Current Drug Targets - Volume 10, Issue 11, 2009

It was my honor and pleasure to prepare this special theme issue entitled “Aiming at new targets for the treatment of affective disorders” for Current Drug Targets. This project was a continuation to the previous thematic issue on this topic, “Recent strategies for potentiation and facilitation of antidepressant treatment”, (Current Drug Targets 2006). As in 2006, the aim was to gather the recent knowledge on patho-physiology of mood and affective disorders and on novel strategies in treatment of these diseases. I would like to thank to the authors of the Issue for their outstanding review manuscripts, to the Editorial Office of Current Drug Targets for invitation, to the reviewers, and to all my colleagues from Brains On-Line and University of Groningen Institute of Pharmacy for their help and support. Especial acknowledgement should be given to the Senior Manager for Publications of Current Drug Targets, Ms. Saima Nayab, who coordinated the entire project.

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Antidepressant drugs modify in different ways the activity of neurons, by increasing monoamines levels and by modulating ion channels. Sodium channels are molecular targets for antiepileptic drugs, which can also be mood stabilizers (i.e. lamotrigine, topiramate, phenytoin, carbamazepine, valproic acid). After a short overview on the sodium channels and the interaction with antidepressants and mood stabilizers, a comparison of the activity of both antidepressants and mood stabilizers with the addition of veratrine (sodium channel opener) on the forced swimming test (FST) in mice was presented. By comparing the antidepressant-like effect of the antidepressants (paroxetine, imipramine and desipramine) with the one of anticonvulsants (lamotrigine, phenytoin and topiramate) on the FST, it seems that the mechanism of action of anticonvulsants and antidepressants is different, because veratrine limits the activity of anticonvulsants but not of antidepressants. The anticonvulsants topiramate and phenytoin reduce the immobility time in the FST in a range of time similar to that induced by antidepressants, suggesting that the FST could be sensitive to both drugs. The magnitude of antidepressant- like effect of the lamotrigine (acting through an increase in monoaminergic neurotransmission and a blockade of sodium channels) in the FST is greater than what is obtained after administration of the other drugs, suggesting that this dual activity could be used as an augmentation strategy. Authors conclude that the development of new drugs acting on sodium channels could potentially be of interest as antidepressants, but also as augmentation strategies for classical antidepressants.

There are numerous lines of evidence pointing to norepinephrine being of crucial importance in pathophysiology of anxiety and mood disorders. First, norepinephrine projections innervate the limbic system, suggesting the involvement of norepinephrine in the regulation of emotions and cognition. Second, norepinephrine closely interacts with serotonin and dopamine systems, which also play very important roles in the regulation of mood. Third, it has been shown that various agents which increase norepinephrine availability, such as norepinephrine reuptake inhibitors, are also effective antidepressant drugs. And fourth, the depletion of norepinephrine causes a resurgence of depressive symptoms after successful treatment with noradrenergic antidepressant drugs. These observations suggest that the intensification of norepinephrine transmission can be beneficial in the treatment of affective disorders. However, various psychotropic medications have indirect effect on norepinephrine transmission. This review examines the effects of psychiatric medications on the norepinephrine system and proposes how they might be used to improve treatment outcome.

Biogenic amine transporters for serotonin and norepinephrine (5-HT and NE respectively), are major targets for currently available antidepressant drugs, particularly those inhibiting the reuptake of 5-HT and/or NE. Compelling evidence suggests that dopamine (DA) is also involved in the pathophysiology and treatment of depression, leading to the development of a new class of antidepressants: the triple reuptake inhibitors that simultaneously inhibit 5-HT, NE and DA reuptake thereby prolonging their duration of action at postsynaptic levels. Although preclinical studies strongly suggest that triple reuptake inhibitors display antidepressant-like activity in various behavioural paradigms, including the forced swimming and the tail suspension tests, it has yet to be demonstrated that the addition of the dopaminergic component produces more robust effects than single- or dual-acting compounds. Several arguments favour this hypothesis and particularly the observation that DA may promote neurotrophic processes in the adult hippocampus, as 5-HT and NE do. It is thus possible that the stimulation of multiple signalling pathways resulting from the elevation of all three monoamines may account, in part, for an accelerated and/or greater antidepressant response. To predict the efficacy of triple reuptake inhibitors, it is important to take into consideration the existence of dense connections between monoaminergic neurons. Indeed, it is well established that the increase in central dopaminergic transmission regulates the neuronal activity of 5-HT and NE in the dorsal raphe (DR) and locus coeruleus (LC), respectively, while in turn, the ventral tegmental area (VTA), is sensitive to changes in 5-HT and NE release. This review synthetizes the pertinent litterature, focusing on the contribution of DA, to illustrate the rationale for designing improved antidepressants.

Serotonin4 (5-HT4) receptors have been shown to be involved in several peripheral and central functions, including control of the gastro-intestinal tract, modulation of memory and food intake, as well as positive regulation of the release of various neurotransmitters. Recently, we have proposed that the study of these receptors may also bring a new hope for treating depression, their agonists possibly acting as fast-acting antidepressants. This hypothesis was based on several studies showing that 5-HT4 receptors play an important role in the modulation of central 5-HT neurotransmission, both at pre- and postsynaptic levels. The possible physiological meaning of this control is discussed, together with the different research perspectives opened by its discovery.

