Parsons L H, Koob G F, Weiss F
Department of Neuropharmacology, Scripps Research Institute, La Jolla, California, USA.
J Pharmacol Exp Ther. 1995 Sep;274(3):1182-91.
To test the hypothesis that cocaine withdrawal is associated with abnormalities in serotonin (5-HT) neurotransmission, 5-HT concentrations in the nucleus accumbens (NAC) of rats were analyzed with microdialysis both during and after 12 h of unlimited-access intravenous cocaine self-administration. For comparison with previous work, dopamine (DA) levels were also monitored. Self-administration produced sustained increases of both 5-HT and DA to approximately 340% of base line. During the first 6 h of withdrawal, dialysate 5-HT concentrations decreased to 41% of base-line levels obtained before self-administration and to 25% of levels in drug-naive control animals. During the same period, dialysate DA decreased to 72% of presession base-line concentrations but did not decline below control levels. Extracellular 5-HT concentrations were subsequently estimated by use of a quantitative microdialysis technique. After 12 h of self-administration extracellular 5-HT levels were significantly lower (0.6 +/- 0.3 nM) than levels in drug-naive animals (2.0 +/- 0.5 nM) or in rats given only limited-access to cocaine (3 h/day; 1.4 +/- 0.2 nM). Additionally, after 12 h of self-administration low concentrations of intra-accumbens 5-HT applied by reverse dialysis significantly elevated DA efflux. This effect was not observed in either control animals or in rats given only limited access to cocaine. These results suggest that deficient 5-HT neurotransmission may be a significant factor in the cocaine withdrawal symptomatology and provide key information regarding nondopaminergic mechanisms involved in cocaine dependence.
为了验证可卡因戒断与血清素（5-羟色胺，5-HT）神经传递异常有关这一假设，在大鼠不限量静脉注射可卡因自我给药12小时期间及之后，采用微透析法分析了伏隔核（NAC）中的5-HT浓度。为了与之前的研究作比较，还监测了多巴胺（DA）水平。自我给药使5-HT和DA均持续升高至基线水平的约340%。在戒断的最初6小时内，透析液中5-HT浓度降至自我给药前基线水平的41%，降至未接触过药物的对照动物水平的25%。在同一时期，透析液中DA降至给药前基线浓度的72%，但未降至对照水平以下。随后使用定量微透析技术估算细胞外5-HT浓度。自我给药12小时后，细胞外5-HT水平（0.6±0.3 nM）显著低于未接触过药物的动物（2.0±0.5 nM）或仅有限接触可卡因的大鼠（每天3小时；1.4±0.2 nM）。此外，自我给药12小时后，通过反向透析施加的低浓度伏隔核内5-HT显著提高了DA流出量。在对照动物或仅有限接触可卡因的大鼠中均未观察到这种效应。这些结果表明，5-HT神经传递不足可能是可卡因戒断症状的一个重要因素，并提供了有关可卡因依赖中非多巴胺能机制的关键信息。
