Effects Of Antidepressant Drugs Research Articles

The effects of antidepressants "fluoxetine and imipramine" on vascular abnormalities and Toll like receptor-4 expression in diabetic and non-diabetic rats exposed to chronic stress.

Several studies reveal that diabetes doubles the odds of comorbid depression with evidence of a pro-inflammatory state underlying its vascular complications. Indeed, little information is available about vascular effects of antidepressant drugs in diabetes. Method: We investigated the effect of chronic administration of fluoxetine “FLU” and imipramine “IMIP” on behavioral, metabolic and vascular abnormalities in diabetic and non-diabetic rats exposed to chronic restraint stress (CRS). Results: Both diabetes and CRS induced depressive-like behavior which was more prominent in diabetic/depressed rats; this was reversed by chronic treatment with FLU and IMIP in a comparable manner. Diabetic and non-diabetic rats exposed to CRS exhibited abnormalities in glucose homeostasis, lipid profile and vascular function, manifested by decreased endothelium-dependent relaxation, increased systolic blood pressure and histopathological atherosclerotic changes. Vascular and metabolic dysfunctions were associated with significant increase in aortic expression of TLR-4, and pro-inflammatory cytokines (TNF-α and IL-1ß). FLU ameliorated these metabolic, vascular and inflammatory abnormalities, while IMIP induced either no change or even worsening of some parameters. Conclusion: FLU has favorable effect over IMIP on metabolic, vascular and inflammatory aberrations associated with DM and CRS in Wistar rats, clarifying the preference of FLU over IMIP in management of comorbid depression in diabetic subjects.

BDNF-TRKB signaling system of the dorsal periaqueductal gray matter is implicated in the panicolytic-like effect of antidepressant drugs

A wealth of evidence implicates the BDNF-TRKB system in the therapeutic effects of antidepressant drugs (ADs) on mood disorders. However, little is known about the involvement of this system in the panicolytic property also exerted by these compounds. In the present study we evaluated the participation of the BDNF-TRKB system of the dorsal periaqueductal gray matter (DPAG), a core structure involved in the pathophysiology of panic disorder, in AD-induced panicolytic-like effects in rats. The results showed that short- (3 days) or long-term (21 days) systemic treatment with the tricyclic ADs imipramine, clomipramine or desipramine increased BDNF levels in the DPAG. Only longterm treatment with the selective serotonin reuptake inhibitor fluoxetine was able to increase BDNF levels in this structure. After 21-day treatment, fluoxetine and the three tricyclic ADs used also increased BDNF concentration in the hippocampus, a key area implicated in their mood-related actions. Neither in the DPAG nor hippocampus did long-term treatment with the standard anxiolytics diazepam, clonazepam or buspirone affect BDNF levels. Imipramine, both after short and long-term administration, and fluoxetine under the latter regimen, raised the levels of phosphorylated TRKB in the DPAG. Short-term treatment with imipramine or BDNF microinjection inhibited escape expression in rats exposed to the elevated T maze, considered as a panicolytic-like effect. This anti-escape effect was attenuated by the intra-DPAG administration of the TRK receptor antagonist k252a. Altogether, our data suggests that facilitation of the BDNF-TRKB system in the DPAG is implicated in the panicolytic effect of ADs.

Advance in studies on natural antidepressant drugs and cytochrome P450

In the fast pace of modern life and under the heavy work pressure, the prevalence of depression has increased year by year. Meanwhile, the demands for antidepressant drugs have also grown, especially the high-efficiency and low-toxicity natural antidepressant drugs, mainly including polyphenols, flavonoids, organic acids, alkaloids and terpenoids. Cytochrome P450 (CYP450) is a type of enzymes involving oxidative metabolism of drugs in vivo, and can change the pharmacokinetics and efficacy of drugs. Therefore, it is of important significant to define the effect of natural antidepressant drugs on CYP450 in human bodies, in order to improve the rational clinical medication, avoid drug interactions and reduce adverse reactions.

