The neuropeptide, arginine vasopressin (AVP) maintains functional tolerance to ethanol in animals that have acquired such tolerance: even in the absence of further ethanol intake. The peptide exerts its effects via V1 receptors in brain, and the objective this proposal is to further elucidate the biochemical and molecular mechanisms underlying this action. Our previous work has shown that chronic ethanol exposure reduces AVP mRNA (synthesis) and it is possible that an adaptive up-regulation of brain AVP receptors during chronic ethanol ingestion could produce increased sensitivity to the existing AVP, that would contribute to its effect on tolerance. To assess this possibility, we will compare brain AVP and oxytocin receptors by autoradiography in control and ethanol-tolerant mice. To further explore the relationship between AVP receptors and tolerance, brain AVP receptors will be characterized in strains of rats that acquire that acquire and lose tolerance at different rates. The consequence of AVP interactions with brain receptors will also be studied. Previous work showed that AVP stimulates the expression of a proto-oncogene, c-fos, that may play a role in synaptic differentiation. The product of this gene, Fos is a nuclear protein that can regulate gene transcription. However, Fos is only effective when combined with the products of other proto-oncogenes, c-jun and possibly jun-B. Analysis of the effect of AVP on the expression of these latter proto-oncogenes by Western and Northern blot and in situ hybridization techniques is proposed. An action of AVP on gene transcription would provide a mechanism whereby the short-lived peptide could produce long-term changes in CNS function. The AVP system has been proposed as an extrinsic one, which modulates, but does not encode ethanol tolerance. Intrinsic systems do encode tolerance, by changes in synaptic efficacy, and a candidate for an intrinsic system is voltage-sensitive calcium channels (VSCC) in brain, which are increased after chronic ethanol exposure. In the proposed work the relationship of VSCC changes to functional ethanol tolerance will be assessed by time course studies, and the ability of AVP to maintain the change in VSCC will be addressed. Since the acquisition of ethanol tolerance may promote excessive ethanol intake, understanding the mechanisms underlying tolerance may lead to means to ameliorate certain aspects of alcohol abuse.
| Szabo, G; Nunley, K R; Hoffman, P L (1996) Antisense oligonucleotide to c-fos blocks the ability of arginine vasopressin to maintain ethanol tolerance. Eur J Pharmacol 306:67-72 |
| Szabo, G; Hoffman, P L (1995) Brain-derived neurotrophic factor, neurotrophin-3 and neurotrophin-4/5 maintain functional tolerance to ethanol. Eur J Pharmacol 287:35-41 |
| Szabo, G; Tabakoff, B; Hoffman, P L (1994) The NMDA receptor antagonist dizocilpine differentially affects environment-dependent and environment-independent ethanol tolerance. Psychopharmacology (Berl) 113:511-7 |
| Hoffman, P L (1994) Neuroadaptive functions of the neuropeptide arginine vasopressin. Ethanol tolerance. Ann N Y Acad Sci 739:168-75 |
