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Major depression disorder (MDD) is one of the most widespread and debilitating psychiatric diseases and may be associated with other mental disorders such as anxiety. Despite advances in neurobiology studies, currently no established mechanism can explain all facets of MDD, and available drugs often show therapeutic delay for clinical effectiveness and response rates in patients are around 50 %. Previous activities of piperazine derivatives on CNS are indicators of its therapeutic potential for treating mental disorders. In this regard, we have previously shown that the piperazine derivative 2,6-di-tert-butyl-4-((4-(2-hydroxyethyl)piperazin-1-yl)methyl)phenol (LQFM212) has anxiolytic-like activity which involves serotonergic pathway, nicotinic receptors and BZD-site of GABA A receptor, without cognitive impairments. Herein, was evaluated the potential antidepressant-like effect of LQFM212 on forced swimming test (FST) after a single dose of 54 μmol/kg and after repeated treatment for 15 days in mice. Pretreatment with WAY-100635, PCPA, prazosin, SCH-23390, sulpiride or AMPT reversed the antidepressant-like effect on FST, suggesting that monoaminergic pathway contributes for effects of LQFM212. Furthermore, repeated treatment with LQFM212 increased hippocampal BDNF levels dosed by ELISA kit. In assessment of possible adverse effects, repeated treatment with LQFM212 did not alter the body weight of the animals, glutathione levels in the liver, and serum levels of AST, ALT, urea, and creatinine. Taken together, the results showed that LQFM212 has an antidepressant-like effect that involves monoaminergic pathway and increased BDNF levels. This compound represents promising candidate for prototype of psychoactive drugs for treatment of anxiety and depression disorders since these pathological conditions may exist in comorbidities., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Unpredictable chronic mild stress (UCMS) has been shown to cause memory loss via increased oxidative stress and deregulation of monoaminergic and cholinergic neurotransmissions. Although the benefits of methyl jasmonate (MJ), a well-known anti-stress plant hormone against chronic stress-induced psychopathologies, have been earlier reported, its effects on antioxidant defense molecules, monoaminergic transmitters, and nuclear factor erythroid 2-related factor 2 (Nrf2) immunopositive cells have not been extensively studied. The present study was designed to examine its effect on memory functions, antioxidant biomarkers, monoaminergic transmitters, and Nrf2 immunopositive cell expression in rats exposed to UCMS. Rats received an intraperitoneal injection of MJ (10, 25, and 50 mg/kg) 30 min before exposure to UCMS daily for 28 days. Memory function was assessed on day 29 using a modified elevated plus maze and novel object recognition tests. The antioxidant biomarkers, level of monoamines (serotonin, noradrenaline, and dopamine), and Nrf2 immunopositive cell expression were determined in the rat brain tissues. The activity of cholinesterase and monoamine oxidase enzymes was also determined. MJ attenuated memory deficits and elevated the brain levels of monoamines in UCMS rats. UCMS-induced increase of brain cholinesterase and monoamine oxidase activities was inhibited by MJ. Also, MJ attenuated UCMS-induced decrease in antioxidant enzymes (CAT, GPx, GST, and SOD) and thiol contents in the brains of rats. UCMS-induced increase in NO level and Nrf2 immunopositive cell expression in the rat's brain was attenuated by MJ. Taken together, these findings suggest that increasing antioxidant defense molecules and monoaminergic/cholinergic neurotransmitters and decreasing the Nrf2 immunopositive cell expressions may contribute to the memory-promoting effects of MJ in rats exposed to UCMS.

Purpose: The purpose of the present study was to investigate the preventive effect of L-arginine (ARG) and carnosine (CAR) on hypoxia-induced neurotoxicity in rats. The impact on neuro-inflammation, apoptosis, angiogenesis, and the brain levels of monoamines and GABA were investigated., Methods: Rats were divided into the following: normal control, hypoxia model induced by sodium nitrite (75 mg/kg s.c), and hypoxic rats pre-treated with CAR (250 mg/kg), ARG (200 mg/kg), and their combination., Results: Data revealed that hypoxia induced significant elevation of hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and its receptor reflecting the stimulation of angiogenesis. Hypoxia also resulted in increased inflammatory mediators-including nuclear factor kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). In addition, hypoxia initiates cerebral apoptosis as revealed by increased caspase-3 and BAX with reduced Bcl-2. These changes were associated with reduced brain levels of GABA and monoamines including noradrenaline (NADR), dopamine (DOP), and serotonin (SER). Pre-treatment with ARG and/or CAR significantly mitigated the neural changes induced by hypoxia and attenuated the elevated levels of NF-κB, TNF-α, IL-6, caspase-3, and BAX, while ameliorated the reduced levels of Bcl-2, NADR, DOP, SER, and GABA, with the best improvement observed with the combination. Further elevation of the angiogenic markers was observed indicating their role in boosting oxygen delivery to brain., Conclusion: CAR, ARG, and, importantly, their combination could effectively protect against hypoxia-induced neurotoxicity, via their angiogenic, anti-inflammatory, and anti-apoptotic properties in addition to reversing the effect on GABA and monoamines.

Serotonin2C receptor (5-HT 2C ) agonists are promising drugs for the treatment of neuropsychiatric diseases. However, their effect is not completely understood in part because they possibly affect several neurobiological networks simultaneously. We studied the effect of the 5-HT 2C receptor agonist WAY-163909 (0.3 and 3 mg/kg; i.p.) on the tissue concentration of dopamine (DA), 5-HT and noradrenaline (NA) in 29 rat brain regions related to motor, cognitive, mood and vegetative networks. We found that WAY-163909, without altering the tissue concentration of NA, increased 5-HT concentrations in the medial orbitofrontal cortex and the motor cortex M2 at 3 mg/kg and decreased it in the dorsolateral orbitofrontal cortex at 0.3 mg/kg. WAY-163909 enhanced DA concentrations in the central nucleus of the amygdala at 0.3 mg/kg and reduced it in the dorsal hypothalamus at 3 mg/kg. Using correlative analysis of the tissue content of monoamines, WAY-163909 dramatically changed the profile and the pattern of the correlations within and between monoaminergic systems without drastically changing the total number of these correlations. The profile of these changes in correlations was dose-dependent as it was very different between the two doses within and among monoaminergic systems. In conclusion, the data indicated that the 5-HT 2C receptor agonist WAY-163909 quantitatively alters monoamine content in very few regions but promotes multiple changes of monoaminergic connectivity in the brain., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

N-acetylcysteine, a precursor molecule of glutathione, is an antioxidant. Ketamine, a pediatric anesthetic, has been implicated in cardiotoxicity and neurotoxicity including modulation of monoaminergic systems in mammals and zebrafish. Here, we show that N-acetylcysteine prevents ketamine's adverse effects on development and monoaminergic neurons in zebrafish embryos. The effects of ketamine and N-acetylcysteine alone or in combination were measured on the heart rate, body length, brain serotonergic neurons and tyrosine hydroxylase-immunoreactive (TH-IR) neurons. In the absence of N-acetylcysteine, a concentration of ketamine that produces an internal embryo exposure level comparable to human anesthetic plasma concentrations significantly reduced heart rate and body length and those effects were prevented by N-acetylcysteine co-treatment. Ketamine also reduced the areas occupied by serotonergic neurons in the brain, whereas N-acetylcysteine co-exposure counteracted this effect. TH-IR neurons in the embryo brain and TH-IR cells in the trunk were significantly reduced with ketamine treatment, but not in the presence of N-acetylcysteine. In our continued search for compounds that can prevent ketamine toxicity, this study using specific endpoints of developmental toxicity, cardiotoxicity and neurotoxicity, demonstrates protective effects of N-acetylcysteine against ketamine's adverse effects. This is the first study that shows the protective effects of N-acetylcysteine on ketamine-induced developmental defects of monoaminergic neurons as observed in a whole organism., (Published by Elsevier B.V.)

