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Different kinds of secondary metabolites present in the medicinal plants play an important role to alleviate different human ailments including neurodegenerative disorders such as Parkinson's, Alzheimer's, epilepsy and schizophrenia etc. Recently we have isolated and characterized a novel bioactive compound viz. 3-(3,4-dimethoxy phenyl)-1-4(methoxy phenyl)prop-2-en-1-one from the methanolic extract of Celastrus paniculatus (CP) which has been widely used for the treatment of neurodegenerative diseases. The present investigation is mainly aimed to evaluate the neuroprotective potential of the above bioactive compound against ketamine-induced schizophrenia with particular reference to catecholaminergic metabolism using in vivo and in silico methods. Ketamine-induced schizophrenia caused significant elevation in biogenic amines (epinephrine, nor epinephrine, dopamine and 5-HT) and monoamine oxidase activity levels which were restored to normal during the treatment with the bioactive compound akin to the reference compound, clozapine. In addition, the compound has shown highest binding score against all the biogenic amine receptors viz. D1, D2, D3, D4 and serotonin receptor, 5-HT2A with lowest inhibition constant values than the reference compound, clozapine. The present findings suggest that modulation of CNS monoamine neurotransmitter system might partly contribute to the impairments associated with schizophrenia and the plant compound alleviates the monoaminergic abnormalities associated with the neurological dysfunction.Communicated by Ramaswamy H. Sarma.

Introduction: Astroglia represent the main cellular homeostatic system of the central nervous system (CNS). Astrocytes are intimately involved in regulation and maintenance of neurotransmission by regulating neurotransmitters removal and turnover and by supplying neurons with neurotransmitters precursors. Astroglial cells are fundamental elements of monoaminergic transmission in the brain and in the spinal cord. Astrocytes receive monoaminergic inputs and control catabolism of monoamines through dedicated transporters and intracellular enzymatic pathways.Areas covered: Astroglial cells express serotonergic receptors; in this review, we provide an in-depth characterization of 5-HT2B receptors. Activation of these receptors triggers numerous intracellular signaling cascades that regulate expression of multiple genes. Astroglial 5-HT2B receptors are activated by serotonin-specific reuptake inhibitors, such as major anti-depressant fluoxetine. Expression of astroglial serotonin receptors undergoes remarkable changes in depression disorders, and these changes can be corrected by chronic treatment with anti-depressant drugs.Expert commentary: Depressive behaviors, which occur in rodents following chronic stress or in neurotoxic models of Parkinson disease, are associated with significant changes in the expression of astroglial, but not neuronal 5-HT2B receptors; while therapy with anti-depressants normalizes both receptors expression and depressive behavioral phenotype. In summary, astroglial serotonin receptors are linked to mood disorders and may represent a novel target for cell- and molecule-specific therapies of depression and mood disorders.

Tramadol is an opioid drug that, unlike classic opioids, also modulates the monoaminergic system by inhibiting noradrenergic and serotoninergic reuptake. For this reason, tramadol is considered an atypical opioid. These special pharmacological characteristics have made tramadol one of the most commonly prescribed analgesic drugs to treat moderate to severe pain. Areas covered: The aim of this review is to provide a historical description of the biochemistry, pharmacokinetics and particularly, the mechanisms of action of tramadol. In addition, a summary is offered of the analgesic effects of tramadol in a variety of animal models of acute and chronic pain. Finally, clinical studies that demonstrate the efficacy and safety of tramadol in the treatment of pain are also assessed. Expert opinion: The discovery that tramadol combines opioid and monoaminergic effects represented a milestone in the evolution of pain treatment. Given its 'mild effect' on opioid receptors, tramadol induces fewer side effects than classic opioids. Tramadol produces satisfactory analgesia against various types of pain and it is currently approved for the treatment of moderate to severe pain. Thus, the combination of monoamine and opioid mechanisms opens new avenues for the design of innovative analgesics.

Classical monoaminergic antidepressants show several disadvantages, such as protracted onset of therapeutic action. Conversely, the fast and sustained antidepressant effect of the N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine raises vast interest in understanding the role of the glutamate system in mood disorders. Indeed, numerous data support the existence of glutamatergic dysfunction in major depressive disorder (MDD). Drawback to this short-latency therapy is its side effect profile, especially the psychotomimetic action, which seriously hampers the common and widespread clinical use of ketamine. Therefore, there is a substantial need for alternative glutamatergic antidepressants with milder side effects. In this article, we review evidence that implicates NMDARs in the prospective treatment of MDD with focus on rapastinel (formerly known as GLYX-13), a novel synthetic NMDAR modulator with fast antidepressant effect, which acts by enhancing NMDAR function as opposed to blocking it. We summarize and discuss current clinical and animal studies regarding the therapeutic potential of rapastinel not only in MDD but also in other psychiatric disorders, such as obsessive-compulsive disorder and posttraumatic stress disorder. Additionally, we discuss current data concerning the molecular mechanisms underlying the antidepressant effect of rapastinel, highlighting common aspects as well as differences to ketamine. In 2016, rapastinel received the Breakthrough Therapy designation for the treatment of MDD from the US Food and Drug Administration, representing one of the most promising alternative antidepressants under current investigation.

Classic antidepressants that modulate monoaminergic systems are not sufficiently effective and require long systematic application. Recent studies suggest that substances that modulate glutamatergic system may produce an antidepressant effect which is not only faster but also more sustained.In this paper, the authors summarize the results of studies on antidepressant action of ketamine in patients with severe refractory depression, which have demonstrated high efficacy in a very short time after a single dose. Due to the adverse effects of ketamine that substantially exclude it from the daily use by patients, efforts have been made to find other NMDA receptor antagonists, which could mimic the therapeutic effect of ketamine but without the side effects. Intensive studies to elucidate ketamine's mechanism of antidepressant action have also been conducted. Herein, the results of research showing that metabotropic glutamate (mGlu) receptors could be the target of novel antidepressants are also presented.The intensive preclinical and clinical research on NMDA and mGlu receptor ligands, which is currently going on, could contribute to the awaited breakthrough in the field of novel antidepressant drug discovery. This line of research may also lead to a new understanding of the biological basis of depression.