Long known for its anti-nociceptive effects, the opioid β-endorphin is also reported to have rewarding and reinforcing properties and to be involved in stress response. In this manuscript we summarize the present neurobiological and behavioral evidence regarding the role of β-endorphin in stress-related psychiatric disorders, depression and PTSD. There is existing data that support the importance of β-endorphin neurotransmission in mediating depression. As for PTSD, however, the data is thus far circumstantial. The studies described herein used diverse techniques, such as biochemical measurements of β-endorphin in various brain sites and behavioral monitoring, in two animal models of depression and PTSD. We suggest that the pathways for stress-related psychiatric disorders, depression and PTSD, converge to a common pathway in which β-endorphin is a modulating element of distress. This may occur its interaction with the mesolimbic monoaminergic system and also by its interesting effects on learning and memory. The possible involvement of β- endorphin in the process of stress-related psychiatric disorders, depression and PTSD, is discussed.

Serotonin (5-HT) exerts its diverse physiological and pharmacological effects through the activation of multiple receptor subtypes. One of the newest members of this family is the 5-HT7 receptor. Increasing investigations on this receptor are currently undertaken to highlight its physiological and physiopathological significance. With the development of selective 5-HT7 receptor ligands, preclinical studies have started to elucidate the functions of this receptor subtype in more details. Hence, growing body of evidence suggests that the 5-HT7 receptor is involved in biological processes such as circadian rhythm and thermoregulation, in addition to disorders in which disturbances of the latter are considered to be an important contributing factor. Moreover, preclinical data support the use of 5-HT7 receptor antagonism as a promising mechanism for the treatment of several dysfunctions such as cognitive deficits and, importantly, have also unveiled anxiolytic and antidepressant-like properties. In this review, we will report major advances in the discovery of 5-HT7 receptor roles, with special emphasis on the potential application of their antagonists as novel anxiolytic and antidepressant drugs.

The serotonergic (5-HT) system has been widely implicated in the pathophysiology of Major Depressive Disorder (MDD). Although the 5-HT system is a popular target for drug therapy in MDD, the role that serotonin plays in MDD is not clearly understood. An abundance of research suggests that several 5-HT receptor subtypes may be dysfunctional in patients with MDD including the 5-HT1B receptor. Evidence implicating 5-HT1B receptors in the pathophysiology of depression comes from a number of converging lines of research. Two common genetic polymorphisms of 5-HT1B receptors, G861C and C129T, have been implicated in affective disorders. Rats predisposed to learned helplessness have exhibited downregulation of 5-HT1B receptor messenger ribonucleic acid (mRNA) in dorsal raphe nucleus (DRN). Pharmacological studies have demonstrated augmentation of extracellular 5-HT levels and antidepressant effects following administration of selective serotonin reuptake inhibitors (SSRIs) in the absence or blockade of 5-HT1B receptors. 5-HT1B receptor agonists administered alone or with antidepressants have been shown to be effective in preclinical models of depression. Recent interest has focused on p11, an s100 EF-hand protein family protein which colocalizes with 5-HT1B receptors. P11 plays a central role in the modulation of 5-HT1B receptor function and is dysregulated in preclinical models of depression and postmortem MDD samples. A review of the literature provides strong evidence that 5-HT1B receptors and related factors such as p11 are involved in the pathophysiology of depression. The following explores possible factors which may render the 5-HT1B receptor dysfunctional, resulting in susceptibility to depression. Implications of using the 5- HT1B receptor as a biomarker for vulnerability to MDD are discussed.

In the past few years there has been an increasing appreciation of the importance of Toll-like receptors (TLRs), not just in immunity, but also in autoimmune diseases. TLRs were first identified as sensors of viral and bacterial pathogens that form an integral part of the innate immune response. It was later discovered that these receptors can also respond to endogenous ligands that are produced as a result of tissue damage. This leads to the hypothesis that TLRs may be key contributors to the pathogenesis of chronic inflammatory conditions. A large body of data supporting the role of TLRs in autoimmunity has emerged from animal models and more data is increasingly being generated from human studies as further tools to examine these receptors have become available. Developing strategies to manipulate TLR function is of great interest in autoimmunity, as well as other diseases that include allergy and cancer. This review explores the evidence that points to a role for TLRs in autoimmunity and highlights some of the potential ways in which modulation of their action may yield clinical benefits.

Cholestasis results in the intrahepatic retention of cytotoxic bile acid and it can thus lead to liver injury and/or liver fibrosis. Cholestatic liver damage is counteracted by a variety of intrinsic hepatoprotective mechanisms including a complex network of drug metabolizing enzymes and transporters. During the last decade, much progress has been made in dissecting the mechanisms which regulate the hepatic xeno- and endobiotic metabolism by nuclear receptors. The xenobiotic receptors CAR and PXR are two important members of the NR1I nuclear receptor family. They function as sensors of toxic byproducts derived from the endogenous metabolism and of exogenous chemicals, in order to enhance their elimination. Ligands for both receptors, including phenobarbital, have already been used to treat cholestatic liver diseases before the mechanisms of these receptors were revealed. Furthermore, Yin Zhi Huang, a traditional Chinese herbal medicine, which has been used to prevent and treat neonatal jaundice, was identified to be a CAR ligand which also accelerates bilirubin clearance. Therefore, CAR and PXR have a protective effect on cholestasis by activating both detoxification enzymes and transporters. As a result, novel compounds targeting CAR and PXR with specific effects and fewer side effects will therefore be useful for the treatment of cholestatic liver diseases. This article will review the current knowledge on xenobiotic-sensing nuclear receptors CAR and PXR, while also discussing their potential role in the treatment of cholestatic liver diseases.