Uptake Processes for Biogenic Amines

Iversen, Leslie L.

doi:10.1007/978-1-4684-3171-1_7

Cited by 122 publications

(87 citation statements)

References 150 publications

(175 reference statements)

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“…In fact, abnormal levels of expression of the human NET (hNET) at the noradrenergic synapse have been proposed to play a role in the pathophysiology of major depression (Klimek et al, 1997). The NET is also the site of action for many antidepressant medications and certain drugs of abuse (Iversen, 1975;Amara and Kuhar, 1993). Given the diverse roles of noradrenergic transmission in modulating behavior (Svensson, 1987;Harley, 1991;Woodward et al, 1991), further clarification of the molecular characteristics, function, and regulation of the NET will facilitate better understanding of the role that this protein may play in the therapeutic actions of psychoactive drugs and in the pathophysiology of psychiatric disorders.…”

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confidence: 99%

Down‐Regulation of the Human Norepinephrine Transporter in Intact 293‐hNET Cells Exposed to Desipramine

Zhu

Blakely

Apparsundaram

et al. 1998

Journal of Neurochemistry

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Abstract:The effects of continuous exposure of cultured cells expressing the human norepinephrine transporter (hNET) to the hNET inhibitor desipramine on hNET expression and function were studied. Exposure of HEK-293 cells transfected stably with the hNET cDNA (293-hNET cells) to desipramine for 3 days reduced the specific binding of rH]nisoxetine in membrane homogenates in a concentration-dependent manner. The magnitude of the reductions in [ 3H]nisoxetine binding to hNET was dependent on the length of time of the exposure to desipramine, reaching 77% after a 21-day exposure. The reduction of rH]nisoxetine binding returned to control levels within 72 h after a 3-day exposure to desipramine. Reductions in [3H]nisoxetine binding to hNET were accompanied by time-dependent and exposure concentration-dependent reductions in hNET protein levels as determined by western blotting. Similar to binding, hNET protein levels returned to control levels 72 h after cessation of desipramine exposure. Northern blotting indicated that exposure of 293-hNET cells to desipramine did not significantly alter hNET mRNA levels. Uptake of [3H]norepinephrine by 293-hNET cells was markedly reduced after a 3-day exposure to desipramine. However, desipramine exposure had no effect on uptake of [3H]glutamate or [3H]-alanine. The present findings imply that down-regulation of the hNET in 293-hNET cells induced by desipramine results from a selective reduction in hNET protein levels, presumably a consequence of either a reduction in the translation of hNET mRNA or from an enhanced degradation of hNET protein. Key Words: Norepinephrine transporter-Norepinephrine uptake-Down-regulationTricyclic antidepressant-Desipramine-Citalopram. J. Neurochem. 70, 1547-1555 (1998).The norepinephrine transporter (NET) is responsible for neuronal reuptake of norepinephrine and is located presynaptically on norepinephrine nerve terminals (Barker and Blakely, 1995). Reuptake of norepinephrifle by the NET is the principal mechanism by which norepinephrine transmission is inactivated at the synapse. A change in the level of expression of the NET on the noradrenergic neuron may in turn cause changes in the amount of norepinephrine in the synaptic cleft. In fact, abnormal levels of expression of the human NET (hNET) at the noradrenergic synapse have been proposed to play a role in the pathophysiology of major depression (Klimek et al., 1997). The NET is also the site of action for many antidepressant medications and certain drugs of abuse (Iversen, 1975;Amara and Kuhar, 1993). Given the diverse roles of noradrenergic transmission in modulating behavior (Svensson, 1987;Harley, 1991;Woodward et al., 1991), further clarification of the molecular characteristics, function, and regulation of the NET will facilitate better understanding of the role that this protein may play in the therapeutic actions of psychoactive drugs and in the pathophysiology of psychiatric disorders.The cloning of the hNET (Pacholczyk et al., 1991) has drawn considerable attention to the molecular d...

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confidence: 99%

Down‐Regulation of the Human Norepinephrine Transporter in Intact 293‐hNET Cells Exposed to Desipramine

Zhu

Blakely

Apparsundaram

et al. 1998

Journal of Neurochemistry

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“…Other projections arising from the substantia nigra and ventral tegmental area ascend through the medial forebrain bundle to innervate widespread regions of the forebrain, including the nucleus accumbens, olfactory tubercle, amygdala, lateral septum, anterior limbic cortex, dorsal hippocampus, and entorhinal area (BjSrklund andLindvall, 1984, 1986). This mesocorticolimbic pathway is especially important in modulating affective and motivational responses, and disturbances of this pathway may contribute to specific symptoms of depression, mania, and schizophrenia (Iversen, 1973(Iversen, . 1977Snyder, 1973;Crow, 1982;Bloom et al, 1989).…”

