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NEUROPHARMACOLOGY

Protection against Cocaine Toxicity in Mice by the Dopamine D₃/D₂ Agonist R-(+)-trans-3,4a,10b-Tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol [(+)-PD 128,907]

Neuroscience Discovery Research (J.M.W., S.P., H.E.S.), Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, Indiana; Behavioral Neuroscience Branch (A.Z., M.G.), National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland; Department of Medicinal Chemistry (D.D.), University Centre of Pharmacy; Groningen, The Netherlands; Department of Pharmacology (B.L.), University of Kansas Medical Center; Kansas City, Kansas; and Neurosciences Pharmacology (H.C.A.), Pfizer Inc., Ann Arbor, Michigan

Cocaine abuse is a public health concern with seizures and death being one consequence of overdose. In the present study, dopamine D_3/D₂ receptor agonists dose dependently and completely prevented the convulsant and lethal effects of cocaine. The D₃-preferring agonists R-(+)-trans-3,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol) [(+)-PD 128,907], (+)-7-hydroxy-dipropylaminotetralin, and the mixed D_3/D₂ agonists quinpirole and quinelorane were all effective against cocaine toxicity in mice. The anticonvulsant effects of these compounds occurred at doses below those that produced motor impairment as assessed in the inverted screen test. Protection against the convulsant effects of the selective dopamine uptake inhibitor 1-[2-[bis(4-fluorophenyl)methoxy] ethyl]-4-[3-phenyl-propyl]piperazine (GBR 12909) was also conferred by (+)-PD 128,907. The possible selectivity of the effects of (+)-PD 128,907 (3 mg/kg) for these dopaminergic compounds was demonstrated by its general lack of protective efficacy against a host of convulsants acting through other neural mechanisms [pentylenetetrazol, (+)-bicuculline, and picrotoxin, 4-aminopyridine, and t-butylbiclyclophosphoorothionate, N-methyl-D-aspartate, kainate, pilocarpine, nicotine, strychnine, aminophylline, threshold electric shock, and 6-Hz electrical stimulation]. Direct and correlational evidence suggests that these effects were mediated by D₃ receptors. Protection was stereospecific and reversible by an antagonist of D₃ receptors [3-{4[1-(4-{2[4-(3-diethyamino-propoxy)-phenyl]-benzoimidazol-l-yl}-butyl)-1H-benzoimidazol-2-yl]-phenoxy}-propyl)-diethyl-amine; PD 58491] but not D₂ receptors [3[[4-(4-chlorophenyl)-4hydroxypipeidin-1-yl]methyl-1H-indole; L-741,626]. Anticonvulsant potencies were positively associated with potencies in a functional assay of D₃ but not D₂ receptor function. Together, these findings suggest that the prevention of cocaine convulsions and lethality by (+)-PD 128,907 may be due to D₃ receptor-mediated events.

Address correspondence to: Dr. J. M. Witkin, Neuroscience Discovery Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285-0501. E-mail: jwitkin{at}lilly.com

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