Antidepressants: past, present and future

Vetulani, Jerzy; Nalepa, Irena

doi:10.1016/s0014-2999(00)00565-3

Cited by 111 publications

(58 citation statements)

References 122 publications

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“…Our autoradiographic studies showed decreased binding of the b-adrenergic ligand [ 3 H]CGP12177 in the cerebral cortex of NET À/À mice, indicating downregulation of badrenergic receptors. This result also indicates that knockout of the NET results in biochemical changes similar to those obtained with ADs treatment, as many studies consistently have shown antidepressant-induced downregulation of these receptors (for review, see Vetulani and Nalepa, 2000). However, it must be added that clinically active selective serotonin reuptake inhibitors administered repeatedly do not induce downregulation of b-adrenergic receptors.…”

Section: Discussionmentioning

confidence: 65%

“…Also desipramine and imipramine, given acutely, were not active in the FST in NET À/À mice. However, the antidepressant-like action of repeatedly administered desipramine (but not imipramine) indicates that the chronic presence of this NET inhibitor may affect also other neurochemical targets such as various subtypes of serotonin or dopamine receptors (Vetulani and Nalepa, 2000;Cryan et al, 2005b;Petit-Demouliere et al, 2005;Renard et al, 2001Renard et al, , 2003Dziedzicka-Wasylewska et al, 2000). The lack of effect of repeated treatment of NET À/À mice with imipramine might result from the additional affinity of this drug for the 5-HTT.…”

Section: Discussionmentioning

confidence: 99%

“…One of the main theories is based on the notion that the neurochemical background of depression involves an impairment of central noradrenergic transmission with a concomitant decrease of the norepinephrine (NE) concentration in the synaptic gap. The noradrenergic hypothesis in depression is supported by the fact that drugs that deplete central nervous system (CNS) monoamines (eg reserpine) can produce depression, and that many antidepressants increase synaptic NE availability by inhibition of the reuptake of NE (Manji et al, 2003;Vetulani and Nalepa, 2000). There is also considerable evidence for alterations in growth hormone response to the noradrenergic agonist clonidine in depression (Schatzberg and Schildkraut, 1995;Siever et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

“…Long-term treatment with ADs is known to cause downregulation of b-adrenergic receptors (Vetulani and Nalepa, 2000), and a role of a 1 -adrenergic receptors in some symptoms of depressive illness and in the mechanism of action of ADs has been postulated (Stone and Quartermain, 1999). As it has been demonstrated (Wang et al, 1999;Xu et al, 2000) that NET À/À mice have elevated extracellular NE concentrations in spite of reduced intraneuronal NE levels, we also examined whether the NET À/À mice show changes in the expression level of cortical b-and a 1 -adrenergic receptors.…”

Section: Introductionmentioning

confidence: 99%

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Effect of Antidepressant Drugs in Mice Lacking the Norepinephrine Transporter

Dziedzicka-Wasylewska

Faron-Górecka

Kuśmider

et al. 2006

Neuropsychopharmacol

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One of the main theories concerning the mechanism of action of antidepressant drugs (ADs) is based on the notion that the neurochemical background of depression involves an impairment of central noradrenergic transmission with a concomitant decrease of the norepinephrine (NE) in the synaptic gap. Many ADs increase synaptic NE availability by inhibition of the reuptake of NE. Using mice lacking NE transporter (NET À/À ) we examined their baseline phenotype as well as the response in the forced swim test (FST) and in the tail suspension test (TST) upon treatment with ADs that display different pharmacological profiles. In both tests, the NET À/À mice behaved like wild-type (WT) mice acutely treated with ADs. Autoradiographic studies showed decreased binding of the b-adrenergic ligand [ 3 H]CGP12177 in the cerebral cortex of NET À/À mice, indicating the changes at the level of b-adrenergic receptors similar to those obtained with ADs treatment. The binding of [ 3 H]prazosin to a 1 -adrenergic receptors in the cerebral cortex of NET À/À mice was also decreased, most probably as an adaptive response to the sustained elevation of extracellular NE levels observed in these mice. A pronounced NET knockout-induced shortening of the immobility time in the TST (by ca 50%) compared to WT mice was not reduced any further by NET-inhibiting ADs such as reboxetine, desipramine, and imipramine. Citalopram, which is devoid of affinity for the NET, exerted a significant reduction of immobility time in the NET À/À mice. In the FST, reboxetine, desipramine, imipramine, and citalopram administered acutely did not reduce any further the immobility time shortened by NET knockout itself (ca 25%); however, antidepressant-like action of repeatedly (7 days) administered desipramine was observed in NET À/À mice, indicating that the chronic presence of this drug may also affect other neurochemical targets involved in the behavioral reactions monitored by this test. From the present study, it may be concluded that mice lacking the NET may represent a good model of some aspects of depression-resistant behavior, paralleled with alterations in the expression of adrenergic receptors, which result as an adaptation to elevated levels of extracellular NE.

