Cannabinoids and monoamine neurotransmission with focus on monoamine oxidase

Progress in understanding the mechanisms of action of cannabinoids was made after discovery of cannabinoid receptors and finding their endogenous ligands. New findings are obtained using both endogenous cannabinoids and plant or synthetic cannabinoids. Activation of cannabinoid receptors on synaptic terminals results in regulation of ion channels, neurotransmitter release and synaptic plasticity. Neuromodulation of synapses by cannabinoids is proving to have a wide range of functional effects, making them potential targets as medical preparations in a variety of illnesses, including some neurodegenerative and mental disorders. Brain monoamines are involved in many of the same processes affected by neuropsychiatric disorders and by different psychotropic drugs, including cannabinoids. Basic information is summarized in the paper about mechanisms of action of cannabinoids on monoaminergic systems, with a view to inhibition of monoamine oxidase.     

Modulatory effects of cannabinoids on brain neurotransmission

Recreational and chronic cannabis use has been associated with a range of acute and chronic effects including; anti‐nociceptive actions, anxiety, depression, psychotic symptoms and neurocognitive impairments. The mechanisms underlying cannabinoid‐based drugs effects are not fully known but given the neuro‐modulatory functions of the endocannabinoid system, it seems likely that agonistic activity at the cannabinoid type‐1 receptors (CB₁) might modulate the functions of other neurotransmitter systems. The present review has summarized the currently available pre‐clinical and clinical data on the interactions of CB₁ and cannabinoid type‐2 receptors (CB₂) with the central neurotransmitters; dopamine, serotonin, noradrenaline, GABA, glutamate and opioids. Acute and chronic exposures to cannabinoids exert pharmacological alterations in the mammalian brain that have profound implications for our understanding of the neuropharmacology of cannabinoid‐based drugs and their effects on mental health and the brain. A recent emergence uses of cannabis for medical purpose together with legalization and decriminalization of cannabis and increasing use of highly potent synthetic cannabinoids raise a growing concern over the effects of cannabinoids and their interaction with other neurotransmitters on physical and mental health.     

Cannabinoid receptor agonists upregulate and enhance serotonin 2A (5‐HT2A) receptor activity via ERK1/2 signaling

Recent behavioral studies suggest that nonselective agonists of cannabinoid receptors may regulate serotonin 2A (5‐HT_2A) receptor neurotransmission. Two cannabinoids receptors are found in brain, CB1 and CB2 receptors, but the molecular mechanism by which cannabinoid receptors would regulate 5‐HT_2A receptor neurotransmission remains unknown. Interestingly, we have recently found that certain cannabinoid receptor agonists can specifically upregulate 5‐HT_2A receptors. Here, we present experimental evidence that rats treated with a nonselective cannabinoid receptor agonist (CP 55,940, 50 µg/kg, 7 days) showed increases in 5‐HT_2A receptor protein levels, 5‐HT_2A receptor mRNA levels, and 5‐HT_2A receptor‐mediated phospholipase C beta (PLCβ) activity in prefrontal cortex (PFCx). Similar effects were found in neuronal cultured cells treated with CP 55,940 but these effects were prevented by selective CB2, but not selective CB1, receptor antagonists. CB2 receptors couple to the extracellular kinase (ERK) signaling pathway by Gα_i/o class of G‐proteins. Noteworthy, GP 1a (selective CB2 receptor agonist) produced a strong upregulation of 5‐HT_2A receptor mRNA and protein, an effect that was prevented by selective CB2 receptor antagonists and by an ERK1/2 inhibitor, PD 198306. In summary, our results identified a strong cannabinoid‐induced upregulation of 5‐HT_2A receptor signaling in rat PFCx. Our cultured cell studies suggest that selective CB2 receptor agonists upregulate 5‐HT_2A receptor signaling by activation of the ERK1/2 signaling pathway. Activity of cortical 5‐HT_2A receptors has been associated with several physiological functions and neuropsychiatric disorders such as stress response, anxiety and depression, and schizophrenia. Therefore, these results may provide a molecular mechanism by which activation of cannabinoid receptors might be relevant to the pathophysiology of some cognitive and mood disorders in humans. Synapse, 2013. © 2012 Wiley Periodicals, Inc.     