Buchholzia coriacea, taken by elderly, has phytochemicals that have neuro-active metabolites, and the folkloredocumented its use in neuro-behavioral despairs. Previous study in our laboratory shows that methanol extracts of Buchholziacoriacea (MEBC) seeds possess antidepressant-like potentials in laboratory rodents. This present study was conducted toinvestigate the probable mechanism(s) of action by which MEBC potentiates its effects using laboratory rodents.Involvements of serotonergic, cholinergic and adrenergic systems were studied using Forced Swimming Test (FST) and TailSuspension Test (TST) models of behavioral despair. Antagonists which including: Prazosin, an alpha-1-adrenergic receptorblocker (62.5 μg/kg, i.p.), metergoline, a 5HT2 receptor blocker (4 mg/kg, i.p.) and atropine, a -muscarinic cholinergicreceptor blocker (1mg/kg i.p.) were administered before effective dose of MEBC (50mg/kg). Also, the hippocampi of theanimals were studied for changes in neuronal density using Nissl Staining. Our findings showed that mobility was reversedin animals pre-treated with atropine, prazosin, and metergoline significantly (P˂0.05), showing a possible involvement ofthe corresponding systems. However, there was a significant reduction in immobility time (P<0.001) during FST afterchronic administration of the MEBC. The hippocampus showed no significant changes (P<0.05) in neuronal density. Inconclusion, MEBC probably potentiates its antidepressant-like potentials via the cholinergic, adrenergic and partly byserotonergic systems.

Diffuse noxious inhibitory controls (DNICs) utilize descending inhibitory controls through poorly understood brain stem pathways. The human counterpart, conditioned pain modulation, is reduced in patients with neuropathy aligned with animal data showing a loss of descending inhibitory noradrenaline controls together with a gain of 5-HT3 receptor-mediated facilitations after neuropathy. We investigated the pharmacological basis of DNIC and whether it can be restored after neuropathy. Deep dorsal horn neurons were activated by von Frey filaments applied to the hind paw, and DNIC was induced by a pinch applied to the ear in isoflurane-anaesthetized animals. Spinal nerve ligation was the model of neuropathy. Diffuse noxious inhibitory control was present in control rats but abolished after neuropathy. α2 adrenoceptor mechanisms underlie DNIC because the antagonists, yohimbine and atipamezole, markedly attenuated this descending inhibition. We restored DNIC in spinal nerve ligated animals by blocking 5-HT3 descending facilitations with the antagonist ondansetron or by enhancing norepinephrine modulation through the use of reboxetine (a norepinephrine reuptake inhibitor, NRI) or tapentadol (μ-opioid receptor agonist and NRI). Additionally, ondansetron enhanced DNIC in normal animals. Diffuse noxious inhibitory controls are reduced after peripheral nerve injury illustrating the central impact of neuropathy, leading to an imbalance in descending excitations and inhibitions. Underlying noradrenergic mechanisms explain the relationship between conditioned pain modulation and the use of tapentadol and duloxetine (a serotonin, NRI) in patients. We suggest that pharmacological strategies through manipulation of the monoamine system could be used to enhance DNIC in patients by blocking descending facilitations with ondansetron or enhancing norepinephrine inhibitions, so possibly reducing chronic pain.

Major depressive disorder (MDD) is a leading cause of disability worldwide. Current first line therapies target modulation of the monoamine system. A large variety of agents are currently available that effectively alter monoamine levels; however, approximately one third of MDD patients remain treatment refractory after adequate trials of multiple monoamine based therapies. Therefore, patients with treatment-resistant depression (TRD) may require modulation of pathways outside of the classic monoamine system. The purpose of this review was thus to discuss novel targets for TRD, to describe their potential mechanisms of action, the available clinical evidence for these targets, the limitations of available evidence as well as future research directions. Several alternate pathways involved in the patho-etiology of TRD have been uncovered including the following: inflammatory pathways, the oxidative stress pathway, the hypothalamic-pituitary-adrenal (HPA) axis, the metabolic and bioenergetics system, neurotrophic pathways, the glutamate system, the opioid system and the cholinergic system. For each of these systems, several targets have been assessed in preclinical and clinical models. Preclinical models strongly implicate these pathways in the patho-etiology of MDD. Clinical trials for TRD have been conducted for several novel targets; however, most of the trials discussed are small and several are uncontrolled. Therefore, further clinical trials are required to assess the true efficacy of these targets for TRD. As well, several promising novel agents have been clinically tested in MDD populations, but have yet to be assessed specifically for TRD. Thus, their applicability to TRD remains unknown.

Tesofensine (TE) is a novel triple monoamine re-uptake inhibitor inducing a potent inhibition of the re-uptake process in the synaptic cleft of the neurotransmitters dopamine, norepinephrine, and serotonin. In recent preclinical and clinical evaluations TE showed a robust anti-obesity effect, but the specific mechanism of this triple monoamine re-uptake inhibitor still needs to be further elucidated. This positron emission tomography (PET) study, using [¹¹C]βCIT-FE, aimed to assess the degree of the dopamine transporter (DAT) occupancy, at constant TE plasma levels, following different oral, multiple doses of TE during totally 8-12 days. In addition, the relationships between DAT occupancy and TE plasma concentrations, or doses, were investigated to enable assessment of DAT occupancies in subsequent clinical trials. The results demonstrated that TE induced a dose-dependent blockade of DAT following multiple doses of 0.125-1 mg TE at anticipated steady-state conditions. The mean striatal DAT occupancy varied dose-dependently between 18% and 77%. A sigmoid E(max) model well described the relationship between striatal DAT occupancy and TE plasma concentrations or doses. It was estimated that the maximum achievable DAT occupancy was about 80% and that half of this effect was accomplished by approximately 0.25 mg TE and a plasma drug concentration of 4 ng/ml. The results indicated an important mechanism of action of TE on DAT. Further, these results suggest that the previously reported dose-dependent weight loss, in TE treated subjects, was in part mediated by an up-regulation of dopaminergic pathways due to enhanced amounts of synaptic dopamine after blockade of DAT., (© 2013 Published by Elsevier B.V. and ECNP.)

N-methyl-d-aspartate (NMDA) receptors can be inhibited by inhalational anesthetics in vitro at clinically relevant concentrations. Here, to clarify the role of NMDA receptors in anesthetic-induced unconsciousness, we examined the hypnotic properties of isoflurane, sevoflurane and nitrous oxide in NMDA receptor GluN2A subunit knockout mice. The hypnotic properties of inhalational anesthetics were evaluated in mice in the loss of righting reflex (LORR) assay by measuring the 50% concentration for LORR (LORR ED(50)). Knockout mice displayed isoflurane and sevoflurane LORR ED(50) values similar to wild-type controls, indicating no significant contribution of these receptors to the hypnotic action of halogenated anesthetics. However, compared with wild-type controls, mutant mice displayed larger isoflurane LORR ED(50) values in the presence of nitrous oxide, indicating a resistance to this gaseous anesthetic. Knockout mice have enhanced brain monoaminergic activity which occurs secondary to NMDA receptor dysfunction, and the observed resistance to the isoflurane LORR ED(50)-sparing effect of nitrous oxide could be abolished by pretreatment with the dopamine D(2) receptor antagonist droperidol or with the serotonin 5-HT(2A) receptor antagonist ketanserin. Thus, resistance to nitrous oxide in knockout mice appears to be a secondary phenomenon of monoaminergic origin and not a direct result of impaired NMDA receptor function. Our results indicate that NMDA receptors are not critically involved in the hypnotic action of conventionally-used inhalational anesthetics. Also, they suggest that increased brain monoaminergic tone can diminish the effects of general anesthesia. Finally, they provide further evidence that changes secondary to genetic manipulation can explain the results obtained in global knockouts., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Depression could hardly get a satisfactory effect from the currently available antidepressants. To get a more effective treatment, antidepressant effect and monoaminergic mechanism of Fructus Aurantii (FRA) in the rat forced swimming test (FST) and open field test (OFT), and its prokinetics were examined. FST and OFT were respectively used to evaluate the antidepressant effect and locomotor activity of FRA. We observed the effects of monoamine receptor antagonists on FRA-induced antidepressant effect in rat. The effects of FRA on intestinal transit, gastric emptying and in vitro jejunum contractile activity were assessed. FRA decreased significantly the immobility time (32.6±8.5, 30.3±5.2 vs 56.4±9.4, all p<0.01) in FST, dose-dependent increased the locomotor activity (102±17.5, 120±18.5 vs 89±9.8, p<0.05 or 0.01), significantly accelerated gastric emptying (GE: 48.1±6.3, 39.5±5.7 vs 19.5±3.8, p<0.01) and intestinal transit (IT: 67.3±9.1, 64.2±6.3 vs 49.1±8.2, p<0.01) of the semi-liquid meal, compared with vehicle. And FRA (1 μM, 10 μM) significantly increased the mean amplitude (0.24±0.021 and 0.281±0.015) of contraction in jejunum of rat compared with vehicle (0.149±0.011) in vitro. FRA (10 μM) could induce a largest amplitude (0.281±0.015) of contraction in jejunum. The anti-immobility effect of FRA in FST was prevented by pre-treatment of rat with p-chlorophenylalanine methyl ester, WAY100635, ketanserin, haloperidol, SCH233390, sulpiride, yohimbine, but not prazosin. FRA could simultaneously induce prokinetics and antidepressant effect, deserves further to investigate., (Copyright © 2012 Elsevier GmbH. All rights reserved.)