Major Depressive Disorder (MDD) is a serious mental health problem that leads to patients' disability and has huge impact on social and economic burden to society. The current available medications for the treatment of depression are mainly targeted on enhancing monoamine neurotransmission. However, antidepressant treatments are still lacking high efficacy in many cases which is associated with low treatment response and remission rates. However, the latest knowledge regarding the pathophysiology of depression indicates that depression is developed by highly complex and integrated mechanisms in which monoaminergic deficiency could only be part of. The paradigm is now shifting from monoaminergic hypothesis to significance of other novel mechanisms that could possibly play substantial role for the development of depression in a highly inter-related manner. In fact, neuroinflammation, amongst other mechanisms does seem to be a key pathological component by having impact on certain pathway pathologies...

The physiological properties of the native, endogenous prion protein (PrP(C)) is a matter of concern, due to its pleiotropic functions and links to neurodegenerative disorders and cancer. In line with our hypothesis that the basic function of PrP(C) is to serve as a cell surface scaffold for the assembly of signaling modules, multiple interactions have been identified of PrP(C) with signaling molecules, including neurotransmitter receptors. We recently reported evidence that PrP(C) may modulate monoaminergic neurotransmission, as well as depressive-like behavior in mice. Here, we discuss how those results, together with a number of other studies, including our previous demonstration that both inflammatory and behavioral stress modulate PrP(C) content in neutrophils, suggest a distributed role of PrP(C) in clinical depression and inflammation associated with neurodegenerative diseases. An overarching understanding of the multiple interventions of PrP(C) upon physiological events may both shed light on the pathogenesis of, as well as help the identification of novel therapeutic targets for clinical depression, Prion and Alzheimer's Diseases.

One third of depressed patients do not respond adequately to conventional antidepressants including the selective serotonin reuptake inhibitors (SSRIs). Therefore, multi-target drugs or augmentation strategies have been developed for the management of SSRIs-resistant patients. In this context, the 5-HT(2) receptor subtypes represent promising targets but their precise roles have yet to be determined.The aim of this review is to shed some light on the preclinical evidence supporting the use of 5-HT(2A) and/or 5-HT(2C) receptor antagonists such as antipsychotics, as potential effective adjuncts in SSRIs-resistant depression. This review synthesizes the current literature about the behavioral, electrophysiological and neurochemical effects of 5-HT(2) receptors ligands on the monoaminergic systems but also on adult hippocampal neurogenesis.Although studies support the hypothesis that the inactivation of 5-HT(2A) and/or 5-HT(2C) receptors might be of interest to reinforce different facets of the therapeutic activity of SSRIs, this pharmacological strategy remains debatable notably because of the lack of chronic data in relevant animal models. Conversely, emerging evidence suggests that the activation of 5-HT(2B) receptor is required for antidepressant-like activity, opening the way to new therapeutic approaches. However, the potential risks related to the enhancement of monoaminergic neurotransmissions could represent a major concern.

Several lines of evidence support the role of monoaminergic and cholinergic dysregulation in attention deficit hyperactivity disorder (ADHD) and the concept that peripheral blood neurotransmission indices may represent valuable surrogate CNS markers. We determined platelet MAO-B activity (p-MAO-B) and lymphocyte muscarinic cholinergic receptor binding (l-MR) in 44 unmedicated ADHD children (aged 9.1 +/- 2.87 years) and in 26 age-matched controls for comparison. Lower levels of p-MAO-B (approximately 35%) and l-MR (approximately 55%) in ADHD were observed compared with controls. Differences were gender-dependent: p-MAO-B was reduced in males only (5.20 +/- 2.99 vs 8.46 +/- 5.1 nmol mg(-1) protein h(-1) in ADHD and controls, respectively) and l-MR in females only (ADHD vs control: 6.63 +/- 1.75 and 15.30 +/- 8.35 fmol 10(-6) cells). The clinical significance was corroborated by the correlation between these markers and severity of specific symptoms: lower p-MAO-B associated with increased inattention scores (Conners' teacher-rating scale); lower l-MR associated with increased score for oppositional-defiant disorder (ODD) (SNAP-IV); and trend towards correlation between increased inattention (SNAP-IV) and lower l-MR.

Major depression and anxiety are two of the major psychiatric disorders that have some overlapping pathophysiologies, the most significant being the dysfunction in the monoaminergic, GABAergic and glutamatergic systems. A large number of drugs that alter these neurotransmitter levels/systems are effective in the treatment of major depression and anxiety. However, full remission of the clinical symptoms has not been achieved, perhaps owing to the complex pathophysiology of the diseases. Thus, the search for newer targets and target-specific drugs continues. Recently, the role of sigma-receptors, particularly the sigma-1 receptor subtype, has been identified as a target for the pathophysiology of neuropsychiatric disorders, and sigma-1 receptor modulators are considered to be the drugs of the future for the treatment of major depression and anxiety. The present review attempts to discuss the role of sigma-1 receptors in the pathophysiology of major depression and anxiety and also tries to position the use of its receptor modulators in the treatment of these two major disorders. The role of sigma-1 receptors in the mechanism of antidepressant action of venlafaxine, bupropion, neurosteroids and one of the herbal antidepressants, berberine, is reviewed. Although, sigma-1 receptor modulators may be future therapeutic options, either as individual agents or adjuvants in the treatment of mental disorders, the topic needs further preclinical and clinical exploration.

