The long term objective of this research is to investigate the relationship of ethanol tolerance to the self-administration of ethanol in lines of rats selectively bred for high and low oral ethanol drinking. One series of studies will examine the replicate pairs of high and low alcohol drinking (HAD 1 /LAD I and HAD2/LAD2) lines to determine whether there is a genetic correlation between the predisposition to consume high and low amounts of alcohol and the sensitivity and tolerance to the motor-impairing effects of ethanol. A parametric examination of ethanol sensitivity, acute (within-session) and chronic (between-session) tolerance will be carried out. A second series of studies will test the hypothesis that tolerance to the aversive effects of ethanol develops during ethanol self-administration. Furthermore, the magnitude of this tolerance may change during the acquisition of the ethanol drinking response and as a function of the rats' ethanol drinking history. A third series of studies is based on the hypothesis that high ethanol preference may be associated with a state of neuroexcitability. This state produces a P3 component in an evoked response potential (ERP) paradigm that is reduced in alcohol-preferring P rats relative to non-preferring NP rats and may produce an enhanced acoustic startle response in alcohol-preferring rats. Proposed experiments will examine P and NP rats to determine any line differences in the effects of ethanol on ERP and acoustic startle. Acute tolerance to the effects of ethanol on ERP and motor coordination in P and NP rats will be examined using a blood ethanol clamp procedure which can maintain blood ethanol levels at a predetermined steady state for prolonged periods. The main hypothesis that will be tested is that selective breeding for high and low alcohol intake will be correlated with differential tolerance development to the aversive and motor-impairing effects of ethanol and to the ability of ethanol to attenuate neuro-physiological and behavioral manifestations of CNS hyperexcitability.
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