Michael F. Miles

Medical Sciences Building, Room 630   Dept. of Pharmacology & Toxicology   Virginia Commonwealth University   1217 E. Marshall St.   Richmond, VA 23298-0599	Tel: 804-225-4054 Fax: E-mail: mfmiles@vcu.edu
Web: www.brainchip.vcu.edu/
Research: Functional genomic approaches to neurobiology of drug abuse

BBSI project: How can we define which changes in expression measured by the microarrays are due to actual alterations in mRNA abundance versus polymorphisms?

Addiction to drugs of abuse likely results from step-wise changes in the expression of specific genes at discreet locations in the brain. These changes in gene expression lead to altered function of networks of neurons, with resultant behavioral changes such as addiction. We have used DNA microarrays to study expression of >10,000 genes simultaneously in mouse brain during exposure to drugs of abuse (cocaine, ethanol or nicotine). Different strains of mice show large differences in the ÅgpatternÅh of genes regulated by these drugs. Some of these measured differences in expression are due to actual changes in the abundance of a particular messenger RNA (mRNA) but some are also due to differences between the DNA sequence of the genes in the mouse lines studied. These sequence differences are referred to as polymorphisms and might have important consequences for the function of the involved genes, and susceptibility of the particular mouse strain to becoming addicted.

Other research interests (see web page for more details)

Use of functional genomics to understand the molecular mechanisms of experience dependent plasticity occurring with drug abuse.
Molecular mechanisms underlying sensitization to cocaine or ethanol
Sensitization refers to increased behavioral responses (e.g. locomotor activity) with repeated exposure to drugs of abuse. Sensitization increases the rewarding properties of addictive drugs. Expression profiling of basal gene expression in microdissected mouse brain regions during initiation of cocaine sensitization shows striking patterns of gene expression in the ventral tegmental area of DBA/2J mice. These expression patterns suggest functional changes that could contribute to increased dopamine release seen in nucleus accumbens with cocaine sensitization. Array studies, in combination with pharmacological, genetic and biochemical approaches, are currently being used to functionally link the regulation of specific genes to behavior of sensitization.

Molecular responses to acute ethanol exposure
There is a robust inverse relationship between acute ethanol sensitivity and long-term rates of ethanol self-administration in many different rodent models and in humans. We are studying patterns of gene regulation following acute ethanol exposure that correlate with long-term behavioral responses. Studies to date have identified a prominent role of prefrontal cortex in acute responses to ethanol. The gene expression patterns suggest several distinct targets of ethanol action. These include GABA-A receptors, a receptor known to be directly modulated by ethanol. Inbred lines, knockouts, gene delivery and pharmacological treatments are being used to correlate expression profiles with behavioral responses to acute ethanol. In addition, we are studying how "experience" with ethanol (sensitization, long-term drinking) alters the expression profiles seen with acute ethanol.

Molecular plasticity during acquisition of ethanol drinking behavior
In a collaborative project with Dr. Clyde Hodge, we are using DNA arrays to study molecular mechanisms of plasticity occurring in brain reward pathways as rats develop ethanol self-administration. We expect to implicate specific patterns of gene expression with the attainment or maintenance of ethanol self-administration. We can also identify subsets of genes serving tolerance or relapse. Initial array studies have identified striking changes in the expression of glutamate and GABA receptor subunits, both of which are known to be targets of acute ethanol action. Some changes identified in ethanol-drinking rats have also been seen in brain tissue from alcoholics. Further time course and pharmacological studies will be used to develop testable hypotheses about specific patterns of gene regulation most likely to be causal in drinking behavior

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