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

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Abstract
Cocaine abuse is a public health concern with seizures and death being one consequence of overdose. In the present study, dopamine D3/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 D3/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.