The long term objective of the proposed work is to gain understanding of the mechanisms involved in the excitatory effect of ethanol. The euphoriant, excitatory effect of a drug is generally considered an important indication of abuse liability. The excitatory effect of ethanol, especially after repeated administration, is a relatively unexamined phenomenon despite its probable role in alcohol abuse. The purposes of the work presented here are: 1) to examine the excitatory effect of ethanol as a function of the schedule and context of administration and 2) to assess the effects of acute and chronic ethanol in a behavioral model of dopamine function.
The specific aims of the proposed research are: 1) to determine if tolerance or sensitization to the locomotor stimulant effect of ethanol in mice develops upon repeated administration, 2) to determine the contribution of intertreatment interval and context (setting) on changes in the locomotor stimulation induced by successive ethanol treatments, 3) to determine if changes in ethanol-induced stimulation can be attributed to changes in blood and brain levels of ethanol, 4) to evaluate stimulation induced by acute and repeated administration of ethanol in a well established whole animal model of central dopamine function, i.e., the unilaterally 6-hydroxydopamine-lesioned mouse rotation model, and 5) to determine if the dopaminergic subsensitivity found in mice withdrawn from chronic ethanol results in changes in rotational response to dopamine agonists. All experiments will be conducted in Swiss Webster and DBA mice.
Specific aims 1) and 2) will be accomplished using electronic activity monitors and systematic variation of intertreatment interval and setting. Head space gas chromatographic determination of blood and brain ethanol will be used to achieve aim 3). To accomplish aims 4) and 5), mice will be lesioned by microinjection of 6-hydroxydopamine into one striatum and will be screened for rotation in response to the dopamine agonists, apomorphine and amphetamine. Such mice will then be tested for rotation in response to acute and repeated ethanol.
Aim 4) will be completed by testing the ability of alpha-methyl-tyrosine, haloperidol and naloxone to block ethanol-induced rotation. To achieve aim 5), lesioned, screened mice will be retested with the dopamine agonists following chronic ethanol treatment.
| Silverman, P B (1987) Ethanol induces rotational behavior in 6-hydroxydopamine lesioned mice. Life Sci 40:967-71 |