Effect of antidepressant drugs on the vmPFC-limbic circuitry

Our recent study indicates that the lesions of the prefrontal cortex in rats result in depressive-like behavior in forced swim test and REM sleep alterations, two well-established biomarkers of depression disorder. We hypothesized that antidepressants may target the PFC to reverse depression. Systemic injections of antidepressants: the tricyclic antidepressant desipramine (DMI), the selective serotonin reuptake inhibitor fluoxetine, and the NMDA-antagonist ketamine selectively increased cFos expression (a marker of neuronal activity) in the deep layers of the ventromedial PFC (vmPFC) in rats. Of the vmPFC's limbic system targets, only the nucleus accumbens (NAc) was also activated by DMI. Using a retrograde tracer and a neuronal toxin, we also found that DMI-activated vmPFC neurons project to the NAc and that NAc activation by DMI was lost following vmPFC lesion. These results suggest that the vmPFC may be an essential target of antidepressant drugs, its projections to the NAc may be a key circuit regulating antidepressant action, and dysfunction of this pathway may contribute to depression.

Study of the effect of antidepressant drugs and donepezil on aluminum-induced memory impairment and biochemical alterations in rats

Alzheimer’s disease is the leading cause of dementia in the elderly. Depression is a common psychiatric disorder affecting individuals across life span and often arises in the context of pre-dementia, dementia, and Alzheimer’s disease. The present study aimed to investigate the effects of the antidepressant drugs clomipramine (14.2 and 56.9 μmol/kg), fluoxetine (14.5 and 57.8 μmol/kg), and sertraline (14.6 and 58.4 μmol/kg) compared with acetylcholinesterase inhibitor donepezil (12 μmol/kg) on oxidative stress, memory impairment, and depressant-like behavior in a model of Alzheimer’s disease induced by prolonged intraperitoneal administration of aluminum chloride (AlCl3) (10 mg/kg/day for 60 days) in rats. Results indicated that the latency to find the hidden platform in Morris water maze (MWM) test increased by 100 %, while the immobility duration in forced swimming test (FST) increased by 51 % in AlCl3-treated rats. The administration of AlCl3 resulted in increased brain malondialdehyde (MDA) by 58.6 % and nitric oxide (nitrite) concentrations by 71.7 %, while reduced glutathione (GSH) decreased by 35.6 % compared with the vehicle-treated group. Catalase and paraoxonase 1 (PON1) activities in the brain decreased by 41.8 and 18.3 %, respectively. Serum acetylcholinesterase (AChE) increased by 47.8 % and brain butyrylcholinesterase (BuChE) decreased by 23.1 % after AlCl3 treatment. In AlCl3-treated rats, memory performance in the MWM test improved following donepezil and the highest dose of clomipramine, fluoxetine, and sertraline. The immobility duration in the FST was decreased by sertraline. Significant decrease in brain MDA occurred after treatment with clomipramine, fluoxetine, and a lower dose of sertraline. Reduced glutathione level increased by donepezil, clomipramine, and 57.8 μmol/kg fluoxetine. The level of nitric oxide decreased by donepezil (42.6 %), clomipramine (45.0 and 62.9 %), fluoxetine (21.9 and 40.9 %), and 14.6 μmol/kg sertraline (28.7 %). Catalase activity was restored by donepezil, fluoxetine, and sertraline and markedly increased by 56.9 μmol/kg clomipramine. Paraoxonase 1 activity was increased by 14.2 μmol/kg clomipramine. BuChE activity was unaltered, but AChE activity was decreased by donepezil, clomipramine, and fluoxetine compared with the AlCl3 control group. AlCl3 resulted in neurodegeneration (gliosis), extensive dark neurons with corkscrew dendrites, and degeneration of some Purkinje cell. Following donepezil treatment, no dark neurons were observed, while increased granular cell layer was observed after the administration of a high dose of clomipramine, fluoxetine, or sertraline. The results suggested that in rats treated with AlCl3, (i) donepezil, sertraline, clomipramine, and fluoxetine improve memory performance; (ii) sertraline was particularly effective in improving depressive-like behavior in this model and might be of value in the treatment of depressive symptoms associated with Alzheimer’s disease; (iii) donepezil, clomipramine, and fluoxetine alleviated oxidative stress; and (iv) neurodegeneration in this model could be modulated by antidepressant drugs and donepezil.

Neurodevelopmental outcome for offspring of women treated for antenatal depression: a systematic review.

