Turchan J, Przewłocka B, Lasoń W, Przewłocki R
Department of Molecular Neuropharmacology, Institute of Pharmacology, Polish Academy of Sciences, Kraków.
Neuroscience. 1998 Aug;85(4):1051-9. doi: 10.1016/s0306-4522(97)00639-8.
The prodynorphin system is implicated in the neurochemical mechanism of psychostimulants. To elucidate the activity of the endogenous prodynorphin system upon treatment with psychostimulants, we investigated the effect of single and repeated cocaine and amphetamine on the prodynorphin messenger RNA level, the prodynorphin-derived peptide alpha-neoendorphin tissue level, and its in vitro release in the nucleus accumbens and striatum of rats. The density of kappa opioid receptors in those brain regions was also assessed. Rats were injected with cocaine following a "binge" administration pattern, 20 mg/kg i.p. every hour for 3 h, one (single treatment) or five days (chronic treatment). Amphetamine, 2.5 mg/kg i.p. was administered once (single treatment) or twice a day for five days (chronic treatment). As shown by an in situ hybridization study, the prodynorphin messenger RNA levels in the nucleus accumbens and striatum were raised following single (at 3 h) and chronic (at 3 and 24 h) cocaine administration. The prodynorphin messenger RNA level in the nucleus accumbens was markedly elevated after single or repeated amphetamine administration. A similar tendency was observed in the striatum. Acute cocaine and amphetamine administration had no effect on the alpha-neoendorphin tissue level, whereas chronic administration of those drugs elevated the alpha-neoendorphin level in the nucleus accumbens and striatum at the late time-points studied. Acute and repeated cocaine administration had no effect on alpha-neoendorphin release in both the nucleus accumbens and striatum at 3 and 48 h after drug injection. In contrast, single and chronic (at 24 and 48 h) amphetamine administration profoundly elevated the release of alpha-neoendorphin in both these structures. Addition of cocaine or amphetamine to the incubation medium (10(-5)-10(-6) M) decreased the basal release of alpha-neoendorphin in the nucleus accumbens slices of naive rats, but it did not change the stimulated release (K+, 57 mM). On the other hand, in the striatum slices, addition of cocaine to the incubation medium depressed basal and stimulated release of the peptide; no significant changes were observed after addition of amphetamine. Cocaine and amphetamine evoked profound and long-term down-regulation of the kappa opioid receptors in both structures. The above data indicate that the amphetamine-induced changes were more abundant than those caused by cocaine; only treatment with amphetamine markedly enhanced the release of prodynorphin-derived peptide. Furthermore, the psychostimulant-induced enhancement of biosynthetic activity of prodynorphin neurons was correlated with a marked and persistent decrease in the kappa opioid receptor density at a late withdrawal time.
前强啡肽系统与精神兴奋剂的神经化学机制有关。为了阐明精神兴奋剂治疗后内源性前强啡肽系统的活性，我们研究了单次和重复给予可卡因和苯丙胺对大鼠伏隔核和纹状体中前强啡肽信使核糖核酸水平、前强啡肽衍生肽α-新内啡肽组织水平及其体外释放的影响。还评估了这些脑区中κ阿片受体的密度。大鼠按照“暴饮暴食”给药模式注射可卡因，腹腔注射20mg/kg，每小时一次，共3小时，给药一次（单次治疗）或五天（慢性治疗）。苯丙胺，腹腔注射2.5mg/kg，给药一次（单次治疗）或每天两次，共五天（慢性治疗）。原位杂交研究表明，单次（3小时时）和慢性（3小时和24小时时）给予可卡因后，伏隔核和纹状体中的前强啡肽信使核糖核酸水平升高。单次或重复给予苯丙胺后，伏隔核中的前强啡肽信使核糖核酸水平显著升高。在纹状体中也观察到类似趋势。急性给予可卡因和苯丙胺对α-新内啡肽组织水平无影响，而长期给予这些药物在研究的后期时间点升高了伏隔核和纹状体中的α-新内啡肽水平。急性和重复给予可卡因在注射药物后3小时和48小时对伏隔核和纹状体中α-新内啡肽的释放均无影响。相反，单次和慢性（24小时和48小时时）给予苯丙胺显著提高了这两个结构中α-新内啡肽的释放。在孵育培养基（10^-5 - 10^-6 M）中添加可卡因或苯丙胺可降低未处理大鼠伏隔核切片中α-新内啡肽的基础释放，但不改变刺激释放（K+，57 mM）。另一方面，在纹状体切片中，向孵育培养基中添加可卡因可抑制该肽的基础释放和刺激释放；添加苯丙胺后未观察到显著变化。可卡因和苯丙胺引起这两个结构中κ阿片受体的深度和长期下调。上述数据表明，苯丙胺诱导的变化比可卡因引起的变化更丰富；只有苯丙胺治疗显著增强了前强啡肽衍生肽的释放。此外，精神兴奋剂诱导的前强啡肽神经元生物合成活性增强与撤药后期κ阿片受体密度的显著且持续降低相关。