Hypocretins (or orexins) are two neuropeptides synthesized by neurons located exclusively in the hypothalamus. Hypocretin-containing neurons have widespread projections throughout the CNS; with particularly dense excitatory projections to monoaminergic and serotonergic brainstem centers. The hypocretin system influences a wide range of physiological processes in mammals, such as feeding, arousal, rewards and drug addiction. Recently, a number of studies in experimental animals showed that hypocretins are involved in pain modulation within the CNS, and suggested the presence of a link between these peptides and nociceptive phenomena observed in primary headaches. The aim of this review is to describe and discuss recent studies in humans suggesting a role for the hypocretin neuronal system in cluster headache and chronic migraine.

The highly evolved architecture of the cerebral cortex is organized across hierarchical levels that maximize functional repertoires (emergent properties) and expedite information processing. Minicolumns are nested within this multiscale architecture as the smallest module capable of processing information. Signals are transmitted within minicolumns through massive ion-gated connections and modulated through slower onset second messenger systems. The terminal zones of the modulatory second messenger systems comprise the laminae of the cortex. A comprehensive review of the literature suggests that schizophrenia results from widely distributed changes at the level of the cerebral cortex and little, if any, neuronal somatic changes: (EsiriCrow, 2002). Concordant with this observation recent studies indicate that schizophrenic patients have an alteration of neuronal connectivity according to both lamina and brain region examined. One possible explanation for this deficit is an alteration in the modulatory system of cortical minicolumns. This ontogenetic deficit propitiates a cascade of neurochemical changes resulting in varying abnormalities relating information processing to behavioural states.

The combination of total steep deprivation (TSD) and light therapy (LT) in bipolar depression causes rapid antidepressant effects, and its mechanism of action has been hypothesized to involve the enhancement of all of the monoaminergic systems targeted by antidepressant drugs (serotonin, dopamine, norepinephrine). It is still unknown if the clinical effects are paralleled by changes in biological rhythms. In a before/after design of a study of biological correlates of response, 39 inpatients affected by Type I Bipolar Disorder whose current depressive episode was without psychotic features were treated for one week with repeated TSD combined with morning LT. Wrist actigraphy was recorded throughout the study. Two-thirds of the patients responded to treatment (50% reduction in Hamilton Depression score). Responders showed an increase in daytime activity, phase-advance of the activity-rest rhythm of 57 min compared to the pre-treatment baseline, and reduced nighttime sleep. Non-responders did not show significant changes in the parameters of their activity-rest rhythm. Phase advance of the activity-rest rhythm is an actimetric correlate of the antidepressant response to TSD and LT in bipolar depression. Results are consistent with the known effects of sleep-wake manipulations and neurotransmitter function on the suprachiasmatic nucleus. The combination of total steep deprivation (TSD) and light therapy (LT) in bipolar depression causes rapid antidepressant effects, and its mechanism of action has been hypothesized to involve the enhancement of all of the monoaminergic systems targeted by antidepressant drugs (serotonin, dopamine, norepinephrine). It is still unknown if the clinical effects are paralleled by changes in biological rhythms. In a before/after design of a study of biological correlates of response, 39 inpatients affected by Type I Bipolar Disorder whose current depressive episode was without psychotic features were treated for one week with repeated TSD combined with morning LT. Wrist actigraphy was recorded throughout the study. Two-thirds of the patients responded to treatment (50% reduction in Hamilton Depression score). Responders showed an increase in daytime activity, phase-advance of the activity-rest rhythm of 57 min compared to the pre-treatment baseline, and reduced nighttime sleep. Non-responders did not show significant changes in the parameters of their activity-rest rhythm. Phase advance of the activity-rest rhythm is an actimetric correlate of the antidepressant response to TSD and LT in bipolar depression. Results are consistent with the known effects of sleep-wake manipulations and neurotransmitter function on the suprachiasmatic nucleus.

The development of conventional antidepressants has been largely based on the hypothesis of monoaminergic dysfunctions and focuses particularly on the serotonin 5-hydroxytryptamine (5-HT) system. Hence, various classes of antidepressant treatments enhance 5-HT neurotransmission with a time course consistent with their delayed therapeutic effect. This delayed onset appears to be associated with the gradual development of specific adaptive changes of functional 5-HT receptors. However, recent theories suggest that major depressive disorders may be associated with impairments of functional plasticity and cellular flexibility. This review discusses several physiological mechanisms by which 5-HT function and hippocampal neuroplasticity are regulated. Knowledge of these long-term adaptations will increase not only our understanding of pathological processes underlying affective disorders, but could also lead to the development of new strategies to treat these devastating illnesses.

While antidepressant pharmacotherapy is an effective treatment of depression, it still is hampered by a delayed time of onset of clinical improvement and a series of side effects. Moreover, a substantial group of patients has only limited response or fails to respond at all. One source accounting for these variations are genetic differences as currently analysed by single nucleotide polymorphisms (SNP) mapping. In recent years a number of pharmacogenetic studies on antidepressant drugs have been published. So far they mostly focused on metabolizing enzymes of the cytochrome P450 (CYP) families and genes within the monoaminergic system with compelling evidence for an effect of CYP2D6 polymorphisms on antidepressant drug plasma levels and of a serotonin transporter promoter polymorphism on clinical response to a specific class of antidepressants, the selective serotonin reuptake inhibitors. It is clear, however, that other candidate systems have to be considered in the pharmacogenetics of antidepressant drugs, such as neuropeptidergic systems, the hypothalamus-pituitary adrenal (HPA) axis and neurotrophic systems. There is recent evidence that polymorphisms in genes regulating the HPA axis have an important impact on response to antidepressants. These studies mark the beginning of an emerging standard SNP profiling system that ultimately allows identifying the right drug for the right patient at the right time.

