Dept. of Behavioral Neuroscience
Oregon Health & Science University
Increased sensitivity to the behavioral stimulant effect of ethanol may be a risk factor for alcohol use disorders, and treatments that reduce the stimulant response may be potential pharmacotherapies. In examining the neurochemical substrates underlying the stimulant response to ethanol in mice selectively bred for extreme sensitivity (FAST) and insensitivity (SLOW) to this response, the [gamma]-aminobutyric acid (GABA) system has repeatedly been implicated. These lines differed in sensitivity to a wide array of GABA[subscript A] receptor muodulators and to the GABA[subscript B] receptor agonist baclofen, and baclofen attenuated the stimulant response to ethanol in FAST mice. Therefore, GABA systems are likely a critical component involved in the stimulant response to ethanol; however, the exact contribution of this system is not known. The main purpose of this dissertation was to examine how selective breeding of the FAST and SLOW lines had altered GABA systems, and GABA[subscript B] receptors in particular, as well as to examine potential mechanisms by which GABAergic drugs attenuate the stimulant response to ethanol. The contribution of GABA transporter was first examined, and the FAST and SLOW lines were found to differ in acute locomotor sensitivity to the transporter inhibitor NO-711, supporting a difference in GABA system function between the two lines. Further, NO-711 attenutated the locomotor stimulant response to ethanol in FAST mice; however this reduction in stimulation was accompanied by an enhancement of the motor incoordinating effects of a low dose of ethanol. Similar results were observed with the GABA[subscrip A] receptor agonist muscimol, suggesting that preferential activation of GABA[subscript A] receptors additively intersects with ethanol to shift the behavioral response towards greater motor impairment and intoxication. Activation of GABA[subscript B] receptors by baclofen, however, did not enhance ethanol-induced motor incoordination, suggesting that baclofen may reduce the stimulant response to ethanol by reducing a neurochemical response to the ethanol-induced stimulation rather than an enhancement of intoxication. To further examine how GABA[subscript B] receptors may contribute to the stimulant response to ethanol, receptor function and microdialysis assays were performed. FAST and SLOW mice differed in GABA[subscript B] function, measured as baclofen-stimulated [[superscript 35]S]GTP[gamma]S binding, in the striatum, with increased efficacy of baclofen in FAST mice. GABA[subscript B] receptors in the ventral midbrain are hypothesized to attenuate the stimulant response to ethanol by attenuating an ethanol-induced stimulation to dopamine signaling. To determine if this was occurring in FAST mice, the effect of baclofen on ethanol-induced locomotor stimulation and ethanol-induced increases in the extracellular dopamine in the nucleus accubens was examined. While there was an elevation of extracellular dopamine levels by ethanol, this effect was not altered by baclofen despite a baclofen-induced attenuation of the stimulant response to ethanol. These data add to the evidence supporting a contribution of GABA systems to acute alcohol sensitivity. The effect of baclofen on ethanol-stimulated behavior may occur independent of alterations in mesolimbic dopamine signaling, suggesting that other pathways should be explored. In addition, these results suggest that the GABA[subscript B] receptor may be an attractive candidate as a pharmacotherapy for alcohol use disorders, because it may block some effects of alcohol without producing undesirable effects.
School of Medicine
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