Administration Of Paroxetine Research Articles

Therapeutic effect of paroxetine on stress-induced gastric lesions in mice

Compared to the well-known anti-ulcerogenic properties of tricyclic antidepressants, the impact of selective serotonin reuptake inhibitors (SSRIs) on gastric mucosa is less clear. Human clinical trials have shown that SSRIs and non-steroidal anti-inflammatory drugs (NSAIDs) act synergistically and promote stomach ulcer formation and upper gastrointestinal tract bleeding. Acute SSRI treatment confers an additional risk for the formation of NSAID-induced gastric ulcers through increase in gastric acid secretion. Stress, which is often experienced by depressed patients, also deteriorates the gastric environment. Thus the potential for exacerbating stress-induced gastric lesions must be considered before prescribing SSRIs. Therefore, we evaluated the effects of paroxetine by using a water-immersion stress-induced stomach ulcer model of mice, by examining single vs. repeated paroxetine treatments for 8 and 22 days before stress induction. Repeated administration of paroxetine significantly decreased the area of stress-induced stomach lesions. Although stress significantly increased the serum corticosterone concentrations, the levels were not affected by the 8-day paroxetine treatment. We confirmed the anxiolytic and antidepressive effects of 8-day paroxetine treatment at 1 and 5 days after stress induction by using the elevated plus-maze and tail-suspension tests. We concluded that repeated paroxetine treatment significantly attenuates the stress-induced ulcerogenic process in the stomach.

Data Mining Approach Shows Promise in Detecting Unexpected Drug Interactions

UP TO 1 MILLION PATIENTS IN THE United States may be taking 2 medications that can lead to unexpected increases in blood glucose levelswhenusedsimultaneously.Dataminingtechniqueshaverevealedthatthecombinationof theantidepressantparoxetine andthecholesterol-loweringmedication pravastatinmaycause this adverseeffect (TatonettiNPetal.ClinPharmacolTher. doi:10.1038/clpt.2011.83 [published online ahead of print May 25, 2011]). “If a physician has a patient on these 2 medications and their diabetes becomes harder to control, the physician may want to consider changing the medications,” said principal investigator Russ Altman, MD, PhD, professor of bioengineering, genetics, and medicine at Stanford University. To uncover the paroxetine-pravastatin association with high glucose effects, the investigators mined the US Food and Drug Administration’s (FDA’s) Adverse Event Reporting System (AERS) (http://tinyurl.com/mbjsdt) for drug interactions with diabetes-related associations. After finding an intriguing indication that pravastatin and paroxetine taken together may influence glucose homeostasis, they retrospectively evaluated changes in blood glucose in 104 patients with diabetes and 135 without diabetes who had received both of these drugs. To accomplish this, they analyzed data in electronic medical record (EMR) systems from 3 institutions and assessedmeanrandombloodglucose levels before and after treatment with the drugs. Administration of both pravastatin and paroxetine together was associated with an average increase in blood glucose levels of 19 mg/dL (1.0 mmol/L) overall and 48 mg/dL (2.7 mmol/L) in individuals with diabetes. Neither drug administered singly was associated with such changes in glucose levels, and no increase was seen with other combinations of selective serotonin reuptake inhibitors and statins. “FDAAERSsometimesgets criticized as filledwithbiasesandnotuseful. It can certainlybeimproved,butithassomeuseful information, for sure,” said Altman. “Also, EMRs were really critical in our studybecause theyallowedustovalidate ourFDA-derivedpredictionsatminimal cost.” Lead author Nicholas Tatonetti addedthattheexpandingpresenceofEMR systemsrepresentsanewandgrowingopportunitytostudydrugeffectsinrealtime. “This is especially important in the case ofdrug-druginteractionswheretheeffect may not appear until a very large cohort of patients has been exposed,” he said. The researchers also looked at the impact of the 2 medications in laboratory mice that were fed a high-fat, highcalorie diet and became insulin resistant. Neither medication alone increased fasting glucose levels in these prediabetic mice, but when they were given paroxetine and pravastatin together for 3 weeks, their glucose levels increased dramatically. “Random data mining of spontaneous reports often leads to blind alleys, but this creative study used the approach to generate a wholly unexpected hypothesis that the authors were then able to confirm in observational studies of patients’ glucose levels in multiple sites, as well as in an animal experiment,” said Jerry Avorn, MD, professor of medicine at Harvard Medical School and chief of the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital in Boston, who was not involved with the work. “This is a very interesting application of informatics employed on a large scale to identify new drug-drug interactions, which are generally not well spotted in clinical trials,” he added. The approach has the potential to help expose numerous other unexpected adverse effects from different drug combinations. “Perhaps best of all, it doesn’t require a super computer to do this type of research. Any modern laptop can run these algorithms in minutes,” said Tatonetti.