There is a biological basis for anticipating a role for the essential fatty acids (EFAs) in the therapeutics of the large number of conditions characterized by impulsivity, hostility and aggression. Abnormalities in these constructs have been linked to dysfunction of several monoaminergic systems, 5-hydroxytryptamine (5-HT) in particular. The EFAs ameliorate the function of these systems and also act through a number of other mechanisms. While limited in volume, a number of EFA supplementation studies support their role in the treatment of such conditions. This paper summarises the literature in terms of epidemiology, clinical science and therapeutics in clinical and non-clinical populations.

Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness and cataplexy. The hypocretin/orexin deficiency is likely to be the key to its pathophysiology in most of cases although the cause of human narcolepsy remains elusive. Acting on a specific genetic background, an autoimmune process targeting hypocretin neurons in response to yet unknown environmental factors is the most probable hypothesis in most cases of human narcolepsy with cataplexy. Although narcolepsy presents one of the tightest associations with a specific human leukocyte antigen (HLA) (DQB1*0602), there is strong evidence that non-HLA genes also confer susceptibility. In addition to a point mutation in the prepro-hypocretin gene discovered in an atypical case, a few polymorphisms in monoaminergic and immune-related genes have been reported associated with narcolepsy. The treatment of narcolepsy has evolved significantly over the last few years. Available treatments include stimulants for hypersomnia with the quite recent widespread use of modafinil, antidepressants for cataplexy, and gamma-hydroxybutyrate for both symptoms. Recent pilot open trials with intravenous immunoglobulins appear an effective treatment of cataplexy if applied at early stages of narcolepsy. Finally, the discovery of hypocretin deficiency might open up new treatment perspectives.

Bioactive lipids, in particular arachidonic acid (AA), are vital for monoaminergic neurotransmission, brain development and synaptic plasticity. Phospholipases A2 (PLA2) are key-enzymes in AA metabolism and are activated during monoaminergic neurotransmission. Reduced membrane AA levels, and an altered activity of PLA2 have been found in peripheral membranes of drug-naïve patients with schizophrenia with some conflicting results in more chronic patient populations. Furthermore, in vivo brain phosphorus-31 magnetic resonance spectroscopy suggests reduced lipid membrane precursors (phosphomonoesters) and increased membrane breakdown products (phosphodiesters) in drug-naïve or early treated first-episode schizophrenia patients compared to age-matched controls or chronic populations and these changes were correlated with peripheral red blood cell membrane AA levels. We postulate that processes modulating membrane lipid metabolism are associated with psychotic illnesses and might partially explain the mechanism of action of antipsychotic agents, as well as experimental agents such as purified ethyl-eicosapentaenoic acid (E-EPA). Recent supplementation trials suggest that E-EPA is a modestly effective augmentation treatment resulting in reduced doses of antipsychotic medication in acutely ill patients with schizophrenia (but not in residual-type schizophrenia). This review investigates the role of bioactive lipids in schizophrenia and its treatment, as well as its potential use in prevention.

Interactions of the serotonergic and noradrenergic system at different sites of the brain may be important for efficacy and side effects of antidepressant drugs. Further, serotonin and noradrenaline play a critical role in the development of neurons during brain maturation. To gain further insight how brain maturation and the two monoaminergic systems are influenced by drug treatment during early postnatal development, this animal study investigated possible effects on the noradrenaline and serotonin transporter density of the frontal cortex very early in postnatal life. Rats were treated from postnatal day 2 to 5 either with fluoxetine (5 mg/kg per day s.c.) or with reboxetine (10 mg/kg per day s.c.). At day 90 the serotonin and noradrenaline transporter density in the frontal cortex was measured by ligand binding assay. Fluoxetine treatment led to a significant long-lasting increase of serotonin (not noradrenaline) transporter density (Bmax = 1231 +/- 34) in the frontal cortex (compared with saline-treated controls (Bmax = 1112 +/- 58)). Reboxetine treatment (surprisingly) led to an even more enhanced serotonin transporter density (Bmax = 1322 +/- 46), while noradrenaline transporter density seemed to be unaffected. There were no significant differences for KD values. The results support the idea that serotonin seems to play an important role during early brain development. Moreover, drug-related modulation of the noradrenergic system during brain maturation seems to cross-influence the serotonergic system.

Selective serotonin reuptake inhibitors (SSRIs) can safely and successfully treat major depression, although a substantial number of patients benefit only partially or not at all from treatment. Genetic polymorphisms may play a major role in determining the response to SSRI treatment. Nonetheless, it is likely that efficacy is determined by multiple genes, with individual genetic polymorphisms having a limited effect size. Initial studies have identified the promoter polymorphism in the gene coding for the serotonin reuptake transporter as moderating efficacy for several SSRIs. The goal of this review is to suggest additional plausible polymorphisms that may be involved in antidepressant efficacy. These include genes affecting intracellular transductional cascades; neuronal growth factors; stress-related hormones, such as corticotropin-releasing hormone and glucocorticoid receptors; ion channels and synaptic efficacy; and adaptations of monoaminergic pathways. Association analyses to examine these candidate genes may facilitate identification of patients for targeted alternative therapies. Determining which genes are involved may also assist in identifying future, novel treatments.

