ALCOHOL AND MESOLIMBIC DOPAMINE PATHWAY

点击翻译按钮获取中文摘要

DESCRIPTION: (Adapted from the Investigator's Abstract) The long-term goal of this project is to elucidate further the neurochemical basis of the reinforcing effects of ethanol and to develop new strategy aimed at decreasing alcoholism in man. The proposed research will be carried out on freely moving rats by using intracerebral microdialysis technique to monitor in vivo dopamine (DA) release in the nucleus accumbens (NACC), a terminal area of the mesolimbic DA pathway. Pharmacologically relevant doses of ethanol will be administered systemically. First, DA and 5-HT in 5-min dialysate samples from the NACC will be measured simultaneously following acute ethanol to detect any changes in extracellular DA and 5-HT which occur during the ascending phase of the brain ethanol concentration curve. In addition, Ethanol-induced DA release in the NACC will be compared with and without the++ treatments with: 1) perfusion with tetrodotoxin (TTX) or Ca -free medium into the NACC, both of which are known to interrupt membrane depolarization; 2) perfusion with quinpirole, a D2 receptor agonist, into the ventral tegmental area (VTA) to suppress the mesolimbic DA neuronal activity; 3) nomifensine, a DA uptake blocker. This will enable us to determine whether and to what extent a carrier-dependent mechanism is involved in ethanol-induced DA release in the NACC. Furthermore, the effects of suppression (Lesioning with 5,7-DHT) or enhancement (pretreatment with 5-hydroxytryptophan and carbidopa) of the serotonergic transmission on ethanol-induced DA release will be evaluated. This will allow us to asses the possible involvement of the 5-HT system in the reinforcing effects of ethanol, the effects of agonists and antagonists at these subtypes of 5-HT2 receptors in the reinforcing effects of ethanol, the effects of agonists and antagonists at these subtypes of 5-HT receptor on ethanol-induced DA release in the NACC will be investigated. This will elucidate the relative contribution of 5-HT2 receptors to the regulation of ethanol-induced DA release and help to explain the effects of 5-HT2 antagonists on alcohol consumption reported in the literature.