Search

The selective serotonin reuptake inhibitors (SSRIs) fluvoxamine and sertraline show a high affinity for sigma-1 receptors. Fluvoxamine enhances nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells via a sigma-1 receptor-mediated mechanism, which suggests that neurogenesis may be involved in the antidepressant action of fluvoxamine. However, the effects of sertraline on neurite outgrowth remain unclear. Here, we report the effects of sertraline on NGF-induced neurite outgrowth in PC12 cells. At concentrations above 0.3 μM, sertraline inhibited neurite outgrowth induced by NGF (50 ng/mL) in PC12 cells in a concentration-dependent manner. At 0.3–3 μM, sertraline inhibited NGF-induced neurite outgrowth; however, had no effect on cell viability. This suggests that at these concentrations, sertraline inhibits NGF-induced neurite outgrowth without causing cell toxicity. Because sertraline has a high affinity for the sigma-1 receptor, we investigated whether this receptor is involved in sertraline's inhibitory effect on NGF-induced neurite outgrowth. The effect was reversed by both the sigma-1 receptor agonist PRE-084 and the sigma-1 receptor antagonist NE-100. These results suggest that sertraline inhibits NGF-induced neurite outgrowth in PC12 cells by acting as an inverse agonist of the sigma-1 receptor in this system. [ABSTRACT FROM AUTHOR]

Selective serotonin reuptake inhibitors (SSRIs) have an inhibitory effect on various ion channels including Ca 2+ channels. We used fluorescent dye-based digital imaging, whole-cell patch clamping and cytotoxicity assays to examine whether dapoxetine, a novel rapid-acting SSRI, affect glutamate-induced calcium signaling, mitochondrial depolarization and neuronal cell death in cultured rat hippocampal neurons. Pretreatment with dapoxetine for 10 min inhibited glutamate-induced intracellular free Ca 2+ concentration ([Ca 2+ ] i ) increases in a concentration-dependent manner (Half maximal inhibitory concentration=4.79 µM). Dapoxetine (5 μM) markedly inhibited glutamate-induced [Ca 2+ ] i increases, whereas other SSRIs such as fluoxetine and citalopram only slightly inhibited them. Dapoxetine significantly inhibited the glutamate-induced [Ca 2+ ] i responses following depletion of intracellular Ca 2+ stores by treatment with thapsigargin. Dapoxetine markedly inhibited the metabotropic glutamate receptor agonist, (S)−3,5-dihydroxyphenylglycine-induced [Ca 2+ ] i increases. Dapoxetine significantly inhibited the glutamate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-induced [Ca 2+ ] i responses in either the presence or absence of nimodipine. Dapoxetine also significantly inhibited AMPA-evoked currents. However, dapoxetine slightly inhibited N-methyl- D -aspartate (NMDA)-induced [Ca 2+ ] i increases. Dapoxetine markedly inhibited 50 mM K + -induced [Ca 2+ ] i increases. Dapoxetine significantly inhibited glutamate-induced mitochondrial depolarization. In addition, dapoxetine significantly inhibited glutamate-induced neuronal cell death and its neuroprotective effect was significantly greater than fluoxetine. These data suggest that dapoxetine reduces glutamate-induced [Ca 2+ ] i increases by inhibiting multiple pathways mainly through AMPA receptors, voltage-gated L-type Ca 2+ channels and metabotropic glutamate receptors, which are involved in neuroprotection against glutamate-induced cell death through mitochondrial depolarization. [ABSTRACT FROM AUTHOR]

Selective serotonin reuptake inhibitors (SSRIs) are widely used as a first-line therapy in postpartum depression. The objective of this study was to determine the mechanism underlying the inhibitory effects of the SSRI, fluvoxamine, on β-casein expression, an indicator of lactation, in MCF-12A human mammary epithelial cells. Expression levels of serotonin (5-hydroxytryptamine; 5-HT) transporter, an SSRI target protein, and tryptophan hydroxylase 1, a rate-limiting enzyme in 5-HT biosynthesis, were increased in MCF-12A cells by prolactin treatment. Treatment with 1 μM fluvoxamine for 72 h significantly decreased protein levels of β-casein and phosphorylated signal transducer and activator transcription 5 (pSTAT5). Extracellular 5-HT levels were significantly increased after exposure to 1 μM fluvoxamine, in comparison with those of untreated and vehicle-treated cells; however, extracellular 5-HT had little effect on the decrease in β-casein expression. Expression of glucose-related protein 78/binding immunoglobulin protein, a regulator of endoplasmic reticulum (ER) stress, was significantly increased after treatment with 1 μM fluvoxamine for 48 h. Exposure to tunicamycin, an inducer of ER stress, also decreased expression of β-casein and pSTAT5 in a manner similar to fluvoxamine. Our results indicate that fluvoxamine suppresses β-casein expression in MCF-12A cells via inhibition of STAT5 phosphorylation caused by induction of ER stress. Further studies are required to confirm the effect of fluvoxamine on the function of mammary epithelial cells. [ABSTRACT FROM AUTHOR]