Recent advances in the identification of the neural circuits, neurochemicals, and signal transduction mechanisms involved in the pathophysiology and treatment of mood disorders have led to much progress toward understanding the roles of genetic factors and psychosocial stressors. The monoaminergic neurotransmitter systems have received the most attention, partly because of the observation that effective antidepressant drugs exert their primary biochemical effects by regulating intrasynaptic concentrations of serotonin and norepinephrine. Furthermore, the monoaminergic systems are extensively distributed throughout the network of limbic, striatal, and prefrontal cortical neuronal circuits thought to support the behavioral and visceral manifestations of mood disorders. Increasing numbers of neuroimaging, neuropathological, and biochemical studies indicate impairments in cellular plasticity and resilience in patients who suffer from severe, recurrent mood disorders. In this paper, we describe studies identifying possible structural, functional, and cellular abnormalities associated with depressive disorders, which are potentially the cellular underpinnings of these diseases. We suggest that drugs designed to enhance cellular plasticity and resilience, and attenuate the activity of maladaptive stress-responsive systems, may be useful for the treatment of severe mood disorders.

Treatment of depression has been dominated by monoamine hypotheses for nearly half a century. Although the ultimate downstream targets of manipulation of biogenic amine transport and metabolism are signal transduction cascades, neurotrophic factors and ultimately genomic fine-tuning, much of drug development has remained focused on strategies to facilitate a rapid initial augmentation of synaptic neurotransmitter levels. Both monoaminergic agents that are highly specific in their target receptor stimulation and agents that modify multiple monoamine systems will move through the stages of drug development in coming years. Furthermore, recent landmark successes and initial pilot data indicates that small molecule peptide receptor antagonists for substance P, corticotrophin releasing factor and eventually others will be of increasing importance, since they may more subtlety modulate neurotransmission and only act on already deranged neural circuits. Eventually treatment strategies may begin to target intracellular kinase and phosphatase activity and other signal systems responsible for transporter and receptor trafficking patterns, as well as via more direct pathways toward mobilization of neurotrophic factor activity. In the near future however, refinement of monoamine strategies to treat depression will continue to guide thinking and development of novel drugs for depression. This review focuses primarily on developments relevant for the evolution of monaminergic and neuropeptide-based drugs for depression.

Removal of retinal input from a restricted region of adult visual cortex leads to a substantial reorganisation of the retinotopy within the deprived zone. To investigate the role of the total (intra- and extracellular) concentration of the monoaminergic neuromodulators in the sub-cortical region of cat visual cortex, which is possibly involved in this reorganisation mechanism, a method for identification and quantification of noradrenaline, dopamine, serotonin, and their major metabolites, 3,4-dihydroxyphenylacetic acid, 4-hydroxy-3-methoxyphenylacetic acid, 5-hydroxyindole-3-acetic acid in small amounts of brain extracts has been developed and validated. Control or retinal lesion cats were killed with pentobarbital; the brains were quickly frozen, and 200 μm cryostat sections were cut. Under visual control through a surgical microscope, the cortical tissue was first separated from the underlying white matter. Three pieces of tissue measuring 2 × 4 mm2, containing the six cortical layers, were sampled out...

Brainstem monoaminergic projections to the suprachiasmatic nucleus (SCN), and to the intergeniculate leaflet (IGL), appear to modulate both photic and non-photic effects on the circadian system. Recent work in this laboratory has concentrated on the role of noradrenaline in the regulation of circadian period and phase. Previously, this lab has shown that chronic administration of the alpha2 adrenergic agonist, clonidine, to rats maintained in constant light (LL) shortens free-running circadian period and promotes dissociation of rhythmicity, while acute clonidine administration to hamsters produces phase shifts similar to those observed with photic stimuli. These results suggest an interaction between clonidine and photic input on circadian rhythmicity, and so the present study was designed to examine systematically the relationship between chronic clonidine administration and photic input in both rats and hamsters. In DD and low intensity LL, clonidine did not alter free-running circadian wheel-running r...

Various monoaminergic measures as well as corticosteroid deviances have repeatedly been linked to depression or suicidal behavior. With the purpose to study these biological markers in relationship with temperament, the Marke-Nyman Temperament (MNT) questionnaire was administered in a sample of 89 suicide attempters. The subjects were diagnosed according to the DSM-III-R and subgrouped according to suicide method into 'violent' and 'nonviolent' attempters, and into 'repeaters' (with previous attempt) and 'nonrepeaters' (without previous attempts). The subjects were also subgrouped according to MNT patterns into 5 MNT clusters. Lumbar punctures were performed and the monoamine metabolites homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycole (MHPG) in the cerebrospinal fluid (CSF) were analysed. The levels of plasma cortisol and 24 h. urinary cortisol were determined and dexamethasone suppression tests (DST) were performed. The activity of the enzyme monoamine oxidase (MAO) in platelets was determined. Among the alcoholic patients, the biological markers showed several specific correlations with temperament. In this group, low Solidity (reflecting impulsiveness) was significantly associated with low levels of CSF HVA, CSF 5-HIAA, urinary cortisol and low platelet MAO activity. The Stability (reflecting emotional distance towards others) was significantly and positively associated with urinary cortisol and platelet MAO activity. This seems to reflect the two previously described subgroups of alcoholism, with early and late onset, respectively. In the whole sample, we found a positive correlation between urinary cortisol and Stability. The biological markers showed no clear differences between the MNT clusters. We could not replicate earlier findings of an association between impulsiveness (low solidity) and low levels of 5-HIAA or low MAO activity in platelets in the whole sample of suicide attempters.

Gilles de la Tourette syndrome (GTS), a chronic, familial, neuropsychiatric disorder of unknown etiology, is characterized clinically by the presence of motor and vocal tics that wax and wane in severity over time and by the occurrence of a variety of neurobehavioral disturbances including hyperactivity, self-mutilatory behavior, obsessive compulsive behavior, learning disabilities, and conduct disorder. Pharmacological studies suggest that the tics of GTS result from dysfunction of monoaminergic systems, more specifically from increased dopaminergic activity due to postsynaptic dopamine receptor supersensitivity. However, given that striatal dopaminergic and cholinergic systems exhibit reciprocal antagonism in other movement disorders such as Parkinsonism and chorea, it is conceivable that the cholinergic system is implicated in the disease. In the present communication it is proposed that: (a) the emergence of motor and vocal tics in GTS is associated with increased central cholinergic activity; (b) cholinergic overactivity is involved in the manifestation of other symptoms in GTS including depression, sleep disorders, motion sickness, pain, sensory tics, and the waxing and waning course of the disease; (c) abnormalities of the cholinergic system support previous evidence linking GTS with delayed cerebral maturation in a subset of young patients; and (d) drugs which stimulate cholinergic receptors may exacerbate symptoms of GTS, and as with dopamine agonists, should be avoided in patients with GTS.