The aim of this systematic review is to appraise existing literature on the effects of treatments for antenatal depression on the neurodevelopment outcomes of the offspring. We conducted a systematic review of the literature to identify studies on different kinds of treatments for antenatal depression (antidepressants and alternative therapies) and their effects on infants’ neurodevelopment. After reading the title, abstract, or full text and applying exclusion criteria, a total of 22 papers were selected. Nineteen papers studied the effects of antidepressant drugs, one on docosahexanoic acid (DHA) (fish oil capsules) and two on massage therapy; however, no studies used a randomized controlled design, and in most studies, the control group comprise healthy women not exposed to depression. Comparisons between newborns exposed to antidepressants in utero with those not exposed showed significant differences in a wide range of neurobehavioral outcomes, although in many cases, these symptoms were transient. Two studies found a slight delay in psychomotor development, and one study found a delay in mental development. Alternative therapies may have some benefits on neurodevelopmental outcomes. Our review suggests that antidepressant treatment may be associated with some neurodevelopmental changes, but we cannot exclude that some of these effects may be due to depression per se.

Antidepressant treatment for postnatal depression.

Antidepressant treatment for postnatal depression.

Effect of genetic and pharmacological blockade of GABA receptors on the 5-HT2C receptor function during stress.

Serotonin (5-HT)2C receptors play a role in psychoaffective disorders and often contribute to the antidepressant and anxiolytic effects of psychotropic drugs. During stress, activation of these receptors exerts a negative feedback on 5-HT release, probably by increasing the activity of GABAergic interneurons. However, to date, the GABA receptor types that mediate the 5-HT2C receptor-induced feedback inhibition are still unknown. To address this question, we assessed the inhibition of 5-HT turnover by a 5-HT2C receptor agonist (RO 60-0175) at the hippocampal level and under conditions of stress, after pharmacological or genetic inactivation of either GABA-A or GABA-B receptors in mice. Neither the GABA-B receptor antagonist phaclofen nor the specific genetic ablation of either GABA-B1a or GABA-B1b subunits altered the inhibitory effect of RO 60-0175, although 5-HT turnover was markedly decreased in GABA-B1a knock-out mice in both basal and stress conditions. In contrast, the 5-HT2C receptor-mediated inhibition of 5-HT turnover was reduced by the GABA-A receptor antagonist bicuculline. However, a significant effect of 5-HT2C receptor activation persisted in mutant mice deficient in the α3 subunit of GABA-A receptors. It can be inferred that non-α3 subunit-containing GABA-A receptors, but not GABA-B receptors, mediate the 5-HT2C -induced inhibition of stress-induced increase in hippocampal 5-HT turnover in mice.

Mice genetically depleted of brain serotonin do not display a depression-like behavioral phenotype.

Reductions in function within the serotonin (5HT) neuronal system have long been proposed as etiological factors in depression. Selective serotonin reuptake inhibitors (SSRIs) are the most common treatment for depression, and their therapeutic effect is generally attributed to their ability to increase the synaptic levels of 5HT. Tryptophan hydroxylase 2 (TPH2) is the initial and rate-limiting enzyme in the biosynthetic pathway of 5HT in the CNS, and losses in its catalytic activity lead to reductions in 5HT production and release. The time differential between the onset of 5HT reuptake inhibition by SSRIs (minutes) and onset of their antidepressant efficacy (weeks to months), when considered with their overall poor therapeutic effectiveness, has cast some doubt on the role of 5HT in depression. Mice lacking the gene for TPH2 are genetically depleted of brain 5HT and were tested for a depression-like behavioral phenotype using a battery of valid tests for affective-like disorders in animals. The behavior of TPH2(-/-) mice on the sucrose preference test, tail suspension test, and forced swim test and their responses in the unpredictable chronic mild stress and learned helplessness paradigms was the same as wild-type controls. While TPH2(-/-) mice as a group were not responsive to SSRIs, a subset responded to treatment with SSRIs in the same manner as wild-type controls with significant reductions in immobility time on the tail suspension test, indicative of antidepressant drug effects. The behavioral phenotype of the TPH2(-/-) mouse questions the role of 5HT in depression. Furthermore, the TPH2(-/-) mouse may serve as a useful model in the search for new medications that have therapeutic targets for depression that are outside of the 5HT neuronal system.

