Subsensitivity of the beta-adrenergic receptor-linked adenylate cyclase system of rat pineal gland following repeated treatment with desmethylimipramine and nialamide

J. A. Moyer, L. H. Greenberg, Alan Frazer, B. Weiss

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

The effects of administering the antidepressant drugs desmethylimipramine and nialamide on the beta-adrenergic receptor-adenylate cyclase system of rat pineal gland were studied. The maximal elevation of cyclic AMP in response to varying concentrations of norepinephrine added in vitro to whole pineal glands was reduced following repeated but not acute administration of desmethylimipramine. Repeated administration of desmethylimipramine also reduced the norepinephrine-induced stimulation of adenylate cyclase activity in pineal gland homogenates. Neither acute nor repeated doses of desmethylimipramine had any significant effect on cyclic AMP phosphodiesterase activity of pineal gland. The loss of norepinephrine sensitivity of the adenylate cyclase system following repeated doses of desmethylimipramine was accompanied by a decreased density of beta-adrenergic receptors, as measured by the specific binding of [3H]dihydroalprenolol. This loss of adrenergic receptors may be related to the action of this drug in blocking the reuptake of norepinephrine into the adrenergic nerve terminals, since the effects of desmethylimipramine were prevented in animals whose pineal glands had been sympathetically denervated by ganglionectomy. Repeated but not acute doses of the monoamine oxidase inhibitor, nialamide, also decreased the binding of [3H]dihydroalprenolol in pineal glands and decreased the accumulation of cyclic AMP in response to intraperitoneal administration of isoproterenol. These findings provide further evidence that excessive noradrenergic input produces a compensatory reduction in the number of postsynaptic beta-adrenergic receptors, which, in turn, causes a decreased sensitivity of the norepinephrine-stimulated adenylate cyclase system. They suggest further that the mechanism by which antidepressant drugs exert their clinical effects should be re-evaluated, since following repeated administration they produce a reduced, rather than enhanced, responsiveness to noradrenergic stimuli.

Original languageEnglish (US)
Pages (from-to)187-193
Number of pages7
JournalMolecular Pharmacology
Volume19
Issue number2
StatePublished - 1981
Externally publishedYes

Fingerprint

Nialamide
Desipramine
Pineal Gland
Receptors, Adrenergic, beta
Adenylyl Cyclases
Norepinephrine
Dihydroalprenolol
Cyclic AMP
Antidepressive Agents
Ganglionectomy
Monoamine Oxidase Inhibitors
Phosphoric Diester Hydrolases
Isoproterenol
Adrenergic Agents
Adrenergic Receptors
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Pharmacology

Cite this

Subsensitivity of the beta-adrenergic receptor-linked adenylate cyclase system of rat pineal gland following repeated treatment with desmethylimipramine and nialamide. / Moyer, J. A.; Greenberg, L. H.; Frazer, Alan; Weiss, B.

In: Molecular Pharmacology, Vol. 19, No. 2, 1981, p. 187-193.

Research output: Contribution to journalArticle

@article{1472c6ed859344cbbd3cc316e2969039,
title = "Subsensitivity of the beta-adrenergic receptor-linked adenylate cyclase system of rat pineal gland following repeated treatment with desmethylimipramine and nialamide",
abstract = "The effects of administering the antidepressant drugs desmethylimipramine and nialamide on the beta-adrenergic receptor-adenylate cyclase system of rat pineal gland were studied. The maximal elevation of cyclic AMP in response to varying concentrations of norepinephrine added in vitro to whole pineal glands was reduced following repeated but not acute administration of desmethylimipramine. Repeated administration of desmethylimipramine also reduced the norepinephrine-induced stimulation of adenylate cyclase activity in pineal gland homogenates. Neither acute nor repeated doses of desmethylimipramine had any significant effect on cyclic AMP phosphodiesterase activity of pineal gland. The loss of norepinephrine sensitivity of the adenylate cyclase system following repeated doses of desmethylimipramine was accompanied by a decreased density of beta-adrenergic receptors, as measured by the specific binding of [3H]dihydroalprenolol. This loss of adrenergic receptors may be related to the action of this drug in blocking the reuptake of norepinephrine into the adrenergic nerve terminals, since the effects of desmethylimipramine were prevented in animals whose pineal glands had been sympathetically denervated by ganglionectomy. Repeated but not acute doses of the monoamine oxidase inhibitor, nialamide, also decreased the binding of [3H]dihydroalprenolol in pineal glands and decreased the accumulation of cyclic AMP in response to intraperitoneal administration of isoproterenol. These findings provide further evidence that excessive noradrenergic input produces a compensatory reduction in the number of postsynaptic beta-adrenergic receptors, which, in turn, causes a decreased sensitivity of the norepinephrine-stimulated adenylate cyclase system. They suggest further that the mechanism by which antidepressant drugs exert their clinical effects should be re-evaluated, since following repeated administration they produce a reduced, rather than enhanced, responsiveness to noradrenergic stimuli.",
author = "Moyer, {J. A.} and Greenberg, {L. H.} and Alan Frazer and B. Weiss",
year = "1981",
language = "English (US)",
volume = "19",
pages = "187--193",
journal = "Molecular Pharmacology",
issn = "0026-895X",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "2",