A sensitive and selective conventional chromatographic method has been developed for the simultaneous measurement of norepinephrine, dopamine, and serotonin from in vivo rat brain microdialysis samples. Ion-pair reversed-phase high performance liquid chromatography was used in combination with coulometric electrochemical detection to generate femtogram-level chromatograms reliably and routinely. Analysis is completed within 10 minutes making it ideally suited for the in vivo study of acute pharmacological manipulation in the rat brain to monitor the effects of drugs on and the potential interactions between monoaminergic systems. System performance was evaluated using in vivo microdialysis perfusate samples obtained from the right ventral hippocampus of the anesthetized rat before and after administration of the D2/D1 receptor agonist apornorphine as well as post-euthanasia. Basal levels and pharmacological effects are reported and discussed.

This study was designed to evaluate the effects of two consecutive ischaemias on extracellular monoaminergic neurotransmitter concentrations. The data on the neuroamine changes induced by the second ischaemia could be used to assess the delay in aminergic neurotransmission subsequent to the primary injury. Dopamine (DA), serotonin (5HT) and their metabolites, homovanillic acid (HVA), dihydroxyphenyl-acetic acid (DOPAC) and 5-hydroxyindolacetic acid (5-HIAA) were measured in vivo through striatal microdialysis of awake rats, using HPLC and electrochemical detection. Pulsinelli and Brierley's four-vessel occlusion model was used to induce a 20-minute global transient ischaemia in the forebrain. Two experimental groups were formed: the second ischaemic period was induced 3 h after the first one in group I (n = 5) and after 24 h in group II (n = 5). Dramatic increases in DA (150 times the baseline level) and 5HT (10 times the baseline level) were recorded during the first ischaemia, consistent with literature data. Metabolites of DA and 5HT (HVA and 5HIAA) decreased significantly. Baseline values were restored after 40 min of reperfusion. There was no significant difference between the effects of the first and second ischaemias on neurotransmitter release in group I. In group II, the second ischaemia did not significantly alter the baseline aminergic neurotransmitter content, although all the clinical signs of global ischaemia were present (in particular the loss of righting reflex). These original data could be explained by delayed impairment of release mechanisms, rather than by exhaustion of the releasable pools of these neurotransmitters one day after the first ischaemia.

Disorders with cognitive impairment in the elderly are age-associated memory impairment, pseudodementias, secondary dementias, vascular dementias, and primary dementias. Pharmacological treatment strategies concern the use of vasodilators, nootropics, acetylcholinergie drugs, monoaminergic drugs, neuropeptides and neuropeptide-like drugs, vitamin B12 substitution, ganglioside GM1, phosphatidylserine, and acetyl-I-carnitine. On the whole, drugs with vasodilator effects were unsuccessful in the past. However, new drugs have been introduced which also enhance the metabolism in the neurons. These drugs, the nootropics, often combine a vasodilator effect with the activation of brain metabolism and the protection of the brain from toxic effects. However, effects of nootropics have mainly been demonstrated in animal experiments. Acetylcholinergic drugs have attracted great interest in dementia treatment, but altogether the trials with these drugs have shown disappointing results. Studies of drugs affecting monoa...

The metabolism of neurotransmitters can be influenced by drugs at different levels. In principle, the levels can be divided into three: the presynaptic, synaptic and postsynaptic levels. Precursors are used to increase the synthesis of neurotransmitters. Thus, the serotonergic system can be activated by dietary regimens and the addition of tryptophan or 5-hydroxy-tryptophan. Enzyme inhibitors are used to reduce the synthesis of neurotransmitters. Inhibitors that can reduce serotonin metabolism are p-chlorophenylalanine (PCPA) and alpha-methyl-5-hydroxytryptophan. Re-uptake blockers are used at the level of the synaptic cleft, and several selective re-uptake blockers are available. At present, especially serotonin reuptake blockers are being tested for clinical efficacy. The release of neurotransmitters can also be manipulated pharmacologically; fenfluramine, for instance, increases the release of serotonin. The use of monoamine oxidase (MAO) inhibitors is a well-known principle for up-regulating the activ...

The prevalence of depression is higher among elderly than among younger people. If atypical depression, masked depression and dysthymic disorders are included, the prevalence is around 15% in a basic population above 65 years of age. In affective disorders in the elderly, not only environmental factors but also biological changes in the old brain in the form of disturbed monoaminergic function are assumed to be of pathogenetic importance. Somatic disorders, nutrition and treatment with drugs are other factors that must be recognized in the pathogenesis of depression in the elderly. Treatment strategies are electroshock therapy, the use of lithium, traditional antidepressants, monoamine oxidase inhibitors and selective serotonin re-uptake inhibitors. Electroshock therapy is recommended for patients who are refractory to drug treatment and patients with severe depression with delusion. The use of tricyclics is hazardous because of side effects and toxicity. Therefore, the new selective reversible monoamine ...

