The Central Reinforcing Properties of Ethanol Are Mediated by Endogenous Opioid Systems: Effects of Mu and Kappa Opioid Antagonists

Abstract

Endogenous opioid systems are implicated in the reinforcing effects of ethanol and may play a substantial role in modulating the central reinforcing effects of ethanol early in ontogeny. This possibility was explored in the present study through the use of an olfactory conditioning paradigm with centrally administered ethanol serving as an unconditioned stimulus (US). In Experiment 1, newborn rat pups were treated with either a selective mu antagonist CTOP or kappa selective antagonist nor-BNI prior to olfactory conditioning. Experiment 2 tested the effectiveness of an alternative, shorter-duration kappa opioid antagonist GNTI in altering ethanol reinforcement. Experiment 3 investigated whether the effectiveness of pharmacological blockade of opioid receptors was due to the disruption of learning per se using an olfactory aversive conditioning paradigm with intraoral quinine serving as a US. Central administration of either mu or kappa opioid antagonists prior to conditioning disrupted the reinforcing effects of ethanol in newborn rats. The kappa opioid antagonist GNTI was as effective as nor-BNI. These effects of opioid antagonists on ethanol reinforcement are unlikely to be due to a disruption of all types of conditioning, since CTOP did not affect aversive reinforcement to intraoral infusions of quinine. The present results support the hypothesis that in newborn rats, the reinforcing properties of ethanol are mediated by the endogenous activity at mu and kappa opioid receptors.

Figure 1

Olfactory IC conditioning: Design for paired and unpaired procedures used in Experiments 1 and 2. IC = into cisterna magna.

Figure 2

Total time attached (A) and mean grasp duration (B) on a surrogate nipple providing water in the presence of lemon odor. One hour prior to testing subjects were injected IC with saline, 1μg of CTOP or 1μg of nor-BNI and then exposed to lemon odor either explicitly paired or unpaired with central injections of 100 mg% ethanol. Bars represent mean values; vertical lines depict the standard error of the mean. Asterisk (*) indicates a significant difference from all other groups.

Figure 3

Total time attached (A) and mean grasp duration (B) on a surrogate nipple providing water in the presence of lemon odor. One hour prior to testing subjects were injected IC with one of the 4 doses of GNTI (0, 0.0174, 0.174 or 0.348 μg) and then exposed to lemon odor either explicitly paired or unpaired with central injections of 100 mg% ethanol. Bars represent mean values; vertical lines depict the standard error of the mean. Asterisk (*) indicates a significant difference from control and both the paired and unpaired GNTI 0.174 and GNTI 0.348 μg groups.

Figure 4

Classical olfactory conditioning: design for paired and unpaired procedures used in Experiments 1 and 2. IC = into cisterna magna

Figure 5

Total time attached (A) and mean grasp duration (B) on a surrogate nipple providing water in the presence of lemon odor. One hour prior to testing subjects were injected IC with either saline or 1.0 μg CTOP and then exposed to lemon odor while receiving intraoral infusions of 0.1% quinine (paired) or exposed to lemon odor 5 min prior to intraoral quinine infusions (unpaired) in Experiment 3. Bars represent mean values; vertical lines depict the standard error of the means. There was a significant main effect of conditioning. Unpaired subjects attached for both longer periods of time and longer bouts than paired rat pups which indicates an aversion.