Abstracts: The sigma-1 receptor chaperone located in the endoplasmic reticulum (ER) may be implicated in the mechanistic action of some antidepressants. The present study was undertaken to examine whether new antidepressant drugs interact with the sigma-1 receptor chaperone. First, we examined the effects of selective serotonin reuptake inhibitors (SSRIs) (fluvoxamine, paroxetine, sertraline, citalopram and escitalopram), serotonin and noradrenaline reuptake inhibitors (SNRIs) (duloxetine, venlafaxine, milnacipran), and mirtazapine, a noradrenaline and specific serotonergic antidepressant (NaSSA), on [3H](+)-pentazocine binding to rat brain membranes. Then, we examined the effects of these drugs on nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells. The order of potency for drugs at the sigma-1 receptor chaperone was as follows: fluvoxamine>sertraline>fluoxetine>escitalopram>citalopram>paroxetine>duoxetine. Venlafaxine, milnacipran, and mirtazapine showed very weak affinity for this chaperone. Furthermore, fluvoxamine, fluoxetine, escitalopram, and mirtazapine significantly potentiated NGF-induced neurite outgrowth in cell assays, and the effects of all these drugs, excluding mirtazapine, were antagonized by NE-100, a selective antagonist of the sigma-1 receptor chaperone. Moreover, the effects of fluvoxamine and fluoxetine on neurite outgrowth were also antagonized by sertraline, indicating that sertraline may be an antagonist at the sigma-1 receptor chaperone. The effect of mirtazapine on neurite outgrowth was antagonized by the selective 5-hydroxytryptamine1A receptor antagonist WAY-100635. These findings suggest that activation at the sigma-1 receptor chaperone may be involved in the action of some SSRIs, such as fluvoxamine, fluoxetine and escitalopram. In contrast, mirtazapine independently potentiated neurite outgrowth in PC12 cells, indicating that this beneficial effect may mediate its pharmacological effect. [Copyright &y& Elsevier]

Abstract: The effects of acute systemic administration of duloxetine, amitriptyline, mirtazapine and fluoxetine were compared in experimental models of gastric ulcer in rats. Compared with the vehicle control group, duloxetine (5, 10 and 20mg/kg, i.p.), amitriptyline (10 and 20mg/kg, i.p.), mirtazapine (10 and 20mg/kg, i.p.) and fluoxetine (5 and 10mg/kg, i.p.) significantly protected against water-immersion plus restraint stress-induced gastric lesions, as evidenced by dose-dependent decrease in ulcer index and score for intraluminal bleeding. Duloxetine (20mg/kg, i.p.), amitriptyline (10 and 20mg/kg, i.p.), fluoxetine (10 and 20mg/kg, i.p.) and mirtazapine (5, 10 and 20mg/kg, i.p.) significantly decreased indomethacin (30mg/kg, i.p.)-induced gastric lesions and intraluminal bleeding. In reserpine (25mg/kg, i.p.)-induced gastric ulcer experiment, duloxetine (5, 10 and 20mg/kg, i.p.), amitriptyline (5, 10 and 20mg/kg, i.p.), fluoxetine (10mg/kg, i.p.) and mirtazapine (5mg/kg, i.p.) significantly attenuated gastric lesions and intraluminal bleeding. These results (a) highlighted the relationship in correlating antiulcer effect of drugs from different antidepressant classes across various animal gastric ulcer models and (b) suggested that antidepressants that differently affected both norepinephrine and serotonin levels (such as duloxetine, amitriptyline and mirtazapine) had more potent and efficacious antiulcer effect in various gastric ulcer animal models than drugs that only affected serotonin level (such as fluoxetine). [Copyright &y& Elsevier]

Abstract: The main clinically used antidepressant drugs are selective monoamine reuptake inhibitors, including selective serotonin reuptake inhibitors (citalopram, sertraline), selective dopamine reuptake inhibitor (nomifensine) and selective noradrenaline reuptake inhibitor (reboxetine), but they have various side effects. Because cannabinoid CB1 receptor antagonists (SR141716A, AM251) enhance monoamine release, they might be beneficial in the therapy of affective disorders. We hypothesized that the use of monoamine reuptake inhibitors in combination with cannabinoid CB1 receptor antagonists would allow a lower dose of monoamine reuptake inhibitors to be used in the therapy of depression, thereby reducing or eliminating the side effects. To test this hypothesis, we examined the combination of SR141716A or AM251 with citalopram, sertraline, nomifensine or reboxetine at subthreshold doses to see whether these combinations would show an additive effect in the forced swimming test and the tail suspension test with mice. Subthreshold doses of cannabinoid CB1 receptor antagonist and selective serotonin reuptake inhibitors, which separately had no effect on the immobility of mice in the tests, showed a clear effect when the drugs were administered at 40 and 30 min, respectively, before the tests, without any change of motor activity. Therefore, the use of subthreshold doses of these agents in combination might be useful to enhance mainly serotonergic neurotransmission, and to reduce or eliminate the side effects of citalopram and sertraline. [Copyright &y& Elsevier]

