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Major depressive disorder (MDD) is the leading cause of disability worldwide. Treatment with antidepressant drugs (ATD), which target monoamine neurotransmitters including serotonin (5HT), are only modestly effective. Monoamine oxidase (MAO) metabolizes 5HT to 5-hydroxy indoleacetic acid (5HIAA). Genetic variants in the X-chromosome-linked MAO-encoding genes, MAOA and MAOB, have been associated with clinical improvement following ATD treatment in depressed patients. Our aim was to analyze the association of MAOA and MAOB genetic variants with (1) clinical improvement and (2) the plasma 5HIAA/5HT ratio in 6-month ATD-treated depressed individuals. Clinical (n = 378) and metabolite (n = 148) data were obtained at baseline and up to 6 months after beginning ATD treatment (M6) in patients of METADAP. Mixed-effects models were used to assess the association of variants with the Hamilton Depression Rating Scale (HDRS) score, response and remission rates, and the plasma 5HIAA/5HT ratio. Variant × sex interactions and dominance terms were included to control for X-chromosome-linked factors. The MAOA rs979605 and MAOB rs1799836 polymorphisms were analyzed. The sex × rs979605 interaction was significantly associated with the HDRS score (p = 0.012). At M6, A allele-carrying males had a lower HDRS score (n = 24, 10.9 ± 1.61) compared to AA homozygous females (n = 14, 18.1 ± 1.87; p = 0.0067). The rs1799836 polymorphism was significantly associated with the plasma 5HIAA/5HT ratio (p = 0.018). Overall, CC/C females/males had a lower ratio (n = 44, 2.18 ± 0.28) compared to TT/T females/males (n = 60, 2.79 ± 0.27; p = 0.047). The MAOA rs979605 polymorphism, associated with the HDRS score in a sex-dependent manner, could be a useful biomarker for the response to ATD treatment. [ABSTRACT FROM AUTHOR]

Since the beginning of the coronavirus disease (COVID)-19 pandemic, the need for effective treatments for COVID-19 led to the idea of "repurposing" drugs for antiviral treatment. Several antipsychotics and antidepressants have been tested for in vitro activity against the severe acute respiratory syndrome coronavirus 2. Chlorpromazine, other phenothiazine antipsychotics, and the antidepressant fluoxetine were found to be rather potent in these studies. However, whether effective plasma concentrations can be obtained with clinically accepted doses of these drugs is not clear. Data of COVID-19 patients are not yet available but several clinical studies are currently underway. The specific serotonin reuptake inhibitor fluvoxamine is a potent Sigma-1 receptor agonist and reduces inflammation in animal models of cytokine-stress. Accordingly, fluvoxamine treatment was superior to placebo in reducing impaired respiratory function and other symptoms of inflammation in COVID-19 patients in a placebo-controlled clinical study and another open clinical trial. The beneficial effects of fluvoxamine on the course of COVID-19 were recently confirmed in a large placebo-controlled double-blind trial with several hundred patients. Inflammation represents a major risk factor for many psychiatric disorders which explains the high susceptibilitiy of COVID-19 patients for psychiatric diseases. Many antidepressants and antipsychotics possess anti-inflammatory properties independent of sigma-1 activity which might be important to reduce psychiatric symptoms of COVID-19 patients and to improve respiratory dysfunction and other consequences of inflammation. This might explain the rather unspecific benefit which has been reported for several cohorts of COVID-19 patients treated with different psychotropic drugs. [ABSTRACT FROM AUTHOR]

Major depressive disorder is a serious neuropsychiatric disease that leads to significant impairment in social functioning and increased morbidity and mortality. Low vitamin D (25-OH D) levels have been hypothesized to contribute to the pathophysiology of MDD. To investigate the therapeutic role of vitamin D in MDD, we recruited 62 male and female patients diagnosed with MDD and randomized them into two groups: the first group (49 patients) received vitamin D supplementation as cholecalciferol vitamin D3 (50,000 I.U.) for 3 months, in addition to standard of care (SOC) which included pharmacological treatment and psychological support, and the second group (13 patients) received only SOC without vitamin D supplementation for 3 months. The Beck depression inventory (BDI) scale was used to assess the severity of MDD symptoms. Immunoassays were utilized to determine levels of serum vitamin D3 and serotonin in all patients. The results showed significant gender differences; female patients showed the most improvement in their depressive symptoms after 3-month vitamin D supplementation. Females with moderate, severe, and extreme depression had significantly lower BDI scores after vitamin D treatment (p < 0.05). Among males, only those diagnosed with severe depression showed significant improvement in their BDI scores (p < 0.05). Serum serotonin levels were significantly increased after vitamin D supplementation compared to baseline in both male and female patients. No significant changes in other biochemical parameters were detected between the two groups. These findings suggest that vitamin D supplementation may ameliorate symptoms of MDD, particularly in females, via a serotonin-dependent mechanism. [ABSTRACT FROM AUTHOR]

Introduction The major depressive disorder (MDD) arises from the interaction of environmental, genetic and epigenetic factors, producing a deficit in monoaminergic transmission within the brain. However, our understanding of its pathophysiology is quite limited. Objective To reach an integrative view of the MDD pathophysiology, as well as the mechanisms of action of antidepressant drugs. Method We used the PubMed database to search for the documents by using the appropriate key words. Most of them are experimental research and molecular genetics and brain imaging studies in humans. Results The pathophysiology of MDD is characterized by: i) shrinkage of the cingulate anterior cortex; ii) hyper-metabolism of the Cg25 area; iii) lower expression of the 5-HT1A receptor; iv) enhanced expression of monoamine oxidase A. Besides, certain gene polymorphisms are strongly linked to the pathophysiology, and there is evidence that 5-HT1A receptor expression is reduced by psychological stress. Antidepressants reverse the hyper-metabolic state of Cg25, stimulate neurogenesis and the cAMP pathway. We found that imipramine increases and reduces the expression of Gαs and Gαz, respectively (data no published). Discussion and conclusion The disruption in monoaminergic transmission could be mediated by: i) the G1463A hTPH2 polymorphism that reduces the serotonin synthesis; ii) the C(-1019)G 5-HT1A polymorphism that increases the receptor expression in the dorsal rafe, and reduces serotonin release; iii) an increase in monoamine degradation. The reduced 5-HT1A expression is discussed considering its inhibitory properties in the prefrontal cortex. The effects of imipramine on Gαs and Gαz are in agreement with the antidepressant-induced stimulation of the cAMP pathway. [ABSTRACT FROM AUTHOR]

