Addiction Biology Unit, Section of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Sweden.
Alcohol Clin Exp Res. 2010 Jan;34(1):39-45. doi: 10.1111/j.1530-0277.2009.01063.x. Epub 2009 Oct 23.
We have previously demonstrated that strychnine-sensitive glycine receptors (GlyRs) in the nucleus accumbens (nAc) and nicotinic acetylcholine receptors (nAChRs) in the ventral tegmental area are involved in mediating ethanol (EtOH)-induced elevation of dopamine in the rat mesolimbic dopamine system. This neuronal circuitry was also demonstrated to mediate dopamine elevation in the nAc after both taurine, an endogenous agonist of GlyRs, and acamprosate, a synthetic derivate of homotaurine. The aim of this study was to investigate whether the EtOH intake-reducing effect of acamprosate involves accumbal GlyRs.
For this purpose, we used a voluntary EtOH consumption model where EtOH medium- and high-preferring rats were implanted with guide cannulae in the nAc. The animals received daily injections of acamprosate or 0.9% NaCl before accessing a bottle of 6% EtOH and a bottle of water. After 2 days, a microinjection of strychnine or vehicle preceded the daily systemic injection and bottle-access period.
Acamprosate, but not saline, decreased EtOH intake. Pretreatment with Ringer in the nAc did not influence EtOH intake in saline or acamprosate-treated animals. Pretreatment with strychnine had no effect on EtOH intake in saline-treated animals, whereas it completely reversed the EtOH intake-reducing effect of acamprosate.
Based on current and previous results, we suggest that acamprosate primarily interacts with accumbal GlyRs and secondarily with ventral tegmental nAChRs, in a similar manner to that previously observed with EtOH and taurine. The interaction between acamprosate and GlyRs does not only influence dopamine output in the nAc but also EtOH consumption, giving further support for our hypothesis that GlyRs are of importance in EtOH reinforcement.
我们之前已经证明，在核 accumbens (nAc) 中的马钱子碱敏感甘氨酸受体 (GlyRs) 和腹侧被盖区中的烟碱型乙酰胆碱受体 (nAChRs) 参与介导乙醇 (EtOH) 诱导的大鼠中脑边缘多巴胺系统中多巴胺的升高。该神经元回路还被证明可介导牛磺酸（GlyRs 的内源性激动剂）和安非他酮（同型牛磺酸的合成衍生物）给药后 nAc 中多巴胺的升高。本研究的目的是研究安非他酮对 EtOH 摄入的减少作用是否涉及 accumbal GlyRs。
为此，我们使用了一种自愿性 EtOH 消耗模型，其中 EtOH 中高偏好大鼠在 nAc 中植入了导水管。动物在接触 6% EtOH 瓶和水瓶之前，每天接受安非他酮或 0.9% NaCl 注射。两天后，在每日全身注射和瓶访问期之前，进行了 strychnine 或载体的微注射。
安非他酮，但不是盐水，可减少 EtOH 的摄入。在 nAc 中用 Ringer 预处理不会影响盐水或安非他酮处理动物的 EtOH 摄入。strychnine 预处理对盐水处理动物的 EtOH 摄入没有影响，而它完全逆转了安非他酮对 EtOH 摄入的减少作用。
根据当前和以前的结果，我们建议安非他酮主要与 accumbal GlyRs 相互作用，并其次与腹侧被盖区的 nAChRs 相互作用，其方式与以前观察到的 EtOH 和牛磺酸相似。安非他酮与 GlyRs 的相互作用不仅影响 nAc 中的多巴胺输出，还影响 EtOH 消耗，这进一步支持了我们的假设，即 GlyRs 在 EtOH 强化中很重要。
