflow to the cutaneous vascular bed. Clozapine reverses hyperthermia and cutaneous vasoconstriction induced by 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) or by lipopolysaccharide (LPS). Clozapine also reverses cutaneous vasoconstriction elicited by exposure to cold. These actions distinguish clozapine from haloperidol. Clozapine could also inhibit sympathetic cutaneous vasomotor alerting responses (SCVARs), vasoconstrictor episodes that reflect emotional/psychological function, and this property might also distinguish clozapine from haloperidol.

OBJECTIVES

Experiments in rats determined whether clozapine and haloperidol inhibit SCVARs, and whether SR46349B (a 5HT2A receptor antagonist), 8-OH-DPAT (a 5-HT1A agonist), L741,626 (a dopamine D2 antagonist) or SCH23390 (a dopamine D1 antagonist) have clozapine-like effects on SCVARs.

METHODS

Mean level and pulse amplitude of the tail artery Doppler flow signal were recorded in conscious freely moving rats before and after alerting stimuli (e.g. tapping the cage), and expressed as a SCVAR index (fall to zero flow implies SCVAR index of 100%, no fall implies 0%).

RESULTS

Clozapine (0.0625-1.0 mg/kg, s.c.) dose-dependently increased resting tail blood flow. After 1 mg/kg, the SCVAR index was 18+/-1%, compared with 83+/-2% after vehicle. SR46349B (0.01-1.0 mg/kg) and 8-OH-DPAT (0.25 mg/kg) had similar but less potent effects on cutaneous blood flow and on SCVARs. Haloperidol (0.005-0.5 mg/kg) and L741,626 (1 mg/kg) had no or little effect on these variables. SCH23390 mildly inhibited SCVARs.

CONCLUSIONS

Clozapine, but not haloperidol, increases resting cutaneous blood flow and decreases SCVARs. Antagonism at 5-HT2A receptors and agonism at 5-HT1A receptors could contribute to these actions.