Role of Serotonergic Input in the Regulation of the β-Adrenergic Receptor-Coupled Adenylate Cyclase System

Janowsky, Aaron; Okada, Fumihiko; Manier, D. Hal; Applegate, CD; Sulser, Fridolin; Steranka, LR

doi:10.1126/science.6291152

Cited by 175 publications

(26 citation statements)

References 14 publications

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“…Whether zimeldine affects the noradrenaline system by uptake inhibition or by another presynaptic mechanism has to be elucidated in further experiments. In contrast to our results, Brunello el aL (1982) and Janowsky et aL (1982) reported that long-term treatment with desipramine was dependent upon intact serotonergic nerve terminals to decrease the fi-adrenoceptors. These discrepant results may be due to the different technique to degenerate the nerve terminals, that is 5,7-dihydroxytryptamine injections in the raphe nucleus visavi parenteral PCA injections.…”

Section: Effects On Fl-adrenoceptorscontrasting

confidence: 85%

“…Desipramine has also been reported to be dependent upon intact serotonergic nerve terminals for its ability to cause a decrease in fl-adrenoceptors (Brunello et aL, 1982;Janowsky et aL, 1982). In the present study we have examined whether the longterm effect of antidepressants on both p-adrenoceptors and 5-HT2 binding sites in rat cerebral cortex is dependent on intact noradrenergic and serotonergic presynaptic nerve terminals.…”

Section: Introductionmentioning

confidence: 91%

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Effect of destruction of central noradrenergic and serotonergic nerve terminals by systemic neurotoxins on the long-term effects of antidepressants on?-adrenoceptors and 5-HT2 binding sites in the rat cerebral cortex

Hall

Ross

Sällemark

1984

J. Neural Transmission

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The dependence of intact noradrenergic and serotonergic nerve terminals for the decrease in the number of beta-adrenoceptors and 5-HT2 binding sites in the cerebral cortex produced by long-term treatment of rats with antidepressant drugs was examined. Noradrenergic nerve terminals were destroyed with the selective noradrenaline neurotoxin DSP4, and serotonergic nerve terminals were destroyed with p-chloroamphetamine (PCA). It was found that lesioning of the noradrenergic nerve terminals abolished the decrease in beta-adrenoceptors produced by desipramine, mianserin and zimeldine and partially antagonized that of the beta-adrenoceptor agonist clenbuterol. PCA pretreatment did not antagonize the long-term effects on the beta-adrenoceptor produced by these compounds. Lesioning of serotonergic nerve terminals affected the down-regulation of 5-HT2 binding sites produced by long-term treatment with mianserin, desipramine and amiflamine. DSP4 pretreatment partially abolished the down-regulation of 5-HT2 binding sites produced by long-term treatment with desipramine, while the effects of mianserin and amiflamine were unaffected by pretreatment with DSP4.

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Section: Effects On Fl-adrenoceptorscontrasting

confidence: 85%

Section: Introductionmentioning

confidence: 91%

Effect of destruction of central noradrenergic and serotonergic nerve terminals by systemic neurotoxins on the long-term effects of antidepressants on?-adrenoceptors and 5-HT2 binding sites in the rat cerebral cortex

Hall

Ross

Sällemark

1984

J. Neural Transmission

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“…These data suggested to us that a neuronal regulatory loop might connect 5HT terminals with the neuron where ,B-adrenergic receptors are located and that this link participates in the attenuation of NE receptor function and, perhaps, in the antidepressant action of imipramine and related drugs (17,18). These findings have been replicated by us with repeated daily injections of imipramine (19) and confirmed by other laboratories (20 21 days with saline, imipramine, or DMI, according to the procedures previously described (23). The protein content was determined colorimetrically as described by Lowry et al (24), using bovine serum albumin as standard.…”

mentioning

confidence: 71%

Modulation of neuronal serotonin uptake by a putative endogenous ligand of imipramine recognition sites.

Barbaccia¹,

Gandolfi²,

Chuang³

et al. 1983

Proc. Natl. Acad. Sci. U.S.A.