Prevalence,clinical features and treatment of depression in Parkinson’s disease: An update

Parkinson’s disease (PD) is one of the most prevalent neurodegenerative diseases which typically affects individuals over 65 years. Although the symptomatology is predominantly motor, neuropsychiatric manifestations, e.g., depression, apathy, anxiety, and cognitive impairment occur in the course of the illness and can have a great impact on the quality of life in these patients. Parkinson’s disease is commonly comorbid with depression with prevalence rates of depression, generally higher than those reported in general population. Depression in PD is frequently underestimated and consequently undertreated, which have significant effects on the quality of life in these patients. The neurobiology of depression in PD is complex and involves alterations in dopaminergic, serotonergic, noradrenergic and possibly other neurotransmitter systems which are affected in the course of the disease. The tricyclic antidepressants and the selective serotonin reuptake inhibitors are the two classes of antidepressant drugs used for depressive symptoms in PD. Several published studies suggested that both classes are of comparable efficacy. Other serotonergic antidepressants, e.g., nefazodone and trazodone have also been of benefit. Meanwhile, there are limited data available on other drugs but these suggest a benefit from the serotonin and noradrenaline reuptake inhibitors such as mirtazapine, venlafaxine, atomoxetine and duloxetine. Some of the drugs used in symptomatic treatment of PD, e.g., the irreversible selective inhibitors of the enzyme monoamine oxidase-B, rasagiline and selegiline as well as the dopamine receptor agonist pramipexole are likely to have direct antidepressant activity independent of their motor improving action. This would make these drugs an attractive option in depressed subjects with PD. The aim of this review is to provide an updated data on the prevalence, clinical features of depression in subjects with PD. The effects of antiparkinsonian and antidepressant drugs on depressive symptoms in these patients are also discussed.     

Relevance of Norepinephrine–Dopamine Interactions in the Treatment of Major Depressive Disorder

Central dopaminergic and noradrenergic systems play essential roles in controlling several forebrain functions. Consequently, perturbations of these neurotransmissions may contribute to the pathophysiology of neuropsychiatric disorders. For many years, there was a focus on the serotonin (5‐HT) system because of the efficacy of selective serotonin reuptake inhibitors (SSRIs), the most prescribed antidepressants in the treatment of major depressive disorder (MDD). Given the interconnectivity within the monoaminergic network, any action on one system may reverberate in the other systems. Analysis of this network and its dysfunctions suggests that drugs with selective or multiple modes of action on dopamine (DA) and norepinephrine (NE) may have robust therapeutic effects. This review focuses on NE‐DA interactions as demonstrated in electrophysiological and neurochemical studies, as well as on the mechanisms of action of agents with either selective or dual actions on DA and NE. Understanding the mode of action of drugs targeting these catecholaminergic neurotransmitters can improve their utilization in monotherapy and in combination with other compounds particularly the SSRIs. The elucidation of such relationships can help design new treatment strategies for MDD, especially treatment‐resistant depression.     

Maternal factors and monoamine changes in stress-resilient and susceptible mice: cross-fostering effects