Highlights: [•] We have previously shown an acute onset by the selective 5-HT6 agonist LY-586713 on hippocampal bdnf expression. [•] Here we show that this effect was still present following sub-chronic (4 days), but not chronic (14 days), treatment. [•] The effect on 5-HT6-mediated cell survival was also dependent on a similar length of treatment. [•] Taken together this suggests a time dependent desensitization of a potential neurotrophic action by 5-HT6 receptors. [ABSTRACT FROM AUTHOR]

Abstract: Several preclinical researches indicate that increased neurogenesis in the adult hippocampus might underlie the therapeutic effect of antidepressant treatment. Most antidepressant drugs have ability to increase serotonin (5-HT) and/or noradrenaline (NA) in brain, and chronic treatment with antidepressant drugs increases the number of proliferating neural precursor cells and neurogenesis in hippocampus. However, the direct effects of antidepressant drugs, 5-HT and NA on the neural precursor cells remain largely unknown. Neural precursor cells in adult hippocampus are divided into stem/progenitor cells of four types based on stages of neural development. We recently established a culture system of adult rat dentate gyrus-derived neural precursor cells (ADPs), which correspond to be type 2a early progenitor cells. Here the direct effects of antidepressant drugs of four types (fluoxetine, imipramine, reboxetine, and tranylcypromine) and two neurotransmitters (5-HT and NA) on the proliferation of ADPs were investigated. Neither antidepressant drugs of all types nor 5-HT increased the number of ADPs. On the other hand, NA increased the number and the DNA synthesis of ADPs. The effect of NA on ADP proliferation was antagonized by propranolol and timolol (β-adrenergic receptor (AR) antagonists), but not by phentolamine (α-AR antagonist), prazosin (α1-AR antagonist), or yohimbine (α2-AR antagonist). Moreover, it was antagonized by ICI 118, 551 (β2-AR selective antagonist) and salmeterol (β2-AR selective agonist) promoted ADP proliferation. These results suggest that NA might increase the proliferation of early progenitor cells in adult hippocampus via β2-AR directly, but antidepressant drugs and 5-HT do not. [Copyright &y& Elsevier]

Abstract: The forced swim test (FST) is a pre-clinical test to short and long term treatment with antidepressant drugs (ADT), which requires between-subject designs. Herein a modified protocol of the FST using within-subject design (repeated rat-FST) was evaluated. Male Wistar rats were submitted to 15min of swimming (Day 1: pretest) followed by three subsequent 5min-swimming tests one week apart (Day 2: test, Day 7: retest 1, Day 14: retest 2). To determine the temporal and factorial characteristics of the variables scored in the repeated rat-FST, the protocol was carried out in untreated animals (E1). To validate the method, daily injections of Fluoxetine (FLX, 2.5mg/kg, i.p.) or saline were given over a 2-week period (E2). Tests and retests have been videotaped for further register of the latency, frequency and duration of behaviors. Over retesting the latency to immobility decreased whereas duration of immobility tended to increase. Factorial analysis revealed that the test, the retest 1 as well as the retest 2 have variables suitable to detection of antidepressant-like effects of ADT. Compared to saline, FLX chronically administrated reduced duration of immobility whereas increased duration of swimming in retest 2. The data suggest that repeated rat-FST detected the gradual increase in the efficacy of low doses of FLX over time. Therefore, repeated rat-FST seemed suitable to detect short and long term effects of selective serotonin reuptake inhibitors, or other ADT, thus reducing the number of animals used in the screenings of this type of compounds. [ABSTRACT FROM AUTHOR]

J. Neurochem. (2010) 115, 438-449. Abstract Stress is known to activate the central 5-hydroxytryptamine (5-HT) system, and this is probably part of a coping response involving several 5-HT receptors. Although 5-HT2C receptors are well known to be implicated in anxiety, their participation in stress-induced changes had not been investigated in parallel at both behavioral and neurochemical levels. We show here that the preferential 5-HT2C receptor agonist, m-chlorophenylpiperazine, as well as restraint stress increased anxiety in the mouse social interaction test. The selective 5-HT2C receptor antagonist, SB 242,084, prevented both of these anxiogenic effects. Restraint stress increased 5-HT turnover in various brain areas, and this effect was prevented by the 5-HT2B/2C receptor agonist RO 60-0175 (1 mg/kg), but not the preferential 5-HT2A agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (1 mg/kg), and in contrast potentiated by SB 242,084 (1 mg/kg), which also blocked the effect of RO 60-0175. Using microdialysis, RO 60-0175 was shown to inhibit cortical 5-HT overflow in stressed mice when 5-HT reuptake was blocked locally. Chronic paroxetine prevented both the anxiogenic effect of m-chlorophenylpiperazine and the inhibitory effect of RO 60-0175 on locomotion and stress-induced increase in 5-HT turnover. The anxiolytic action of chronic paroxetine might be associated with an enhancement of 5-HT neurotransmission caused by a decreased 5-HT2C receptor-mediated inhibition of stress-induced increase in 5-HT release. [ABSTRACT FROM AUTHOR]

