Pharmacology and Toxicology - Research

Thomas A. Green, Ph.D.

Assistant Professor

Research Interests

There is almost unanimous agreement among scientists that complex psychiatric conditions such as addiction, depression and anxiety are a function of interactions between genes and environment. Exposure to environmental factors such as drugs of abuse or stress activate signaling cascades within neurons that in turn alter gene transcription in specific brain regions involved in addiction, depression and anxiety. These changes in gene transcription are typically homeostatic, leaving the person better adapted to the changing environment. However, in a minority of cases the drug or stress insult triggers maladaptive changes in brain chemistry, leading to psychiatric conditions such as addiction or depression.

In contrast to drugs and stress, positive environmental stimuli such as novelty, social contact and exercise produce a protective phenotype that can render some people resistant to addiction or depression, even after exposure to drugs of abuse or stress. We can model this effect in rats using the environmental enrichment paradigm. Rats at 21 days of age are assigned either to an isolated condition (IC), where they are single housed with no social contact or novelty, or an enriched condition (EC) where they are housed 12 per cage in large home cages with novel objects (children toys) and social contact with cohorts. After a month in these environmental conditions, EC rats exhibit protective phenotypes for addiction- and depression-like behavior. Regarding addiction-like behavior, EC rats do not self-administer intravenous cocaine or amphetamine as readily as IC rats, despite being more sensitive to the rewarding effects of the drug (as measured by conditioned place preference). Specific to depression-like behavior, EC rats show less signs of behavioral despair than IC rats in the Forced Swim Test and greater preference for natural rewards such as sucrose. Not surprisingly, EC rats also engage in social grooming more than IC rats.

Our current research is focused on the molecular mechanisms underlying the protective addiction and depression phenotype. We have already identified the transcription factor cAMP response-element binding protein (CREB) as one major mechanism in the EC phenotype. We have shown that we can reproduce the EC phenotype in normal pair-housed animals simply by blocking CREB function in the nucleus accumbens shell using novel viral vectors. However, CREB itself is only a transcription factor, meaning that it can only be a distal mechanism. Our future plans are to utilize well-established genomic expression profiling techniques in EC and IC rats to identify CREB target genes as proximal mechanisms mediating the EC phenotype. Once identified, additional viral vectors will be constructed to validate the role of these CREB target genes in mediating the protective EC phenotype. The overall goal of the project is to identify new mechanisms of resistance to addiction and depression to target for treatment as well as prevention of addiction and depression.

Selected Publications

Rogge, G. A., Jones, D. C., Green, T., Nestler, E., Kuhar, M. J. (2008) Regulation of CART peptide expression by CREB in the rat nucleus accumbens in vivo. Brain Res 1251:42-52.

Winstanley, C. A., Green, T. A., Theobald, D. E., Renthal, W., Laplant, Q., DiLeone, R. J., Chakravarty, S., Nestler, E. J. (2008) ^FosB induction in orbitofrontal cortex potentiates locomotor sensitization despite attenuating the cognitive dysfunction caused by cocaine. Pharmacol Biochem Behav 93:278-84. PMC2820241

Winstanley, C. A., Bachtell, R. K., Theobald, D. E. H., Laali, S., Green, T. A., Kumar, A., Chakravarty, S., Self, D. W., Nestler, E. J. (2009) Increased impulsivity during withdrawal from cocaine self-administration: Role for FosB in the orbitofrontal cortex. Cerebral Cortex. 19(2):435-44. PMC2733325

Russo, S. J., Wilkinson, M., Mazei-Robison, M., Dietz, D. M., Maze, I., Krishnan, V., Robison, B., Renthal, W., Graham, A., Birnbaum, S. G., Green, T. A., Lesselyong, A., Perotti, L. I., Bolanos, C. A., Kumar, A., Clark, M. S., Neumaier, J. F., Neve, R. L., Bhakar, A. L., Barker, P. A., Nestler, E. J. (2009) NFKappaB signaling regulates neuronal morphology and cocaine reward. J Neurosci 29:3529-37. PMC2677656

Green, T. A., Bardo, M. T., Alibhai, I. N., Nestler, E. J. (2009) Environmental enrichment produces a consistent behavioral phenotype indicative of decreased cAMP response element transcriptional activity in the nucleus accumbens. Biol Psychiatry 67(1):28-35.

Moron, J. A., Green, T. A. (2010) Exploring the molecular basis of addiction: drug-induced neuroadaptations. Neuropsychopharmacology 35(1):337-8.

Sun, H., Green, T. A., Theobald, D. E. H., Laali, S., Shrikhande, G., Birnbaum, S., Kumar, A., Chakravarty, S., Graham, D., Nestler, E. J., Winstanley, C. A. (2009) The pharmacological stressor yohimbine increases impulsivity through activation of CREB in the orbitofrontal cortex. Biol Psychiatry 67:649-56.