Genetic factors influence stressor-provoked monoamine changes associated with anxiety and depression, but such effects might be moderated by early life experiences. To assess the contribution of maternal influences in determining adult brain monoamine responses to a stressor, strains of mice that were either stressor-reactive or -resilient (BALB/cByJ and C57BL/6ByJ, respectively) were assessed as a function of whether they were raising their biological offspring or those of the other strain. As adults, offspring were assessed with respect to stressor-provoked plasma corticosterone elevations and monoamine variations within discrete stressor-sensitive brain regions. BALB/cByJ mice demonstrated poorer maternal behaviors than C57BL/6ByJ dams, irrespective of the pups being raised. In response to a noise stressor, BALB/cByJ mice exhibited higher plasma corticosterone levels and elevated monoamine turnover in several limbic and hypothalamic sites. The stressor-provoked corticosterone increase in BALB/cByJ mice was diminished among males (but not females) raised by a C57BL/6ByJ dam. Moreover, increased prefrontal cortical dopamine utilization was attenuated among BALB/cByJ mice raised by a C57BL/6ByJ dam. These effects were asymmetrical as a C57BL/6ByJ mice raised by a BALB/cByJ dam did not exhibit increased stressor reactivity. It appears that stressors influence multiple neurochemical systems that have been implicated in anxiety and affective disorders. Although monoamine variations were largely determined by genetic factors, maternal influences contributed to stressor-elicited neurochemical changes in some regions, particularly dopamine activation within the prefrontal cortex.     

Neuropsychiatric consequences of cardiovascular medications

The use of cardiovascular medications can have a variety of neuropsychiatric consequences. Many cardiovascular agents cause higher rates of fatigue and sedation than placebo, and case reports of medication-induced mood syndromes, psychosis, and cognitive disturbances exist for many cardiovascular drugs. Depression has been associated with P3-blockers, methyldopa, and reserpine, but more recent syntheses of the data have suggested that these associations are much weaker than originally believed. Though low cholesterol levels have been associated with depression and suicide, lipid-lowering agents have not been associated with these adverse effects. Finally, cardiovascular medications may have beneficial neuropsychiatric consequences; for example, the use of clonidine in patients with attention deficit-hyperactivity disorder, the use of prazosin for patients with post-traumatic stress disorder; and the use of propranolol for performance anxiety and akathisia.     

CB1 receptor knockout mice show similar behavioral modifications to wild-type mice when enkephalin catabolism is inhibited

Behavioral and biochemical studies have suggested a functional link between the endogenous cannabinoid and opioid systems. Different hypotheses have been proposed to explain the interactions between opioid and cannabinoid systems such as a common pathway stimulating the dopaminergic system, a facilitation of signal-transduction- and/or a cannabinoid-induced enhancement of opioid peptide release. However, at this time, all the studies have been performed with exogenous agonists (delta-9-tetrahydrocannabinol or morphine), leading to a generally excessive stimulation of receptors normally stimulated by endogenous effectors (anandamide or opioid peptides) in various brain structures. To overcome this problem, we have measured various behavioral responses induced by the stimulation of the endogenous opioid system using the dual inhibitor of enkephalin-degrading enzymes, RB101, in CB1 receptor knockout mice. Thus, analgesia, locomotor activity, anxiety and antidepressant-like effects were measured after RB101 administration (80 and 120 mg/kg i.p. or 10 mg/kg, i.v.) in CB1 receptor knockout mice and their wild-type littermates. In all the experiments, inhibition of enkephalin catabolism produced similar modifications in behavior observed in CB1 knockout and wild-type mice. These results suggest limited physiological interaction between cannabinoid and opioid systems.     

Prevalence,clinical features and treatment of depression in Parkinson's disease: An update

Parkinson's disease(PD) is one of the most prevalent neurodegenerative diseases which typically affects individuals over 65 years. Although the symptomatology is predominantly motor, neuropsychiatric manifestations, e.g., depression, apathy, anxiety, and cognitive impairment occur in the course of the illness and can have a great impact on the quality of life in these patients. Parkinson's disease is commonly comorbid with depression with prevalence rates of depression, generally higher than those reported in general population. Depression in PD is frequently underestimated andconsequently undertreated, which have significant effects on the quality of life in these patients. The neurobiology of depression in PD is complex and involves alterations in dopaminergic, serotonergic, noradrenergic and possibly other neurotransmitter systems which are affected in the course of the disease. The tricyclic antidepressants and the selective serotonin reuptake inhibitors are the two classes of antidepressant drugs used for depressive symptoms in PD. Several published studies suggested that both classes are of comparable efficacy. Other serotonergic antidepressants, e.g., nefazodone and trazodone have also been of benefit. Meanwhile, there are limited data available on other drugs but these suggest a benefit from the serotonin and noradrenaline reuptake inhibitors such as mirtazapine, venlafaxine, atomoxetine and duloxetine. Some of the drugs used in symptomatic treatment of PD, e.g., the irreversible selective inhibitors of the enzyme monoamine oxidase-B, rasagiline and selegiline as well as the dopamine receptor agonist pramipexole are likely to have direct antidepressant activity independent of their motor improving action. This would make these drugs an attractive option in depressed subjects with PD. The aim of this review is to provide an updated data on the prevalence, clinical features of depression in subjects with PD. The effects of antiparkinsonian and antidepressant drugs on depressive symptoms in these patients are also discussed.     

