ANTIDEPRESSANTS & MONOAMINE RECEPTORS & RESPONSES

点击翻译按钮获取中文摘要

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.