Ethanol Modulation of Striatal Dopamine Receptors

Hruska, Robert

Abstract

Ethanol use is a major medical concern. The use of ethanol acutely and chronically alters the function of the central nervous system by interfering with neuronal activity. The mechanism of this action has been proposed to result from the dissociations of neuronal membrane functions. As a means to monitor the dissociative effects of ethanol, striatal dopamine (DA) receptor subtypes and localizations will be measured. The direct effect of ethanol in vitro and the chronic in vivo effects of ethanol related to tolerance development will be compared, as measured by the density and affinity of the two striatal DA receptor subtypes (D-1 and D-2). The effect of ethanol will also be measured on the inhibition by specific agonists and antagonists of the receptor subtypes. The dissociative effects of ethanol on specific neuronal localizations of DA receptors will be made after specific neuronal lesions. The striatal tissue is chosen because of the known neuronal localizations and because several reports have identified alterations in striatal DA function after acute and chronic exposure to ethanol. The methodologies are as follows: DA receptors are measured by the specific and saturable binding of [3H]cis(Z)-flupenthixol for D-1 receptors and [3H]domperidone for D-2 receptors and analysed for affinity and density. The action of agonists and antagonists to displace specific binding to each receptor subtype is performed using the D-1 agonist SKF-38393, the D-1 antagonist SCH-23390, the D-2 agonist LY-141865, and the D-2 antagonist domperidone. Ethanol exposure in vitro is by direct addition to the tissue, in vivo it is by a liquid Sustacal diet containing 6.7 percent (v/v) ethanol to provide about 10 g ethanol/kg/d for 24 days. Lesions to remove specific neuronal sub-populations of DA receptors in the striatum are by the intranigral injection of 6-hydroxydopamine, the intrastriatal injection of kainic acid, and by limited cortical ablation.