Our major working hypothesis has been that osmosensitive and glucose-sensitive neurons of the lateral hypothalamus (LHA) that are involved in drinking and eating circuits are also sensitive to ethanol. These LHA circuits have embedded within them angiotensin (Ang) neurons that release Ang onto dentate gyrus granule cells and modulate synaptic plasticity in this brain region which plays an important role in learning and memory. This assumption is based upon the following facts. Angiotensin applied directly to the dentate gyrus inhibits long term potentiation (LTP) induction and the inhibition can be prevented by pretreating the animals with losartan, an Ang II AT1 receptor antagonist. LTP is a type of frequency-dependent synaptic plasticity. Ethanol drinking or ethanol applied directly to the LHA also inhibits LTP as well as impairs maze learning. Both the impairment of maze learning and LTP inhibition can be prevented by pretreatment with losartan. Because diazepam produces similar effects and these effects can also be prevented by pretreatment with losartan, we also assume that the ethanol triggering event in the LHA is mediated by GABAergic inhibitory interneurons.
The specific aims of this proposal are: (a) To measure angiotensin release in the dentate gyrus before, during, and after various amounts of ethanol are applied either by intragastric intubulation or by direct pervasion to the LHA, (b) To determine the effects of diazepam and muscimol, a GABAA receptor agonist, on Ang release; and (c) To determine the relative effectiveness of bicuculline, a competitive GABAA antagonist, on Ang release when combined with 30 mM ethanol in the LHA perfusate. The expected results will provide critical data in support of our general hypothesis and establish a physiological meaningful neural circuit sensitive to ethanol with clearly identified afferents, a known neuromediator involved, and post synaptic effects important in cognitive processes associated with learning and memory. It will also provide a basis for expanding this research to identify other transmitters that might be released by these axon terminals. Losartan combined with diazepam might have therapeutic potential in treating alcoholism.
| Wayner, M J; Armstrong, D L; Phelix, C F (2004) Ethanol effects on dentate granule cell LTP. Neurotox Res 5:599-604 |
| Wayner, Matthew J (2002) Craving for alcohol in the rat: adjunctive behavior and the lateral hypothalamus. Pharmacol Biochem Behav 73:27-43 |