Effect of Noise and Crowding Stresses on Hypothalamic–Pituitary–Gonadal Axis and Protective Effect of Sulpiride Drug in Adult Female Albino Rats

Background: Noise and crowdingare the most stressful factors which cause depressant effects on human beings, especially females.Therfore this study was aimed at clarifying their effects on hypothalamus pituitary gonadal axis hormones (luteinizing hormone (LH) and follicle-stimulating hormone (FSH), estrogen (E2)and progesterone as well as prolactin (PRL)and the possible protective effect of antidepressant drug;sulpiride. Material and Methods: Sixty adult female rats were divided into six groups (10/each): 1- Rats served ascontrol, 2- Rats treated with sulpiride drug only, 3- Rats exposed to noise (90db, 3hr. per day) for 45 days, 4- Rats exposed to noise and treated with sulpiride drug, 5- Rats exposed to crowding and 6- Rats exposed to crowding and treated with sulpiride drug. Results: Noise and crowding stresses caused a significant decrease of estrogen (E2), progesterone (P), LH and FSH levels and high significant increase in PRL level. Sulpiride drug ameliorated these parameters changes except PRL level which showed a high significant level compared to control group. Conclusion: it is useful to use antidepressant drug (e.g. sulpiride) with people who are exposing to noise and crowding stress.

Effect of Noise and Crowding Stresses on Hypothalamic–Pituitary–Gonadal Axis and Protective Effect of Sulpiride Drug in Adult Female Albino Rats

Background: Noise and crowdingare the most stressful factors which cause depressant effects on human beings, especially females.Therfore this study was aimed at clarifying their effects on hypothalamus pituitary gonadal axis hormones (luteinizing hormone (LH) and follicle-stimulating hormone (FSH), estrogen (E2)and progesterone as well as prolactin (PRL)and the possible protective effect of antidepressant drug;sulpiride. Material and Methods: Sixty adult female rats were divided into six groups (10/each): 1- Rats served ascontrol, 2- Rats treated with sulpiride drug only, 3- Rats exposed to noise (90db, 3hr. per day) for 45 days, 4- Rats exposed to noise and treated with sulpiride drug, 5- Rats exposed to crowding and 6- Rats exposed to crowding and treated with sulpiride drug. Results: Noise and crowding stresses caused a significant decrease of estrogen (E2), progesterone (P), LH and FSH levels and high significant increase in PRL level. Sulpiride drug ameliorated these parameters changes except PRL level which showed a high significant level compared to control group. Conclusion: it is useful to use antidepressant drug (e.g. sulpiride) with people who are exposing to noise and crowding stress.

Differential effects of antidepressant drugs on mTOR signalling in rat hippocampal neurons.

Recent studies suggest that ketamine produces antidepressant actions via stimulation of mammalian target of rapamycin (mTOR), leading to increased levels of synaptic proteins in the prefrontal cortex. Thus, mTOR activation may be related to antidepressant action. However, the mTOR signalling underlying antidepressant drug action has not been well investigated. The aim of the present study was to determine whether alterations in mTOR signalling were observed following treatment with antidepressant drugs, using ketamine as a positive control. Using Western blotting, we measured changes in the mTOR-mediated proteins and synaptic proteins in rat hippocampal cultures. Dendritic outgrowth was determined by neurite assay. Our findings demonstrated that escitalopram, paroxetine and tranylcypromine significantly increased levels of phospho-mTOR and its down-stream regulators (phospho-4E-BP-1 and phospho-p70S6K); fluoxetine, sertraline and imipramine had no effect. All drugs tested increased up-stream regulators (phospho-Akt and phospho-ERK) levels. Increased phospho-mTOR induced by escitalopram, paroxetine or tranylcypromine was significantly blocked in the presence of specific PI3K, MEK or mTOR inhibitors, respectively. All drugs tested also increased hippocampal dendritic outgrowth and synaptic proteins levels. The mTOR inhibitor, rapamycin, significantly blocked these effects on escitalopram, paroxetine and tranylcypromine whereas fluoxetine, sertraline and imipramine effects were not affected. The effects of escitalopram, paroxetine and tranylcypromine paralleled those of ketamine. This study presents novel in vitro evidence indicating that some antidepressant drugs promote dendritic outgrowth and increase synaptic protein levels through mTOR signalling; however, other antidepressant drugs seem to act via a different pathway. mTOR signalling may be a promising target for the development of new antidepressant drugs.

Desvenlafaxine may accelerate neuronal maturation in the dentate gyri of adult male rats.

