New insights into the mechanisms of antidepressant therapy

Compelling evidence suggests that mood disorders are characterized by reduced neuronal plasticity that might be normalized by pharmacological intervention. Our study aimed to establish whether chronic antidepressant treatment could alter the modulation of the neurotrophin brain-derived neurotrophic factor (BDNF) under a stressful condition. Therefore, adult male Sprague-Dawley rats were treated for 21 days with vehicle or with the SNRI duloxetine and, 24 h after the last injection, exposed to an acute swim stress (5 min) before being killed 15 min later. We found that chronic duloxetine treatment was able to modulate the rapid transcriptional changes of BDNF isoforms produced by an acute swim stress. Indeed whereas the mRNA levels of BDNF exon IV were upregulated by stress in vehicle as well as in duloxetine-treated rats, a significant increase of exon VI and exon IX was only found in rats that were pretreated with the antidepressant. These differential effects are in part because of selective changes in signaling pathways involved in the control of BDNF transcription. Moreover, the acute stressful episode significantly increased the levels of mature BDNF protein in the synaptosomal compartment in rats that were pretreated with the antidepressant, but not in control animals. Our results suggest that chronic antidepressant treatment might affect the responsiveness of BDNF under stressful conditions, suggesting that pharmacological intervention could 'prime' neuroprotective pathways and render them more responsive to preserve cell function and viability.

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“…It is widely accepted that antidepressant drugs produce relevant neuroplastic changes, when chronically administered Schloss and Henn, 2004). …”

Section: Discussionmentioning

confidence: 99%

Acute Stress Responsiveness of the Neurotrophin BDNF in the Rat Hippocampus is Modulated by Chronic Treatment with the Antidepressant Duloxetine

Molteni

Calabrese

Cattaneo

et al. 2008

Neuropsychopharmacol

116

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“…Specifi cally, changes to a 2 -adrenergic receptors are known to occur when examining antidepressants that specifi cally inhibit NET with changes being dependent on the type of antidepressant. 49 Interestingly, Ansah and colleagues 60 recently reported that a 2 -adrenergic receptor activation could inhibit SERT activity both in vitro and in vivo, and the presence of Ca 2+ was essential for this inhibition. Application of an a 2 -adrenergic receptor agonist at a concentration that resulted in maximal SERT inhibition in synaptosomal preparations did not decrease SERT activity in transfected cell lines suggesting activation of a pathway in vivo that was unavailable in transfected cells rather than a direct interaction of the receptor or drug with SERT.…”

Section: Receptor Regulation Of Sertmentioning

confidence: 99%

Serotonin Transporters: Implications for Antidepressant Drug Development

White¹,

Walline²,

Barker³

2008

Drug Addiction

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A BSTRACTDue to the complexity of the disease, several hypotheses exist to explain the etiology of depression. The monoamine theory of depression suggests that disruptions in the sero tonergic and noradrenergic systems result in depressive symptoms. Therefore, the serotonin transporter (SERT) has become a pharmacological target for treating these symptoms. This review will discuss what is known about the molecular interactions of antidepressants with SERT. The effects of antidepressants on SERT regulation and expression in addition to the receptors that may be involved in mediating these effects will be addressed. Specifically, how changes to SERT expression following chronic antidepressant treatment may contribute to the therapeutic benefi ts of antidepressants will be discussed. Furthermore, the effects of SERT gene polymorphisms on antidepressant effi cacy will be examined. Finally, a brief overview of other hypotheses of depression will be addressed as well as factors that must be considered for future antidepressant development. K EYWORDS:SSRIs , antidepressant , serotonin transporter , depression , reuptake MONOAMINE THEORY OF DEPRESSIONFunctional defi ciencies in serotonin (5-hydroytryptamine, 5-HT) and norepinephrine (NE) have been implicated in the pathophysiology of depressive syndromes, and restoring the normal function of 5-HT-and NE-associated signaling pathway has been the target of antidepressants. Restoration of monoamine defi ciencies to normal levels as a therapeutic strategy is based on the monoamine hypothesis of depression. 1 The oldest antidepressants, the monoamine oxidase inhibitors (MAOIs), increase synaptic levels of 5-HT and NE by inhibiting the enzymatic degradation of these neurotransmitters. The tricyclic antidepressants (TCAs), as well as newer selective 5-HT reuptake inhibitors (SSRIs) and 5-HT/ NE reuptake inhibitors (SNRIs), all increase synaptic levels of 5-HT or NE by inhibiting reuptake via the 5-HT transporter (SERT) or NE transporter (NET), respectively. Emerging evidence indicates that the monoamine hypothesis of 5-HT and NE modulation fails to explain the whole mechanism of antidepressants. Other hypotheses, including the cytokine hypothesis of depression, the hypothalamic-pituitary-thyroid hypothesis of depression, as well as the role of brain-derived neurotrophic factor and cyclic AMP response element binding protein will be considered later in this review.

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“…Thus, the current pharmacotherapy is based on the discovery of the enhancement of serotonergic and/or noradrenergic neurotransmission by either inhibiting the intracellular degradation of the monoamines with monoamine oxidase inhibitors or blocking their reuptake back into the 5-HT and/or NA nerve terminal by selective serotonin/norepinephrine reuptake inhibitors, or tricyclic antidepressants (see Fuxe et al, 1983d;Duman et al, 1997;Skolnick, 1999;Nestler et al, 2002;Manji et al, 2001;Nemeroff, 1998), that in turn lead to an increase of extracellular monoamines (Iversen, 2000;Taylor et al, 2005;Schloss and Henn, 2004).…”

mentioning

confidence: 99%

From the Golgi–Cajal mapping to the transmitter-based characterization of the neuronal networks leading to two modes of brain communication: Wiring and volume transmission

Fuxé¹,

Dahlström²,

Höistad³

et al. 2007

Brain Research Reviews

234

219

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After Golgi-Cajal mapped neural circuits, the discovery and mapping of the central monoamine neurons opened up for a new understanding of interneuronal communication by indicating that another form of communication exists. For instance, it was found that dopamine may be released as a prolactin inhibitory factor from the median eminence, indicating an alternative mode of dopamine communication in the brain. Subsequently, the analysis of the locus coeruleus noradrenaline neurons demonstrated a novel type of lower brainstem neuron that monosynaptically and globally innervated the entire CNS.Furthermore, the ascending raphe serotonin neuron systems were found to globally innervate the forebrain with few synapses, and where deficits in serotonergic function appeared to play a major role in depression. We propose that serotonin reuptake This will lead to the unified execution of information handling and trophism for optimal brain function and survival.

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New insights into the mechanisms of antidepressant therapy

Cited by 104 publications

References 130 publications

Acute Stress Responsiveness of the Neurotrophin BDNF in the Rat Hippocampus is Modulated by Chronic Treatment with the Antidepressant Duloxetine

Acute Stress Responsiveness of the Neurotrophin BDNF in the Rat Hippocampus is Modulated by Chronic Treatment with the Antidepressant Duloxetine

Serotonin Transporters: Implications for Antidepressant Drug Development

From the Golgi–Cajal mapping to the transmitter-based characterization of the neuronal networks leading to two modes of brain communication: Wiring and volume transmission

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