Currently used antidepressants elevate monoamine levels in the synaptic cleft. There is good reason to assume that this is not the only source for antidepressant therapeutic activities and that secondary downstream effects may be relevant for alleviating symptoms of depression. We attempted to elucidate affected biochemical pathways downstream of monoamine reuptake inhibition by interrogating metabolomic profiles in DBA/2Ola mice after chronic paroxetine treatment. Metabolomic changes were investigated using gas chromatography-mass spectrometry profiling and group differences were analyzed by univariate and multivariate statistics. Pathways affected by antidepressant treatment were related to energy metabolism, amino acid metabolism and hormone signaling. The identified pathways reveal further antidepressant therapeutic action and represent targets for drug development efforts. A comparison of the central nervous system with blood plasma metabolite alterations identified GABA, galactose-6-phosphate and leucine as biomarker candidates for assessment of antidepressant treatment effects in the periphery.

Introduction: Major depression is one of the most prevalent forms of mental illnesses and is among the leading causes of disability, affecting about 121 million people worldwide. Approximately 30% of patients fail to respond to present therapies. Therefore, the search for novel antidepressant drugs continues., Areas Covered: The most prescribed antidepressants are serotonin reuptake inhibitors and/or noradrenaline reuptake inhibitors, which only indirectly affect dopaminergic neurotransmission. As a consequence, residual symptoms remain, including impaired motivation and impaired pleasure. This article reviews the development of new broad-spectrum antidepressants, the triple reuptake inhibitors, which also increase brain dopamine levels., Expert Opinion: In this review, a distinction is made between the subtypes of melancholic and atypical depressions and their associated brain abnormalities and dysfunctions in neurotransmitter systems. Subsequently, we propose a hypothetical model: 'the monoamine hypothesis revisited' to predict what kind of pharmacological treatment will be effective in the different subtypes of depression. It is expected that the triple reuptake inhibitors, inhibiting the reuptake of all three monoamines, can produce a greater efficacy than traditional antidepressants especially in atypical depression. Since triple reuptake inhibitors may also dampen states of hyperglutamatergic activity and subsequent excitotoxicity, it is suggested that these new drugs have a considerable neuroprotective potential in major depression, especially in melancholic depression.

The relationship between depression and monoaminergic systems has been hypothesized for many years. In this study, we have investigated the possible antidepressant-like effect of scopoletin, a coumarin from Polygala sabulosa in the tail suspension test and forced swimming test. Moreover, the ability of scopoletin to reverse the depression-like behavior in the forced swimming test induced by immobility stress in mice was evaluated. Scopoletin reduced the immobility time in the tail suspension test (10-100mg/kg, p.o.), but not in the forced swimming test. Fluoxetine (positive control) decreased the immobility time in the forced swimming and tail suspension tests (20mg/kg, p.o. and 10mg/kg. p.o., respectively). Immobility stress caused an increase in the immobility time in the forced swimming test (depression-like behavior), which was reversed by scopoletin (1-100mg/kg, p.o.) and fluoxetine (10mg/kg, p.o.). Scopoletin produced no psychostimulant effect in the open-field test. The pretreatment of mice with ketanserin (5mg/kg, i.p., a preferential 5-HT(2A) receptor antagonist), prazosin (1mg/kg, i.p., an alpha(1)-adrenoceptor antagonist), yohimbine (1mg/kg, i.p., an alpha(2)-adrenoceptor antagonist), haloperidol (0.2mg/kg, i.p., a dopaminergic receptor antagonist), SCH23390 (0.05 mg/kg, s.c., a dopamine D(1) receptor antagonist) or sulpiride (50mg/kg, i.p., a dopamine D(2) receptor antagonist), but not WAY100635 (0.1mg/kg, s.c., a selective 5-HT(1A) receptor antagonist) prevented the antidepressant-like effect of scopoletin (10mg/kg, p.o.) in the tail suspension test. The results indicate that its antidepressant-like effect is dependent on the serotonergic (5-HT(2A) receptors), noradrenergic (alpha(1)- and alpha(2)-adrenoceptors) and dopaminergic (dopamine D(1) and D(2) receptors) systems., (2010 Elsevier B.V. All rights reserved.)

Tesofensine is a (triple) reuptake inhibitor of noradrenaline, dopamine, and serotonin that is in development for the treatment of obesity. The abuse potential of triple reuptake inhibitors is not yet known, and so this study was undertaken to evaluate the potential abuse-related effects of tesofensine in humans. It was designed as a single-dose, randomized, double-blind, crossover study involving tesofensine vs. placebo, D-amphetamine (positive control for dopaminergic/stimulant effects), bupropion, and atomoxetine (negative/unscheduled controls) in recreational stimulant users (N = 52). Subjective and objective measures were assessed for 48 h after drug administration. The study results show that the effects of D-amphetamine were significantly greater than those of placebo on all primary and secondary subjective measures. The effects of tesofensine were not significantly different from those of placebo and were lower than those of D-amphetamine 30 mg on all primary and most secondary measures. The effects of tesofensine were either lower than or not different from those of bupropion or atomoxetine. These results demonstrate that the abuse potential for tesofensine is no greater than that of bupropion or atomoxetine, and tesofensine is therefore unlikely to be recreationally abused.

Effective therapeutic options for Alzheimer's disease (AD) are limited and much research is currently ongoing. The high attrition rate in drug development is a critical issue. Here, the quantitative pharmacology approach (QP-A) and model-based drug development (MBDD) provide a valuable opportunity to support early selection of the most promising compound and facilitate a fast, efficient, and rational drug development process. The aim of this analysis was to exemplify the QP-A by eventually predicting the clinical outcome of a proof-of-concept (PoC) trial of tesofensine in AD patients from two small phase IIa trials. Retrospective population pharmacokinetic/pharmacodynamic (PK/PD) modeling of tesofensine, its metabolite M1, and assessment scale-cognitive subscale data from two 4-week placebo-controlled studies in 62 mild AD patients was performed using non-linear mixed effects modeling. The final PK/PD model was used to predict data of a negative 14-week phase IIb PoC trial (430 AD patients). For the PK, one-compartment models for tesofensine and M1 with first-order absorption and elimination were sufficient. An extended Emax model including disease progression best described the PK/PD relationship using effect compartments. The placebo effect was also implemented in the final PK/PD model based on a published placebo model developed in a large AD cohort. Various internal evaluation techniques confirmed the reliability and predictive performance of the PK/PD model, which also successfully predicted the 14-week PoC data. For tesofensine, the dose concentration-effect relationship has successfully been described in mild AD patients demonstrating the supportive value of PK/PD models in QP-A/MBDD in early phases of clinical development for decision-making.

Unlabelled: The present studies assessed the potential abuse liability and likely mechanism(s) of action of the wake-promoting agent modafinil., Methods: Experiments assessed the locomotor sensitization (LS) and discriminative stimulus (DS) properties of modafinil in mouse and rat, respectively. Comparative data were generated with a range of psychostimulants and monoamine reuptake inhibitors., Results: Repeated administration of d-amphetamine and cocaine, psychostimulants with high abuse liability, resulted in the induction and expression of LS in mice. Bupropion and caffeine, two psychostimulants not abused in humans, were not associated with LS. GBR12909 induced LS during repeated exposure, but there was no evidence of expression of LS after acute challenge following withdrawal. In contrast, repeated administration of modafinil resulted in the expression, but not induction, of LS. d-amphetamine, but not the mu-opioid agonist morphine or the nAChR agonist nicotine, fully substituted for the cocaine DS in rats. The selective dopamine transporter (DAT) inhibitor GBR12909 fully substituted, the preferential norepinephrine transporter (NET) inhibitor desipramine partially substituted, and the selective serotonin reuptake inhibitor citalopram failed to substitute for cocaine. Modafinil fully substituted for cocaine, similar to the mixed DAT/NET inhibitor bupropion., Conclusions: Two preclinical assays indicated potential abuse liability of modafinil; drug discrimination studies suggest DAT blockade by modafinil is a likely mechanism of action in vivo., (Copyright 2010 Elsevier Inc. All rights reserved.)