Adult hippocampal neurogenesis has been linked to the effects of anti-depressant drugs on behavior in rodent models of depression. To explore this link further, we tested whether the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine impacted adult hippocampal neurogenesis differently than its primary active SNRI metabolite desvenlafaxine. Adult male Long Evans rats (n = 5–6 per group) were fed vehicle, venlafaxine (0.5 or 5 mg) or desvenlafaxine (0.5 or 5 mg) twice daily for 16 days. Beginning the third day of drug treatment, the rats were given a daily bromodeoxyuridine (BrdU; 50 mg/kg) injection for 5 days to label dividing cells and then perfused 2 weeks after the first BrdU injection to confirm total new hippocampal cell numbers and their phenotypes. The high desvenlafaxine dose increased total new BrdU+ cell number and appeared to accelerate neuronal maturation because fewer BrdU+ cells expressed maturing neuronal phenotypes and more expressed mature neuronal phenotypes in the dentate gyri of these versus vehicle-treated rats. While net neurogenesis was not increased in the dentate gyri of rats treated with the high desvenlafaxine dose, significantly more mature neurons were detected. Our data expand the body of literature showing that antidepressants impact adult neurogenesis by stimulating NPC proliferation and perhaps the survival of neuronal progeny and by showing that a high dose of the SNRI antidepressant desvenlafaxine, but neither a high nor low venlafaxine dose, may also accelerate neuronal maturation in the adult rat hippocampus. These data support the hypothesis that hippocampal neurogenesis may indeed serve as a biomarker of depression and the effects of antidepressant treatment, and may be informative for developing novel fast-acting antidepressant strategies.

Inhibition of serotonin reuptake by antidepressants and cerebral microbleeds in the general population.

Serotonin reuptake inhibiting antidepressants decrease platelet aggregation. This may cause an increased risk of intracerebral hemorrhage. However, the risk of subclinical microbleeds, which are highly prevalent in middle-aged and elderly people, is unknown. We studied whether serotonin reuptake inhibiting antidepressants increase the frequency of cerebral microbleeds and secondarily whether they lower the presence of ischemic vascular damage. Within the population-based Rotterdam Study, information on antidepressant use was obtained from continuously monitored pharmacy records. Brain MRI was available in 4945 participants (55% women, mean age 64 years) between 2005 and 2011. We categorized antidepressants based on affinity for the serotonin transporter: high, intermediate, or low. Microbleeds (presence and location) and ischemic lesions (lacunes, white matter lesions) were rated on MRI. Logistic and linear regression, adjusted for age, sex, depressive symptoms, and cardiovascular risk were used to study the association of antidepressants with microbleeds and ischemic vascular lesions. Antidepressant use with strong serotonin reuptake inhibition was not associated with microbleed presence (odds ratio compared with nonuse, 1.03; confidence interval, 0.75-1.39) irrespective of microbleed location in the brain. Exclusion of antithrombotic users or persons with cortical infarcts did not change our results. Furthermore, serotonin reuptake inhibition was not related to ischemic vascular brain damage. In the general population, use of serotonin reuptake inhibiting antidepressants is not related to presence of cerebral microbleeds. This strengthens the idea that the platelet inhibitor effects of antidepressant drugs with affinity for serotonin are minimal and further supports the safety of selective serotonin reuptake inhibitors for nongastrointestinal bleedings.

The antidepressant tranylcypromine alters cellular proliferation and migration in the adult goldfish brain.

The goldfish (Carassius auratus) is a widely studied vertebrate model organism for studying cell proliferation in the adult brain, and provide the experimental advantage of growing their body and brain throughout their ∼30-year life time. Cell proliferation occurs in the teleost brain in widespread proliferation zones. Increased cell proliferation in the brain has been linked to the actions of certain antidepressants, including tranylcypromine (TCP), which is used in the treatment of depression. We hypothesized that proliferation zones in the adult goldfish brain can be used to determine the antidepressant effects on cellular proliferation. Here, we report that bromodeoxyuridine (BrdU) labeling over a 24-hr period can be used to rapidly identify the proliferation zones throughout the goldfish brain, including the telencephalon, diencephalon, optic tectal lobes, cerebellum, and facial and vagal lobes. In the first 24 hr of BrdU administration, TCP caused an approximate and significant doubling of labeled cells in the combined brain regions examined, as detected by BrdU immunohistochemistry. TCP caused the greatest increase in cell proliferation in the cerebellum. The normal migratory paths of the proliferating cells within the cerebellum were not affected by TCP treatment. These results indicate that the goldfish provide significant advantages as a vertebrate model for rapidly investigating the effects of antidepressant drugs on cellular proliferation and migration in the normal and injured brain.