Mapping the central effects of chronic ketamine administration in an adolescent primate model by functional magnetic resonance imaging (fMRI)

Ketamine, a noncompetitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, is capable of triggering excessive glutamate release and subsequent cortical excitation which may induce psychosis-like behavior and cognitive anomalies. Growing evidence suggests that acute ketamine administration can provoke dose-dependent positive and negative schizophrenia-like symptoms. While the acute effects of ketamine are primarily linked to aberrant activation of the prefrontal cortex and limbic structures with elevated glutamate and dopamine levels, the long-term effects of ketamine on brain functions and neurochemical homeostasis remain incompletely understood. In recent years, reports of ketamine abuse, especially among young individuals, have surged rapidly, with profound socioeconomic and health impacts. We herein investigated the chronic effects of ketamine on brain function integrity in an animal model of adolescent cynomolgus monkeys (Macaca fascicularis) by functional magnetic resonance imaging (fMRI). Immunohistochemical study was also conducted to examine neurochemical changes in the dopaminergic and cholinergic systems in the prefrontal cortex following chronic ketamine administration. Our results suggest that repeated exposure to ketamine markedly reduced neural activities in the ventral tegmental area, substantia nigra in midbrain, posterior cingulate cortex, and visual cortex in ketamine-challenged monkeys. In contrast, hyperfunction was observed in the striatum and entorhinal cortex. In terms of neurochemical and locomotive changes, chronically ketamine-challenged animals were found to have reduced tyrosine hydroxylase (TH) but not choline acetyltransferase (ChAT) levels in the prefrontal cortex, which was accompanied by diminished total movement compared with the controls. Importantly, the mesolimbic, mesocortical and entorhinal-striatal systems were found to be functionally vulnerable to ketamine's chronic effects. Dysfunctions of these neural circuits have been implicated in several neuropsychiatric disorders including depression, schizophrenia and attention deficit disorder (ADD). Collectively, our results support the proposition that repeated ketamine exposure can be exploited as a pharmacological paradigm for studying the central effects of ketamine relevant to neuropsychiatric disorders.     

Opioid receptor genes inactivated in mice: the highlights

The opioid system controls nociception, stress responses, and addictive behaviors. Exogenous alkaloid opiates and endogenous opioid peptides stimulate mu-, delta- and kappa-opioid receptors, whose activities have long been analyzed by pharmacological tools. Mice lacking opioid receptor and opioid peptide precursor genes have now been produced by gene targeting. Behavioral analysis of mutant animals in the absence of drug has highlighted a distinct role of opioid receptors or peptides in nociception and revealed an important role for delta receptors in emotional behaviors. The examination of responses to drugs has clarified involvement of each receptor as molecular targets for exogenous opiates in vivo. Those data have also demonstrated the critical role of mu-receptor in cannabinoid and alcohol reinforcement and confirmed the involvement of kappa receptor in several dysphoric responses. Ongoing studies therefore help in understanding the molecular basis of opioid-controlled behaviors and will contribute to the development of novel therapeutics for pain, anxiety, and drug abuse.     

