Abstract

This project focuses on the pharmacology of brain serotonin (5-HT) neurons after chronic exposure to 5-HT uptake blockers. Impaired function of 5-HT1A receptors has been associated with neurological and psychiatric disorders. Chronic exposure to 5-HT uptake blockers reduces 5-HT1A receptor function of serotonergic cells in the midbrain. However, little information is currently available regarding the effect of 5-HT uptake blockers on hypothalamic post-synaptic 5-HT1A receptors. Moreover, no studies have investigated such fundamental issues as the time- course, dose-response relationship or duration of the effects of 5-HT uptake blockers on 5- HT1A receptor function. The applicant has recently found that the 5-HT uptake blocker fluoxetine (10 mg/kg/day, 21 days) reduces 5-HT1A receptor-mediated plasma ACTH and oxytocin responses in a time-dependent manner. A single injection of fluoxetine had no effect. The hypothesis is advanced that chronic exposure to 5-HT uptake blockers causes adaptational changes in serotonergic neurotransmission, resulting in reduced 5-HT1A receptor function in the hypothalamus. The proposed studies will characterize the changes in hypothalamic post-synaptic 5- HT1A receptors induced by chronic exposure to 5-HT uptake blockers. Biochemical approaches will focus on changes in 5-HT1A receptor density and their signal transduction mechanisms (coupling to G-proteins). In addition, the responsiveness of hypothalamic 5-HT1A receptors will be determined from the neuroendocrine responses to specific 5- HT1A agonists.
Specific Aim 1 will investigate the time-course of effects of 5-HT uptake blockers on hypothalamic 5-HT1A receptors, their signal transduction mechanisms, and endocrine responses to 5-HT1A agonists.
Specific Aim 2 will determine the dose-response effects of chronic exposure to 5-HT uptake blockers on 5-HT1A receptors, their signal transduction mechanisms, and hormone responses mediated by 5-HT1A receptors. So far, studies have used doses that are 10 fold higher than clinically relevant doses. This study will determine the minimal dose of fluoxetine that will reduce 5-HT1A receptor function. The final Specific Aim will determine the duration of altered 5- HT1A receptor function after withdrawal from 5-HT uptake blockers. A comparison of endocrine changes with biochemical indices of 5-HT1A receptor function may provide a model of withdrawal from 5-HT uptake blockers.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS034153-06
Application #
6393717
Study Section
Special Emphasis Panel (ZRG1-BDCN-6 (01))
Program Officer
Edwards, Emmeline
Project Start
1995-09-30
Project End
2003-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
6
Fiscal Year
2001
Total Cost
$296,239
Indirect Cost

  Institution

Name
Loyola University Chicago
Department
Pharmacology
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153

  Publications

Grippo, Angela J (2009) Mechanisms underlying altered mood and cardiovascular dysfunction: the value of neurobiological and behavioral research with animal models. Neurosci Biobehav Rev 33:171-80
Grippo, Angela J; Johnson, Alan Kim (2009) Stress, depression and cardiovascular dysregulation: a review of neurobiological mechanisms and the integration of research from preclinical disease models. Stress 12:1-21
Petrunich, Maureen L; Garcia, Francisca; Carrasco, Gonzalo A et al. (2008) Prolonged 5-HT1A/5-HT2A receptor cross-talk is absent prior to adulthood in rats. Neuroreport 19:1457-61
Crane, James W; Shimizu, Keiko; Carrasco, Gonzalo A et al. (2007) 5-HT1A receptors mediate (+)8-OH-DPAT-stimulation of extracellular signal-regulated kinase (MAP kinase) in vivo in rat hypothalamus: time dependence and regional differences. Brain Res 1183:51-9
Shi, Ju; Damjanoska, Katerina J; Singh, Rakesh K et al. (2007) Agonist induced-phosphorylation of Galpha11 protein reduces coupling to 5-HT2A receptors. J Pharmacol Exp Ther 323:248-56
Carrasco, Gonzalo A; Van de Kar, Louis D; Jia, Cuihong et al. (2007) Single exposure to a serotonin 1A receptor agonist, (+)8-hydroxy-2-(di-n-propylamino)-tetralin, produces a prolonged heterologous desensitization of serotonin 2A receptors in neuroendocrine neurons in vivo. J Pharmacol Exp Ther 320:1078-86
Carrasco, G A; Van de Kar, L D; Sullivan, N R et al. (2006) Cocaine-mediated supersensitivity of 5-HT2A receptors in hypothalamic paraventricular nucleus is a withdrawal-induced phenomenon. Neuroscience 143:7-13
Sullivan, Nicole R; Crane, James W; Damjanoska, Katerina J et al. (2005) Tandospirone activates neuroendocrine and ERK (MAP kinase) signaling pathways specifically through 5-HT1A receptor mechanisms in vivo. Naunyn Schmiedebergs Arch Pharmacol 371:18-26
Landry, Michelle; Frasier, Mark; Chen, Zhuo et al. (2005) Fluoxetine treatment of prepubescent rats produces a selective functional reduction in the 5-HT2A receptor-mediated stimulation of oxytocin. Synapse 58:102-9
Li, Qian; Holmes, Andrew; Ma, Li et al. (2004) Medial hypothalamic 5-hydroxytryptamine (5-HT)1A receptors regulate neuroendocrine responses to stress and exploratory locomotor activity: application of recombinant adenovirus containing 5-HT1A sequences. J Neurosci 24:10868-77

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