}

TY - JOUR

T1 - Subsensitivity of the beta-adrenergic receptor-linked adenylate cyclase system of rat pineal gland following repeated treatment with desmethylimipramine and nialamide

AU - Moyer, J. A.

AU - Greenberg, L. H.

AU - Frazer, Alan

AU - Weiss, B.

PY - 1981

Y1 - 1981

N2 - The effects of administering the antidepressant drugs desmethylimipramine and nialamide on the beta-adrenergic receptor-adenylate cyclase system of rat pineal gland were studied. The maximal elevation of cyclic AMP in response to varying concentrations of norepinephrine added in vitro to whole pineal glands was reduced following repeated but not acute administration of desmethylimipramine. Repeated administration of desmethylimipramine also reduced the norepinephrine-induced stimulation of adenylate cyclase activity in pineal gland homogenates. Neither acute nor repeated doses of desmethylimipramine had any significant effect on cyclic AMP phosphodiesterase activity of pineal gland. The loss of norepinephrine sensitivity of the adenylate cyclase system following repeated doses of desmethylimipramine was accompanied by a decreased density of beta-adrenergic receptors, as measured by the specific binding of [3H]dihydroalprenolol. This loss of adrenergic receptors may be related to the action of this drug in blocking the reuptake of norepinephrine into the adrenergic nerve terminals, since the effects of desmethylimipramine were prevented in animals whose pineal glands had been sympathetically denervated by ganglionectomy. Repeated but not acute doses of the monoamine oxidase inhibitor, nialamide, also decreased the binding of [3H]dihydroalprenolol in pineal glands and decreased the accumulation of cyclic AMP in response to intraperitoneal administration of isoproterenol. These findings provide further evidence that excessive noradrenergic input produces a compensatory reduction in the number of postsynaptic beta-adrenergic receptors, which, in turn, causes a decreased sensitivity of the norepinephrine-stimulated adenylate cyclase system. They suggest further that the mechanism by which antidepressant drugs exert their clinical effects should be re-evaluated, since following repeated administration they produce a reduced, rather than enhanced, responsiveness to noradrenergic stimuli.

AB - The effects of administering the antidepressant drugs desmethylimipramine and nialamide on the beta-adrenergic receptor-adenylate cyclase system of rat pineal gland were studied. The maximal elevation of cyclic AMP in response to varying concentrations of norepinephrine added in vitro to whole pineal glands was reduced following repeated but not acute administration of desmethylimipramine. Repeated administration of desmethylimipramine also reduced the norepinephrine-induced stimulation of adenylate cyclase activity in pineal gland homogenates. Neither acute nor repeated doses of desmethylimipramine had any significant effect on cyclic AMP phosphodiesterase activity of pineal gland. The loss of norepinephrine sensitivity of the adenylate cyclase system following repeated doses of desmethylimipramine was accompanied by a decreased density of beta-adrenergic receptors, as measured by the specific binding of [3H]dihydroalprenolol. This loss of adrenergic receptors may be related to the action of this drug in blocking the reuptake of norepinephrine into the adrenergic nerve terminals, since the effects of desmethylimipramine were prevented in animals whose pineal glands had been sympathetically denervated by ganglionectomy. Repeated but not acute doses of the monoamine oxidase inhibitor, nialamide, also decreased the binding of [3H]dihydroalprenolol in pineal glands and decreased the accumulation of cyclic AMP in response to intraperitoneal administration of isoproterenol. These findings provide further evidence that excessive noradrenergic input produces a compensatory reduction in the number of postsynaptic beta-adrenergic receptors, which, in turn, causes a decreased sensitivity of the norepinephrine-stimulated adenylate cyclase system. They suggest further that the mechanism by which antidepressant drugs exert their clinical effects should be re-evaluated, since following repeated administration they produce a reduced, rather than enhanced, responsiveness to noradrenergic stimuli.

UR - http://www.scopus.com/inward/record.url?scp=0019362072&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0019362072&partnerID=8YFLogxK

M3 - Article

C2 - 6262613

AN - SCOPUS:0019362072

VL - 19

SP - 187

EP - 193

JO - Molecular Pharmacology

JF - Molecular Pharmacology

SN - 0026-895X

IS - 2

ER -