JAY HIRSH

    Professor of Biology

Research Interest

Fruit flies: A novel genetic system for the study of drugs of abuse.

My laboratory is using the fruit fly, Drosophila melanogaster, as a model system for studying the molecular genetics of responsiveness to cocaine and other drugs of abuse. We have shown that exposure to aerosolized free base cocaine induces multiple reflexive motor responses that resemble cocaine induced behaviors in vertebrates, and also resemble dopamine agonist induced behaviors previously observed in decapitated flies (Yellman et al, 1997). Furthermore, Drosophila develop behavioral sensitization to intermittent doses of cocaine. Sensitization has been linked to the addictive processes in vertebrates, and it is of great interest to understand the basic mechanisms leading to sensitization in a simple model system. Our results suggest that the pathways leading to cocaine induced responses are evolutionarily conserved between Drosophila and higher vertebrates, and that this genetically tractable animal can be used as a new model system to help determine the biological mechanisms underlying these processes.

Recent studies are uncovering some unexpected gene products and small molecules involved in sensitization in flies. We have found that regulated production of the trace amine tyramine is essential for the development of sensitization (McClung & Hirsh, 1999). In addition, we have found that a subset of genes essential for fly circadian functions are required for sensitization (Andretic et al, 1999). Given the conservation of structure and function of these circadian genes in animals from flies to higher vertebrates, there is a strong likelihood of conserved functions for these genes in modulating drug responses across evolution. Ongoing studies are aimed at further elucidating the mechanisms and genes involved in modulating sensitization and drug responsiveness.

PLEASE NOTE: Funded Postdoctoral position available to work on the above studies. Contact Jay for further information.

Representative Publications

  1. Andretic, R., Chaney, S. & Hirsh, J. (1999) A Role for Circadian Genes in Cocaine Sensitization in Drosophila melanogaster. Science, 285, 1066-1068.
  2. Andretic, R., Hirsh, J. (2000) Circadian modulation of dopamine receptor responsiveness in Drosophila melanogaster. Proc. Natl. Acad. Sci., USA 97, 1873-1878.
  3. Li, H., Chaney, S., Roberts, I.J.H., Forte, M. & Hirsh, J. (2000) Ectopic G-protein expression in dopamine and serotonin neurons blocks cocaine sensitization in Drosophila melanogaster. Curr Biol, 10, 211-214.
  4. Park, S., Sedore, S., Cronmiller, C. & Hirsh, J. (2000) PKAII-Deficient Drosophila are Viable but Show Developmental, Circadian and Drug Response Phenotypes. J. Biol. Chem., 275, 20588-20596.
  5. Peter Pörzgen, Sang Ki Park, Jay Hirsh, Mark S. Sonders and Susan G. Amara (2001) The Antidepressant Sensitive Drosophila Dopamine Transporter: a Primordial Catecholamine Carrier. Mol Pharm, 59, 83-95.
  6. Friggi-Grelin, F., Coulom, H., Meller, M., Gomez, D., Hirsh J. and Birman S. Targeted gene expression in Drosophila dopaminergic cells using regulatory sequences from tyrosine hydroxylase. J. Neurobiol, (2003) in press.

 

For more information email jh6u@virginia.edu.