The focus of the research is on elucidating noradrenergic mechanisms involved in antidepressant activity. The research plan describes experiments to test two overall hypotheses. First, it is hypothesized that beta-2 adrenergic autoreceptors are present on noradrenergic terminals in the central nervous system and that these receptors are involved in mediating the antidepressant-like behavioral effects of centrally acting beta adrenergic agonists. Second, it is hypothesized that atypical/beta-3 adrenergic receptors are present in the central nervous system and that stimulation of these receptors produces antidepressant-like effects on behavior. These hypotheses will be tested using both behavioral and neuropharmacological techniques. The specific procedures to be employed include examination of drug effects on behavior maintained under a differential-reinforcement-of-low-rate operant schedule, measurement of drug-receptor interactions using receptor and adenylyl cyclase assays, and assessment of norepinephrine release in vitro using superfusion and in vivo using microdialysis. The second, related area of research, which is not a formal component of the research plan, involves the examination of the antidepressant potential of inhibitors of Type IV phosphodiesterase and the study of how the activity of this enzyme and its sensitivity to pharmacological inhibition are regulated by central noradrenergic neurons.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Scientist Development Award - Research (K02)
Project #
1K02MH001231-01
Application #
2240793
Study Section
Behavioral Neuroscience Review Committee (BNR)
Project Start
1994-08-01
Project End
1999-07-31
Budget Start
1994-08-01
Budget End
1995-07-31
Support Year
1
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Louisiana State University Hsc Shreveport
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Shreveport
State
LA
Country
United States
Zip Code
71103
Cashman, John R; Voelker, Troy; Zhang, Han-Ting et al. (2009) Dual inhibitors of phosphodiesterase-4 and serotonin reuptake. J Med Chem 52:1530-9
Hajjhussein, Hassan; Suvarna, Neesha U; Gremillion, Carmen et al. (2007) Changes in NMDA receptor-induced cyclic nucleotide synthesis regulate the age-dependent increase in PDE4A expression in primary cortical cultures. Brain Res 1149:58-68
Zhang, Han-Ting; Zhao, Yu; Huang, Ying et al. (2004) Inhibition of the phosphodiesterase 4 (PDE4) enzyme reverses memory deficits produced by infusion of the MEK inhibitor U0126 into the CA1 subregion of the rat hippocampus. Neuropsychopharmacology 29:1432-9
Ye, Y; Jackson, K; Houslay, M D et al. (2001) Development of rolipram-sensitive, cyclic AMP phosphodiesterase (PDE4) in rat primary neuronal cultures. Brain Res Dev Brain Res 130:115-21
Crissman, A M; Makhay, M M; O'Donnell, J M (2001) Discriminative stimulus effects of centrally administered isoproterenol in rats: mediation by beta-1 adrenergic receptors. Psychopharmacology (Berl) 154:70-5
Zhang, H T; Crissman, A M; Dorairaj, N R et al. (2000) Inhibition of cyclic AMP phosphodiesterase (PDE4) reverses memory deficits associated with NMDA receptor antagonism. Neuropsychopharmacology 23:198-204
Zavecz, J H; Bueno, O; Maloney, R E et al. (2000) Cardiac excitation-contraction coupling in the portal hypertensive rat. Am J Physiol Gastrointest Liver Physiol 279:G28-39
O'Donnell, J M (1997) Pharmacological characterization of the discriminative stimulus effects of clenbuterol in rats. Pharmacol Biochem Behav 58:813-8
Ye, Y; Conti, M; Houslay, M D et al. (1997) Noradrenergic activity differentially regulates the expression of rolipram-sensitive, high-affinity cyclic AMP phosphodiesterase (PDE4) in rat brain. J Neurochem 69:2397-404
Ye, Y; O'Donnell, J M (1996) Diminished noradrenergic stimulation reduces the activity of rolipram-sensitive, high-affinity cyclic AMP phosphodiesterase in rat cerebral cortex. J Neurochem 66:1894-902

Showing the most recent 10 out of 15 publications