The goal of this research is to provide a better understanding of the pharmacological effects of antidepressant treatments, when administered over time, on central biogenic amine neuronal systems. This would be expected to lead to an improved understanding of the biology of affective illnesses and toward improved treatment of these illnesses. In particular, we intend to study whether chronic treatment of rats with a variety of established and newer antidepressant treatments causes the development of beta-adrenergic receptor subsensitivity. Beta-adrenergic receptors will be studied with the use of the radioactive beta-adrenergic antagonist (minus)3H-dihydroalrenolol (3H-DHA). In addition, experiments are planned that should provide some information on the clinical relevance of the antidepressant drug-induced development of central beta-adrenergic receptor subsensitivity. An expansion of this type of investigation will be our use of 3H-5hydroxytryptamine (serotonin) to label central serotonergic receptors so as to investigate the effects of repeated treatment of rats with different types of psychotropic drugs on these receptors. The pineal gland will be used to measure the effect of antidepressant treatments on adrenergic responsiveness both in vivo and in vitro. Catecholamines will be administered exogenously to rats treated either acutely or chronically with antidepressant drugs and the concentration of adenosine 3',5' monophosphate (cyclic AMP) in the pineal gland measured. In addition, the ability of acute and chronic treatment of rats with desmethylimipramine to modify adrenergic responses in the pineal gland caused by norepinephrine released endogenously from the sympathetic nerve innervating the pineal gland will be studied.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH029094-09
Application #
3375080
Study Section
(BPNA)
Project Start
1976-09-15
Project End
1985-11-30
Budget Start
1984-12-01
Budget End
1985-11-30
Support Year
9
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Frazer, A (2000) Norepinephrine involvement in antidepressant action. J Clin Psychiatry 61 Suppl 10:25-30
Daws, L C; Toney, G M; Gerhardt, G A et al. (1998) In vivo chronoamperometric measures of extracellular serotonin clearance in rat dorsal hippocampus: contribution of serotonin and norepinephrine transporters. J Pharmacol Exp Ther 286:967-76
Daws, L C; Lopez, R; Frazer, A (1998) Effects of antidepressant treatment on inhibitory avoidance behavior and amygdaloid beta-adrenoceptors in rats. Neuropsychopharmacology 19:300-13
Frazer, A (1997) Pharmacology of antidepressants. J Clin Psychopharmacol 17 Suppl 1:2S-18S
Daws, L C; Toney, G M; Davis, D J et al. (1997) In vivo chronoamperometric measurements of the clearance of exogenously applied serotonin in the rat dentate gyrus. J Neurosci Methods 78:139-50
Frazer, A (1997) Antidepressants. J Clin Psychiatry 58 Suppl 6:9-25
Thielen, R J; Fangon, N B; Frazer, A (1996) 4-(2'-Methoxyphenyl)-1-[2'-[N-(2""-pyridinyl)-p-iodobenzamido]ethyl] piperazine and 4-(2'-methoxyphenyl)-1-[2'-[N-(2""-pyridinyl)-p- fluorobenzamido]ethyl]piperazine, two new antagonists at pre- and postsynaptic serotonin-1A receptors. J Pharmacol Exp Ther 277:661-70
Kovachich, G B; Frazer, A; Aronson, C E (1993) Effect of chronic administration of antidepressants on alpha 2-adrenoceptors in the locus coeruleus and its projection fields in rat brain determined by quantitative autoradiography. Neuropsychopharmacology 8:57-65
Tejani-Butt, S M (1992) [3H]nisoxetine: a radioligand for quantitation of norepinephrine uptake sites by autoradiography or by homogenate binding. J Pharmacol Exp Ther 260:427-36
Kovachich, G B; Aronson, C E; Brunswick, D J (1992) Effect of repeated administration of antidepressants on serotonin uptake sites in limbic and neocortical structures of rat brain determined by quantitative autoradiography. Neuropsychopharmacology 7:317-24

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