The antidepressant-like effect of the ethanolic extract obtained from barks of Tabebuia avellanedae, a plant widely employed in folk medicine, was investigated in two predictive models of depression: forced swimming test (FST) and tail suspension test (TST) in mice. Additionally, the mechanisms involved in this antidepressant-like action and the effects of the association of the extract with the antidepressants fluoxetine, desipramine and bupropion in the TST were investigated. The extract from T. avellanedae produced an antidepressant-like effect, in the FST (100 mg/kg, p.o.) and in the TST (10-300 mg/kg, p.o.), without accompanying changes in ambulation when assessed in the open-field test. The anti-immobility effect of the extract (30 mg/kg, p.o.) in the TST was prevented by pre-treatment of mice with ketanserin (5 mg/kg, i.p., a preferential 5-HT(2A) receptor antagonist), prazosin (1 mg/kg, i.p., an alpha(1)-adrenoceptor antagonist), yohimbine (1 mg/kg, i.p., an alpha(2)-adrenoceptor antagonist), propranolol (2 mg/kg, i.p., a beta-adrenoceptor antagonist), sulpiride (50 mg/kg, i.p., a dopamine D(2) receptor antagonist) and SCH23390 (0.05 mg/kg, s.c., a dopamine D(1) receptor antagonist). The combined administration of a subeffective dose of WAY100635 (0.1 mg/kg, s.c., a selective 5-HT(1A) receptor antagonist) and a subeffective dose of the extract (1 mg/kg, p.o.) produced a significant reduction in the immobility time in the TST. In addition, the combination of fluoxetine (1 mg/kg, p.o.), desipramine (0.1 mg/kg, p.o.), or bupropion (1 mg/kg, p.o.) with a subeffective dose of the extract (1 mg/kg, p.o.) produced a synergistic antidepressant-like effect in the TST, without causing hyperlocomotion in the open-field test. It may be concluded that the extract from T. avellanedae produces an antidepressant-like effect in the FST and in the TST that is dependent on the monoaminergic system. Taken together, our results suggest that T. avellanedae deserves further investigation as a putative alternative therapeutic tool that could help the conventional pharmacotherapy of depression., (Copyright 2009 Elsevier Inc. All rights reserved.)

Results of a neurochemical study of the effects of the new anxiolytic drugs afobazole and ladasten on the synthesis and metabolism of monoamines and their metabolites determined by HPLC on the model of monoamine synthesis blockade induced by NSD-1015 (aromatic L-amino acid decarboxylase) in the brain structures of Wistar rats are reported. A decrease in the levels of DOPAC in hypothalamus and HVA in striatum after afobazole injection may be evidence of an inhibitory action of this drug on the activity of monoamine oxidase (MAO-A), which is the main enzyme involved in dopamine biodegradation. Afobazole was also found to increase the content of serotonin (5-HT) as well as its precursor (5-OTP) and its main metabolite (5-HIAA) in hypothalamus by up to 50, 60 and 50%, respectively, which confirms a hypothesis that this anxiolytic drug can modulate the activity of tryptophan hydroxylase (5-OTP synthesis enzyme). In contrast to afobazole, ladasten demonstrated the ability to increase the level of L-DOPA (a dopamine precursor) in virtually all functional structures of the brain (except for hippocamp), which may support the hypothesis suggestion concerning a predominant action of this drug on the activity of tyrosine hydroxylase. Ladasten exhibited selectivity with respect to the dopaminergic system and affected only parameters of the dopamine metabolism, in particular, by increasing the HVA content in nucleus accumbens and decreasing it in the hypothalamus. The drug also affected the dopamine turnover parameters, producing an increase in both HVA/dopamine ratio in nucleus accumbens and DOPAC/dopamine ratio in hippocamp.

The indirubins long have been used in Chinese medicine for treatment of myelocytic leukemia. Among the many more recently described biological activities of the indirubins, attention has been directed toward the ability of these compounds to inhibit GSK-3 and CDKs, kinases implicated in neurodegenerative conditions. Little information is available on effects of indirubins on chemically-induced neurodegeneration. Here we examined the influence of three indirubins on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- and kainic acid (KA)-induced neurotoxicity in the mouse. The three indirubins examined were 6-bromoindirubin-3'-oxime (6BIO), 5-bromoindirubin-3'-oxime (5BIO) and 5-amino-6-bromoindirubin (5A6BI). The first two derivatives were previously described indirubins with low nanomolar inhibitory activity against GSK-3 and CDKs. The third compound was synthesized by the dimerization of 5-amino-6-bromoisatin with 3-acetoxyindol. The synthesis of the key compound 5-amino-6-bromoisatin was based on the bromination of the ketal of 5-amino-isatin. All indirubins examined decreased various measures associated with dopaminergic neurotransmission in striatum. These effects occurred alone or over and above the decrements seen following administration of the dopaminergic neurotoxicant, MPTP. Striatal serotonin and serotonin turnover were decreased by the indirubins in MPTP-treated mice. None of these striatal effects of the indirubins alone were associated with evidence of astrogliosis, an indicator of underlying neuropathology, nor did they potentiate the astrogliosis accompanying administration of MPTP. In general, the indirubins reduced KA-associated mortality and striatal but not hippocampal astrogliosis due to this toxicant. The data suggest that indirubins affect striatal biogenic amine levels and turnover in intact mice. The data do not indicate a neuroprotective action of indirubins in mice treated with MPTP but that they do suggest that they may be neuroprotective against KA-induced injury of the neostriatum., (Published by Elsevier Inc.)

The pathophysiological neural mechanism underlying the depressogenic and anxiogenic effects of chronic adolescent cannabinoid use may be linked to perturbations in monoaminergic neurotransmission. We tested this hypothesis by administering the CB(1) receptor agonist WIN55,212-2, once daily for 20 days to adolescent and adult rats, subsequently subjecting them to tests for emotional reactivity paralleled by the in vivo extracellular recordings of serotonergic and noradrenergic neurons. Chronic adolescent exposure but not adult exposure to low (0.2 mg/kg) and high (1.0 mg/kg) doses led to depression-like behaviour in the forced swim and sucrose preference test, while the high dose also induced anxiety-like consequences in the novelty-suppressed feeding test. Electrophysiological recordings revealed both doses to have attenuated serotonergic activity, while the high dose also led to a hyperactivity of noradrenergic neurons only after adolescent exposure. These suggest that long-term exposure to cannabinoids during adolescence induces anxiety-like and depression-like behaviours in adulthood and that this may be instigated by serotonergic hypoactivity and noradrenergic hyperactivity., (2009 Elsevier Inc. All rights reserved.)

Background: Recent studies demonstrate that diverse antidepressant agents increase the cellular production of the nucleolipid CDP-diacylglycerol and its synthetic derivative, phosphatidylinositol, in depression-relevant brain regions. Pharmacological blockade of downstream phosphatidylinositide signaling disrupted the behavioral antidepressant effects in rats. However, the nucleolipid responses were resistant to inhibition by serotonin receptor antagonists, even though antidepressant-facilitated inositol phosphate accumulation was blocked. Could the neurochemical effects be additional to the known effects of the drugs on monoamine transmitter transporters? To examine this question, we tested selected agents in serotonin-depleted brain tissues, in PC12 cells devoid of serotonin transporters, and on the enzymatic activity of brain CDP-diacylglycerol synthase - the enzyme that catalyzes the physiological synthesis of CDP-diacylglycerol., Results: Imipramine, paroxetine, and maprotiline concentration-dependently increased the levels of CDP-diacylglycerol and phosphatidylinositides in PC12 cells. Rat forebrain tissues depleted of serotonin by pretreatment with p-chlorophenylalanine showed responses to imipramine or maprotiline that were comparable to respective responses from saline-injected controls. With fluoxetine, nucleolipid responses in the serotonin-depleted cortex or hippocampus were significantly reduced, but not abolished. Each drug significantly increased the enzymatic activity of CDP-diacylglycerol synthase following incubations with cortical or hippocampal brain tissues., Conclusion: Antidepressants probably induce the activity of CDP-diacylglycerol synthase leading to increased production of CDP-diacylglycerol and facilitation of downstream phosphatidylinositol synthesis. Phosphatidylinositol-dependent signaling cascades exert diverse salutary effects in neural cells, including facilitation of BDNF signaling and neurogenesis. Hence, the present findings should strengthen the notion that modulation of brain phosphatidylinositide signaling probably contributes to the molecular mechanism of diverse antidepressant medications.