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Abstract: We developed a structure–property–activity relationship (SPAR)-model for psychopharmacological drugs acting as non-competitive 5-HT3A receptor antagonists by using a decision-tree learner provided by the RapidMiner machine learning tool. A single molecular descriptor, namely the molecular dipole moment per molecular weight (μ/MW), predicts whether or not a substance non-competitively antagonizes 5-HT-induced Na+ currents. A low μ/MW is compatible with drug-cumulation in apolar lipid rafts. This study confirms that size-intensive descriptors allow the development of compact SPAR models. [Copyright &y& Elsevier]

Previous work has shown that repeated desipramine treatment causes downregulation of the norepinephrine transporter (NET) and persistent antidepressant-like effects on behavior, ie effects observed 2 days after discontinuation of drug treatment when acute effects are minimized. The present study examined whether this mechanism generalizes to other antidepressants and also is evident for the serotonin transporter (SERT). Treatment of rats for 14 days with 20 mg/kg per day protriptyline or 7.5 mg/kg per day sertraline reduced NET and SERT expression, respectively, in cerebral cortex and hippocampus; these treatments also induced a persistent antidepressant-like effect on forced-swim behavior. Increased serotonergic neurotransmission likely mediated the behavioral effect of sertraline, as it was blocked by inhibition of serotonin synthesis with p-chlorophenylalanine; a parallel effect was observed previously for desipramine and noradrenergic neurotransmission. Treatment with 20 mg/kg per day reboxetine for 42, but not 14, days reduced NET expression; antidepressant-like effects on behavior were observed for both treatment durations. Treatment for 14 days with 70 mg/kg per day venlafaxine, which inhibits both the NET and SERT, or 10 mg/kg per day phenelzine, a monoamine oxidase inhibitor, produced antidepressant-like effects on behavior without altering NET or SERT expression. For all drugs tested, reductions of NET and SERT protein were not accompanied by reduced NET or SERT mRNA in locus coeruleus or dorsal raphe nucleus, respectively. Overall, the present results suggest an important, though not universal, role for NET and SERT regulation in the long-term behavioral effects of antidepressants. Understanding the mechanisms underlying transporter regulation in vivo may suggest novel targets for the development of antidepressant drugs.Neuropsychopharmacology (2009) 34, 1467–1481; doi:10.1038/npp.2008.183; published online 15 October 2008 [ABSTRACT FROM AUTHOR]

Abstract: There is evidence that antidepressant drug treatment during a critical period of postnatal development renders mice susceptible to depression- and anxiety-related behaviour in adulthood. The mechanism of how early antidepressant treatment brings about long-term effects in emotional behaviour is not yet understood, but neurotrophins, particularly brain-derived neurotrophic factor (BDNF), have been implicated in this context. We examined the long-term effects of a transient early postnatal fluoxetine treatment on depression- and anxiety-related behaviours as well as gene expression of BDNF and its receptor TrkB in C57BL/6J mice. Treatment with fluoxetine between postnatal days P4 and P21 resulted in a significant loss of body weight and long-lasting behavioural inhibition in adult mice in response to stressful events such as the light–dark or open field tests. Postnatal fluoxetine exposure also decreased behavioural despair in the forced swim test. Both body weight and behavioural alterations were restored by chronic fluoxetine treatment in adulthood. The behavioral alterations were accompanied by changes in hippocampal BDNF mRNA. Specifically, we show that early-life fluoxetine exposure resulted in the long-term upregulation of BDNF expression in adult mice. However, chromatin immunoprecipitation studies did not reveal any changes in the acetylation or trimethylation of histone H3 at the BDNF promoters. Our experiments show that behavioural and molecular changes induced by early postnatal fluoxetine administration are reversed by chronic fluoxetine treatment of adult mice to control levels. [Copyright &y& Elsevier]

Among the multiple possibilities to study human depressive disorders, animal models remain important preclinical tools. They allow the understanding of the mechanisms of action of antidepressant drugs. Primarily developed in rat, animal models of depression have been adapted to the mouse, an easy-to-use mammal with better genetic possibilities than rats. As an example, genetic manipulation of the serotoninergic 5-hydroxytryptamine-HT; (5-HT) system provided important opportunities to investigate the role of this monoamine in mood disorders. The contribution of either constitutive knockout (KO), tissue specific, or inducible KO mice and animal models in the current knowledge of the pathophysiology and treatment of depression is unanimously recognized. The phenotype of genetically manipulated animals is strongly influenced by both the genetic background of the animal as well as environmental factors. For these reasons, it is necessary to underline that KO mice have been generated on various genetic backgrounds, which strongly influence the behavioral and neurochemical responses to the tests. The present review will thus focus on KO mice lacking G protein-coupled monoaminergic receptors (e.g; 5-HT1B, 5-HT1A, and 5-HT4 receptors) and the 5-HT serotonin transporter, which is the main target of antidepressant drugs (or strategies). The importance of KO mice for neurotrophic factors, particularly for brain-derived neurotrophic factor and its main receptor displaying a tyrosine kinase activity, will also be addressed to illustrate the fact that in preclinical studies, combination of genetic manipulations with pharmacological ones should allow further progress in the field of neuropsychopharmacology. [ABSTRACT FROM AUTHOR]

