An understanding of neuronal mechanisms which mediate the behavioral effects of ethanol is critical to the understanding of alcohol intoxication, alcohol abuse, and alcoholism. The influences of the noradrenergic innervation on neuronal function may well regulate alterations in neuronal responsiveness to ethanol with e.g. stress or arousal, and the phenotype of the individual in terms of neuronal sensitivity to ethanol and regulation of neuronal ethanol effects by central sympathetic neurons will likely influence an individual's response to, and abuse of, alcohol in those behavioral states. The proposed studies will focus on LAS and HAS rats, which are genetic variants that differentially manifest an alcohol-related behavior, as a model system for examining acute ethanol interactions with neurotransmitter actions norepinephrine and GABA in the cerebellum, and rapid acute neuronal tolerance (RANT) to those effects. The effects of ethanol exposure on mammalian central nervous system function will be pursued using extracellular recordings of action potential activity of single neurons, whole-cell patch clamp recordings GABAA/C1 channel function, and in vivo electrochemistry to monitor presynaptic release and uptake of norepinephrine and other monoamines. Recordings will be carried out in rat brain in vivo and in brain slices in vitro, and drugs and transmitters will be applied by pathway activation, superfusion (in vitro), systemic administration (in vivo) and locally to the microenvironment of the cell from multibarrel micropipettes. The long- term objectives of this research program are three fold. First, to identify neuronal ethanol actions that are relevant to the behavioral ethanol sensitivities bred into LAS and HAS rats. Second, to characterize the mechanisms of these ethanol actions. Third, to characterize changes in neuronal responses to ethanol, as well as alterations in the function of neurotransmitter systems, which occur with the induction of RANT, explore the neuronal mechanisms of those changes and to determine the role of this phenomenon in the mechanisms of acute ethanol sensitivity.
The specific aims for this project period are as follows: 1) To investigate the hypothesis that neuronal EtOH sensitivity and RANT in the cerebellum are behaviorally relevant EtOH phenotypes. 2) To determine if RANT to EtOH in the cerebellum is mediated by a desensitization of b-adrenergic mechanisms. 3) To study the presynaptic role of cerebellar catecholamine synapses in RANT.
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| Freund, Ronald K; Gerhardt, Greg A; Marshall, Kriste E et al. (2003) Differences in norepinephrine clearance in cerebellar slices from low-alcohol-sensitive and high-alcohol-sensitive rats. Alcohol 30:9-18 |
| Wang, Y; Freund, R K; Palmer, M R (1999) Potentiation of ethanol effects in cerebellum by activation of endogenous noradrenergic inputs. J Pharmacol Exp Ther 288:211-20 |