Activity of mitochondrial respiratory chain is increased by chronic administration of antidepressants

Depressive disorders, including major depression, are serious and disabling for affected patients. Although the neurobiological understanding of major depressive disorder focuses mainly on the monoamine hypothesis, the exact pathophysiology of depression is not fully understood. Animals received daily intra-peritoneal injections of paroxetine (10 mg/kg), nortriptyline (15 mg/kg) or venlafaxine (10 mg/kg) in 1.0 ml/kg volume for 15 days. Twelve hours after the last injection, the rats were killed by decapitation, where the brain was removed and homogenised. The activities of mitochondrial respiratory chain complexes in different brain structures were measured. We first verified that chronic administration of paroxetine increased complex I activity in prefrontal cortex, hippocampus, striatum and cerebral cortex. In addition, complex II activity was increased by the same drug in hippocampus, striatum and cerebral cortex and complex IV activity in prefrontal cortex. Furthermore, chronic administration of nortriptyline increased complex II activity in hippocampus and striatum and complex IV activity in prefrontal cortex, striatum and cerebral cortex. Finally, chronic administration of venlafaxine increased complex II activity in hippocampus, striatum and cerebral cortex and complex IV activity in prefrontal cortex. On the basis of the present findings, it is tempting to speculate that an increase in brain energy metabolism by the antidepressant paroxetine, nortriptyline and venlafaxine could play a role in the mechanism of action of these drugs. These data corroborate with other studies suggesting that some antidepressants modulate brain energy metabolism.

Abstract 2152: Paroxetine, a selective serotonin re-uptake inhibitor, induces growth inhibition and apoptosis in prostate cancer cells

Abstract Introduction and Objective: Recently, neuroendocrine cells is suggested to be involved in prostate cancer (PC) progression through the secretion of a variety of neuroendocrine products, such as serotonin, which have mitogenic effects on adjacent cancer cells and thus can contribute to the androgen independent proliferation of PC cells. With having experience that a patient with hormone refractory prostate cancer responded to paroxetine, a selective serotonin re-uptake inhibitor (SSRI), in serum prostate specific antigen (PSA) level, we investigated the effect of paroxetine on the growth and apoptosis induction in PC cell lines. Methods: Paroxetine was administered to four patients with hormone refractory, metastatic PC and their serum PSA levels were determined. The effects of paroxetine on the growth and apoptosis induction in PC cell lines (PC3, DU145, 22RV1 and LNCaP) were confirmed. Cell growth inhibition was assessed in vitro by cell number count. The induction of apoptosis was examined by flow cytometry analysis and caspase activations were confirmed by western blot analysis. Results: Serum PSA levels decreased soon after the administration of paroxetine but increased again in all four patients but one in whom it decreased from 0.485 ng/ml to undetectable level (less than 0.008 ng/ml) for over three years. In vitro study, paroxetine inhibited cell growth in a dose and time dependent manner. The 50% inhibitory concentration (IC50 values) of paroxetine in PC3, 22RV1, DU145 and LNCaP cells were 38.8, 30.1, 35.9 and 21µM, respectively. Apoptosis induction following the treatment of paroxetine was revealed in prostate cancer cells by the increase of sub-G1 population in flow cytometry analysis and a cleavage of procaspase-3 in western blot analysis. Conclusions: A potent SSRI, paroxetine, induces growth inhibition and apoptosis in PC cells. These results suggest that SSRIs have the potential of anti-tumor effect against PC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2152. doi:10.1158/1538-7445.AM2011-2152

The Selective Serotonin Reuptake Inhibitor Paroxetine Does Not Alter Consummatory Concentration-Dependent Licking of Prototypical Taste Stimuli by Rats