Noradrenaline (NA) has been implicated as a neuromodulator in plasticity, presumably facilitating adaptive processes. Since the flocculus receives noradrenergic afferents, and ablation of the flocculus interferes with the normal adaptive changes in the VOR gain, experiments were performed to find out whether bilateral injection of monoaminergic substances into the flocculus of rabbits could modify the adaptive changes of the VOR. The visual world surrounding the rabbit was oscillated in opposite direction to the platform on which the rabbit was mounted, which resulted in an adaptive increase in the VOR gain; this adaptation was measured either in light or in darkness. Floccular injection of the beta-agonist isoproterenol did not greatly affect the adaptation of the VOR measured in light. In darkness, however, the increase in gain after injection of isoproterenol was larger than during normal adaptation. The beta-antagonist sotalol reduced the adaptation of the VOR gain significantly in light as well as in darkness. In a control condition without pressure for adaptation (only intermittent testing of the VOR gain over a period of 2.5 h), the gain of the VOR was not significantly affected by similar injections of beta-adrenergic agents. We conclude that the noradrenergic system facilitates the adaptation of the VOR gain to retinal slip in rabbits without affecting the VOR gain directly. At least part of this influence is exerted through beta-receptors located in the cerebellar flocculus.

Engel JA, Soderpalm B. Pharmacologic aspects of treating anxiety. Non-benzodiazepines.The need for pharmacologic alternatives to the benzodiazepines (BZD) in the treatment of anxiety disorders has led to the development of non-benzodiazepine anxiolytics. These drugs can be divided in two subgroups: drugs that structurally are not related to the BZD but have affinity to some of the sites of the GABAA-BZD-chloride-ionophore receptor complex (such as imidazopyridines, pyrazolopyridines, cyclopyrrolones) and drugs that have no affinity to this supramolecular receptor complex (such as drugs that in various ways interfere with monoaminergic systems such as tricyclic antidepressants, monoamin oxidase inhibitors, 5-HT-precursors, or 5-HT1,2,3-receptor active drugs). The preclinical and clinical pharmacology of these drugs is discussed. On the basis of results from our own animal experiments it is suggested that, although the primary mode of action of these non-BZD differ from that of the BZD, there may be a commo...

The prevailing view of antidepressants' (ADs) mode of action primarily focuses on their impact on neurotransmitter circuits, since the corresponding transporters and receptors are common targets of ADs. However, mounting evidence points to additional target structures, which may either support the beneficial effects or account for undesired side effects of ADs. Recently, we analyzed the influence of three ADs of different classes on autophagy-related processes in primary astrocytes and neurons. While amitriptyline (AMI) and citalopram (CIT) upregulate the expression of autophagic markers such as LC3B-II or Beclin 1, venlafaxine fails to exert these effects. Autophagy triggered by AMI and CIT is functional in terms of autophagic flux, and is partially mediated by class III PtdIns 3-kinase- and ROS dependent-pathways. Together, our study's results highlight a novel mode of action of ADs beyond monoaminergic neurotransmission.

Marty Hinz1, Alvin Stein2, Thomas Uncini31Clinical Research, NeuroResearch Clinics, Inc, Cape Coral, FL, 2Stein Orthopedic Associates, Plantation, FL, 3Fairview University Medical Center, Hibbing, MN, USABackground: The monoamine hypothesis has been recognized for over half a century as a reference point to understanding electrical dysfunction associated with disease states, and/or regulatory dysfunction related to synaptic, centrally acting monoamine concentrations (serotonin, dopamine, norepinephrine, and epinephrine).Methods: Organic cation transporters (OCT) are a primary force controlling intracellular and extracellular (including synaptic) concentrations of centrally acting monoamines and their amino acid precursors. A new type of research was analyzed in this paper (previously published by the authors) relating to determining the functional status of the nutritionally driven organic cation transporters. It was correlated with the claims of the monoamine hypothesis.Results: Results of laboratory assays from subjects not suffering from a hyperexcreting tumor show that centrally acting monoamine concentrations are indistinguishable in subjects with and without disease symptoms and/or regulatory dysfunction. Analysis of centrally acting monoamine concentrations in the endogenous state reveals a significant difference in day-to-day assays performed on the same subject with and without monoamine-related disease symptoms and/or regulatory dysfunction. The day-to-day difference renders baseline testing in the endogenous state non-reproducible in the same subject.Conclusion: It is asserted that the monoamine hypothesis, which claims that low synaptic levels of monoamines are a primary etiology of disease, is not a valid primary reference point for understanding chronic electrical dysfunction related to the centrally acting monoamines. Furthermore, the "bundle damage theory" is a more accurate primary model for understanding chronic dysfunction. The "bundle damage theory" advocates that synaptic monoamine levels are normal but not adequate in states associated with chronic electrical dysfunction and that levels need to be increased to compensate for the chronic postsynaptic electrical dysfunction due to existing damage. The monoamine hypothesis, in failing to accurately explain the etiology of chronic neuronal electrical flow dysfunction in the endogenous state, is reduced to no more than a historical footnote.Keywords: monoamine hypothesis, monoamine theory, serotonin, dopamine, neuronal dysfunction, bundle damage theory

Pierre Blier1, Mike Briley21Institute of Mental Health Research, University of Ottawa, Ottawa, Ontario, Canada; 2NeuroBiz Consulting and Communication, Castres, FranceAbstract: Signs and symptoms of depression can be linked to one or more monoaminergic systems, specifically the norepinephrine (NE), the dopamine (DA), and the serotonin (5-HT) systems. In particular, the modulation of energy, vigilance, and arousal can be directly linked to the NE system. There is, however, a great deal of overlap in the modulation of the symptoms of depression between these monoaminergic systems. There are considerable reciprocal interactions between the NE, DA, and the 5-HT systems. When using a selective serotonin reuptake inhibitor (SSRI), for example, 5-HT transmission is enhanced, but at the same time there is a dampening of the activity of NE and DA neurons through inhibitory 5-HT2A and 5-HT2C receptors, respectively. This could explain the residual symptoms of fatigue, lack of energy, and anhedonia, often seen after patients present an overall positive response to a SSRI. Using a dual 5-HT and NE reuptake inhibitor (SNRI), such as milnacipran, would result in an additional increase in NE activity. Futhermore, inhibiting NE reuptake increases DA availability in the frontal cortex since DA is mainly cleared by the NE transporters in several brain regions. A risk inherent in increased NE activity is that of provoking anxiety. This is avoided however by the attenuation of the phasic reactivity of the firing of NE neurons through prolonged administration of SSRI and SNRI.Keywords: norepinephrine, dopamine, serotonin, residual symptoms, norepinephrine paradox

