Vincent J. Aloyo, Ph.D.
Research Professor
Ph.D. (1978) University of Tennessee
Email: vincent.aloyo@drexelmed.edu
My interests are in contemporary receptor theory and the clues that it provides concerning various neuropathologies. Serotonin (5-HT) interactions with numerous receptors grouped into seven families are involved in many neurobiologic functions including learning and memory and the regulation of mood and anxiety. Drugs interacting with a variety of serotonergic receptors are effective in the treatment of obsessive-compulsive disorder, anxiety disorders, depression and schizophrenia.
Recently we have developed a model system to investigate the relationship of the serotonin system to stress/anxiety. We have demonstrated that 5-HT and the 5-HT2A receptor modulate the behavioral response to stress/anxiety (Aloyo et al., 2007). This paradigm will be used to explore the interactions of stress hormones and serotonin.
Exposing rabbits to the novel environment (open-field chamber) selectively increases the 5-HT2A mediated behavior, head bobs (Aloyo et al., 2007).
Although it is well known that atypical antipsychotic drugs are antagonists at the 5-HT2A receptor, their mechanism of action is not understood. In order to investigate the potential mechanism of atypical antipsychotic drugs, my work has centered on the plasticity demonstrated by serotonin receptors, especially the 5-HT2A subtype. We have found that chronic administration of various 5-HT2A antagonists results in the up- or down- regulation of brain 5-HT2A receptors with resultant increases and decreases, respectively, in their functional status as measured by specific receptor mediated behaviors (Dave et al., 2007). Thus, it is possible to produce functional remodeling of brain circuits (Harvey et al., 2004), which may be a possible mechanism to correct developmental or environmentally induced neuropathologies. We are currently investigating the hypothesis that 5-HT2A receptor ligands that up-regulate 5-HT2A receptor density and function are inverse agonists, that is, compounds that have effects that are opposite to those produced by agonists. A corollary hypothesis is that atypical antipsychotics (which are 5-HT2A receptor antagonists) may also be inverse agonists that up-regulate 5-HT2A receptor density and enhance function. This inverse agonist activity may contribute to the therapeutic potential of atypical antipsychotics.
The 5-HT2A antagonist MDL 11939 up-regulates cortical 5-HT2A receptors and increases 5-HT2A mediated behaviors (Dave et al., 2007).
We are also investigating inverse agonist properties of drugs using in vitro assays. For G-protein Coupled Receptors (GPCRs), the first step in the receptor activation cascade is the initiation of the exchange of GTP for GDP within the alpha subunit of the G-protein. Thus, measuring GTP/GDP exchange is a powerful in vitro tool for measuring receptor function. For GPCRs coupled to Gi/o G-proteins, monitoring GTP/GDP exchange is readily performed by measuring the incorporation of a GTP analogue [35S]GTPγS into the G-protein using either modified binding techniques or receptor autoradiography. However, for GPCRs coupled to other G-proteins (for example, Gz, Gs or Gq), measurement of GTPγS incorporation assay is more difficult. We are currently developing such techniques. Detection of constitutive receptor activity by measuring down stream second messenger production is also under development. Enhanced understanding of drug modulation of serotonin receptors will lead to the development of novel therapeutic compounds.
Selected Publications:
Dave, K.D., Harvey, J.A. and Aloyo, V.J. (2007) The time-course for up- and down-regulation of the cortical 5-HT2A receptor density predicts 5-HT2A receptor-mediated behavior in the rabbit. Journal Pharmacology and Experimental Therapeutics 323:327-335.
Aloyo, V.J., Dave, K.D. (2007) Serotonin and serotonin2A (5-HT2A) receptors modulate the behavioral response to emotional stress in rabbits. Behavioural Pharmacology 18:651-659.
Romano, A.G., Quinn, J.L., Liu, R., Dave, K.D., Schwab, D., Alexander, G., Aloyo, V.J., Harvey, J.A. (2006) Effect of serotonin depletion on 5-HT2A-mediated learning in the rabbit: evidence for constitutive activity of the 5-HT2A in vivo. Psychopharmacology. 184(2):173-81.
Harvey, J.A., Quinn, J.L., Liu, R., Aloyo, V.J., and Romano, A.G. (2004) Selective remodeling of rabbit cortex: relationship between 5-HT2A receptor density and associative learning. Psychopharmacology 172:435-442.
Simansky, K.J, Dave, K.D., Inemer, B.R., Nicklous, D.M., Padron, J.M., Aloyo, V.J. and Romano, A.G. (2004) A 5-HT2C agonist elicits hyperactivity and oral dyskinesia with hypophagia in rabbits. Physiology and Behavior. 82: 97-107.
Dave, K.D., Fernando, G.S., Quinn, J.L., Harvey, J.A., and Aloyo, V.J. (2004) Serotonin 5-HT2A receptors in the CA1 Field of the hippocampus mediate head movements in the rabbit. Psychopharmacology. 176:287-295.
Dave, K.D., Harvey, J.A., and Aloyo, V.J. (2002) A novel behavioral model that discriminates between 5-HT2A and 5-HT2C receptor activation. Pharmacology, Biochemistry and Behavior 72: 371-378.
Aloyo, V.J., Dave, K.D., Rahman, T., and Harvey, J.A. (2001) Selective and divergent regulation of cortical 5-HT2A receptors in rabbit. J. Pharm. Exp. Ther. 299: 1066-1072. |