Abstract: Although major metabolites of some antidepressant drugs are known to be active, their pharmacological effects are poorly characterized. Two of the most selective antidepressants, desipramine (selectively inhibits norepinephrine reuptake) and citalopram (selectively inhibits serotonin reuptake) are frequently used in animal studies of antidepressant action, as well as being useful therapeutically. The primary aim of this study was to determine the affinity of desmethyldesipramine, an active metabolite of desipramine, for the rat norepinephrine and serotonin transporters, as well as for the rat α2-adrenoceptor. The pharmacological characteristics of desmethyldesipramine and desmethylcitalopram, an active metabolite of citalopram, were also determined for various human transporters and neurotransmitter receptors. Competition binding studies using [3H]nisoxetine and [3H]citalopram showed desipramine to be 25 times more selective for the rat norepinephrine as compared to serotonin transporter (6.2 nM vs. 158 nM) whereas desmethyldesipramine is 12 times more selective for the serotonin over the norepinephrine transporter (12.8 nM vs. 153 nM). Interestingly, the affinity of desmethyldesipramine for the serotonin transporter is similar to the affinity of desipramine for the norepinephrine transporter. Desipramine and desmethyldesipramine were found to have a lower affinity for the rat α2A(D)-adrenoceptor than the transporters, suggesting that this receptor is not a major site of action for either compound. Thus, the pharmacological effects of desipramine in rats may be attributed not only to the inhibition of the norepinephrine transporter by desipramine but also to the inhibition of serotonin transporter by the active metabolite desmethyldesipramine. [Copyright &y& Elsevier]

Abstract: To clarify the therapeutic interaction between serotonin and noradrenaline reuptake inhibition on fear, this study examined the acute and subchronic effects of combined treatment with the selective serotonin reuptake inhibitor citalopram and the selective noradrenaline reuptake inhibitor reboxetine on the expression of conditioned fear (re-exposure to an environment paired previously with inescapable electric footshocks). After fear conditioning was achieved with footshocks, the drugs were administered to rats and freezing behavior, as an index of fear, was observed in the shock chamber. Acute and subchronic treatment with citalopram was reproducibly anxiolytic against conditioned freezing. Acute reboxetine worsened conditioned freezing and reversed the acute anxiolytic effects of citalopram, but this anxiogenic effect of noradrenaline reuptake inhibition was not observed after subchronic treatment. These results suggest that adding noradrenaline reuptake inhibitors to serotonin reuptake inhibitors adversely affects fear, at least with acute treatment. [Copyright &y& Elsevier]

Abstract: The purpose of this study was to evaluate the auditory effects of selective serotonin reuptake inhibitors (SSRI), known to enhance serotonin (5-HT) transmission in the brain. The experimental group consisted of 14 clinically depressed female subjects, and the control group consisted of 11 non-depressed females. A battery of tests was administered to the experimental group while on and off of SSRI medication. The control group was also administered the test battery twice. Results indicated no significant differences in the control group between sessions. The experimental group showed significantly smaller transient evoked emissions, higher SCAN-A (auditory processing test) composite scores, and smaller amplitude growth functions for Auditory brainstem response peak V and Auditory late response peak N1P2 while on SSRI medication. The increased 5-HT levels in the presence of SSRI (due to reduced reuptake of 5-HT) may be contributing to the significant changes seen in auditory measures with the experimental group. [Copyright &y& Elsevier]

Abstract: The role of 5-HT (5-hydroxytryptamine, 5-HT)1A receptor activation in the sexual side-effects, in particular delayed ejaculation, of selective serotonin reuptake inhibitors (SSRIs) was studied. Male Wistar rats were treated for 15 days with vehicle, the SSRI citalopram (10 mg/kg/day p.o.), the 5-HT1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl]-N-(2-pyridinyl) cyclohexane carboxamide 3HCL (WAY 100635, 0.1 mg/kg/ day s.c.), or both drugs combined. Sexual behavior was assessed weekly. One h after the last sexual behavior test, rat brains were processed for Fos-immunohistochemistry. Acute and chronic citalopram mildly inhibited ejaculation, which was strongly augmented by co-administration of WAY 100635. WAY 100635 alone did not alter sexual behavior. Brain sites associated with ejaculation showed reduced Fos-immunoreactivity in rats treated with both citalopram and WAY 100635. Citalopram reduced Fos-immunoreactivity in the arcuate hypothalamic nucleus, an area that might link serotonergic neurotransmission to ejaculation. [Copyright &y& Elsevier]