121

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Imipramine inhibits the serotonin uptake by binding with high affinity to regulatory sites of this uptake located on axons that release serotonin. The number of imipramine recognition sites located on crude synaptic membrane preparations is reduced by two daily injections of imipramine or desmethylimipramine for 3 weeks. When the binding sites for [3H]imipramine are down-regulated the Vma of the neuronal uptake of serotonin is increased. Moreover, in minces prepared from the brain hippocampus of rats receiving imipramine in a dose regimen that reduces the number of [3H]imipramine recognition sites, the efficiency of imipramine as a blocker of the serotonin uptake is diminished. Hence the high-affinity binding sites for [3H]imipramine may have a physiological role in modulation of serotonin reuptake. Probably this is mediated by an endogenous effector of these regulatory sites. A nonpeptidic constituent of rat brain capable of displacing [3H]imipramine from its high-affinity binding site and of inhibiting the serotonin uptake in a dose-related manner has been extracted and its partial purification is described.Imipramine and desmethylimipramine (DMI) have been used for longer than two decades to relieve the symptoms of depression (1, 2). Their capacity to block norepinephrine (NE) and serotonin (5-hydroxytryptamine; 5HT) uptake has been considered to be important for their therapeutic action, but when it was noted that imipramine and DMI block amine uptake almost instantaneously, whereas their antidepressant action occurs with a latency time of 1-2 weeks (1), the importance of the uptake inhibition in explaining their therapeutic action was deemphasized. Upon repeated daily administration to rats imipramine and a number of its congeners down-regulate the function of NE recognition sites in several brain structures (3-6); because the onset of this down-regulation and that of the antidepressant action are delayed with respect to the beginning of the treatment, it has been suggested that the NE response downregulation and the antidepressant action may be related (6). An additional tool to study the mechanism of the down-regulation of /3-adrenergic receptors became available when Langer and his colleagues reported that specific Na+-dependent and highaffinity binding sites for [3H]imipramine are located in crude synaptic membranes prepared from various structures of mammalian brains (7,8). The maximal number, Bmax, of [3H]imipramine binding sites is down-regulated by repeated injections of imipramine or DMI (9-11). These recognition sites are located on 5HT axon terminals (12)(13)(14) and appear to be anatomically and functionally associated with the 5HT uptake mechanism (15)(16)(17).In 1981 at a symposium on the mode of action of antidepressants we reported that the selective destruction of 5HT axons by 5,7-dihydroxytryptamine (5,7-DHT), which eliminates[3H]imipramine recognition sites, prevented the down-regulation of f3-adrenergic recognition sites elicited by two daily injections of DMI repeated for 3 wee...

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“…Thus, whatever antidepressant treatments have in common, it is not a consistent change in 5-HT2 function. However, this is not to deny any involvement of 5-HT in the action of antidepressant treatments since intact 5-HT innervation is required for the decrease in P-adrenoceptor number produced by desipramine (Brunello et al, 1982;Janowsky et al, 1982).…”

Section: Effects Ofantidepressants On 5-ht2-mediated Behaviourmentioning

confidence: 99%

5‐HT₂ receptor characteristics in frontal cortex and 5‐HT₂ receptor‐mediated head‐twitch behaviour following antidepressant treatment to mice

Goodwin

Green

Johnson

1984

British J Pharmacology

158

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Role of Serotonergic Input in the Regulation of the β-Adrenergic Receptor-Coupled Adenylate Cyclase System

Cited by 175 publications

References 14 publications

Effect of destruction of central noradrenergic and serotonergic nerve terminals by systemic neurotoxins on the long-term effects of antidepressants on?-adrenoceptors and 5-HT2 binding sites in the rat cerebral cortex

Effect of destruction of central noradrenergic and serotonergic nerve terminals by systemic neurotoxins on the long-term effects of antidepressants on?-adrenoceptors and 5-HT2 binding sites in the rat cerebral cortex

Modulation of neuronal serotonin uptake by a putative endogenous ligand of imipramine recognition sites.

5‐HT₂ receptor characteristics in frontal cortex and 5‐HT₂ receptor‐mediated head‐twitch behaviour following antidepressant treatment to mice

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Role of Serotonergic Input in the Regulation of the β-Adrenergic Receptor-Coupled Adenylate Cyclase System

Cited by 175 publications

References 14 publications

Effect of destruction of central noradrenergic and serotonergic nerve terminals by systemic neurotoxins on the long-term effects of antidepressants on?-adrenoceptors and 5-HT2 binding sites in the rat cerebral cortex

Effect of destruction of central noradrenergic and serotonergic nerve terminals by systemic neurotoxins on the long-term effects of antidepressants on?-adrenoceptors and 5-HT2 binding sites in the rat cerebral cortex

Modulation of neuronal serotonin uptake by a putative endogenous ligand of imipramine recognition sites.

5‐HT2 receptor characteristics in frontal cortex and 5‐HT2 receptor‐mediated head‐twitch behaviour following antidepressant treatment to mice

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5‐HT₂ receptor characteristics in frontal cortex and 5‐HT₂ receptor‐mediated head‐twitch behaviour following antidepressant treatment to mice