Serotonin and the 5HT(1A) receptor are expressed in a subset of taste receptor cells, and the 5HT(3) receptor is expressed on afferent fibers innervating taste buds. Exogenous administration of the selective serotonin reuptake inhibitor, paroxetine, has been shown to increase taste sensitivity to stimuli described by humans as sweet and bitter. Serotonergic agonists also decrease food and fluid intake, and it is possible that modulations of serotonin may alter taste-based hedonic responsiveness; alternatively, or in combination, serotonin may interact with physiological state to impact ingestive behavior. In this study, the unconditioned licking of prototypical taste stimuli by rats in brief-access taste tests was assessed following paroxetine administration (0.3-10 mg/kg intraperitoneal). We also measured sucrose licking by rats in different deprivation states after paroxetine (5 mg/kg). In neither experiment did we find any evidence of an effect of paroxetine on licking relative to water to any of the taste stimuli in the brief-access test at doses that decreased food intake. However, in some conditions, paroxetine decreased trials initiated to tastants. Therefore, a systemic increase in serotonin via paroxetine administration can decrease appetitive behavior in brief-access tests but is insufficient to alter taste-guided consummatory behavior.

Functional magnetic resonance imaging study on the effects of acute single administration of paroxetine on motivation‐related brain activity

The aim of the present study was to investigate the effects of acute paroxetine administration on brain activity related to motivation. Sixteen healthy subjects participated in a randomized, single-blind, no-drug/placebo-controlled, cross-over study. After administration of no drug, placebo or paroxetine (selective serotonin reuptake inhibitor; 20 mg), subjects underwent functional magnetic resonance imaging while performing a monetary incentive delay task. We analyzed the differences in brain activities of the reward anticipation/motor preparation period that are subject to motivational modulation. For this purpose, we subdivided the incentive trials on the basis of whether the reaction times (RT) were slower or faster than the subject's mean RT (slow RT and fast RT trials). No drug and placebo showed robust activation differences in the globus pallidus and putamen for the fast RT trials compared to the slow RT trials, whereas paroxetine showed none. Paroxetine showed significantly lower activations in the globus pallidus, insula, putamen and dorsolateral prefrontal cortex compared to no drug in the fast RT trials. Paroxetine single acute administration diminished brain activity induced by motivation in healthy subjects. This may partially explain the increased lack of motivation seen in patients with relatively mild symptoms after taking a dose of paroxetine for the first time.

Effects of selective inhibitors of serotonin reuptake on the anxiety behavior and activity of the pituitary-adrenal system in prenatally stressed male rats

We studied effects of the selective inhibitors of serotonin reuptake fluoxetine and paroxetine, which were orally administered at a dose of 5.0 mg/kg from the 1st to 14th days of postnatal life, on the anxiety behavior and hormonal stress reactivity of mature prenatally stressed male rats. We found that prenatal stress decreased the anxiety level in mature male rats. Chronic treatment with paroxetine did not the alter the anxiety behavior of prenatally stressed males. In contrast, treatment with fluoxetine had an anxiogenic effect on their behavior, canceling the effect of prenatal stress on the anxiety behavior of male rats. Prenatal stress considerably affected the dynamics of the stress response of the pituitary-adrenal system, which was seen as disturbances in the regulation of system feedback under conditions of stress-induced activation. Chronic administration of paroxetine or fluoxetine corrected the dynamics of stress-induced levels of corticosterone in the blood of prenatally stressed males.

Characterization of 5-HT1A/1B−/− mice: An animal model sensitive to anxiolytic treatments

Selective serotonin (5-HT) re-uptake inhibitors (SSRIs) are commonly used in the treatment of generalized anxiety disorder in Humans. However, because only few animal models display overt anxious-like behavior, detailed preclinical studies of the anxiolytic properties of antidepressants are still lacking. Here, we studied the neurochemical and behavioral effects of a double 5-HT1A/1B receptor knockout in mice (5-HT1A/1B−/−) as compared to their wild-type littermates (5-HT1A/1B+/+). It is known that single deletion of either 5-HT1A or 5-HT1B receptor induces behavioral changes that are not correlated with differences in brain serotonergic tone. Deletion of both receptors resulted in (i) higher emotionality of animals, as observed in three unconditioned paradigms of anxiety (open field, elevated plus maze and novelty suppressed feeding tests); (ii) a ≈200% increase in the mean spontaneous firing rate of 5-HT neurons in the dorsal raphe nucleus (DRN) compared to 5-HT1A/1B+/+ mice; (iii) elevated basal dialysate levels of 5-HT in the DRN and frontal cortex; (iv) an exaggerated response to acute paroxetine administration in microdialysis experiments, and (v) increased basal core body temperature. These findings suggest that the deletion of both autoreceptors induces a strong anxious-like behavioral state associated with increased 5-HT neurotransmission. Interestingly, 5-HT1A/1B−/− mice are still sensitive to the acute administration of diazepam. Moreover, while deletion of both receptors impacted on the response to acute SSRI treatment in the forced swim test, anxiolytic-like effects of a chronic SSRI treatment were still observed in 5-HT1A/1B−/− mice. Thus, the 5-HT1A/1B−/− mouse model could be of great interest to unveil the mechanisms of action of the anxiolytic effects of SSRIs.