Selective serotonin reuptake inhibitors are first-line treatment for most anxiety disorders, but their mechanism of anxiolytic action has not been clarified. Selective serotonin reuptake inhibitors are anxiolytic in conditioned fear stress (re-exposure to an environment paired previously with inescapable electric footshocks). To clarify the brain regions where selective serotonin reuptake inhibitors act, we examined the effect of microinjection of the selective serotonin reuptake inhibitor, citalopram, into the amygdala, medial prefrontal cortex and mediodorsal nucleus of the thalamus on freezing behavior, an index of fear, induced by conditioned fear stress. Bilateral injection of citalopram into the amygdala before testing reduced freezing significantly, while bilateral injection into the medial prefrontal cortex or mediodorsal nucleus of the thalamus did not. These results suggest that the anxiolytic effect of a selective serotonin reuptake inhibitor in conditioned fear is mediated by its effect in the amygdala, and support the hypothesis of serotonin function in anxiety by which facilitation of serotonin neurotransmission decreases anxiety. [Copyright &y& Elsevier]

Paroxetine is one of the most effective selective serotonin reuptake inhibitors used to treat depressive and panic disorders that reduce the viability of human T lymphocytes, in which Kv1.3 channels are highly expressed. We examined whether paroxetine could modulate human Kv1.3 channels acutely and directly with the aim of understanding the biophysical effects and the underlying mechanisms of the drug. Kv1.3 channel proteins were expressed in Xenopus oocytes. Paroxetine rapidly inhibited the steady-state current and peak current of these channels within 6 min in a concentration-dependent manner; IC 50 s were 26.3 μM and 53.9 μM, respectively, and these effects were partially reversed by washout, which excluded the possibility of genomic regulation. At the same test voltage, paroxetine blockade of the steady-state currents was higher than that of the peak currents, and the inhibition of the steady-state current increased relative to the degree of depolarization. Paroxetine decreased the inactivation time constant in a concentration-dependent manner, but it did not affect the activation time constant, which resulted in the acceleration of intrinsic inactivation without changing ultrarapid activation. Blockade of Kv1.3 channels by paroxetine exhibited more rapid inhibition at higher activation frequencies showing the use-dependency of the blockade. Overall, these results show that paroxetine directly suppresses human Kv1.3 channels in an open state and accelerates the process of steady-state inactivation; thus, we have revealed a biophysical mechanism for possible acute immunosuppressive effects of paroxetine. • Paroxetine acutely inhibited amplitude of human Kv1.3 channel current. • Kv1.3 steady-state current block by paroxetine was voltage-dependent and reversible. • Paroxetine decreased time constants of steady-state inactivation of Kv1.3. • Kv1.3 block by paroxetine exhibited faster inhibition at higher activation frequency. [ABSTRACT FROM AUTHOR]

Significant unmet needs exist for development of better pharmacotherapeutic agents for major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) as the current drugs are inadequate. Our goal in this study is to investigate behavioral pharmacological characterization of a novel triple reuptake inhibitor (TRI) D-578 which exhibits nanomolar potency at all three monoamine transporters (Ki; 16.2. 16.2, 3.23 nM, and 29.6, 20.6, 6.10 nM for the rat brain and cloned human dopamine, serotonin and norepinephrine transporters, respectively) and exhibited little to no affinity for other off-target CNS receptors. In a rat forced swim test, compound D-578 upon oral administration displayed high efficacy and not stimulating in locomotor behavior. The effects of D-578 and paroxetine were next evaluated in a rat model for traumatic stress exposure - the single prolonged stress (SPS) model - which has been shown to have construct, predictive, and behavioral validity in modeling aspects of PTSD. Our results show that SPS had no effect on the acquisition of conditioned fear, but impaired extinction learning and extinction retention of fear behavior compared to sham treatment. D-578, but not paroxetine, attenuated the extinction and extinction-retention deficit induced by SPS. These findings suggest that D-578 has greater efficacy in normalizing traumatic stress-induced extinction-retention learning in a model for PTSD compared to paroxetine. Overall these results suggest that D-578, in addition to producing a robust and efficacious antidepressant effect, may attenuate maladaptive retention of fearful memories and support further testing of this agent for the pharmacotherapy of depression and PTSD. [ABSTRACT FROM AUTHOR]