Role of dopamine D1 receptors in cocaine lethality

One group of heterogeneously bred HS mice was assigned to test coadministration of the selective D1 antagonist SCH 23390 with a dose of cocaine (95 mg/kg) that was observed to produce 80% lethality, whereas a second group was tested by cotreatment with the newly developed full-efficacy D1 agonist dihydrexidine (DHX) and a dose of (60 mg/kg) cocaine previously shown to be nonlethal. The mice in the former group displayed decreased lethality going from 80% with coadministered vehicle to 15% after pretreatment with the highest dose (0.45 mg/kg) of SCH 23390. In the other group of mice there was no lethality seen when vehicle or 10 mg/kg DHX was coadministered with 60 mg/kg cocaine, but a dose-responsive increase in lethality with increasing DHX doses; the maximal lethality of 80% occurred when 25 mg/kg DHX was coadministered with cocaine. These results confirm the effects of D1 antagonism decreasing cocaine lethality as reported previously when rats were used, and extend the findings to D1 agonism; both observations evidence a role for the D1 receptor in the lethal effects, be they central, cardiopulmonary, or anesthetic, of cocaine.