Depression and Anxiety in People with Epilepsy

Many recent epidemiological studies have found the prevalence of depression and anxiety to be higher in people with epilepsy (PWE) than in people without epilepsy. Furthermore, people with depression or anxiety have been more likely to suffer from epilepsy than those without depression or anxiety. Almost one-third of PWE suffer from depression and anxiety, which is similar to the prevalence of drug-refractory epilepsy. Various brain areas, including the frontal, temporal, and limbic regions, are associated with the biological pathogenesis of depression in PWE. It has been suggested that structural abnormalities, monoamine pathways, cerebral glucose metabolism, the hypothalamic-pituitary-adrenal axis, and interleukin-1b are associated with the pathogenesis of depression in PWE. The amygdala and the hippocampus are important anatomical structures related to anxiety, and γ-aminobutyric acid and serotonin are associated with its pathogenesis. Depression and anxiety may lead to suicidal ideation or attempts and feelings of stigmatization. These experiences are also likely to increase the adverse effects associated with antiepileptic drugs and have been related to poor responses to pharmacological and surgical treatments. Ultimately, the quality of life is likely to be worse in PWE with depression and anxiety than in PWE without these disorders, which makes the early detection and appropriate management of depression and anxiety in PWE indispensable. Simple screening instruments may be helpful for in this regard, particularly in busy epilepsy clinics. Although both medical and psychobehavioral therapies may ameliorate these conditions, randomized controlled trials are needed to confirm that.     

Implications of efavirenz for neuropsychiatry: a review

Antiretroviral therapy has revolutionized the treatment of the human immunodeficiency virus because it has improved the clinical outcomes of patients. It is essential that these drugs cross the blood-brain barrier, since the virus is present in the central nervous system (CNS). Efavirenz passes through this barrier satisfactorily and can reduce the deleterious central effects of the human immunodeficiency virus. However, patients treated with efavirenz have been observed to experience psychiatric symptoms such as mania, depression, suicidal thoughts, psychosis, and hallucinations. The aim of this review is to describe the pharmacokinetic and pharmacodynamic properties of efavirenz and its major neuropsychiatric symptoms and the neurochemical pathways associated with these changes in the CNS. The databases Medline and Lilacs were used to search for review articles and preclinical and clinical research articles published from January 1996 to 2010. The search terms used were efavirenz, central nervous system, neuropsychiatry, neurotransmitters, adverse effects, and neurochemistry. Subject categories considered included effects on viral replication, pharmacokinetic and pharmacodynamic properties of efavirenz, and neuropsychiatric adverse effects including time course, duration, and probable mechanisms involved. The mechanisms involved in these changes include interference with cytochrome P450 enzymes, cytokines, tryptophan-2-3-dioxygenase, and brain creatine kinase.     

Cannabinoid-induced stimulation of motor activity in planaria through an opioid receptor-mediated mechanism

Planaria, the most primitive example of centralization and cephalization of the nervous system along phylogeny, shows specific stereotyped behavioral patterns following exposure to drugs acting on neural transmission. In this study, the authors investigated the effects of exposure to the synthetic cannabinoid receptor agonist WTN55212.2 on motor activity in planaria. WTN55212.2 produced dose-dependent stimulation of motor behavior. High doses of the drug caused stereotyped activities identical to those seen previously with opioid agonists. These effects were antagonized by coexposure to cannabinoid or opioid receptor antagonists. The results indicate that functional interactions between cannabinoid and opioid systems are highly conserved along phylogeny, at least at the behavioral level.     

Central anandamide deficiency predicts stress-induced anxiety: behavioral reversal through endocannabinoid augmentation