Human ETHER-A-Go-Go-Related Gene (HERG) K + Channel Inhibition by the Antidepressant Paroxetine

Paroxetine is a selective serotonin reuptake inhibitor (SSRI) for psychiatric disorders that can induce QT prolongation, which may lead to torsades de pointes. We studied the effects of paroxetine on human ether-a-go-go-related gene (hERG) channels expressed in Xenopus oocytes and on action potential in guinea pig ventricular myocytes. The hERG encodes the pore-forming subunits of the rapidly-activating delayed rectifier K+ channel (Ikr) in the heart. Mutations in hERG reduce Ikr and cause type 2 long QT syndrome (LQT2), a disorder that predisposes individuals to life-threatening arrhythmias. Paroxetine induced concentration-dependent decreases in the current amplitude at the end of the voltage steps and hERG tail currents. The inhibition was concentration-dependent and time-dependent, but voltage-independent during each voltage pulse. The S6 domain mutation Y652A did not affect the drug-induced hERG current block. In guinea-pig ventricular myocytes held at 36°C, treatment with 0.4 μM paroxetine for 5 min decreased the action potential duration at 90% of repolarization (APD90) by 4.3%. Our results suggest that paroxetine is a blocker of the hERG channels, providing a molecular mechanism for the arrhythmogenic side effects during the clinical administration of paroxetine.

Elevated central serotonin levels inhibit emotional crying

AbstractPrevious research has suggested a possible role of serotonin in emotional expressions, such as crying. We have found that a transient increase of central serotonin levels by means of oral administration of paroxetine reduces crying in response to emotional movies in healthy female volunteers. This is the first direct evidence of an important role of serotonin in this uniquely human emotional response.

Evaluation of Krebs cycle enzymes in the brain of rats after chronic administration of antidepressants

Several works report brain impairment of metabolism as a mechanism underlying depression. Citrate synthase and succinate dehydrogenase are enzymes localized within cells in the mitochondrial matrix and are important steps of Krebs cycle. In addition, citrate synthase has been used as a quantitative enzyme marker for the presence of intact mitochondria. Thus, we investigated citrate synthase and succinate dehydrogenase activities from rat brain after chronic administration of paroxetine, nortriptiline and venlafaxine. Adult male Wistar rats received daily injections of paroxetine (10 mg/kg), nortriptiline (15 mg/kg), venlafaxine (10 mg/kg) or saline in 1.0 mL/kg volume for 15 days. Twelve hours after the last administration, the rats were killed by decapitation, the hippocampus, striatum and prefrontal cortex were immediately removed, and activities of citrate synthase and succinate dehydrogenase were measured. We verified that chronic administration of paroxetine increased citrate synthase activity in the prefrontal cortex, hippocampus, striatum and cerebral cortex of adult rats; cerebellum was not affected. Chronic administration of nortriptiline and venlafaxine did not affect the enzyme activity in these brain areas. Succinate dehydrogenase activity was increased by chronic administration of paroxetine and nortriptiline in the prefrontal cortex, hippocampus, striatum and cerebral cortex of adult rats; cerebellum was not affected either. Chronic administration of venlafaxine increased succinate dehydrogenase activity in prefrontal cortex, but did not affect the enzyme activity in cerebellum, hippocampus, striatum and cerebral cortex. Considering that metabolism impairment is probably involved in the pathophysiology of depressive disorders, an increase in these enzymes by antidepressants may be an important mechanism of action of these drugs.

The role of the striatum in compulsive behavior in intact and orbitofrontal-cortex-lesioned rats: possible involvement of the serotonergic system.

