Michael F. Miles, M.D., Ph.D.
Molecular Medicine Research Building, Room 6036
1220 East Broad Street
P.O. Box 980599
Richmond, Virginia 23298-0599
Phone: (804) 827-4054
Fax: (804) 828-6432
- M.D., Northwestern University, 1983
- Ph.D., Northwestern University, Ph.D., 1982
- 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 Clyde Hodge, Ph.D., 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 also can 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 also have 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.
Farris SP, Wolen AR and Miles MF. (2010) Using expression genetics to study the neurobiology of ethanol and alcoholism. International Review of Neurobiology. 91:95-128.
Li Z, Mulligan MK, Wang X, Miles MF, Lu L and Williams RW. (2010) A transposon in comt generates mRNA variants and causes widespread expression and behavioral differences among mice. PLoS One. 5(8):e12181.
Potkin SG, Macciardi F, Guffanti G, Fallon JH, Wang Q, Turner JA, Lakatos A, Miles MF, Lander A, Vawter MP and Xie X. (2010) Identifying gene regulatory networks in schizophrenia. NeuroImage. 53(3):839-47.
Jackson KJ, Walters CL, Miles MF, Martin BR and Damaj MI. (2009) Characterization of pharmacological and behavioral differences to nicotine in C57Bl/6 and DBA/2 mice. Neuropharmacology. 57(4):347-55.
Guo AY, Webb BT, Miles MF, Zimmerman MP, Kendler KS and Zhao Z. (2009) ERGR: An ethanol-related gene resource. Nucleic Acids Research. 37(Database issue):D840-5.