The vasoconstrictor substance named serotonin was identified as 5-hydroxytryptamine (5-HT) by Maurice Rapport in 1949. In 1951, Rapport gave Gaddum samples of 5-HT substance allowing him to develop a bioassay to both detect and measure the amine. Gaddum and colleagues rapidly identified 5-HT in brain and showed that lysergic acid diethylamide (LSD) antagonized its action in peripheral tissues. Gaddum accordingly postulated that 5-HT might have a role in mood regulation. This review examines the role of UK scientists in the first 20 years following these major discoveries, discussing their role in developing assays for 5-HT in the CNS, identifying the enzymes involved in the synthesis and metabolism of 5-HT and investigating the effect of drugs on brain 5-HT. It reviews studies on the effects of LSD in humans, including Gaddum's self-administration experiments. It outlines investigations on the role of 5-HT in psychiatric disorders, including studies on the effect of antidepressant drugs on the 5-HT concentration in rodent and human brain, and the attempts to examine 5-HT biochemistry in the brains of patients with depressive illness. It is clear that a rather small group of both preclinical scientists and psychiatrists in the UK made major advances in our understanding of the role of 5-HT in the brain, paving the way for much of the knowledge now taken for granted when discussing ways that 5-HT might be involved in the control of mood and the idea that therapeutic drugs used to alleviate psychiatric illness might alter the function of cerebral 5-HT. [ABSTRACT FROM AUTHOR]

Abstract: In vivo intracerebral microdialysis is an important neurochemical technique that has been applied extensively in genetic and pharmacological studies aimed at investigating the relationship between neurotransmitters. Among the main interests of microdialysis application is the infusion of drugs through the microdialysis probe (reverse dialysis) in awake, freely moving animals. As an example of the relevance of intracerebral microdialysis, this review will focus on our recent neurochemical results showing the impact of Brain-Derived Neurotrophic Factor (BDNF) on serotonergic neurotransmission in basal and stimulated conditions. Indeed, although the elevation of 5-HT outflow induced by chronic administration of selective serotonin reuptake inhibitors (SSRIs) causes an increase in BDNF protein levels and expression (mRNA) in the hippocampus of rodents, the reciprocal interaction has not been demonstrated yet. Thus, the neurochemical sight of this question will be addressed here by examining the consequences of either a constitutive decrease or increase in brain BDNF protein levels on hippocampal extracellular levels of 5-HT in conscious mice. [Copyright &y& Elsevier]

Abstract: Down-regulation of 5-hydroxytryptamine2A (5-HT2A) receptors has been a consistent effect induced by most antidepressant drugs. In contrast, electroconvulsive shock (ECS) up-regulates the number of 5-HT2A receptor binding sites. However, the effects of antidepressants on 5-HT2A receptor-mediated responses on identified cells of the cerebral cortex have not been examined. The purpose of the present study was to compare the effects of the tricyclic antidepressant imipramine and ECS on 5-HT2A receptor-mediated electrophysiological responses involving glutamatergic and GABAergic neurotransmission in the rat medial prefrontal cortex (mPFC) and piriform cortex, respectively. The electrophysiological effects of activating 5-HT2A receptors were consistent with 5-HT2A receptor binding regulation for imipramine and ECS except for the mPFC where chronic ECS decreased the potency of 5-HT at a 5-HT2A receptor-mediated response. These findings are consistent with the general hypothesis that chronic antidepressant treatments shift the balance of serotonergic neurotransmission towards inhibitory effects in the cortex. [Copyright &y& Elsevier]

Abstract: Down-regulation of 5-hydroxytryptamine2A (5-HT2A) receptors has been a consistent effect induced by most antidepressant drugs. The evidence for down-regulation of 5-HT2A receptor binding following subchronic treatment with fluoxetine and other selective serotonin reuptake inhibitors (SSRIs) is mixed. The question of 5-HT2A receptor sensitivity during chronic administration of antidepressants is important since activation of 5-HT2A receptors is associated with impulsivity. Continued activation of 5-HT2A receptors may functionally oppose activation of other non-5-HT2A receptors in the prefrontal cortex associated with the clinical efficacy of SSRI treatment. Therefore, the effects of repeated daily administration of fluoxetine (10mg/kg, i.p. ×3 weeks) on pharmacologically characterized electrophysiological response mediated by 5-HT2A receptor activation, 5-HT-induced excitatory postsynaptic currents (EPSCs), in rat prefrontal cortical slices was examined. The concentration–response curve for 5-HT-induced EPSCs was unchanged following subchronic fluoxetine treatment. This subchronic fluoxetine treatment failed to modify electrophysiological responses to AMPA in layer V pyramidal cells as well. These findings would be consistent with the hypothesis that blockade of 5-HT2A receptors may enhance the effects of SSRIs or serotonin/norepinephrine reuptake inhibitors (SNRIs). [Copyright &y& Elsevier]

We used the microdialysis technique to compare basal extracellular serotonin (5-HT) and the response to citalopram in different strains of mice with functionally different allelic forms of tryptophan hydroxylase-2 (TPH-2), the rate-limiting enzyme in brain 5-HT synthesis. DBA/2J, DBA/2N and BALB/c mice carrying the 1473G allele of TPH-2 had less dialysate 5-HT in the medial prefrontal cortex and dorsal hippocampus (DH) (20–40% reduction) than C57BL/6J and C57BL/6N mice carrying the 1473C allele. Extracellular 5-HT estimated by the zero-net flux method confirmed the result of conventional microdialysis. Citalopram, 1.25, 5 and 20 mg/kg, dose-dependently raised extracellular 5-HT in the medial prefrontal cortex of C57BL/6J mice, with maximum effect at 5 mg/kg, but had significantly less effect in DBA/2J and BALB/c mice and in the DH of DBA/2J mice. A tryptophan (TRP) load enhanced basal extracellular 5-HT in the medial prefrontal cortex of DBA/2J mice but did not affect citalopram’s ability to raise cortical and hippocampal extracellular 5-HT. The impairment of 5-HT synthesis quite likely accounts for the reduction of basal 5-HT and the citalopram-induced rise in mice carrying the mutated enzyme. These findings might explain why DBA/2 and BALB/c mice do not respond to citalopram in the forced swimming test. Although TRP could be a useful strategy to improve the antidepressant effect of citalopram ( Cervo et al. 2005 ), particularly in subjects with low 5-HT synthesis, the contribution of serotonergic and non-serotonergic mechanisms to TRP’s effect remains to be elucidated. [ABSTRACT FROM AUTHOR]