The content and intra-axonal transport of acetylcholine (ACh) and the ACh-metabolizing enzymes choline-acetyl-transferase (CAT) and ACh-esterase (AChE) in the rat sciatic nerve were studied after various experimental procedures. The procedures involved: (1) spinal cord transection (SCT) at the thoracic level 1 day to 3 weeks prior to experiments, to abolish nerve activity of the lower motor neurons (in the lumbar intumescence-sciatic nerve) from supraspinal centres; (2) physical training for 2 h daily during 2 weeks in a rodent treadmill, to increase nerve activity from supraspinal levels; and (3) the use of selective neurotoxins to cause degeneration of descending bulbospinal monoaminergic (MA) neurons. The results of these studies demonstrate that supraspinal nerve influence can modify the axonal transport of ACh and cholinergic enzymes in the rat sciatic nerve, and that descending monoamine (MA) pathways may, at least to some extent, participate in this modulation of intraneuronal dynamics in the motor neuron. Since it has been shown by many investigators that factors which have a trophic influence on skeletal muscle cells both in vitro and in vivo are present in motor nerves and transported along the axons in a distal direction, we suggest that the synthesis and axonal transport of such factors may also be under control of supraspinal nerve activity. Therefore, it is possible that metabolic changes and dystrophy of muscles occurring in patients with lesions of the 'upper motor neuron-type' may also, in addition to other factors, be dependent on changes in intra-axonal transport of various substances in the lower motor neuron.

The monoamine hypothesis for affective disorders indicates a functional impairment of the monoamine systems in CNS as the causative factor for the development of depression. Pharmacological manipulations of the monoaminergic neuronal system using tricyclics and monoamine oxidase inhibitors produced promising therapeutic effects as well as certain unwanted side effects, which urged the search of a physiological means to activate the central monoamine systems. In the present paper, evidence from animal experiments is presented to show that acupuncture or electroacupuncture (EA) is capable of accelerating the synthesis and release of serotonin (5-HT) and norepinephrine (NE) in the CNS. Clinical data indicate that EA is effective in treating depressive patients, and at least as effective and with a higher therapeutic index than tricyclic amitriptyline.

The long term effects of 5.7-DHT on nerves in the Venus clam heart were studied to elucidate further the structure of serotoneragic nerves detected earlier. At least 2 types of monoaminergic nerves...

Monoamine oxidase (MAO; E.C. 1.4.3.4) activity in platelets is one of the few hitherto known biological markers which might be useful in clinical psychiatric practice. Thus, as is discussed in more detail below, there are obvious connections between platelet MAO activity and certain personality traits. In this way, however, low (and possibly high) platelet MAO activity is a marker for “vulnerability” rather than for illness. The present knowledge about relationships between temperament and central monoaminergic activity does not permit any definite conclusions about which monoamine system is involved. Available data, however, favour the notion that the activity of the serotonin system is most closely connected to the personality traits of interest. Thus, the simplest interpretation would be that there is a positive correlation between central serotonergic activity and platelet MAO activity. Such an interpretation is supported by the findings of a positive correlation between CSF levels of 5-HIAA and plate...

The influence of an i.v. perfusion of buspirone on the firing rate of central monoaminergic neurons was studied in rats anaesthetized with chloral hydrate. Buspirone increased the firing rate of A10 dopaminergic neurons and blocked the inhibitory effect of iontophoretically applied dopamine on these neurons. A slight attenuation of the inhibitory effect of iontophoretically applied GABA was also observed. Buspirone increased the firing rate of locus coeruleus (LC) noradrenergic neurons and induced an attenuation of the inhibitory effect of iontophoretically applied clonidine. A slight attenuation of the inhibitory effect of iontophoretically applied GABA was also observed. Furthermore buspirone was a very potent inhibitor of the firing rate of dorsal raphe (DR) serotonergic neurons. It is concluded that activation of A10 neurons by buspirone is due to blockade of dopaminergic autoreceptors and that activation of LC neurons is related to blockade of alpha-2 autoreceptors. The significance of the interaction with gabaergic inhibition is unclear. The mechanisms involved in the inhibition of DR neurons remain to be investigated.

The aim of the present study was to investigate a possible central monoaminergic influence on the control mechanism of the urinary bladder in rats. A selective central nervous stimulation was accomplished by injection of monoaminergic precursor (L-dopa and 5-HTP) after enzymatic blockade of its peripheral metabolisation. The bladder response was recorded with a cytometric procedure. The central adrenergic stimulation with L-dopa resulted in a hyperactive bladder response, with higher intravesical pressure and more prominent detrusor contractions than in control rats. Injection of 5-HTP had no such effect. The hyperactive bladder response to L-dopa was abolished by prior administration of a central dopamine receptor blocking agent (spiroperiodol). This indicated that the central effect on the bladder was elicited by dopaminergic structures. Peripheral adrenergic stimulation with metabolites of L-dopa--dopamine and noradrenaline--gave no measurable bladder response. The study showed that activation of central adrenergic mechanisms influenced urinary bladder control, i.e. evoked a hyperactive bladder response.