Neurochemical and behavioral studies on ethanol and brain opiod interactions in the brain

Abstract

Substance dependence is a devastating disorder that produces enormous socio-economic costs, personal tragedies and health related problems. The brain mesolimbic dopamine pathway originating in the ventral tegmental area (VTA) with projections to limbic brain structures such as the nucleus accumbens has been implicated in the reinforcing effects of different drugs of abuse. The basal and drug-induced activity of mesolimbic dopamine neurons is modulated by endogenous opioids. Non-selective opioid receptor antagonists are increasingly used in the treatment of alcohol dependence, and ligands selective for the different opioid receptor types have recently been suggested to be effective in the treatment of cocaine and heroin addiction in humans. The present thesis examined the neurobiological and behavioral interactions between ethanol and endogenous opioids, with specific focus on the dynorphin/kappa-opioid receptor system. In addition, the effects of concurrent ethanol and cocaine administration on kappa-opioid receptor mRNA and dopamine transmission in the mesolimbic pathway were studied.

Repeated ethanol administration significantly increased the dynorphin B levels in the nucleus accumbens at 30 min and at 21 days after the last dose. The kappa-receptor mRNA levels were significantly reduced in both the VTA and the nucleus accumbens after separate as well as concurrent administration of ethanol and cocaine. These results suggest that repeated exposure to ethanol may lead to neuroadaptive changes in the dynorphin/kappa-receptor system associated with the mesolimbic pathway, some of which may be long lasting. Following repeated ethanol administration, extracellular dopamine concentrations in the nucleus accumbens were significantly increased in rats pre-treated with ethanol, but not in the controls. Conversely, the inibitory effect of the kappa-receptor agonist U50,488H on dopamine levels was more pronounced in saline- than in ethanol -pre-treated rats. This suggests that repeated ethanol changes the sensitivity of the dynorphin/kappa-receptor system, and/or enhances the activity of the endogenous agonist dynorphin. Pre-treatment with ethanol increased the effect of cocaine on dopamine levels in the nucleus accumbens. Cocaine-induced stereotypic behavior was unaffected by ethanol pre-treatment. The enhanced dopamine release in the nucleus accumbens may be related to the heightened experience produced by concurrent intake of ethanol and cocaine in humans, and could influence the probability of co- abuse. Naltrexone and the selective delta-receptor antagonists ICI-174,864 and naltrindole significantly decreased voluntary ethanol intake, whereas the mu1-antagonist naloxonazine had no significant effect. The kappa-receptor agonist U50,488H decreased ethanol intake, whereas the kappa-receptor antagonist nor-BNI lacked effect by itself, but reduced the effect of U50,488H. This suggests that not only the mu-/delta-receptor systems, but also the kappa-receptor systems modulate volitional ethanol intake in the rat.

In summary, repeated exposure to ethanol andlor cocaine produces alterations in the brain dynorphin/kappa-opioid receptor system. Further, voluntary ethanol intake is reduced by selective opioid receptor ligands. It is suggested that the dynorphinergic system is involved in the pathophysiology of alcohol dependence, and may represent a potential pharinacotherapeutic target in the treatment of this disorder.