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RSA 2003 Abstracts
The Scripps Research Institute, La Jolla
AFFECTIVE RESPONSES TO ACUTE ETHANOL AND ETHANOL WITHDRAWAL IN MU- AND DELTA-OPIOID RECEPTOR KNOCKOUT MICE
S. Ghozland; K. Chu; H.W. Matthes; B. Kieffer; A. RobertsDepartment of Neuropharmacology, The Scripps Research Institute, La Jolla, CA
It has been shown that mice lacking the mu-opioid receptor present a decreased ethanol drinking behavior, while mice lacking the delta-opioid receptor display increased drinking behavior compared to their respective wild-type controls. Interestingly, these mouse strains also differ in basal emotional responses, with mu-opioid receptor knockout mice showing decreased and delta-opioid receptor knockout mice showing increased anxiety-like behavior in several tests. In order to begin to investigate the relationship between ethanol drinking behavior, anxiety-like behavior, and the opioid systems, we have examined the effects of both acute ethanol as well as ethanol withdrawal and protracted abstinence on the anxiety-like behavior of both mu- and delta-opioid receptor knockout mice. Specifically, we performed a complete dose-response study of acute affective responses in the light/dark transfer paradigm and have examined affective signs of ethanol withdrawal in both strains of knockout mice after induction of a robust ethanol dependence using ethanol vapor chambers. A major finding was that mu-opioid receptor knockout mice do not display any acute anxiolytic-like response to ethanol at any of the doses that elicit strong anxiolytic-like responses in their wild-type littermates. This suggests that mu-opioid receptor knockout mice may not consume ethanol because they do not experience the positive reinforcing effect of this drug. More generally, this finding supports a role of mu opioid receptors in the link between affect and reinforcement.
This work was supported by the Integrative Neuroscience Initiative on Alcoholism, AA13482 and AA13523.
THE EFFECTS OF NEUROACTIVE STEROIDS ON ETHANOL SELF-ADMINISTRATION IN DEPENDENT AND NONDEPENDENT RATS
O'Dell, L.E.; Purdy, R.H.; Roberts, A.J., Brennan, M.A.; Koob, G.K.The Scripps Research Institute, Department of Neuropharmacology, 10550 N. Torrey Pines Rd., La Jolla, CA 92037
Previous research in our laboratory has demonstrated that rats trained in an operant procedure for ethanol self-administration that are made dependent on ethanol using chronic exposure to ethanol vapor exhibit increased responding for ethanol when tested during ethanol withdrawal. Studies in monkeys have demonstrated that the neurosteroid pregnanolone is similar to alcohol in drug discrimination assays. This study utilized a synthetic compound 20-oxo-5b-pregnan-3a-yl-carboxylic acid (PCA) that is structurally similar to pregnanolone and has been demonstrated to potentiate GABA currents and inhibit NMDA currents in electrophysiological studies using transfected cells in culture. We have also been involved in the synthesis of an inactive epimer of PCA which contains different stereochemical properties that presumably alter the effects of this compound on GABA transmission. The effects of PCA and an inactive epimer of this compound were tested on operant responding for ethanol prior to and following ethanol vapor exposure. PCA dose-dependently attenuated ethanol intake, and this effect was similar in dependent and nondependent rats. The inactive epimer did not alter alcohol or water intake. The ability of PCA to alter ethanol intake appears to be related to actions of this compound on GABA neurotransmission, and the modulation of neuroactive steroid sites in the brain may be a potential target for treating alcoholism.
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