MAPK signaling correlates with the antidepressant effects of ketamine

Studies have pointed to a relationship between MAPK kinase (MEK) signaling and the behavioral effects of antidepressant drugs. So, in the present study we examined the behavioral and molecular effects of ketamine, an antagonist of the N-methyl-d-aspartate receptor (NMDA), which has been shown to have an antidepressant effect after the inhibition of MEK signaling in Wistar rats. Our results showed that acute administration of the MEK inhibitor PD184161, produced depressive-like behavior and stopped antidepressant-like effects of ketamine in the forced swimming test. The phosphorylation of extracellular signal-regulated kinase 1/2 (pERK 1/2) was decreased by PD184161 in the amygdala and nucleus accumbens, and the effects of ketamine on pERK 1/2 in the prefrontal cortex and hippocampus were inhibited by PD184161. The ERK 2 levels were decreased by PD184161 in the nucleus accumbens; and the effects of ketamine were blocked in this brain area. The p38 protein kinase (p38MAPK) and proBDNF were inhibited by PD184161, and the MEK inhibitor prevented the effects of ketamine in the nucleus accumbens. In addition, ketamine increased pro-BDNF levels in the hippocampus. In conclusion, our findings demonstrated that an acute blockade of MAPK signaling lead to depressive-like behavior and stopped the antidepressant response of ketamine, suggesting that the effects of ketamine could be mediated, at least in part, by the regulation of MAPK signaling in these specific brain areas.

P.1.017 Isoflurane anesthesia rapidly activates TrkB receptor signaling and produces antidepressant-like behavioral effects

Purpose of the study: Emerging evidence suggests that induction of TrkB signaling and the subsequent changes in synaptic plasticity are involved in the therapeutic effects of antidepressant drugs, including rapid-acting antidepressant ketamine [1]. Intriguingly, isoflurane, a commonly used volatile anesthetic, has been shown to produce rapid antidepressant effects in treatment resistant depressive patients [2]. The mechanism of isoflurane’s antidepressant action, however, is completely unknown. We have here investigated the effects of isoflurane anesthesia on TrkB activation and on its downstream signaling pathways related to synaptogenesis and neuronal plasticity. Furthermore, we have studied the effects of single isoflurane treatment on cortical spine formation and morphology, hippocampal long-term potentiation and antidepressant-like behavior in mice. Methods: Adult mice were anesthetized with isoflurane (maximum 30min). For biochemical experiments the animals were killed during the anesthesia or after described recovery period. Hippocampus and prefrontal cortex were dissected out and protein and mRNA levels were analysed using western blotting/ELISA and qPCR, respectively. For electrophysiological recordings mice were decapitated by guillotine 24 h after isoflurane treatment. Parasagittal 400mm hippocampal slices were cut using vibroslicer. Field excitatory potentials (fEPSP) were evoked in Schaffer collateral pathway of the hippocampal slices and LTP was induced by 100 Hz tetanic stimulation. For spine density analysis animals expressing YFP in a subset of cortical layer V pyramidal neurons were perfused with PFA 24 hours after isoflurane treatment. Brains were extracted and 70mm sections were cut using a vibratome. Immunohistochemistry was performed to enhance the fluorescence and sections were analyzed using confocal microscope. Isoflurane-induced antidepressantlike behavior in the forced swim test was monitored 15 minutes and 2 weeks after anesthesia. Results: Isoflurane anesthesia (30min) increased TrkB phosphorylation and its downstream signaling related to neuronal plasticity (pCREB, pAkt) and to synaptogenesis (pmTOR, pP70S6k) in the mouse hippocampus and prefrontal cortex but BDNF protein and mRNA levels remained unaltered. Increased pTrkB, pCREB and pmTOR levels were detected already within 2 minutes from isoflurane treatment onset. Isoflurane’s effects on TrkB signaling could not be blocked with pre-treatment of AMPA receptor blocker NBQX (10mg/kg, ip). LTP was facilitated in hippocampal slices obtained from mice treated with isoflurane 24 h before but any change in cortical spine density and morphological types could not be observed. A single isoflurane anesthesia led to rapid antidepressant-like behavioral effect in the forced swim test that persisted for at least 2 weeks. Conclusions: We show that isoflurane anesthesia rapidly activates TrkB neurotrophin signaling in the mouse brain. This phenomenon is followed by antidepressantlike behavioral responses and facilitation of LTP but not by changes in spine formation or morphology. The biochemical, functional and behavioral effects of isoflurane partially resemble those of rapid-acting antidepressant ketamine. Our findings may provide the neurobiological basis for the previously observed rapid antidepressant effect of isoflurane narcotherapy and encourage investigating further the therapeutic potential of isoflurane.