Prostaglandin E(2) (PGE(2)) and its analogue sulprostone inhibit noradrenaline and serotonin release in rodent tissues. We examined whether the receptor involved is blocked by the EP(3) antagonist L-826,266, whether such receptors also occur on central cholinergic neurones and retinal dopaminergic cells, whether PGE(2) is produced by the degradation of the endocannabinoid virodhamine and whether EP(3) receptor activation stimulates (35)S-GTPgammaS binding. Transmitter release was studied as electrically evoked tritium overflow in superfused tissues preincubated with (3)H-noradrenaline (which in the guinea pig retina labels dopaminergic cells), (3)H-serotonin or (3)H-choline. (35)S-GTPgammaS binding, a measure of G protein activation, was studied in mouse and guinea pig hippocampal membranes. L-826,266 antagonised the effect of sulprostone on noradrenaline release in the rat cortex, yielding a Schild plot-based pA(2) value of 7.56. Apparent pA(2) values in mouse cortex and rat vas deferens (noradrenaline release) and rat cortex (serotonin release) were 7.55, 7.87 and 7.67, respectively. PGE(2) did not affect acetylcholine release in rat brain and dopamine release in guinea pig retina. In seven mice tissues, noradrenaline release was inhibited by sulprostone but not affected by virodhamine. (35)S-GTPgammaS binding was not altered by sulprostone but stimulated by the cannabinoid agonist WIN 55,212-2. Prostaglandins of the E series inhibit monoamine release via EP(3) receptors at which L-826,266 is a competitive antagonist. EP(3) receptors that inhibit transmitter release are not present on central cholinergic neurones and retinal dopaminergic cells. Virodhamine is not converted to PGE(2). An EP(3) receptor model based on (35)S-GTPgammaS binding could not be identified.

A series of 2beta-carbomethoxy-3beta-phenyl tropanes with conformationally constrained nitrogen substituents were synthesized as potential selective dopamine transporter ligands. These novel compounds were examined for their monoamine uptake inhibition potency at the human dopamine transporter (hDAT), the human serotonin transporter (hSERT) and the human noradrenalin transporter (hNET), stably expressed in human embryonic kidney cells (HEK). A SAR-study was conducted to determine the contribution of extended, 4-fluorinated, conformationally constrained C4 chains at the tropane nitrogen to human monoamine transporter affinity and selectivity.

Despite adequate antidepressant monotherapy, the majority of depressed patients do not achieve remission. Even optimal and aggressive therapy leads to a substantial number of patients who show minimal and often only transient improvement. In order to address this substantial problem of treatment-resistant depression, a number of novel targets for antidepressant therapy have emerged as a consequence of major advances in the neurobiology of depression. Three major approaches to uncover novel therapeutic interventions are: first, optimizing the modulation of monoaminergic neurotransmission; second, developing medications that act upon neurotransmitter systems other than monoaminergic circuits; and third, using focal brain stimulation to directly modulate neuronal activity. We review the most recent data on novel therapeutic compounds and their antidepressant potential. These include triple monoamine reuptake inhibitors, atypical antipsychotic augmentation, and dopamine receptor agonists. Compounds affecting extra-monoamine neurotransmitter systems include CRF(1) receptor antagonists, glucocorticoid receptor antagonists, substance P receptor antagonists, NMDA receptor antagonists, nemifitide, omega-3 fatty acids, and melatonin receptor agonists. Focal brain stimulation therapies include vagus nerve stimulation (VNS), transcranial magnetic stimulation (TMS), magnetic seizure therapy (MST), transcranial direct current stimulation (tDCS), and deep brain stimulation (DBS).

Ascorbic acid is highly concentrated in the brain, being considered as a neuromodulator. This study investigated the effect of ascorbic acid in the tail suspension test (TST) and in the forced swimming test (FST) in mice and the contribution of the monoaminergic system to its antidepressant-like effect. Moreover, the effects of fluoxetine, imipramine and bupropion in combination with ascorbic acid in the TST were investigated. Ascorbic acid (0.1-10 mg/kg, i.p., 1-10 mg/kg p.o. or 0.1 nmol/mice i.c.v.) produced an antidepressant-like effect in the TST, but not in the FST, without altering the locomotor activity. The effect of ascorbic acid (0.1 mg/kg, i.p.) in the TST was prevented by i.p. pre-treatment with NAN-190 (0.5 mg/kg), ketanserin (5 mg/kg), MDL72222 (0.1 mg/kg), prazosin (62.5 microg/kg), yohimbine (1 mg/kg), propranolol (2 mg/kg), haloperidol (0.2 mg/kg), sulpiride (50 mg/kg), but not with SCH23390 (0.05 mg/kg, s.c.). Additionally, ascorbic acid (1 mg/kg, p.o.) potentiated the effect of subeffective doses (p.o. route) of fluoxetine (1 mg/kg), imipramine (0.1 mg/kg), or bupropion (1 mg/kg) in the TST. The combined treatment of ascorbic acid with antidepressants produced no alteration in the locomotion in the open-field test. In conclusion, our results show that administration of ascorbic acid produces an antidepressant-like effect in TST, which is dependent on its interaction with the monoaminergic system. Moreover, ascorbic acid caused a synergistic antidepressant-like effect with conventional antidepressants. Therefore, the present findings warrant further studies to evaluate the therapeutical relevance of ascorbic acid for the treatment of depression and as a co-adjuvant treatment with antidepressants.

This study characterized the ion channel activities in the hippocampus of diabetic rats by monitoring the levels of monoamines. Extracellular levels of serotonin and dopamine were measured in the hippocampus of awake, freely moving streptozotocin-induced diabetic rats, spontaneously diabetic rats, and non-diabetic rats, using in vivo microdialysis. Sodium, calcium, and potassium ion channel blockers were used to assess the ion channel activities. The results suggest that there are no abnormalities in the ion channels of diabetic brain, but the reduced levels of monoamines could be due to any problems of reuptake, release, and rate of breakdown of these molecules.

Objective: Tesofensine (TE) is a norepinephrine, dopamine, and serotonin reuptake inhibitor. We conducted a meta-analysis of TE's effect on body weight in trials investigating its potential for treatment of Parkinson's or Alzheimer's disease., Methods and Procedures: Four randomized, double-blind, multicenter trials compared TE (n = 740) and placebo (n = 228), two in each disease. Patients received oral TE or placebo once daily for 14 weeks without any weight loss program. Results were adjusted for baseline values, age, and study., Results: In the placebo group, 14% were obese and 21% were in the TE group. In the total cohort, weight change after 14 weeks was +0.5, -0.5, -0.9, -1.8, -2.8% in the placebo, 0.125, 0.25, 0.5 and 1.0 mg in the TE groups, respectively (P = 0.015 for dose effect). In the obese subgroup, weight changes were -0.2, -1.7, -1.6, -1.5, -3.7%, and 2.1, 8.2, 14.1, 20.9, 32.1% of the obese patients achieved > or = 5% weight loss (P < 0.001 for 0.25, 0.5, and 1.0 mg vs. placebo for both end points). Changes in heart rate were -0.4, 2.1, 4.2, 6.0, and 6.8 bpm after 14 weeks (TE vs. placebo: P < 0.001 from 0.25 mg), but no effect on blood pressure was observed., Discussion: TE produced a placebo-subtracted weight loss of approximately 4% for >14 weeks without any diet and lifestyle therapy, which is similar to that of sibutramine, but with no effect on blood pressure. On the basis of these results, TE is now being developed for obesity management.