In the signal attenuation rat model of obsessive-compulsive disorder (OCD), 'compulsive' behavior is induced by attenuating a signal indicating that a lever-press response was effective in producing food. We have recently found that lesions to the rat orbitofrontal cortex (OFC) led to an increase in compulsive lever-pressing that was prevented by systemic administration of the selective serotonin reuptake inhibitor paroxetine, and paralleled by an increase in the density of the striatal serotonin transporter. This study further explored the interaction between the OFC, the striatum, and the serotonergic system in the production of compulsive lever-pressing. Experiment 1 revealed that OFC lesions decrease the content of serotonin, dopamine, glutamate, and GABA in the striatum. Experiment 2 showed that intrastriatal administration of paroxetine blocked OFC lesion-induced increased compulsivity, but did not affect compulsive responding in intact rats. Experiments 3 and 4 found that pre-training striatal lesions had no effect on compulsive lever-pressing, whereas post-training striatal inactivation exerted an anticompulsive effect. These results strongly implicate the striatum in the expression of compulsive lever-pressing in both intact and OFC-lesioned rats. Furthermore, the results support the possibility that in a subpopulation of OCD patients a primary pathology of the OFC leads to a dysregulation of the striatal serotonergic system, which is manifested in compulsive behavior, and that antiobsessional/anticompulsive drugs exerts their effects, in these patients, by normalizing the dysfunctional striatal serotonergic system.

Oxazepam and temazepam attenuate paroxetine-induced elevation of serotonin levels in guinea-pig hippocampus

Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are used as a first-line treatment in depression. However, many depressed patients are also treated with benzodiazepines to alleviate increased anxiety and sleep disturbances normally associated with depression. Since benzodiazepines inhibit 5-HT neuronal firing activity, they might attenuate SSRI-induced increase in extracellular 5-HT levels. This study aimed to assess, using in-vivo microdialysis, the effects of the benzodiazepines oxazepam or temazepan on the SSRI paroxetine-induced 5-HT increase in the hippocampus of freely moving guinea-pigs. It was found that the acute systemic administration of paroxetine increased extracellular 5-HT levels. Pre-administration of oxazepam or temazepam significantly diminished the paroxetine-induced elevation of extracellular 5-HT levels (from 350% to 200% of baseline). It was concluded that benzodiazepines attenuate the ability of SSRIs to elevate hippocampal 5-HT levels. Thus, co-administration of benzodiazepines might affect the therapeutic efficacy of SSRI treatment.

Brain creatine kinase activity is increased by chronic administration of paroxetine

Major depression is a serious and recurrent disorder often manifested with symptoms at the psychological, behavioral, and physiological levels. In addition, several works also suggest brain metabolism impairment as a mechanism underlying depression. Creatine kinase (CK) plays a central role in the metabolism of high-energy consuming tissues such as brain, where it functions as an effective buffering system of cellular ATP levels. Considering that CK plays an important role in brain energy homeostasis and that some antidepressants may modulate energy metabolism, we decided to investigate CK activity from rat brain after chronic administration of paroxetine (selective serotonin reuptake inhibitor), nortriptiline (tricyclic antidepressant) and venlafaxine (selective serotonin–norepinephrine reuptake inhibitor). Adult male Wistar rats received daily injections of paroxetine (10 mg/kg), nortriptiline (15 mg/kg), venlafaxine (10 mg/kg) or saline in 1.0 mL/kg volume for 15 days. Twelve hours after the last administration, the rats were killed by decapitation, the hippocampus, striatum and prefrontal cortex were immediately removed, and activity of CK was measured. Our results demonstrated that chronic administration of paroxetine increased CK activity in the prefrontal cortex, hippocampus and striatum of adult rats. On the other hand, nortriptiline and venlafaxine chronic administration did not affect CK activity in these brain areas. In order to verify whether the effect of paroxetine on CK is direct or indirect, we also measured the in vitro effect of this drug on the activity of the enzyme. We verified that paroxetine did not affect CK activity in vitro. Considering that metabolism impairment is probably involved in the pathophysiology of depressive disorders, an increase in CK activity by antidepressants may be an important mechanism of action of these drugs.

