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


OBJECTIVE
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.
Blessing
William Walter
WW
Department of Physiology, Centre for Neuroscience, Flinders University, Adelaide, Australia. w.w.blessing@flinders.edu.au
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001143:Arousal / Q000187:drug effects*; D003024:Clozapine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D017078:Laser-Doppler Flowmetry; D008070:Lipopolysaccharides; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D051381:Rats; D017207:Rats, Sprague-Dawley; D058825:Serotonin 5-HT1 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D012867:Skin / Q000098:blood supply*; D012881:Skin Temperature / Q000187:drug effects; D013564:Sympathetic Nervous System / Q000187:drug effects*; D014661:Vasoconstriction / Q000187:drug effects; D014666:Vasomotor System / Q000187:drug effects*
D014150:Antipsychotic Agents; D008070:Lipopolysaccharides; D058825:Serotonin 5-HT1 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D003024:Clozapine; D006220:Haloperidol; D018817:N-Methyl-3,4-methylenedioxyamphetamine