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]

被引:17
作者
Witkin, JM [1 ]
Dijkstra, D
Levant, B
Akunne, HC
Zapata, A
Peters, S
Shannon, HE
Gasior, M
机构
[1] Eli Lilly & Co, Lilly Corp Ctr, Lilly Res Labs, Neurosci Discovery Res, Indianapolis, IN 46285 USA
[2] NIDA, Behav Neurosci Branch, NIH, Baltimore, MD USA
[3] Univ Groningen, Ctr Pharm, Dept Med Chem, NL-9713 AW Groningen, Netherlands
[4] Univ Kansas, Med Ctr, Dept Pharmacol, Kansas City, KS 66103 USA
[5] Pfizer Inc, Neurosci Pharmacol, Ann Arbor, MI USA
关键词
D O I
10.1124/jpet.103.059980
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Cocaine abuse is a public health concern with seizures and death being one consequence of overdose. In the present study, dopamine D-3/D-2 receptor agonists dose dependently and completely prevented the convulsant and lethal effects of cocaine. The D-3-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/D-2 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 D-3 receptors. Protection was stereospecific and reversible by an antagonist of D-3 receptors [3-{4[1-(4-{2[4-(3-diethyamino-propoxy)-phenyl]benzoimidazol-1-yl}-butyl)-1H-benzoimidazol-2-yl]-phenoxy}propyl)-diethyl-amine; PD 58491] but not D-2 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 D-3 but not D-2 receptor function. Together, these findings suggest that the prevention of cocaine convulsions and lethality by (+)-PD 128,907 may be due to D-3 receptor-mediated events.
引用
收藏
页码:957 / 964
页数:8
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