We review the cardiovascular effects of newer antidepressants. Although further studies are warranted, the safety of the selective serotonin reuptake inhibitors and the serotonin norepinephrine reuptake inhibitors on patients with comorbid cardiac conditions is impressive. Newer antidepressants should be considered as first-line agents for the treatment of depression in patients with and without cardiovascular disease. [ABSTRACT FROM AUTHOR]

A large body of literature has implicated serotonin [5-hydroxytryptamine (5-HT)] in descending modulation of nociceptive transmission. Here, we have studied the pain behavior of Lmx1b conditional knock-out mice (Lmx1bf/f/p), which lack 5-HT neurons in the CNS. Lmx1bf/f/p mutant mice showed normal thermal and visceral pain responses but were less sensitive to mechanical stimuli and exhibited enhanced inflammatory pain compared with their littermate control mice. Importantly, the analgesic effect of several antidepressant drugs, including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants, was either abolished or greatly attenuated in Lmx1bf/f/p mice. Moreover, in the acute versus persistent pain settings, the analgesic actions of the SNRI duloxetine and the SSRI fluoxetine were differentially affected. Together, our results provide in vivo genetic evidence demonstrating that although the predominant role of the central 5-HT system in inflammatory pain is inhibitory, its role in acute mechanical pain is facilitatory. The findings that the analgesic effects of various antidepressant drugs are differentially dependent on the central 5-HT system should help us to understand the mechanism of the analgesic action of different classes of antidepressants in the management of persistent pain. [ABSTRACT FROM AUTHOR]

Infant maternal separation, a paradigm of early life stress in rodents, elicits long-lasting changes in gene expression that persist into adulthood. In BALB/c mice, an inbred strain with spontaneously elevated anxiety and stress reactivity, infant maternal separation led to increased depression-like behavioral responses to adult stress and robustly increased editing of serotonin 2C receptor pre-mRNA. Chronic fluoxetine treatment of adult BALB/c mice exposed to early life stress affected neither their behavioral responses to stress nor their basal 5-HT2C pre-mRNA editing phenotype. However, when fluoxetine was administered during adolescence, depression-like behavioral responses to stress were significantly diminished in these mice, and their basal and stress-induced 5-HT2C pre-mRNA editing phenotypes were significantly lower. Moreover, when BALB/c mice exposed to early life stress were raised in an enriched postweaning environment, their depression-like behavioral responses to adult stress were also significantly diminished. However, their 5-HT2C premRNA editing phenotype remained unaltered. Hence, the similar behavioral effects of enrichment and fluoxetine treatment during adolescence were not accompanied by similar changes in 5-HT2C pre-mRNA editing. Enriched and nonenriched BALB/c mice exposed to early life stress also exhibited significantly increased expression of mRNA and protein encoding the Gαq subunit of G-protein that couples to 5-HT2A/2C receptors. In contrast, Gαq expression levels were significantly lower in fluoxetine-treated mice. These findings suggest that compensatory changes in Gαq expression occur in mice with persistently altered 5-HT2C pre-mRNA editing and provide an explanation for the dissociation between 5-HT2C receptor editing phenotypes and behavioral stress responses. [ABSTRACT FROM AUTHOR]

This review outlines the history of our knowledge of the neuropharmacology of 5-hydroxytryptamine (5-HT; serotonin), focusing primarily on the work of U.K. scientists. The existence of a vasoconstrictive substance in the blood has been known for over 135 years. The substance was named serotonin and finally identified as 5-HT in 1949. The presence of 5-HT in the brain was reported by Gaddum in 1954 and it was Gaddum who also demonstrated that the action of 5-HT (in the gut) was antagonised by the potent hallucinogen lysergic acid diethylamide. This provoked the notion that 5-HT played a pivotal role in the control of mood and subsequent investigations have generally confirmed this hypothesis. Over the last 50 years a good understanding has been gained of the mechanisms involved in control of the storage, synthesis and degradation of 5-HT in the brain. Knowledge has also been gained on control of the functional activity of this monoamine, often by the use of behavioural models. A considerable literature also now exists on the mechanisms by which many of the drugs used to treat psychiatric illness alter the functional activity of 5-HT, particularly the drugs used to treat depression. Over the last 20 years the number of identified 5-HT receptor subtypes has increased from 2 to 14, or possibly more. A major challenge now is to utilise this knowledge to develop receptor-specific drugs and use the information gained to better treat central nervous system disorders. [ABSTRACT FROM AUTHOR]