Rapid response to paroxetine is associated with plasma paroxetine levels at 4 but not 8 weeks of treatment, and is independent of serotonin transporter promoter polymorphism in Japanese depressed patients

In the present study, we investigated the relationship between the serotonin transporter gene linked polymorphic regions (5-HTTLPR) or plasma paroxetine levels and clinical response to paroxetine in depressed patients. Sixty patients who met the DSM-IV criteria for major depressive disorder were enrolled in the study. Twenty-two were male and 38 were female, with ages ranging from 25 to 71 (mean +/- SD = 42 +/- 16) years. The clinical improvement of patients was assessed using the Hamilton rating scale for depression (Ham-D) before and every week after paroxetine administration. According to the data reported previously, patients with an at least 50% decrease in their Ham-D score were classified as responders. The results showed that the plasma paroxetine levels at 4 weeks were significantly higher in responders (rapid responders) than in nonresponders. On the other hand, no significant associations were found between the L genotype (L/L, L/S) or S genotype (S/S) and the response rates either at 4 weeks or 8 weeks. These results suggest that patients with higher plasma levels at 4 weeks might respond rapidly to paroxetine treatment, but the final response rate at 8 weeks will be independent of the plasma paroxetine levels and the 5-HTTLPR L/S genotype.

Investigating the Efficacy of Paroxetine in Developmental Stuttering

Paroxetine has been reported to be useful for management of stuttering symptoms, but only a few reports have examined its effects. We have investigated the efficacy of paroxetine in a randomized, placebo-controlled study. Five stuttering subjects received paroxetine at 20 mg once daily at night for 12 weeks, and 5 received placebo. The percentages of stuttered words and stuttering-associated movements during speech were measured at baseline and after 6 and 12 weeks of treatment. Moreover, left primary motor cortex excitability was measured using transcranial magnetic stimulation. Specifically, resting and active motor thresholds and the cortical silent period (CSP) were obtained at the same periods in both groups. Paroxetine did not affect the percentage of stuttered words between groups. Stuttering-associated movements, however, during speech in facial muscular districts were significantly reduced in subjects treated with paroxetine. Finally, paroxetine administration shortened the CSP with no effect on motor thresholds. Paroxetine may be useful in qualitative management of stuttering symptoms and may act on the stuttering brain by diminution of intracortical inhibition, as revealed by the shortening of the CSP after paroxetine administration.

The brain 5‐HT4 receptor binding is down‐regulated in the Flinders Sensitive Line depression model and in response to paroxetine administration

The 5-hydroxytryptamine (5-HT(4)) receptor may be implicated in depression and is a new potential target for antidepressant treatment. We have investigated the brain 5-HT(4) receptor [(3)H]SB207145 binding in the Flinders Sensitive Line rat depression model by quantitative receptor autoradiography, and related this to 5-HT transporter (S)-[N-methyl-(3)H]citalopram binding. We also determined the regulation of 5-HT(4) receptor binding by 1, 14, and 21 days of paroxetine administration and subchronic 5-HT depletion, and compared this with changes in 5-HT(2A) receptor [(3)H]MDL100907 binding. In the Flinders Sensitive Line, the 5-HT(4) receptor and 5-HT transporter binding were decreased in the dorsal and ventral hippocampus, and the changes in binding were directly correlated within the dorsal hippocampus. Chronic but not acute paroxetine administration caused a 16-47% down-regulation of 5-HT(4) receptor binding in all regions evaluated including the basal ganglia and hippocampus, while 5-HT depletion increased the 5-HT(4) receptor binding in the dorsal hippocampus, hypothalamus, and lateral globus pallidus. In comparison, the 5-HT(2A) receptor binding was decreased in the frontal and cingulate cortices after chronic paroxetine administration, and markedly reduced in several regions after 5-HT depletion. Thus, the 5-HT(4) receptor binding was decreased in the Flinders Sensitive Line depression model and in response to chronic paroxetine administration.

Long-term anxiolytic and antidepressant-like behavioural effects of tiagabine, a selective GABA transporter-1 (GAT-1) inhibitor, coincide with a decrease in HPA system activity in C57BL/6 mice