Stress is a major risk factor for the development of mood and anxiety disorders; elucidation of novel approaches to mitigate the deleterious effects of stress could have broad clinical applications. Pharmacological augmentation of central endogenous cannabinoid (eCB) signaling may be an effective therapeutic strategy to mitigate the adverse behavioral and physiological consequences of stress. Here we show that acute foot-shock stress induces a transient anxiety state measured 24 h later using the light–dark box assay and novelty-induced hypophagia test. Acute pharmacological inhibition of the anandamide-degrading enzyme, fatty acid amide hydrolase (FAAH), reverses the stress-induced anxiety state in a cannabinoid receptor-dependent manner. FAAH inhibition does not significantly affect anxiety-like behaviors in non-stressed mice. Moreover, whole brain anandamide levels are reduced 24 h after acute foot-shock stress and are negatively correlated with anxiety-like behavioral measures in the light–dark box test. These data indicate that central anandamide levels predict acute stress-induced anxiety, and that reversal of stress-induced anandamide deficiency is a key mechanism subserving the therapeutic effects of FAAH inhibition. These studies provide further support that eCB-augmentation is a viable pharmacological strategy for the treatment of stress-related neuropsychiatric disorders.     

Innovative approaches for the development of antidepressant drugs: Current and future strategies

Depression is a highly debilitating disorder that has been estimated to affect up to 21% of the world population. Despite the advances in the treatment of depression with selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs), there continue to be many unmet clinical needs with respect to both efficacy and side effects. These needs range from efficacy in treatment resistant patients, to improved onset, to reductions in side effects such as emesis or sexual dysfunction. To address these needs, there are numerous combination therapies and novel targets that have been identified that may demonstrate improvements in one or more areas. There is tremendous diversity in the types of targets and approaches being taken. At one end of a spectrum is combination therapies that maintain the benefits associated with SSRIs but attempt to either improve efficacy or reduce side effects by adding additional mechanisms (5-HT_1A, 5-HT_1B, 5-HT_1D, 5-HT_2C, α-2A). At the other end of the spectrum are more novel targets, such as neurotrophins (BDNF, IGF), based on recent findings that antidepressants induce neurogenesis. In between, there are many approaches that range from directly targeting serotonin receptors (5-HT_2C, 5-HT₆) to targeting the multiplicity of potential mechanisms associated with excitatory (glutamate, NMDA, mGluR2, mGluR5) or inhibitory amino acid systems (GABA) or peptidergic systems (neurokinin 1, corticotropin-releasing factor 1, melanin-concentrating hormone 1, V1b). The present review addresses the most exciting approaches and reviews the localization, neurochemical and behavioral data that provide the supporting rationale for each of these targets or target combinations.     

SSRIs and conditioned fear

Among drugs that act on serotonergic neurotransmission, selective serotonin (5-HT) reuptake inhibitors (SSRIs) are now the gold standard for the treatment of anxiety disorders. The precise mechanisms of the anxiolytic actions of SSRIs are unclear. We reviewed the literature related to the effects of SSRIs and the neurochemical changes of 5-HT in conditioned fear. Acute SSRIs and 5-HT_1A receptor agonists reduced the acquisition and expression of contextual conditioned fear. Chronic SSRI administration enhanced anxiolytic-like effects. Microinjection studies revealed the amygdala as the target brain region of both classes of serotonergic drugs, and the hippocampus as the target of 5-HT_1A receptor agonists. These findings highlight the contribution of post-synaptic 5-HT receptors, especially 5-HT_1A receptors, to the anxiolytic-like effects of serotonergic drugs. These results support the new 5-HT hypothesis of fear/anxiety: the facilitation of 5-HT neurotransmission ameliorates fear/anxiety. Furthermore, these behavioral data provide a new explanation of neurochemical adaptations to contextual conditioned fear: increased 5-HT transmission seems to decrease, not increase, fear.     

Prenatal and postnatal exposure to bisphenol a induces anxiolytic behaviors and cognitive deficits in mice