Animal models of chronic pain serve as an experimental basis for testing new therapeutic interventions and for mechanistic investigations. In an animal model of chronic pain, based on the injection of formalin into the paw of a rodent, inhibitors of noradrenaline reuptake such as nisoxetine, nortriptyline and maprotiline and dual inhibitors of the noradrenaline andserotonin reuptake such as imipramine and milnacipran produce potent anti-nociceptive effects, whereas selective serotonin reuptake inhibitors, such as fluvoxamine, are much less potent. In another model, neuropathicpain resulting from the chronic constriction injury of the sciatic nerve was prevented by the dual uptake inhibitor, venlafaxine. The experimental model involving ligation of the 5th spinal nerve induces behavioural signs in rats and mice that are similar to the symptoms of human neuropathic pain. In this model amitriptyline, a non-selective serotonin and noradrenaline reuptake blocker, the preferential noradrenaline reuptake inhibitor, desipramine and the selective serotonin and noradrenaline reuptake inhibitors, milnacipran and duloxetine, produce a decrease in pain sensitivity whereas the selective serotonin reuptake inhibitor, fluoxetine, is ineffective. Antidepressants acting on the noradrenergic or both the noradrenergic and serotonergic systems thus appear to be more effective than those working on the serotonin system alone. Copyright © 2004 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The present study investigated the effect of three antidepressant drugs (ADs), desipramine (DMI, a noradrenaline reuptake inhibitor), citalopram (CIT, a selective serotonin reuptake inhibitor) and mianserin (MIA, thought to act as an antagonist of pre-synaptic α2 adrenoceptor) on the transcriptional activity of the dopamine D2 receptor gene promoter. The fragment of dopamine D2 receptor gene promoter (-850 to +133) was subcloned into pGL3 vector (Promega), which has an insert coding for luciferase used as a reporter gene. Such construct (pGL3-D2R) was used to transiently transfect the neuroblastoma cell lines, Neuro 2a, SH-SY5Y and NB41A3, which endogenously express the dopamine D2 receptor protein.The obtained results indicate that transcriptional activity of dopamine D2 receptor gene promoter was dose-dependently increased by retinoic acid, forskolin, rolipram and phorbol 12 myristate 13-acetate, as well as by DMI, CIT and MIA. In the Neuro 2a cells, the most significant increase was observed after the ADs were present in the incubation medium at a doses of 0.1–1 μM for 72 h. In the SH-SY5Y cells, the significant increase in the transcriptional activity of D2 receptor gene promoter was observed already after 24-h exposure to DMI. Incubation of the Neuro 2a cells in the presence of forskolin (1 μM) or rolipram (50 μM) (but not phorbol 12-myristate 13-acetate at 0.1 μM) in combination with DMI resulted in the further increase in transcriptional activity of the studied promoter, indicating the involvement of protein kinase A pathway in these effects. [Copyright &y& Elsevier]

The therapeutic effect of an antidepressant drug takes at least 2 to 3 weeks to develop and a significant proportion of patients have no or only partial benefit regardless of the class of antidepressant used. Research into the neurobiological basis of antidepressant action has suggested new strategies to improve the antidepressant effect. Recent microdialysis studies show that hypofunction of the presynaptic autoreceptors enhances the increase of extracellular serotonin (5-HT) induced by selective serotonin reuptake inhibitors (SSRIs) so it has been suggested that the antidepressant effect may be speeded up by blockade of the autoreceptors. The similarity between the synaptic mechanisms controlling serotonergic and noradrenergic transmission has stimulated preclinical research into the role of presynaptic α2-adrenoceptors in the effect of noradrenaline (NA) reuptake inhibitors (NRIs) on NA availability at central synapses. The microdialysis studies reviewed here indicate that NRIs including desipramine, reboxetine and atomoxetine, the mixed 5-HT/NA reuptake inhibitors sibutramine, duloxetine, venlafaxine or the NA/DA reuptake inhibitor amineptine, increased extracellular NA in various regions of the rat brain. The effect was enhanced by chronic treatment and even more by the co-administration of α2-adrenoceptor antagonists. The results support the theory that desensitization of the α2-adrenoceptor contributes to enhancing the effect of NRIs seen after chronic administration and may account for the slow onset of the antidepressant effect. Finally, they suggest that co-administration of an α2-adrenoceptor antagonist may improve the therapeutic effect of NRI. [Copyright &y& Elsevier]

The rat isolated jejunum was used as a functional model to screen some antidepressant drugs at the 'atypical' 5-HT[sub7] receptor. Mianserin acted as a surmountable antagonist of 5-CT with a pA[sub2] value of 8.22 ± 0.33. The apparent pK[subB] of maprotiline against 5-CT was 7.67 ± 0.24 at 100 nmol/l, but higher concentrations suppressed the maxima. An apparent pK[subB] could not be obtained for amitriptyline, because 10 nmol/l reduced the E[submax] of 5-CT without causing parallel displacement. Higher concentrations of 30 and 100 nmol/l caused further suppressions. Amoxapine, loxapine and desipramine (each at 100 nmol/l) caused similar effects, suppressing the E[submax] values to 5-HT by approximately 50%, while lower concentrations failed to cause parallel displacements. These results further extend the activity profiles of the drugs investigated. [ABSTRACT FROM AUTHOR]

VN2222 (1-(benzo[b]thiophen-3-yl)-3-[4-(2-methoxiphenyl piperazin-1-yl]propan-1-ol) is a potential antidepressant with high affinity for the serotonin transporter and 5-HT1A receptors. Locally applied, VN2222 enhanced the extracellular 5-hydroxytryptamine (5-HT) concentration (5-HText) in rat striatum to 780% of baseline whereas its systemic administration (1-10 mg/kg s.c.) reduced 5-HText. In the presence of citalopram, 8-OH-DPAT or VN2222 applied in medial prefrontal cortex reduced 5-HText. Fluoxetine, VN2222, and 8-OH-DPAT suppressed the firing rate of dorsal raphe 5-HT neurons (ED50: 790, 14.9, and 0.8 µg/kg i.v., respectively). These effects were antagonized by WAY 100635. Administration of VN2222 for 2 weeks desensitized 5-HT1A receptors as assessed by microdialysis and single-unit recordings (ED50 values for 8-OH-DPAT were 0.45 and 2.34 µg/kg i.v. for controls and rats treated with 6 mg/kg day VN2222). These results show that VN2222 is a mixed 5-HT reuptake inhibitor/5-HT1A agonist that markedly desensitizes 5-HT1A autoreceptors. These properties suggest that it may be a clinically effective dual action antidepressant drug. [ABSTRACT FROM AUTHOR]

