Date

September 2007

Document Type

Dissertation

Degree Name

Ph.D.

Department

Dept. of Behavioral Neuroscience

Institution

Oregon Health & Science University

Abstract

Drug abuse is a complex trait that is influenced by both genetic and environmental factors. Endophenotypes are simple traits that are genetically related to complex traits. Understanding the biological basis of an endophenotype is thought to be a way to understand a partial component of a complex trait. The acute locomotor responses to ethanol and psychostimulants are examined here as putative endophenotypes for drug and alcohol abuse. In this dissertation I set out to determine if nicotinic acetylcholine receptors are involved in ethanol, cocaine, and methamphetamine stimulation, and to confirm the presence of a quantitative trait locus (QTL) for the acute locomotor responses to these drugs on mouse chromosome 9 using congenic strains of mice. In this region of chromosome 9, there is a cluster of genes encoding acetylcholine receptor subunits. Therefore, the α3, α5, and β4 subunits of the nicotinic receptor (Chrna3, Chrna5, and Chrnb4, respectively) were examined as candidate genes for the acute locomotor response to ethanol. To achieve this goal, gene and protein expression assays were used. Behavioral pharmacological studies provided evidence that neuronal nicotinic acetylcholine receptors are involved in the acute locomotor response to ethanol, but not cocaine or methamphetamine. Mecamylamine, a nonspecific acetylcholine receptor antagonist, decreased ethanol-induced locomotor activation in two genetic models of enhanced sensitivity (DBA/2J [D2] and FAST mice). Hexamethonium, a nicotinic acetylcholine receptor antagonist which does not cross the blood brain barrier, did not attenuate this response. Antagonists specific for α4β2 and α7 receptors did not affect stimulation, therefore providing evidence against the role of these receptors. A QTL on mouse chromosome 9 was confirmed for ethanol, cocaine, and methamphetamine stimulation. The location of the QTL for ethanol and methamphetamine stimulation was further narrowed using a congenic F2 population and interval-specific congenic strains (ISCS), respectively. To determine if nicotinic acetylcholine receptors containing an α3 subunit were involved, molecular assays were utilized since antagonists specific for these receptors are not commercially available. The D2 strain of mice, which is robustly stimulated by ethanol, had less Chrna3 expression compared to the chromosome 9 D2.B6 congenic mice, which are less stimulated by ethanol. Mice selectively bred for sensitivity (FAST) and insensitivity (SLOW) to the stimulant effects of ethanol had similar Chrna3 expression. The assays currently used to assess protein expression of nicotinic acetylcholine receptors subunits are inadequate; therefore the question of differences in Chrna3 protein levels remains unresolved. These data provide evidence that a gene on chromosome 9 accounts for part of the variation in the acute locomotor responses to ethanol and psychostimulants. There is evidence that Chrna3 is a candidate gene for the acute response to ethanol, but this gene does not appear to be involved in psychostimulant-induced locomotor activation. Further work is needed to determine if Chrna3 is the quantitative trait gene (QTG) on chromosome 9 for ethanol stimulation, and to identify the QTG on chromosome 9 for the locomotor responses to cocaine and methamphetamine.

Identifier

doi:10.6083/M4348HBV

School

School of Medicine

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