Zocchi A, Orsini C, Cabib S, Puglisi-Allegra S
Dip. Psicologia, Università di Roma La Sapienza, Rome, Italy.
Neuroscience. 1998 Jan;82(2):521-8. doi: 10.1016/s0306-4522(97)00276-5.
Vulnerability to develop drug abuse could be related to differential sensitivity to some central effects of such drugs. Several results point to mesoaccumbens dopamine release elicited by psychostimulants as the rate-limiting factor of their reinforcing, hence addictive, effects and to locomotor stimulation as an indirect index of such a response. In this paper, we report parallel differences in sensitivity to amphetamine-induced locomotor stimulation and mesoaccumbens dopamine release in two inbred strains of mice characterized by differential susceptibility to develop drug self-administration. Thus, mice of the C57BL/6 strain responded with a simultaneous increase of locomotor activity and mesoaccumbens dopamine release measured by intracerebral microdialysis to amphetamine challenge. On the contrary, mice of the DBA/2 strain did not present either response. No strain differences in mesoaccumbens dopamine outflow or 3,4-dihydroxyphenylacetic acid concentration were found in basal conditions or following saline challenges. However, mice of the C57BL/6 strain were characterized by higher levels of accumbal homovanillic acid in basal conditions, in line with the results obtained in rats rendered more sensitive to the locomotor effects of psychostimulants by repeated administration. Finally, in both strains amphetamine decreased accumbal levels of the two metabolites. These results suggest that genotype modulates the locomotor effects of amphetamine through sensitivity of the mesoaccumbens system to amphetamine-stimulated dopamine release. Moreover, they provide a basis to test the hypothesis of mesoaccumbens dopamine involvement in individual susceptibility to the addictive effects of drugs by quantitative trait loci analysis in recombinant inbred strains.
易患药物滥用可能与对这类药物某些中枢效应的不同敏感性有关。多项研究结果表明，精神兴奋剂引起的中脑伏隔核多巴胺释放是其强化作用（即成瘾作用）的限速因素，而运动刺激则是这种反应的间接指标。在本文中，我们报告了两种近交系小鼠对苯丙胺诱导的运动刺激和中脑伏隔核多巴胺释放的敏感性存在平行差异，这两种小鼠对药物自我给药的易感性不同。因此，C57BL/6品系的小鼠在接受苯丙胺激发后，运动活性同时增加，通过脑内微透析测定的中脑伏隔核多巴胺释放也增加。相反，DBA/2品系的小鼠没有出现任何一种反应。在基础条件下或给予生理盐水激发后，未发现中脑伏隔核多巴胺流出或3,4 -二羟基苯乙酸浓度存在品系差异。然而，C57BL/6品系的小鼠在基础条件下伏隔核高香草酸水平较高，这与通过反复给药对精神兴奋剂运动效应更敏感的大鼠所获得的结果一致。最后，在两个品系中，苯丙胺均降低了这两种代谢产物在伏隔核中的水平。这些结果表明，基因型通过中脑伏隔核系统对苯丙胺刺激的多巴胺释放的敏感性来调节苯丙胺的运动效应。此外，它们为通过重组近交系中的数量性状位点分析来检验中脑伏隔核多巴胺参与个体对药物成瘾效应易感性的假说提供了基础。