Fluoxetine is a widely used antidepressant compound having selective serotonin reuptake inhibitor properties. In this study, the actions of fluoxetine were analyzed in guinea pig, rat, rabbit and canine ventricular myocardiac preparations using conventional microelectrode and whole cell voltage clamp techniques. Low concentrations of fluoxetine (1–10 µmol/l) caused significant shortening of action potential duration (APD) and depression of the plateau potential in guinea pig and rabbit papillary muscles and single canine ventricular myocytes. In rat papillary muscle, APD was not affected by fluoxetine (up to 100 µmol/l), however, the drug decreased the force of contraction with EC50 of 10 µmol/l. Fluoxetine (10 µmol/l) also decreased the maximum velocity of depolarization and action potential overshoot in each species studied. At this concentration no effect was observed on the resting membrane potential; high concentration (100 µmol/l), however, caused depolarization. In voltage clamped canine ventricular myocytes, fluoxetine caused concentration-dependent block of the peak Ca2+ current at 0 mV with EC50 of 5.4±0.94 µmol/l and Hill coefficient of 1.1±0.14 (n=6). In addition, 10 µmol/l fluoxetine shifted the midpoint of the steady-state inactivation curve of the Ca2+ current from –20.7±0.65 to –26.7±1 mV (P<0.001, n=8) without changing its slope factor. These effects of fluoxetine developed rapidly and were fully reversible. Fluoxetine did not alter voltage-dependence of activation or time constant for inactivation of ICa. Fluoxetine had no effect on the amplitude of K+ currents (IK1 and Ito). The inhibition of cardiac Ca2+ and Na+ channels by fluoxetine may explain most cardiac side effects observed occasionally with the drug. Our results suggest that fluoxetine may have antiarrhythmic (class I + IV type), as well as proarrhythmic properties (due to impairment of atrioventricular or intraventricular conduction and shortening of repolarization). Therefore, in depressed patients with cardiac disorders, ECG control may be suggested during fluoxetine therapy. [ABSTRACT FROM AUTHOR]

Objective: Controlled trials do not suggest differences in efficacy between antidepressant compounds. Psychiatrists, however, frequently express the view that real differences do exist and are relevant to clinical practice. Since multiple comparative trials are not feasible, an alternative method for expanding the evidence base is to survey regularly the opinions of practising psychiatrists. Method: Two surveys of psychiatrists’ opinions were conducted. Participants in the first survey were drawn from contact with ‘SPHERE: A National Depression Project’, while those in the second survey responded to a brief questionnaire distributed with Australasian Psychiatry. Results: Reported volumes of scripts written, ratings of efficacy and tolerability, and preferences in specific clinical situations indicate that clinical psychiatrists now strongly prefer the newer antidepressant agents. They rate serotonin and noradrenalin re-uptake inhibitors (SNRIs) and selective serotonin re-uptake inhibitors (SSRIs) highest for antidepressant efficacy, serotonin receptor subtype 2 (5HT2) antagonists and some SSRIs highest for anti-anxiety efficacy, and some SSRIs and reversible inhibitors of monoamine oxidase inhibitor-A (RIMAs) lowest for side-effect burden. Further, SSRIs were their first preferences for most clinical situations. Serotonin and noradrenalin re-uptake inhibitors were the preferred choice for treatment-resistant depression and patients who had failed to respond to one SSRI. Serotonin receptor subtype 2 antagonists were the second choice to SSRIs for mixed anxiety and depression, and major depression with sleep disturbance. Reversible inhibitors of monoamine oxidase inhibitor-A were the second choice to SSRIs for adolescents with major depression, patients aged over 65 years, patients with serious medical illnesses and patients with chronic fatigue. Tricyclic antidepressants (TCAs) were the preferred choice for patients with chronic pain, and... [ABSTRACT FROM AUTHOR]

Administration of the selective serotonin (5-HT) uptake inhibitor sertraline produced a dose-dependent reduction of food intake in rats. Doses of sertraline of 10 mg/kg or greater reduced the intake of solid pellets significantly ( P<0.01) during the 1st hour of a 4-h feeding test in rats deprived of food and water for 24 h. Food intake during the remaining 3 h and water intake during the feeding test was unaffected by sertraline. Sertraline (2-18 mg/kg IP) also reduced milk consumption in food-deprived rats. Pretreatment with the nonselective 5-HT antagonists metergoline (2 mg/kg IP) or methysergide (3.3 mg/kg IP) blocked sertraline's inhibition of dry food intake, whereas pretreatment with the selective 5-HT receptor antagonist ketanserin (3.3 mg/kg IP) or the peripheral 5-HT antagonist xylamidine (2.5 mg/kg IP) failed to block sertraline's anorexic effect. The feeding-suppressant effect of 10 mg/kg sertraline was prevented following the destruction of central 5-HT neurons by the 5-HT neurotoxic agent, 5,7-dihydroxytryptamine (200 μg ICV). This result is consistent with sertraline's anorexic effect depending on intact 5-HT neurotransmission. Therefore, sertraline appears to reduce feeding by enhancing the action of endogenous serotonin at central synapses mediated by 5-HT rather than 5-HT receptors. [ABSTRACT FROM AUTHOR]

