Lethal effects of cocaine are reduced by the dopamine-1 receptor antagonist SCH 23390 but not by haloperidol.
The prevalence of cocaine abuse has been associated with a host of medical complications and deaths. We investigated the effects of two dopamine antagonists with different affinities for dopamine-1 and dopamine-2 receptor subtypes on cocaine-induced lethality. Male Fischer-344 rats were given cocaine HCl (i.p.) and observed for lethality at 24 hrs. Cocaine was not lethal at 50 mg/kg and produced a steep dose-effect function from 60 to 100 mg/kg. Lethality was 88.9% at 100 mg/kg and the LD 50 was 79.7 mg/kg (95% CL: 74.8-84.9). Doses as high as 180 mg/kg failed to kill all rats. Lethality was often but not invariably associated with convulsions. Haloperidol (0.3-3 mg/kg i.p.) given 30 min prior to cocaine did not alter the lethal effects of cocaine but did reduce the lethality of methamphetamine. SCH 23390 (0.1-1 mg/kg i.p., 30 min prior) shifted the cocaine dose-effect function to the right at 0.3 mg/kg. Maximum protection was conferred by 0.3 mg/kg SCH 23390 where the LD 50 was increased to 100.1 mg/kg (95% CL: 91.5-109.5). Comparable protection was not observed if SCH 23390 was given 5 min after cocaine. These results suggest that dopamine receptors may play a role in the lethal effects of cocaine and that the D1 dopamine receptor subtype appears to be more relevant to lethality than the D2 subtype.
Witkin
J M
JM
Preclinical Pharmacology Branch, National Institute on Drug Abuse, Baltimore, MD 21224.
Goldberg
S R
SR
Katz
J L
JL
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D003042:Cocaine / Q000037:antagonists & inhibitors / Q000633:toxicity*; D018492:Dopamine Antagonists; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D011954:Receptors, Dopamine / Q000187:drug effects / Q000502:physiology*; D017447:Receptors, Dopamine D1
D001552:Benzazepines; D018492:Dopamine Antagonists; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D003042:Cocaine; D006220:Haloperidol