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 D2 receptor antagonist action, also increases baseline cutaneous blood flow and lowers body temperature. However dopamine D2 receptor agonists lower temperature, suggesting that a dopamine D2agonist action might also reduce SCVARs. The present study determined whether a dopamine D2agonist 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 μg/kg) but not the D1 antagonist SCH-23390 or the peripheral dopamine D2 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 D2 receptor agonism, not dopamine D2 receptor antagonism, calling into question the mechanism of the drug's therapeutic action in schizophrenia.