The head shake reflex is a rapid rhythmic shaking of the head in a radial motion and is a prominent part of the behavior of most mammalian species. The administration of agonists at 5-hydroxytryptamine (5-HT) receptors to rats increases apparently-spontaneous head shaking behavior. The present study examined the relationship between the head shake reflex, elicited by stimulation of the aural ampullae with Tween 80, with a similar-appearing behavior, the head shake response caused by the administration of 5-HT agonists to rats. Head shaking was attenuated by the subcutaneous infiltration of the local anesthetic procaine into the posterior border of the external auditory meatus. However, the local anesthetic did not alter head shake behavior produced by administering either the 5-HT agonist quipazine or the 5-HT precursor 5-hydroxy- L-tryptophan ( l-5-HTP). The magnitude of the head shake reflex was also diminished after habituation of the reflex by repeatedly applying Tween 80 to the ampullae, yet this treatment had no effect on the head shaking behavior caused by quipazine. In a complementary manner, pretreatment with the 5-HT receptor antagonist ketanserin potently blocked shaking behavior caused by quipazine without significantly altering the head shake reflex. Chronic administration of the atypical antidepressant drug iprindole to rats for 7 days reduced quipazine-induced shaking behavior without affecting the head shake reflex. In contrast, chronic administration of the monoamine oxidase inhibitor phenelzine to rats for 7 days reduced head shaking behavior caused by either stimulus, indicating that an attenuation of motor reflex activity could play a role in the reduced response to quipazine. When shaking behavior caused by the auricular application of Tween 80 was combined simultaneously with quipazine, these two treatments produced additive effects on shaking behavior. No support was found in these experiments using rats that head shaking behavior caused by 5-HT agonists involved the enhanced perception of normally-subliminal cutaneous stimuli from the pinna region that usually elicit the head shake reflex. Instead, 5-HT agonists and aural pinna stimulation appeared to produce head shaking behavior in rats by independent physiological mechanisms. However, these mechanisms may intersect insofar as the motor pathways of the head shake reflex may be common with the motor pathway for eliciting shaking behavior by the stimulation of central 5-HT receptors. [ABSTRACT FROM AUTHOR]

The effects of various drugs on the hypermotility induced in mice by 4,α-dimethyl-m-tyramine (H 77/77) was investigated. The H 77/77-induced hypermotility was strongly inhibited by centrally acting dopamine-(DA-) receptor blockers (e.g., benperidol, fluspirilene, haloperidol) and potentiated by drugs increasing central DA activity by release of DA, by uptake inhibition ( d- and l-amphetamine, nomifensine), or by inhibition of monoamine oxidase (e.g., parglyline, chlorgyline). While DA-receptor agonists (e.g., bromocriptine, ergocornine) potentiated hypermotility, the effects of those having a short duration of action (apomorphine, piribedil) were partly obscured. The catecholamine precursor L-dopa increased hypermotility only slightly, but its effect was markedly potentiated after inhibition of dopa decarboxylase. Inhibition of tyrosine hydroxylase with α-methyltyrosine methyl ester HCl (H 44/68) totally blocked H 77/77 hypermotility. Inhibition of noradrenaline (NA) synthesis with bis-(4-methyl-l-homopiperazinyl thiocarbonyl)-disulphide (FLA 63) had no significant effect, whereas after sodium diethyldithiocarbamate (DDC) there was a moderate decrease in motility of about 25%. Blockers of α- and β-adrenoceptors either did not affect H 77/77 hypermotility (e.g., WB 4101, pindolol) or inhibited it only at very high doses (e.g., phentolamine, propranolol). α-Adrenoceptor agonists (clonidine, guanfacine) had no clear effects. No correlation was found between the H 77/77-inhibiting effect of antidepressant drugs and their ability to inhibit NA uptake. Several antiserotoninergic compounds (pizotifen, 27-096, 29-245) blocked the effects of H 77/77, and a 65% drop in hypermotility was obtained after inhibition of 5-HT-synthesis with 6-flourotryptophan. Substances that increase central serotoninergic activity ( l-5-HTP, fenfluramine), however, were inactive. Anticholinergic drugs (e.g., atropine, dexetimide) increased H 77/77 hypermotility, whereas cholinergic drugs (e.g., arecoline, physostigmine) produced no dose-related effect. It is cocluded that DA plays a dominant role in the H 77/77-induced hypermotility in mice, although functional NA and 5-HT systems appear to be a prerequisite for the full H 77/77 effect. [ABSTRACT FROM AUTHOR]

Despite the extensive research conducted in recent decades, the molecular mechanisms underlying major depressive disorder (MDD) and relative evidence-based treatments remain unclear. Various hypotheses have been successively proposed, involving different biological systems. This narrative review aims to critically illustrate the main pathogenic hypotheses of MDD, ranging from the historical ones based on the monoaminergic and neurotrophic theories, through the subsequent neurodevelopmental, glutamatergic, GABAergic, inflammatory/immune and endocrine explanations, until the most recent evidence postulating a role for fatty acids and the gut microbiota. Moreover, the molecular effects of established both pharmacological and non-pharmacological approaches for MDD are also reviewed. Overall, the existing literature indicates that the molecular mechanisms described in the context of these different hypotheses, rather than representing alternative ones to each other, are likely to contribute together, often with reciprocal interactions, to the development of MDD and to the effectiveness of treatments, and points at the need for further research efforts in this field. [ABSTRACT FROM AUTHOR]

Parker G. Differential effectiveness of newer and older antidepressants appears mediated by an age effect on the phenotypic expression of depression. Acta Psychiatr Scand 2002: 106: 168–170. © Blackwell Munksgaard 2002. Objective: A possible mechanism whereby the serotonin reuptake inhibitor (SSRI) antidepressants may not (overall) be as effective as the tricyclic (TCA) antidepressants is explored. Method: Clinical psychiatrists rated the effectiveness of past antidepressant medications in a clinical panel study of patients with a major depressive disorder, with 200 having previously received a TCA and 219 an SSRI. Results: Analyses indicated decreased SSRI effectiveness with age in those with the melancholic subtype. TCA effectiveness appeared uninfluenced by age and depressive subtype. Conclusion: Findings suggest why the broader-based TCAs may be more effective than the SSRIs in implicating age and depressive subtype influences. [ABSTRACT FROM AUTHOR]