Schizophrenia is a disabling psychiatric disorder characterized by positive, negative, and cognitive symptoms. The first pharmacological treatments for schizophrenia were discovered by serendipitous, albeit carefully documented, clinical observations. The discovery of chlorpromazine and other dopamine D2 receptor antagonists as antipsychotic agents set the early course of drug discovery in the context of schizophrenia and other psychiatric disorders, and various monoamine receptors became the prime focus of neuropharmacological studies. Success in treating the positive symptoms nevertheless remained limited by the general lack of efficacy in addressing negative symptoms and cognitive impairment. In recent years, several new experimental approaches have emerged for the identification and treatment of different symptom clusters that do not rely on blockade of monoamine receptors. Muscarinic, nicotinic, and glutamatergic signaling mechanisms have become essential to neuropharmacological and behavioral models of discrete aspects of schizophrenia. And as a consequence of these insights, novel drug entities have become available to study and potentially treat the disabling cognitive and negative symptoms of psychiatric disease. Current attempts to target a new range of receptors entail unprecedented fine-tuning in the pharmacological manipulation of specific receptor subtypes.

Absorption, metabolism, and excretion of paliperidone, an atypical antipsychotic, was studied in five healthy male subjects after a single dose of 1 mg of [(14)C]paliperidone oral solution ( approximately 16 microCi/subject). One week after dosing, 88.4 to 93.8% (mean 91.1%) of the administered radioactivity was excreted: 77.1 to 87.1% (mean 79.6%) in urine and 6.8 to 14.4% (mean 11.4%) in the feces. Paliperidone was the major circulating compound (97% of the area under the plasma concentration-time curve at 24 h). No metabolites could be detected in plasma. Renal excretion was the major route of elimination with 59% of the dose excreted unchanged in urine. About half of the renal excretion occurred by active secretion. Unchanged drug was not detected in feces. Four metabolic pathways were identified as being involved in the elimination of paliperidone, each of which accounted for up to a maximum of 6.5% of the biotransformation of the total dose. Biotransformation of the drug occurred through oxidative N-dealkylation (formation of the acid metabolite M1), monohydroxylation of the alicyclic ring (M9), alcohol dehydrogenation (formation of the ketone metabolite M12), and benzisoxazole scission (formation of M11), the latter in combination with glucuronidation (M16) or alicyclic hydroxylation (M10). Unchanged drug, M1, M9, M12, and M16 were detected in urine; M10 and M11 were detected in feces. The monohydroxylated metabolite M9 was solely present in urine samples of extensive CYP2D6 metabolizers, whereas M10, another metabolite monohydroxylated at the alicyclic ring system, was present in feces of poor metabolizers as well. In conclusion, paliperidone is not metabolized extensively and is primarily renally excreted.

Microinjections of serotonin and glutamic acid into the globus pallidus in conditions of free selection between a light and a dark chamber showed these substances to have antiaversive activity in rats in the "threatening situation" test but not in the "illuminated area" test. Local administration of dopamine and GABA into this basal ganglia formation had no effect on the mechanisms of voluntary movement but countered anxiety states in both behavioral models. These results provide evidence that the neurotransmitter systems of the dorsal pallidum have different degrees of involvement in the operative control of behavior when the modality of the aversive stimulus changes.

5-Methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) is a synthetic orally active hallucinogenic tryptamine derivative, known also as Foxy or Foxy methoxy. However, few studies have examined its effects in vitro. In the present study, we investigated the actions of 5-MeO-DIPT against monoamine neurotransmitter transporters, including the transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT), using COS-7 cells heterologously expressing these transporters and rat brain synaptosomes. 5-MeO-DIPT specifically inhibited the uptake of [3H]serotonin (5-HT) by the SERT-expressing COS-7 cells and rat striatal synaptosomes in a high affinity manner at concentrations similar to those for cocaine. The effect was reversible and competitive. 5-MeO-DIPT failed to stimulate reverse transport of [3H]5-HT through SERT, while it prevented the releasing action of methamphetamine. 5-MeO-DIPT induced cell toxicity at high concentrations in COS-7 cells, and it was not influenced by the expression of SERT. These results demonstrated that 5-MeO-DIPT acts as a competitive SERT inhibitor and has an inability to cause reverse transport, underlying its serotonergic actions.

The biogenic amine octopamine is known to be present in the abdominal ganglia of some insects, but the expression of functional octopamine receptors in these neuronal structures has not yet been characterized. In the present study, we describe the presence in the female gypsy moth terminal abdominal ganglion (TAG), a key structure in the control of the insect reproductive behavior, of an octopamine receptor coupled to stimulation of adenylyl cyclase through the GTP-binding protein G(s). The rank order of potency of different antagonists, which discriminate between the different classes of octopamine receptors, indicated the involvement of the neuronal type 3 receptor. The octopamine-stimulated adenylyl cyclase activity was inhibited by Ca(2+) in the low micromolar range and by activation of either protein kinase A or protein kinase C. In the isolated TAG, bath application of octopamine caused an increase of the spontaneous bursting activity of the emerging nerve of the 5th pair (V), whereas the antagonist mianserin reduced the nerve spiking activity and blocked the stimulatory effect of octopamine. These data demonstrate that the gypsy moth TAG expresses functional octopamine receptors, which may participate in the neuronal control of the insect reproductive behavior.

The potent tropane analog, WF-23 [2beta-propanoyl-3beta-(2-naphthyl) tropane], blocks dopamine, serotonin, and norepinephrine transporters with high affinity in vitro and blocks transporters for at least 2 days following a single in vivo administration. Previous studies demonstrated desensitization of monoamine receptor-coupled G-proteins in brain following chronic treatment of rats with WF-23. The current study sought to determine the time course of this desensitization and the behavioral effects of receptor desensitization. Rats were treated with 1 mg/kg WF-23 and injected i.p. every 48 h for 1 to 21 days. Receptor activation of G-proteins was determined by guanosine 5'-O-(3-[(35)S]thiotriphosphate) ([(35)S]GTPgammaS) binding in brain sections for monoamine receptors, as well as mu opioid receptors as a nonmonoamine receptor control. Chronic treatment with WF-23 produced significant reductions in D(2), 5-hydroxytryptamine 1A, and alpha(2)-adrenergic receptor-stimulated [(35)S]GTPgammaS binding; however, the time course of desensitization varied with different receptors. There was no effect of WF-23 treatment on mu opioid-stimulated [(35)S]GTPgammaS binding at any time point. Consistent with previous studies, there was no effect of WF-23 treatment on D(2) receptor binding, as determined by [(3)H]spiperone autoradiography. Locomotor activity was significantly increased for up to 48 h following acute administration of WF-23, demonstrated by increased photocell beam interruptions. WF-23-induced increases in locomotor activity occurred following repeated administration, as above, for up to 7 days. Following 7 days of treatment, there was a significant decrease in WF-23-increased locomotor activity. This reduction occurred at the same time point as the decrease in D(2) receptor/G-protein coupling, suggesting a role of D(2) desensitization in producing tolerance to WF-23-mediated behavior.

Monoamine transporters were originally associated simply with the termination of synaptic monoamine function. In addition to amine reuptake, however, the transporters can act as ion channels that affect exocytotic neurotransmitter release and can operate in reverse mode, mediating non-exocytotic amine release. Activity at the plasma membrane is controlled by trafficking, which is modulated by interaction with both substrates and inhibitors and by cytosolic kinases and phosphatases. Monoamine transporters also constitute the principal sites of action of many psychoactive drugs, including amphetamines and cocaine, as well as therapeutic drugs for the treatment of depression, addiction and attention deficit hyperactivity disorder, each modifying the balance of presynaptic neurotransmitter function.

