Activation of dopamine D2 receptors in the CNS inhibits sympathetic cutaneous vasomotor alerting responses (SCVARs), contributing to clozapine's SCVAR-inhibiting action.
Sympathetic neural outflow to thermoregulatory cutaneous vascular beds is selectively activated when the individual is aroused, so that cutaneous blood flow is characterized by sudden alerting-related falls to near zero levels ("SCVARs", sympathetic cutaneous vasomotor alerting responses). Our previous work shows that clozapine, an atypical antipsychotic drug used in schizophrenia, profoundly inhibits SCVARs. Clozapine, conventionally assumed to have a dopamine D(2) receptor antagonist action, also increases baseline cutaneous blood flow and lowers body temperature. However dopamine D(2) receptor agonists lower temperature, suggesting that a dopamine D(2)agonist action might also reduce SCVARs. The present study determined whether a dopamine D(2)agonist action contributes to clozapine's SCVAR-inhibiting effect. SCVARs were measured in conscious rats with a Doppler ultrasonic flow probe chronically implanted around the base of the artery, with probe wires passing subcutaneously to a headpiece. Doppler signals were monitored via a flexible connection between the headpiece and a swivel device in the roof of the cage. Apomorphine (0.1-0.5 mg/kg), quinpirole (0.05-0.25 mg/kg) and 7-OH-DPAT (0.02-0.5 mg/kg) dose-dependently reduced SCVARs. Pre-treatment with the dopamine receptor antagonist spiperone (20 microg/kg) but not the D(1) antagonist SCH-23390 or the peripheral dopamine D(2) antagonist domperidone, abolished this effect. Spiperone pre-treatment reduced the SCVAR-inhibiting action of clozapine (0.06-1.0 mg/kg). Chlorpromazine (0.1-10 mg/kg) also dose-dependently inhibited SCVARs, but this effect was not reduced by pre-treatment with spiperone. Mechanisms underlying clozapine's SCVAR-inhibiting effect include dopamine D(2) receptor agonism, not dopamine D(2) receptor antagonism, calling into question the mechanism of the drug's therapeutic action in schizophrenia.
Blessing
W W
WW
Department of Human Physiology, Centre for Neuroscience, Flinders University, Adelaide, Australia. w.w.blessing@flinders.edu.au
Ootsuka
Y
Y
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002490:Central Nervous System; D003024:Clozapine / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D017078:Laser-Doppler Flowmetry / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; 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; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D017448:Receptors, Dopamine D2; D003024:Clozapine