INTERACTION OF ALCOHOL AND THE HPT AXIS

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The neurobiology of alcohol preference is complex and likely involves several neurochemical systems. In animals, the peptide neuromodulator thyrotropin-releasing hormone (TRH) has been shown to counteract the depressant effects of ethanol and, paradoxically, to potentiate its anticonflict effects. In humans, TRH may relieve tension and anxiety, and there is now evidence suggesting it can counteract some of the depressant effects of ethanol. Based primarily on the pharmacological profile of TRH, we tested the hypothesis that a TRH analog with reported high central and low endocrine potency (TA-0910) would reduce alcohol preference in alcohol preferring (P) rats. We showed that one intraperitoneal (ip) injection of TA-0910, dose- dependently reduced alcohol (and commensurately increased water) intake but did not reduce food or caloric intake in P rats accustomed to alcohol. These effects were not produced by thyrotropin or T4 indicating a lack of endocrine involvement. These findings suggest that brain TRH systems have a role in alcohol preference in rats and imply involvement of TRH systems in alcohol abuse in man. The specific aims of this project are: 1) To further characterize the effects of TA-0910 on alcohol preference in P rats. We will determine: a) the effects of single ip inductions of different doses of TA-0910 on alcohol preference 1,2,4,6,8,12,16,20 and 24 hrs. later; b) the effects of repeated injections of TA-0910 (administration will be based on profiles of acute effects); c) if tolerance to TA-0910 develops an how long it lasts; d) whether TA-0910 will reduce alcohol withdrawal symptoms; and e) if TA-0910 can affect alcohol preference and alcohol consumption in alcohol naive-p rats and alcohol preference in alcohol-withdrawn P rats. 2) To determine the neurochemical mechanisms by which TA-0910 reduces alcohol preference in P rats. We will determine if effects of TA-0910 on alcohol preference are altered by prior administration of different doses of selective dopamine (DA) or serotonin (5-HT) antagonists, injected ip or into specific brain sites 3) To determine the neuroanatomical sites where TA-0910 reduces alcohol preference in P rats. We will inject different doses of TA-0910 (1-100 ng/site) into five different brain sites to determine where the analog reduces alcohol preference. Sites where TA-0910 may act to reduce alcohol preference include nucleus accumbens, medial septum, and amygdala. Sites thought not to be involved in preference (cerebellum, hippocampus) will also be tested. 4) To compare brain TRH systems in and non-preferring (NP) rats. We will determine if: a) brain TRH immunoreactive levels and b) brain TRH receptor binding are different in P and NP rats before and after acute and chronic exposure to alcohol. Preliminary data from another laboratory indicate regional differences in brain TRH levels and possible differences in brain TRH receptor affinity between P and NP rats. Achievement of these aims will provide scientific evidence upon which to judge the potential of TA-0910 and other TRH analogs with similar properties to attenuate alcohol consumption and reduce craving for alcohol in humans.