This study examines the effect of long-term elevation of brain monoamine levels on receptor/G-protein coupling by chronic administration of a highly potent tropane analog, WF-23 (2beta-propanoyl-3beta-(2-naphthyl) tropane). WF-23 blocks dopamine, serotonin and norepinephrine transporters with high affinity in vitro, and blocks transporters for at least two days following a single in vivo administration. Rats were chronically treated for 15 days with 1mg/kg WF-23, injected i.p. every two days. Receptor activation of G-proteins was determined by [35S]GTPgammaS autoradiography in brain sections for D2, 5-HT1A and alpha2-adrenergic receptors, as well as mu opioid receptors as a non-monoamine receptor control. Chronic treatment with WF-23 produced significant reductions in D2, 5-HT1A, and alpha2-adrenergic receptor-stimulated [35S]GTPgammaS binding in caudate/putamen, hippocampus and amygdala, respectively. There were no effects of WF-23 treatment on mu opioid-stimulated [35S]GTPgammaS binding. Additionally, there was no effect of WF-23 treatment on D2 receptor binding, as determined by [3H]spiperone autoradiography. These data show that chronic blockade of monoamine transporters produces specific uncoupling of receptors and G-proteins in specific brain regions in the absence of receptor downregulation.

We analyzed the ability of the mu opioid peptide receptor ligands morphine and naloxone and several antidepressant drugs that are serotonin (fluoxetine), noradrenaline (reboxetine), mixed serotonin and noradrenaline (milnacipram and venlafaxine), dopamine (nomifensine) reuptake inhibitors, as well as roxindole (a nonselective drug) to substitute for, or alter, tramadol discrimination. Male Wistar rats were trained to discriminate tramadol (20 mg/kg) from saline in a two-choice water-reinforced paradigm. Out of the drugs studied, only morphine substituted for tramadol. In combination experiments, naloxone (0.1-1 mg/kg) attenuated the stimulus effects of tramadol (20 mg/kg) and the substitution evoked by morphine (2 mg/kg). Milnacipram (10 mg/kg) or reboxetine (10 mg/kg) enhanced the effects of tramadol (2.5-10 mg/kg); the other antidepressant drugs used failed to modulate tramadol discrimination. Our results indicate that tramadol can be used as a stimulus cue in rats, and that mu opioid peptide mechanisms are involved in its effects, while noradrenergic uptake inhibitors can enhance tramadol discrimination.

The monoamines, dopamine, epinephrine, histamine, norepinephrine, octopamine, serotonin and tyramine serve many functions in animals. Many different venoms have evolved to manipulate monoaminergic systems via a variety of cellular mechanisms, for both offensive and defensive purposes. One common function of monoamines present in venoms is to produce pain. Some monoamines in venoms cause immobilizing hyperexcitation which precedes venom-induced paralysis or hypokinesia. A common function of venom components that affect monoaminergic systems is to facilitate distribution of other venom components by causing vasodilation at the site of injection or by increasing heart rate. Venoms of some scorpions, spiders, fish and jellyfish contain adrenergic agonists or cause massive release of catecholamines with serious effects on the cardiovascular system, including increased heart rate. Other venom components act as agonists, antagonists or modulators at monoaminergic receptors, or affect release, reuptake or synthesis of monoamines. Most arthropod venoms have insect targets, yet, little attention has been paid to possible effects of these venoms on monoaminergic systems in insects. Further research into this area may reveal novel effects of venom components on monoaminergic systems at the cellular, systems and behavioral levels.

The rat medial prefrontal cortex is known to have diverse brain functions such as learning and memory, attention, and behavioral flexibility. Although these functions are affected by monoamines (dopamine (DA), noradrenaline (NA) and serotonin (5-HT)) and acetylcholine (ACh), the detailed mechanisms remain unclear. These neuromodulators also have effects on synapse formation and maintenance, and regulate plasticity in the central nervous system (CNS). To clarify the effects of these neuromodulators on changes in the density of synapses in the rat medial prefrontal cortex, we separately administered a D1- or D2-antagonist, NA neurotoxin, 5-HT synthetic inhibitor, or muscarinic ACh antagonist for 1 week, and counted the number of synapses on electron microscopic photographs taken from the prelimbic area of the medial prefrontal cortex. The density of synapses in lamina I was regulated by DA via D1-like receptors, and that in laminae II/III was decreased by depletion of NA or ACh. However, 5-HT did not have a regulatory effect on the synaptic density throughout the layers in this brain region. The data in this study and our previous studies indicate that there are appreciable regional differences in the magnitude of biogenic amine-mediated synaptic plasticity in the rat CNS. These neuromodulators may have a trophic-like effect on the selected neuronal circuit to maintain synaptic contacts in the rat CNS. The synaptic density in the medial prefrontal cortex regulated by monoamines and ACh could be important not only for synaptic plasticity in this region but also for pharmacotherapeutic drug treatment., (Copyright 2004 Elsevier B.V.)

Extracts of Hypericum perforatum L. (St John's wort) are now successfully competing for status as a standard antidepressant therapy. Because of this, great effort has been devoted to identifying the active antidepressant compounds in the extract. From a phytochemical point of view, St John's wort is one of the best-investigated medicinal plants. A series of bioactive compounds has been detected in the crude material, namely flavonol derivatives, biflavones, proanthocyanidines, xanthones, phloroglucinols and naphthodianthrones. Although St John's wort has been subjected to extensive scientific studies in the last decade, there are still many open questions about its pharmacology and mechanism of action. Initial biochemical studies reported that St John's wort is only a weak inhibitor of monoamine oxidase-A and -B activity but that it inhibits the synaptosomal uptake of serotonin, dopamine and noradrenaline (norepinephrine) with approximately equal affinity. However, other in vitro binding assays carried out using St John's wort extract demonstrated significant affinity for adenosine, GABA(A), GABA(B) and glutamate receptors. In vivo St John's wort extract leads to a downregulation of beta-adrenergic receptors and an upregulation of serotonin 5-HT(2) receptors in the rat frontal cortex and causes changes in neurotransmitter concentrations in brain areas that are implicated in depression. In studies using the rat forced swimming test, an animal model of depression, St John's wort extracts induced a significant reduction of immobility. In other experimental models of depression, including acute and chronic forms of escape deficit induced by stressors, St John's wort extract was shown to protect rats from the consequences of unavoidable stress. Recent neuroendocrine studies suggest that St John's wort is involved in the regulation of genes that control hypothalamic-pituitary-adrenal axis function. With regard to the antidepressant effects of St John's wort extract, many of the pharmacological activities appear to be attributable to the naphthodianthrone hypericin, the phloroglucinol derivative hyperforin and several flavonoids. This review integrates new findings of possible mechanisms that may underlie the antidepressant action of St John's wort and its active constituents with a large body of existing literature.

Fibromyalgia is a chronic pain disorder of which other clinical features, such as persistent fatigue and disordered sleep, may be a secondary consequence. The initial pharmacological approach to treating the disorder is the management of the pain. Tricyclic antidepressants are the most effective drugs in use so far, especially when administered in combination with other therapies (e.g., selective serotonin re-uptake inhibitors), which suggests modulation of the neurotransmitters serotonin and noradrenaline. The effectiveness of amitriptyline and related tricyclic antidepressants, however, is consistent with the involvement of mechanisms, such as potassium channel modulation and NMDA receptor antagonism, in addition to or in place of the modulation of monoamine neurotransmitters. Investigation of the importance of each of the pharmacological properties of amitriptyline and related molecules in the management of fibromyalgia could provide clues for the rational design of new drugs.

The conformation and alignment of cocaine analogues bound to the monoamine transporter proteins were explored using the tensor decomposition 3-D QSAR method. It is proposed from these calculations that the bound conformation of these ligands to the three transporter proteins has the 3beta-aryl substituent in a conformation in which the aryl group is orthogonal or approximately orthogonal to the tropane ring. Based on these results, rigid and semi-rigid tropane analogues were designed, synthesized and their affinities for the monoamine transporters were determined.

Monoamine-based therapies that selectively target serotonin, norepinephrine, or dopamine uptake are effective as antidepressants. However, many depressed patients do not achieve remission with these single-action agents. Treatment strategies that target more than one neurotransmitter, either through augmentation, combination treatment, or the development of single agents with dual or triple reuptake mechanisms, may prove to be even more effective than traditional antidepressants and merit further research.

Advances in antidepressant therapy have resulted in agents with fewer serious side effects than, for example, nonselective monoamine oxidase inhibitors and tricyclic antidepressants. Nonetheless, these newer agents are far from the ideal. Many of the drawbacks associated with these newer agents--slow onset, low rate of response, and low rate of remission--are likely to be mechanism related. In order to overcome these problems, researchers must either improve upon these traditional, biogenic amine-based mechanisms or explore nontraditional mechanisms. Strategies for improving biogenic amine-based antidepressants include the so-called serotonin augmentation strategy and the broad spectrum agent that simultaneously blocks reuptake at the serotonin, norepinephrine, and dopamine transporters. Two nontraditional approaches employ modulation of glutamate receptor function. At face value, these glutamate-based approaches (N-methyl-D-aspartate [NMDA] antagonists and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid [AMPA] receptor potentiators) appear diametrically opposed. However, these 2 mechanisms may ultimately impact similar cellular endpoints.