Gamma-aminobutyric acid (GABA) system plays a pivotal role in the pathophysiology of anxiety and mood disorders. This study was aimed to assess the anxiolytic and antidepressant-like properties of tiagabine, an inhibitor of the GABA transporter-1 (GAT-1), after acute and chronic administration in C57BL/6JOlaHsD mice with paroxetine as a positive control. In first experiments, the acute administration of tiagabine (7.5 mg/kg, orally [PO]) and paroxetine (10 mg/kg PO) induced anxiolytic effects in the elevated plus maze test and the modified hole board test and an antidepressant-like effect in the forced swim test. Chronic application of tiagabine (7.5 mg/kg PO) and paroxetine (10 mg/kg PO) for 22 days revealed an anxiolytic and antidepressant-like efficacy of tiagabine only. In a further experiment, we analysed the impact of chronic tiagabine versus paroxetine treatment on the hypothalamic-pituitary-adrenocortical (HPA) system regulation. GAT-1 blockade induced a setpoint-shift of the stress hormone system toward lower levels as indicated by decreased plasma corticosterone concentrations and attenuated gene expression levels of corticotropin-releasing factor in the paraventricular nucleus of the hypothalamus and of hippocampal steroid receptors. This data indicate that both acute and long-term anxiolytic and antidepressant-like properties of brain GAT-1 inhibition coincide with a reduction in HPA system activity in mice.

A pilot study of the effects of chronic paroxetine administration on hippocampal N-acetylaspartate in generalized anxiety disorder

The neural basis of generalized anxiety disorder (GAD) is poorly characterized. The effect of chronic administration (12 weeks) of paroxetine, a selective serotonin reuptake inhibitor, on N-acetylaspartate (NAA), a marker of neuronal viability, was evaluated in adults with GAD using proton magnetic resonance spectroscopic imaging ((1)H MRSI) at 1.5 T. We hypothesized that, pretreatment abnormalities in hippocampal NAA/creatine (NAA/Cr) would normalize with symptomatic improvement. Nine GAD patients (mean age = 41.7 year; 4 females) received 12 weeks of open-label paroxetine treatment, flexibly dosed up to 60 mg/day. Clinical outcome was assessed with the Hamilton Anxiety Rating Scale (HAM-A). Multislice ( 1)H MRSI scans were performed at unmedicated baseline and following 6 and 12 weeks of treatment. Ten untreated healthy volunteers (HVs) (mean age = 37.1 year; 4 females) received scans at the same intervals. All patients achieved remission (HAM-A <or= 7) by week 12. Compared to HVs, GAD patients showed persistently lower levels of bilateral hippocampal NAA/Cr (17.7% mean decrease; Cohen's d = 1.29) that were maintained across all three time points, despite marked symptom improvement. This pilot study failed to support an association between a hippocampal neuronal marker and anxiolytic response to paroxetine, and suggests further investigation of potential trait-like hippocampal abnormalities in GAD.

Antidepressants Inhibit P2X4 Receptor Function: a Possible Involvement in Neuropathic Pain Relief

BackgroundNeuropathic pain is characterized by pain hypersensitivity to innocuous stimuli (tactile allodynia) that is nearly always resistant to known treatments such as non-steroidal anti-inflammatory drugs or even opioids. It has been reported that some antidepressants are effective for treating neuropathic pain. However, the underlying molecular mechanisms are not well understood. We have recently demonstrated that blocking P2X4 receptors in the spinal cord reverses tactile allodynia after peripheral nerve injury in rats, implying that P2X4 receptors are a key molecule in neuropathic pain. We investigated a possible role of antidepressants as inhibitors of P2X4 receptors and analysed their analgesic mechanism using an animal model of neuropathic pain.ResultsAntidepressants strongly inhibited ATP-mediated Ca2+ responses in P2X4 receptor-expressing 1321N1 cells, which are known to have no endogenous ATP receptors. Paroxetine exhibited the most powerful inhibition of calcium influx via rat and human P2X4 receptors, with IC50 values of 2.45 μM and 1.87 μM, respectively. Intrathecal administration of paroxetine produced a striking antiallodynic effect in an animal model of neuropathic pain. Co-administration of WAY100635, ketanserin or ondansetron with paroxetine induced no significant change in the antiallodynic effect of paroxetine. Furthermore, the antiallodynic effect of paroxetine was observed even in rats that had received intrathecal pretreatment with 5,7-dihydroxytryptamine, which dramatically depletes spinal 5-hydroxytryptamine.ConclusionThese results suggest that paroxetine acts as a potent analgesic in the spinal cord via a mechanism independent of its inhibitory effect on serotonin transporters. Powerful inhibition on P2X4 receptors may underlie the analgesic effect of paroxetine, and it is possible that some antidepressants clinically used in patients with neuropathic pain show antiallodynic effects, at least in part via their inhibitory effects on P2X4 receptors.