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confidence: 99%

Cell-type-specific expression of catecholamine transporters in the rat brain

1994

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The dopamine transporter (DAT) and norepinephrine transporter (NET) terminate catecholaminergic neurotransmission at synapses by high- affinity sodium-dependent reuptake into presynaptic terminals, and are the initial sites of action for drugs of abuse and antidepressants. In the present study, we used in situ hybridization combined with immunohistochemistry to study the distribution of DAT and NET mRNA in the adult rat brain. Cells were first immunolabeled with antisera directed against one of the catecholamine-synthetic enzymes, tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (DBH), or phenylethanolamine-N-methyltransferase (PNMT), in order to identify dopaminergic, noradrenergic, or epinephrine-containing cells. The immunolabeled cells were subsequently assayed for their ability to express catecholamine transporter mRNAs by in situ hybridization using either a rat DAT or NET cRNA probe. All dopaminergic cell groups of the mesencephalon contained high levels of DAT mRNA but only the A12 and A13 dopaminergic cell groups of the diencephalon appear to express detectable levels of DAT. All norepinephrine-containing cell bodies in the brainstem (locus coeruleus and lateral tegmentum) appear to express NET mRNA. In contrast, epinephrine-containing cell bodies of the brainstem do not appear to express NET mRNA, which raises the possibility that epinephrine may utilize a transporter that is distinct from the other bioactive amines, or may act as an endocrine regulator that does not require rapid reuptake mechanisms. Moreover, the cell- type-specific expression of catecholamine transporters suggests that DAT and NET gene expression may be closely linked to cellular mechanisms that specify transmitter phenotype. The termination of neurotransmission is a critical component of neural signaling and depends on the rapid removal of neurotransmitters from the synaptic cleft. Pharmacological evidence indicates that the action of monoamines at the synapse is terminated predominantly by rapid reuptake into presynaptic nerve endings via neurotransmitter-specific, high-affinity, Na(+)-dependent membrane transporter proteins. The cDNAs encoding distinct transporter proteins for the monoamines dopamine, norepinephrine, and serotonin have been cloned, expressed, and characterized in a variety of heterologous systems (Blakely et al., 1991; Giros et al., 1991; Hoffman et al., 1991; Kilty et al., 1991; Pacholczyk et al., 1991; Shimada et al., 1991; Usdin et al., 1991). Although the monoamine transporters share a high degree of sequence homology, they are distinguished by their monoamine substrate specificities and by their differential sensitivities to a wide spectrum of transport antagonists. For example, pharmacological agents that potently inhibit norepinephrine and serotonin transport, such as desmethylimipramine and citalopram, have little effect on the activity of the dopamine transporter (Javitch et al., 1983).(ABSTRACT TRUNCATED AT 400 WORDS)

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“…Finally, it was of major importance, for understanding the action of prenylamine, to rule out an indirect effect of the drug via the action of endogenous catecholamines, which may be present even in single myocytes, since there have been reports of noradrenaline uptake into non neuronal tissue in the heart (Farnebo & Malmfors, 1969;Iversen, 1971). Furthermore, some calcium channel blockers interact with adrenoceptors (Nayler et al, 1982).…”

Section: Resultsmentioning

confidence: 99%

The effects of prenylamine on single ventricular myocytes of guinea‐pig

Shimoni

Posner²,

Spindler³

et al. 1988

British J Pharmacology

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1 The action of prenylamine, an antianginal drug, was studied in single ventricular guinea-pig myocytes. In concentrations of 10-50 pm, prenylamine significantly (P <0.01) shortened action potentials, and significantly (P < 0.001) reduced the inward calcium current by 29% to 76% (n = 7). This effect was also present in the presence of adrenoceptor-blockade (with phentolamine and propranolol), and was thus not due to indirect changes in endogenous catecholamine action. 2 Prenylamine did not affect the steady state level of current at the end of long pulses, and does therefore not act by changing time-dependent outward currents. Since the resting potential in the unclamped mode is unchanged during gross changes in action potential duration, it is also unlikely that there are any changes in the background, time-independent potassium conductance. 3 It is concluded that prenylamine has a direct effect on cardiac calcium channels, not mediated by adrenoceptor activation.

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Uptake Processes for Biogenic Amines

Cited by 122 publications

References 150 publications

Down‐Regulation of the Human Norepinephrine Transporter in Intact 293‐hNET Cells Exposed to Desipramine

Down‐Regulation of the Human Norepinephrine Transporter in Intact 293‐hNET Cells Exposed to Desipramine

Cell-type-specific expression of catecholamine transporters in the rat brain

The effects of prenylamine on single ventricular myocytes of guinea‐pig

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