The goals of this project are to determine: (1) if different types of antidepressants alter the density and/or affinity of subtypes of either beta adrenoceptors (BARs) or 5-HT-1 receptors either throughout the brain or in localized areas; (2) how serotonergic nerves alter the ability of antidepressants to decrease the density of BARs; (3) factors involved in the regulation of central BARs in vivo; and (4) if alterations in central receptors for certain monamines occur in an animal model of depression. All experiments will use rats and receptors will be visualized and quantified using the technique of in vitro quantitative autoradiography. Many antidepressants decrease the density of BARs and this pharmacological effect has been speculated to be involved in their clinical effects. The experiments proposed will evaluate if a particular subtype of BAR is preferentially affected by antidepressants and whether changes are produced in common areas of the brain. In addition to affecting noradrenegic responsiveness, antidepressants change both electrophysiological and behavior responses elicited by serotonin (5-HT) agonists. The responses altered have been linked to subtypes of a receptor for 5-HT, termed the 5-HT-1 receptor. By using quantitative autoradiography, it will be possible to determine whether antidepressant-induced changes in these subtypes account for the alterations in responsiveness. In the experiments involving subtypes of BARs or 5-HT-1 receptors, rats will be given antidepressant of different types for 21 days. Antidepressants studied will be those that block selectively the uptake of norepinephrine or serotonin or inhibit selectively type A or type B monoamine oxidase. Serotonin neurons are involved in antidepressant-induced decreases in the density of BARs. To study this, the ability of either the antidepressant, desipramine, or the beta-agonist, isoproterenol (ISO), to decrease the density of BARs will be measured in intact rats or rats with lesions of central serotonergic neurons. Lesions will be made with the neurotoxin, 5,7-dihydroxytryptamine, given not only intraventricularly but also directly into areas containing noradrenegic cell bodies or nerve terminals. Lesions with a neurotoxin for catecholaminergic nerves, 6-hydroxydopamine, will be made in separate groups of rats to determine how central noradrenegic neurons influence the ability of ISO to decrease the density of beta-1 adrenoceptors. In these experiments, ISO will be given into the right lateral ventricle of rats through a permanently indwelling cannula connected to an Alzet minipump. This experiment will provide information about the feasibility of using beta agonists as antidepressants. The status pf central monoamine receptors will also be measured in rats exposed to uncontrolled shock, as this may be an animal model of depression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH029094-12A1
Application #
3564442
Study Section
Neurosciences Research Review Committee (BPN)
Project Start
1976-09-15
Project End
1993-06-30
Budget Start
1988-08-01
Budget End
1989-06-30
Support Year
12
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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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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