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NEUROPHARMACOLOGY

The Dopamine D₃/D₂ Agonist (+)-PD-128,907 [(R-(+)-trans-3,4a,10b-Tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol)] Protects against Acute and Cocaine-Kindled Seizures in Mice: Further Evidence for the Involvement of D₃ Receptors

Psychiatric Drug Discovery, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana (J.M.W.); Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (B.L.); and Behavioral Neuroscience Branch, National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland (A.Z., R.K., M.G.)

Previous findings have demonstrated a protective role for dopamine D₃/D₂ receptor agonists in the convulsant and lethal effects of acutely administered cocaine. Data are provided here to establish that the protection occurs through a D₃-linked mechanism and that protection is extended to seizure kindling. The D₃ antagonist SB-277011-A [4-quinolinecarboxamide,N-[trans-4-[2-(6-cyano-3,4-dihydro-2(1H)-isoquinolinyl)ethyl]-cyclohexyl]-(9CI)] prevented the anticonvulsant effect of the D₃/D₂ receptor agonist (+)-PD-128,907 [(R-(+)-trans-3,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol)] on cocaine-induced seizures. The protection afforded by the D₃/D₂ agonist, (+)-PD-128,907, was eliminated in D₃ receptor-deficient mice. In D₂ receptor knockout mice, the anticonvulsant effects of (+)-PD-128,907 were preserved. (+)-PD-128,907 also prevented the acquisition and expression of cocaine-kindled seizures engendered by repeated daily dosing with 60 mg/kg cocaine. (+)-PD-128,907 also blocked the seizures induced in mice fully seizure kindled to cocaine. Although repeated dosing with cocaine increased the potency of cocaine to produce seizures and lethality (decreased ED₅₀ values), daily coadministration of (+)-PD-128,907 significantly prevented this potency shift. In mice treated daily with cocaine and (+)-PD-128,907, the density, but not the affinity, of D₃ receptors was increased. The specificity with which (+)-PD-128,907 acts upon this cocaine-driven process was demonstrated by the lack of a significant effect of (+)-PD-128,907 on seizure kindling to a GABA_A receptor antagonist, pentylenetetrazol. Taken together and with literature findings, the data indicate that dopamine D₃ receptors function in the initiation of a dampening mechanism against the toxic effects of cocaine, a finding that might have relevance to psychiatric disorders of drug dependence, schizophrenia, and bipolar depression.

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