Are Both Antidepressant Drug Effects and Test Scores Unspecific?

Are Both Antidepressant Drug Effects and Test Scores Unspecific? Background: Disappointingly small clinical effects of antidepressant drugs have recently been reemphasized. It is also unclear to what degree the 17 questions in the Hamilton Rating Scale of Depression and other questionnaires represent true aspects of depression or rather can be said to measure unspecific symptoms. Methods: Within all clinical study reports concerning citalopram submitted to the Danish Health Authorities before registration in 1988 we identified among 49 studies two studies with placebo groups reporting individual patient scores. A multiple regression analysis was performed by treating questionnaire item no 1 (depressed mood) as the dependent variable and the scores for all other items as potentially explanatory variables. The questionnaire items were sorted in two groups: items with p-value less than 0.05 considered related to depression and items with p-value above 0.05 considered unrelated. By pooling the data together we performed an analysis of the effect size (standardized differences in means; citalopram versus placebo treatment, baseline score minus end score) for each of the two questionnaire groups, as well as for the total HAM-D 17 score.

Effects of a polypeptide drug—XMT on depression mouse models

Objective To study the antidepressant effect of a polypeptide drugs—XMT. Methods Using the suspension test, forced swim test,5-hydroxy-L-tryptophan( 5-HTP) induced head twitch response test and yohimbine induced lethality test in mice,the antidepressant effect and the possible mechanisms of XMT were measured. Results In the tail suspension test,repeated administration( 0. 3-10 mg/kg,sc) with XMT for 5 d reduced the immobility time in mice( P 0. 05 vs the normal saline control). XMT( 0. 3-5. 0 mg / kg,sc for 5 d) can reduced the immobility time in the forced swim test in mice( P 0. 05 vs the normal saline control),while there was no central stimulated effect during the effective doses( 0. 3-5. 0 mg / kg). Furthermore,XMT in repeated doses( 5. 0 and 1. 0 mg / kg,sc for 5 d) decreased the 5-HTP induced head twitch response in mice( P 0. 01,P 0. 05 vs the normal saline control), while it had no effect on the yohimbine toxicity( P 0. 05 vs the normal saline control). Conclusion XMT has antidepressant effect which may be related to the property of inhibition the 5-HT2 receptor,etc.

Effects of antidepressant drugs on synaptic protein levels and dendritic outgrowth in hippocampal neuronal cultures

The alteration of hippocampal plasticity has been proposed to play a critical role in both the pathophysiology and treatment of depression. In this study, the ability of different classes of antidepressant drugs (escitalopram, fluoxetine, paroxetine, sertraline, imipramine, tranylcypromine, and tianeptine) to mediate the expression of synaptic proteins and dendritic outgrowth in rat hippocampal neurons was investigated under toxic conditions induced by B27 deprivation, which causes hippocampal cell death. Postsynaptic density protein-95 (PSD-95), brain-derived neurotrophic factor (BDNF), and synaptophysin (SYP) levels were evaluated using Western blot analyses. Additionally, dendritic outgrowth was examined to determine whether antidepressant drugs affect the dendritic morphology of hippocampal neurons in B27-deprived cultures. Escitalopram, fluoxetine, paroxetine, sertraline, imipramine, tranylcypromine, and tianeptine significantly prevented B27 deprivation-induced decreases in levels of PSD-95, BDNF, and SYP. Moreover, the independent application of fluoxetine, paroxetine, and sertraline significantly increased levels of BDNF under normal conditions. All antidepressant drugs significantly increased the total outgrowth of hippocampal dendrites under B27 deprivation. Specific inhibitors of calcium/calmodulin kinase II (CaMKII), KN-93, protein kinase A (PKA), H-89, or phosphatidylinositol 3-kinase (PI3K), LY294002, significantly decreased the effects of antidepressant drugs on dendritic outgrowth, whereas this effect was observed only with tianeptine for the PI3K inhibitor. Taken together, these results suggest that certain antidepressant drugs can enhance synaptic protein levels and encourage dendritic outgrowth in hippocampal neurons. Furthermore, effects on dendritic outgrowth likely require CaMKII, PKA, or PI3K signaling pathways. The observed effects may be may be due to chronic treatment with antidepressant drugs.