High-Affinity [
            <sup>3</sup>
            H]Imipramine Binding in Rat Hypothalamus: Association with Uptake of Serotonin But Not of Norepinephrine

Langer, S.Z.; Moret, Chantal; Raisman, Rita; Dubocovich, M. L.; Briley, Mike

doi:10.1126/science.7444441

Cited by 373 publications

(55 citation statements)

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“…Although DMI is less selective-than imipramine as an inhibitor of the 5HT uptake, it can displace the [3H]imipramine specifically bound to crude synaptic membranes (8,15,30). At the present level of knowledge the down-Tegulation of brain A-adrenergic receptors elicited by DMI could be explained by its binding to 5HT axons and could be considered to be unrelated to the specific 3H-DMI binding to noradrenergic axons.…”

Section: Characterizationmentioning

confidence: 87%

mentioning

confidence: 99%

“…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 weeks (18). 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).…”

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confidence: 99%

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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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Section: Characterizationmentioning

confidence: 87%

mentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…[3H]imipramine binding parallel affinities for the serotonin uptake system, and selective destruction of serotonin neuronal systems reduces [3]imipramine binding (10)(11)(12).…”

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confidence: 99%

Norepinephrine neuronal uptake binding sites in rat brain membranes labeled with [3H]desipramine.

Lee¹,

Snyder²

1981

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

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Neuronal uptake recognition sites in norepinephrine neurons have been labeled with the antidepressant [3H]desipramine. A high-affinity component of [3H]desipramine binding to rat cerebral cortex membranes is abolished selectively by 6-hydroxydopamine lesions, which destroy central catecholamine neurons. The high-affinity [3H]desipramine binding has a nanomolar affinity constant for desipramine and is inhibited by tricyclic antidepressants with potencies that correlate with their ability to inhibit the neuronal uptake of norepinephrine.[3H]Desipramine binding to the uptake sites is markedly stimulated by sodium, with potassium, lithium, and choline being much less effective. The ability to monitor norepinephrine neuronal uptake "receptors" in simple binding studies should permit a differential analysis ofdrug influences on the norepinephrine recognition site and the translocation mechanism. The regulation of [3H]desipramine binding by sodium may help clarify how sodium influences neurotransmitter uptake.After its synaptic release the neurotransmitter norepinephrine (NE) is reaccumulated into nerve terminals by a specific uptake system, which serves to terminate its synaptic actions (1-3). The tricyclic antidepressants are potent inhibitors of the neuronal uptake of both NE and serotonin, effects which are thought to explain their clinical antidepressant actions (4). Among the tricyclic antidepressants, the tertiary amine forms tend to be relatively more potent competitive inhibitors of serotonin than of NE uptake, whereas the reverse holds true for secondary amine antidepressants such as desipramine (DMI) (5, 6). Tris.HC1/120 mM NaCV5 mM KCl, pH 7.4) with a Brinkmann Polytron PT-10 at a setting of5 for 10 sec. The homogenate was centrifuged at 50,000 x g for 10 min. The pellet was resuspended in 30 vol of the assay buffer by a Polytron at setting 5 for 5 sec and centrifuged again. This washing procedure was repeated twice and the final pellet was resuspended in 30 vol of assay buffer.The binding of [3H]DMI was routinely measured in triplicate at 0°C for 1 hr, using 200 ,ul of the membrane preparation with 0.2-10 nM [3H]DMI in the presence or absence of various tested drugs in a final volume of 250 pl. At the end of the incubation period, 5 ml ofice-cold assay buffer was added to each tube and its content was filtered immediately under reduced pressure through Millipore glass fiber filters. Each ofthe filters was then washed three times with 5 ml of ice-cold buffer and radioactivity was measured by liquid scintillation spectrometry, using Formula 947 scintillation mixture (New England Nuclear Abbreviations: DMI, desipramine; NE, norepinephrine; 6-OH-dopamine, 6-hydroxydopamine. * To whom reprint requests should be addressed. 5250The publication costs ofthis article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate this fact.

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“…The concentration of desipramine in the perfusate was 1 µM, and the amount of desipramine delivered through the probe to the PFC by reverse dialysis would only be a small percentage (~10%) of that. Since desipramine has a very low affinity for the 5-HT transporter (21) , this is most likely not a direct effect.…”

mentioning

confidence: 99%

Differential Interactions of Desipramine with Amphetamine and Methamphetamine: Evidence that Amphetamine Releases Dopamine from Noradrenergic Neurons in the Medial Prefrontal Cortex

2004

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Amphetamine is more effective than methamphetamine at raising dopamine levels in the prefrontal cortex. The present study tested the hypothesis that norepinephrine transporters are involved in this difference. Using microdialysis, dopamine, norepinephrine, and serotonin were measured in the rat prefrontal cortex after administration methamphetamine or amphetamine, with and without perfusion of desipramine. Amphetamine raised norepinephrine levels more than methamphetamine did. Desipramine raised dopamine and serotonin levels but did not alter metabolite levels. Desipramine attenuated the increase in dopamine by amphetamine while increasing the dopamine released by methamphetamine. These data suggest that methamphetamine and amphetamine differ in altering prefrontal cortical dopamine levels and in interacting with norepinephrine transporters. It is proposed that amphetamine releases dopamine in the prefrontal cortex primarily through norepinephrine transporters, while methamphetamine interacts minimally with norepinephrine transporters.

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High-Affinity [ ³ H]Imipramine Binding in Rat Hypothalamus: Association with Uptake of Serotonin But Not of Norepinephrine

Cited by 373 publications

References 13 publications

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

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

Norepinephrine neuronal uptake binding sites in rat brain membranes labeled with [3H]desipramine.

Differential Interactions of Desipramine with Amphetamine and Methamphetamine: Evidence that Amphetamine Releases Dopamine from Noradrenergic Neurons in the Medial Prefrontal Cortex

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High-Affinity [ 3 H]Imipramine Binding in Rat Hypothalamus: Association with Uptake of Serotonin But Not of Norepinephrine

Cited by 373 publications

References 13 publications

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

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

Norepinephrine neuronal uptake binding sites in rat brain membranes labeled with [3H]desipramine.

Differential Interactions of Desipramine with Amphetamine and Methamphetamine: Evidence that Amphetamine Releases Dopamine from Noradrenergic Neurons in the Medial Prefrontal Cortex

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High-Affinity [ ³ H]Imipramine Binding in Rat Hypothalamus: Association with Uptake of Serotonin But Not of Norepinephrine