Bisphenol A (BPA), an environmental endocrine‐disrupting chemical, has been extensively evaluated for reproductive toxicity and carcinogenicity. However, little is known about the behavioral and neurochemical effects of BPA exposure. This study examined whether chronic daily exposure to an environmental endocrine‐disrupting chemical, bisphenol A [(BPA); 100 μg/kg/day or 500 μg/kg/day, p.o.], from prenatal Day 7 to postnatal Day 36 would lead to changes in anxiety and memory in mice. First, we observed the behavioral alterations of BPA‐treated mice using two anxiety‐related models, the open field test and elevated plus maze (EPM) test. In the open field test, BPA treatment (100 μg/kg/day) increased movement in the central zone. BPA treatment (500 μg/kg/day) also increased the time spent in the open arms in the EPM test. Second, we measured cognitive ability in the Y‐maze test and novel object test. BPA‐treated mice showed decreased alternation behavior in the Y‐maze at both of doses, indicating working memory impairment. BPA‐treated mice (100 μg/kg/day) also showed decreased novel object recognition as expressed by central locomotion and frequency in the central zone, showing recognition memory impairment. Finally, to measure changes in the dopaminergic and NMDAergic systems in the brain, we performed autoradiographic receptor binding assays for dopamine D₁ and D₂ receptors, the NMDA receptor, and the dopamine transporter. BPA treatment increased D₂ receptor binding in the caudate putamen (CPu) but decreased DAT binding. BPA treatment also decreased NMDA receptor binding in the frontal cortex and CA1, CA3, and DG of the hippocampus. Taken together, our results suggest that long‐term BPA exposure in mice can induce anxiolytic behaviors, cognitive deficits and changes in the dopaminergic and NMDAergic systems. Synapse 64:432–439, 2010. © 2010 Wiley‐Liss, Inc.     

Non-monoamine-based approach for the treatment of depression and anxiety disorders

Although currently prescribed antidepressants with actions mediated through alteration of monoaminergic transmission have been proven to be useful for the treatment of depressive and anxiety disorders, they are far from ideal due to their slow onset of action and low rate of responses. Although the brain monoamine systems have long been the focus of drug therapy for depression and anxiety disorders, current drug discovery has aimed at new molecular targets outside the monoamine systems to overcome these problems. Recent increase in understanding of the molecular mechanisms of depression and anxiety has provided alternative molecular targets for these disorders. In particular, receptors within the glutamate, gamma-aminobutyric acid and neuropeptide systems provide a diversity of drug targets, and molecular biological and behavioral studies of these receptors have revealed the important roles they play in depression and anxiety. Here, we review recent patents and advances in research on these emerging molecular targets for the treatment of depression and anxiety, and discuss their advantages over currently used antidepressants and anxiolytics.     

Role of norepinephrine in depression

This article reviews the role of norepinephrine (NE) and serotonin (5-HT) in depression and the therapeutic effects of antidepressant drugs from the perspective of human neurotransmitter depletion studies. The data reviewed suggest that both noradrenergic and serotonergic systems are involved in antidepressant action, but the specific impairment that underlies depression is unclear and is likely to vary among patients. Results from neurotransmitter depletion studies in depressed patients who have responded to treatment suggest that, while interactions between NE and 5-HT are likely, neither of these 2 neurotransmitter systems is the final common pathway for the therapeutic effect of antidepressant drugs. NE-selective antidepressant drugs appear to be primarily dependent on the availability of NE for their effects. Likewise, 5-HT-selective antidepressants appear to be primarily dependent on the availability of 5-HT for their effects. Antidepressants that cause effects on both noradrenergic and serotonergic systems-such as mirtazapine-may be dependent on the availability of both neurotransmitters for their effects. Neither 5-HT nor NE depletion induced clinical depression in healthy subjects or worsened depression in unmedicated symptomatic patients with major depression. This finding suggests that the cause of depression is more complex than just an alteration in the levels of 5-HT and/or NE. For some patients, depression may be more directly caused by dysfunction in brain areas or neuronal systems modulated by monoamine systems. We propose that antidepressant drugs may enhance neurotransmission in normal noradrenergic or serotonergic neurons and, through a time-dependent but as yet undiscovered process, restore function to brain areas modulated by monoamine neurons. Future research should focus on understanding the adaptive changes that follow enhancement of synaptic levels of monoamines in neuronal circuits of the frontal cortex, amygdala, and hippocampus. Research investigating the neurobiology of depression may be more informed if the focus is shifted to investigating areas of the brain modulated by monoamine systems rather than the monoamine systems themselves.