A study was made of the effects of several monoamine-uptake inhibitors on membrane currents elicited by acetylcholine (ACh-currents) generated by rat neuronal alpha2beta4 and mouse muscle nicotinic acetylcholine receptors (AChRs) expressed in Xenopus laevis oocytes. For the two types of receptors the monoamine-uptake inhibitors reduced the ACh-currents albeit to different degrees. The order of inhibitory potency was norfluoxetine > clomipramine > indatraline > fluoxetine > imipramine > zimelidine > 6-nitro-quipazine > trazodone for neuronal alpha2beta4 AChRs, and norfluoxetine > fluoxetine > imipramine > clomipramine > indatraline > zimelidine > trazodone > 6-nitro-quipazine for muscle AChRs. Thus, the most potent inhibitor was norfluoxetine, whilst the weakest ones were trazodone, 6-nitro-quipazine and zimelidine. Effects of the tricyclic antidepressant imipramine were studied in more detail. Imipramine inhibited reversibly and non-competitively the ACh-current with a similar inhibiting potency for both neuronal alpha2beta4 and muscle AChRs. The half-inhibitory concentrations of imipramine were 3.65 +/- 0.30 microM for neuronal alpha2beta4 and 5.57 +/- 0.19 microM for muscle receptors. The corresponding Hill coefficients were 0.73 and 1.2 respectively. The inhibition of imipramine was slightly voltage-dependent, with electric distances of approximately 0.10 and approximately 0.12 for neuronal alpha2beta4 and muscle AChRs respectively. Moreover, imipramine accelerated the rate of decay of ACh- currents of both muscle and neuronal AChRs. The ACh-current inhibition was stronger when oocytes, expressing neuronal alpha2beta4 or muscle receptors, were preincubated with imipramine alone than when it was applied after the ACh-current had been generated, suggesting that imipramine acts also on non-activated or closed AChRs. We conclude that monoamine-uptake inhibitors reduce ACh-currents and that imipramine regulates reversibly and non- competitively neuronal alpha2beta4 and muscle AChRs through similar mechanisms, perhaps by interacting externally on a non-conducting state of the AChR and by blocking the open receptor-channel complex close to the vestibule of the channel. These studies may be important for understanding the regulation of AChRs as well as for understanding antidepressant- and side-effects of monoamine-uptake inhibitors.

Neurochemical analysis using anxiosedative and anxioselective agents injected into the hypothalamus revealed that antiaversive action of camprione is only realised under conditions of domineering fear motivation whereas that of chlordiazepoxide, phenibut, indoter may also be realised under conditions of negative stressful zoo-social impacts mediated by serotonin.

Previous studies have shown that direct-acting dopamine agonists modulate the multisecond oscillations which are present in globus pallidus spike trains in vivo in awake rats. To investigate possible modulation by endogenous dopamine and by other monoamines, and by drugs with abuse potential, cocaine or selective monoamine uptake blockers were injected systemically during extracellular recording of single globus pallidus neurons and the results analyzed with spectral and wavelet methods. Both cocaine and the selective dopamine uptake blocker GBR-12909 significantly shortened the period of multisecond oscillations, as well as increasing overall firing rate. Cocaine effects were blocked by dopamine antagonist pretreatment, as well as by N-methyl-D-aspartate receptor antagonist (MK-801) pretreatment. Desipramine and fluoxetine (blockers of norepinephrine and serotonin uptake, respectively) had no significant effects on multisecond oscillations. The results suggest that dopamine has a primary role among monoamines in modulating multisecond oscillations in globus pallidus activity, and that tonic dopaminergic and glutamatergic transmission is necessary for normal slow oscillatory function.

The experiments using "illuminated site" and "threatening situation" avoidance tests on rats microinjected with GABA, glutamic acid, monoamines and their agonists and antagonists, as well as anxiosedative and anxioselective agents into the anterior hypothalamus revealed functional ambiguity in the neurochemical profile of this limbic brain formation in the anxiety states of various aversive genesis. Preliminary intraperitoneal injection of the monoamine and GABA antagonists, followed by the local administration of the antianxiety drugs studied, showed that the antiaversive action of chlordiazepoxide, fenibut, and indoter is manifested in both anxiety models via a GABAergic mechanism in the anterior hypothalamus. The anxiolytic effect of campiron is manifested only under negative-stressor zoosocial conditions and is mediated by the serotoninergic systems of this limbic brain formation.

A series of novel diamine, amine-amide, and piperazinone analogues of N-[2-(bisarylmethoxy)ethyl]-N'-(phenylpropyl)piperazines, GBR 12909 and 12935, were synthesized and evaluated as inhibitors of presynaptic monoamine neurotransmitter transporters. The primary objective of the study was to determine the structural requirements for selectivity of ligand binding and potency for neurotransmitter reuptake inhibition. In general, the target compounds retained transporter affinity; however, structural variations produced significant effects on reuptake inhibition and transporter selectivity. For example, analogues prepared by replacing the piperazine ring in the GBR structure with an N, N'-dimethylpropyldiamine moiety displayed enhanced selectivity for binding and reuptake inhibition at the norepinephrine (NE) transporter site (e.g. 4 and 5). Congeners in which the amide nitrogen atom was attached to the aralkyl moiety of the GBR molecule showed moderate affinity (K(i) = 51-61 nM) and selectivity for the dopamine transporter (DAT) site. In contrast, introduction of a carbonyl group adjacent to either nitrogen atom of the piperazine ring (e.g. 25 and 27) was not well tolerated. From the compounds prepared, analogue 16 was selected for further evaluation. With this congener, locomotor activity induced by cocaine at a dose of 20 mg/kg was attenuated with an AD(50) (dose attenuating cocaine-induced stimulation by 50%) of 60.0 +/- 3.6 mg/kg.

Extrapyramidal symptoms, such as tardive dyskinesia, often develop in patients on long-term treatment with haloperidol. It has been proposed that these symptoms could be caused by neurotoxic effects of haloperidol metabolites following uptake by monoamine transporters, in an analogous mechanism to the neurotoxic effect of MPP+ (1-methyl-4-phenylpyridinium) metabolised from MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). In this study, the hypothesis was partially investigated by determining the potencies of haloperidol and reduced haloperidol and the corresponding pyridinium and tetrahydropyridine metabolites, compared with MPP+ and MPTP, as inhibitors of the noradrenaline transporter (NAT), dopamine transporter (DAT) and 5-HT transporter (SERT). Two days after COS-7 cells were transiently transfected with the cDNA for the human NAT, DAT or SERT (Lipofectamine method), the cells were incubated with 10 nM [3H]noradrenaline, dopamine or 5-HT, respectively, for 2 min at 37 C, in the absence or presence of various concentrations of the eight compounds or a specific uptake inhibitor (NAT: nisoxetine 1 microM; DAT: GBR 12909 1 microM; SERT: citalopram 10 microM). Specific amine uptake (fmol/ mg protein) was calculated as the difference in uptake in the absence and presence of the specific uptake inhibitor. Ki values were calculated for the eight compounds for inhibition of NAT, DAT and SERT. Haloperidol, its five metabolites and MPP+ and MPTP all inhibited NAT, DAT and SERT. For the pyridinium and tetrahydropyridine metabolites of haloperidol, there were not marked differences between their potencies as inhibitors between each other for NAT or DAT or between NAT and DAT, with all of the Ki values in the range of 5.8-16 microM. However, there were more marked differences for SERT, with all but one of the metabolites showing selectivity for inhibition of SERT relative to NAT and DAT. Haloperidol and reduced haloperidol had similar inhibitory potencies for all three transporters, and were clearly less potent than the other haloperidol metabolites only for inhibition of SERT. The lack of correlation between the inhibitory potencies of the haloperidol metabolites and their structural analogues, MPTP and MPP+, suggests that they are not likely to cause neurotoxicity by a mechanism analogous to that of the latter neurotoxin.