| The goal of this dissertation was to investigate the role of mu-opioid receptors in the mechanism of ethanol-stimulated dopamine release in the nucleus accumbens shell (NAcS) of rats. The underlying hypothesis is that blockade of the mu-opioid receptors leads to an attenuation of ethanol-stimulated mesolimbic dopamine release. We prepared ethanol-naive male Long Evans rats (n = 95) for intravenous (i.v.) drug administration and in vivo microdialysis (in awake, freely moving animals), and analyzed our samples using HPLC and GC for dopamine and ethanol detection, respectively. In one set of experiments, we looked at the effects of naltrexone, a non-selective opioid antagonist, on ethanol-stimulated mesolimbic dopamine release. First of all, we checked to see if naltrexone affected basal dopamine levels in the NAcS. Thereafter, we looked for a dose of naltrexone (i.v.) that was effective in suppressing the release of dopamine in the NAcS evoked by morphine (1 mg/kg, i.v.). Subsequently, we checked to see if doses of naltrexone that inhibited morphine-evoked dopamine were also effective in attenuating dopamine release due to ethanol (1g/kg, 10% w/v, i.v.). To do this, we pretreated rats with naltrexone doses, followed 20 min later by morphine, ethanol or saline (all drugs were administered i.v.). In another set of experiments, we looked at the effect of beta-funaltrexamine, a selective mu-opioid antagonist, on ethanol-stimulated dopamine release in the NAcS. Similarly to the previous set of experiments, we looked for a dose of beta-funaltrexamine (s.c.) that was effective in suppressing the release of dopamine the NAcS evoked by morphine (1 mg/kg, i.v.), and checked to see if this dose of beta-funaltrexamine was also effective in attenuating ethanol-stimulated dopamine release in the NAcS. For the beta-funaltrexamine experiments, rats were pretreated with beta-funaltrexamine (s.c.) 20-25 h before i.v. infusions of saline, morphine and ethanol.;Morphine increased dopamine release in the NAcS. Naltrexone and beta-funaltrexamine significantly attenuated morphine-evoked dopamine release. Also, ethanol increased dopamine release in the NAcS. Naltrexone and beta-funaltrexamine, at doses effective in attenuating morphine-evoked dopamine release, suppressed the prolongation, but not the initiation of dopamine release in the NAcS due to ethanol. Naltrexone and beta-funaltrexamine did not affect the peak concentration and clearance of ethanol in the brain. The conclusion of this study is that the mu-opioid receptors are involved in a delayed component of ethanol-stimulated dopamine release in the NAcS in ethanol-naive rats. This is the first study to show that the ethanol-stimulated dopamine response consists of a delayed mu-opioid mechanism. |