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Section: Discussionmentioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of Antidepressant Drugs in Mice Lacking the Norepinephrine Transporter

Dziedzicka-Wasylewska

Faron-Górecka

Kuśmider

et al. 2006

Neuropsychopharmacol

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“…There is strong evidence concerning the antidepressant effects of TRH, which were intensively investigated late last century [1,20,21,50]. The initial clues that lead to studying TRH as a putative antidepressant were observations of common clinical manifestations of patients with depression and hypothyroidism.…”

Section: Stimulatory Effects Of Trh In the Cns And Its Potential Clinmentioning

confidence: 99%

Tyreoliberin (Trh) – The Regulatory Neuropeptide of Cns Homeostasis

Jantas¹

2010

Advances in Cell Biology

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Summary:The physiological role of thyreoliberin (TRH) is the preservation of homeostasis within four systems (i) the hypothalamic-hypophsysiotropic neuroendocrine system, (ii) the brain stem/midbrain/spinal cord system, (iii) the limbic/cortical system, and (iv) the chronobiological system. Thus TRH, via various cellular mechanisms, regulates a wide range of biological processes (arousal, sleep, learning, locomotive activity, mood) and possesses the potential for unique and widespread applications for treatment of human illnesses. Since the therapeutic potential of TRH is limited by its pharmacological profile (enzymatic instability, short half-life, undesirable effects), several synthetic analogues of TRH were constructed and studied in mono-or adjunct therapy of central nervous system (CNS) disturbances. The present article summarizes the current state of understanding of the physiological role of TRH and describes its putative role in clinical indications in CNS maladies with a focus on the action of TRH analogues.

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Antidepressants

Iversen¹,

Glennon²

2003

Burger's Medicinal Chemistry and Drug Discovery

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This chapter reviews the 26 antidepressant drugs currently available in Europe and/or the United States from the perspectives of their clinical efficacy, pharmacokinetics, pharmacology, structure‐activity relationships, metabolism, and mechanisms of action. The older nonselective monoamine oxidase inhibitors (e.g., phenelzine, tranylcypromine) have largely been replaced by compounds that selectively inhibit monoamine oxidase A (e.g., moclobemide) or by inhibitors of norepinephrine/serotonin monoamine transporter reuptake mechanisms. The first generation of such drugs, the tricyclic antidepressants, suffered from a number of dangerous and unpleasant adverse side effects caused by their many other pharmacological actions on the heart and on cholinergic and other monoamine receptors in the brain. Most of the current generation of antidepressants are serotonin‐selective reuptake inhibitors, which possess a safer side‐effect profile. These drugs have gained widespread use in the treatment of depression and a number of related psychiatric conditions. Some agents that act as norepinephrine‐selective reuptake inhibitors (e.g., reboxetine) are also clinically effective and there is considerable overlap between noradrenergic and serotonergic mechanisms in the CNS. Monoamine selectivity can also be altered by the formation of active metabolites in vivo . All antidepressants require several weeks of treatment before the maximum clinical benefit is seen. This may be attributable to drug‐induced alterations in the expression of receptors in brain (e.g., downregulation of 5‐HT 1A receptors) and/or alterations in the expression of neurotrophic factors (e.g., brain derived neurotrophic factor). New approaches to future antidepressant drug discovery include antagonists for glutamate NMDA receptors, substance P NK1 receptors, or corticotrophin releasing factor receptors.

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Antidepressants: past, present and future

Cited by 111 publications

References 122 publications

Effect of Antidepressant Drugs in Mice Lacking the Norepinephrine Transporter

Effect of Antidepressant Drugs in Mice Lacking the Norepinephrine Transporter

Tyreoliberin (Trh) – The Regulatory Neuropeptide of Cns Homeostasis

Antidepressants

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