Mark J. Millan

Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy

Studies of psychiatric disorders have traditionally focused on emotional symptoms such as depression, anxiety and hallucinations. However, poorly controlled cognitive deficits are equally prominent and severely compromise quality of life, including social and professional integration. Consequently, intensive efforts are being made to characterize the cellular and cerebral circuits underpinning cognitive function, define the nature and causes of cognitive impairment in psychiatric disorders and identify more effective treatments. Successful development will depend on rigorous validation in animal models as well as in patients, including measures of real-world cognitive functioning. This article critically discusses these issues, highlighting the challenges and opportunities for improving cognition in individuals suffering from psychiatric disorders.

Serotonin2C receptors tonically suppress the activity of mesocortical dopaminergic and adrenergic, but not serotonergic, pathways: A combined dialysis and electrophysiological analysis in the rat

The present study evaluated, via a combined electrophysiological and dialysis approach, the potential influence of serotonin (5‐HT)2C as compared to 5‐HT2A and 5‐HT2B receptors on dopaminergic, adrenergic, and serotonergic transmission in frontal cortex (FCX). Whereas the selective 5‐HT2A antagonist MDL100,907 failed to modify extracellular levels of dopamine (DA), noradrenaline (NA) or 5‐HT simultaneously quantified in single dialysate samples of freely‐moving rats, the 5‐HT2B/5‐HT2C antagonist SB206,553 dose‐dependently increased levels of DA and NA without affecting those of 5‐HT. This action was attributable to 5‐HT2C receptor blockade inasmuch as the selective 5‐HT2C antagonist SB242,084 likewise increased FCX levels of DA and NA, whereas the selective 5‐HT2B antagonist SB204,741 was ineffective. Further, the preferential 5‐HT2C receptor agonist Ro60‐0175 dose‐dependently depressed FCX levels of DA. The suppressive influence of 5‐HT2C receptors on DA release was also expressed on mesolimbic and nigrostriatal dopaminergic pathways, in that levels of DA in nucleus accumbens and striatum were likewise reduced by Ro60‐0175 and elevated, though less markedly, by SB206,553. In line with the above findings, Ro60‐0175 dose‐dependently decreased the firing rate of ventrotegmental dopaminergic and locus coeruleus (LC) adrenergic perikarya, whereas their activity was dose‐dependently enhanced by SB206,553. Furthermore, SB206,553 transformed the firing pattern of ventrotegmental dopaminergic neurons into a burst mode. In contrast to SB206,553, MDL100,907 had little affect on the firing rate of dopaminergic or adrenergic neurons. In conclusion, as compared to 5‐HT2A and 5‐HT2B receptors, 5‐HT2C receptors exert a tonic, suppressive influence on the activity of mesocortical — as well as mesolimbic and nigrostriatal — dopaminergic pathways, likely via indirect actions expressed at the level of their cell bodies. Frontocortical adrenergic, but not serotonergic, transmission is also tonically suppressed by 5‐HT2C receptors. Synapse 36:205–221, 2000.

Multiple opioid systems and pain

Probably the most familiar and intensively studied property of synthetic opioids and their naturally occurring counterparts, the endogenous opioid peptides (endorphins), is their ability to elicit an analgesia (antinociception) both in experimental animals and in man. Indeed, opioids such as morphine are universally employed in the treatment of many types of severe and/or long-term pain. It hardly needs emphasis, therefore, that experimental and clinical investigations aimed at the elucidation of the mechanisms whereby administration of exogenous opioids alleviate pain and of the functional response of endogenous opioid systems to noxious stimulation are of considerably more than academic interest. A number of reviews concerned with the neuronal mechanisms whereby opioids modulate nociception and the conditions under which they are active have appeared previously [14,50,55,78,154,155,183,226,249,264,272,273]. However, in recent years it has been established that there is a multiplicity both of endogenous opioid ligands and of opioid receptor types: these apparently subserve a diversity of roles in the control of nociception. The primary purpose of the present article is to review our present knowledge concerning the functional relationship between opioids and pain in the light of this multiplicity of endogenous opioid systems. In this respect, especial emphasis is afforded to data concerned with the roles of individual opioid ligands and receptor types as regards their response to noxious stimuli and possible roles in the modulation of nociception. In addition, particular attention is directed towards recent studies of chronic pain not only in view of their especial clinical pertinence but also since these investigations were conducted with the specific aim of differentiating between the activity of particular opioid systems.

Serotonin (5-HT)2C receptors tonically inhibit dopamine (DA) and noradrenaline (NA), but not 5-HT, release in the frontal cortex in vivo.

The novel, preferential 5-HT2C receptor agonist, Ro 60-0175 ((S)-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine) (2.5 mg,kg, s.c.), markedly suppressed dialysate levels of dopamine (DA) and noradrenaline (NA) levels in the frontal cortex of freely-moving rats without affecting levels of 5-HT. In contrast, the novel and selective 5-HT2C receptor antagonist, SB-242084 (6-chloro-5-methyl-1-[6-(2-methylpyridin-3-yloxy) pyridin-3-yl carbamoyl] indoline) (10.0 mg/kg, i.p.), markedly increased dialysate levels of DA and NA without modifying those of 5-HT. These data suggest that 5-HT2C receptors exert a tonic, inhibitory influence upon frontocortical dopaminergic and adrenergic, but not serotonergic, transmission.

Agomelatine, the first melatonergic antidepressant: discovery, characterization and development

Current management of major depression, a common and debilitating disorder with a high social and personal cost, is far from satisfactory. All available antidepressants act through monoaminergic mechanisms, so there is considerable interest in novel non-monoaminergic approaches for potentially improved treatment. One such strategy involves targeting melatonergic receptors, as melatonin has a key role in synchronizing circadian rhythms, which are known to be perturbed in depressed states. This article describes the discovery and development of agomelatine, which possesses both melatonergic agonist and complementary 5-hydroxytryptamine 2C (5-HT2C) antagonist properties. Following comprehensive pharmacological evaluation and extensive clinical trials, agomelatine (Valdoxan/Thymanax; Servier) was granted marketing authorization in 2009 for the treatment of major depression in Europe, thereby becoming the first approved antidepressant to incorporate a non-monoaminergic mechanism of action.

Reciprocal autoreceptor and heteroreceptor control of serotonergic, dopaminergic and noradrenergic transmission in the frontal cortex: relevance to the actions of antidepressant agents

The frontal cortex (FCX) plays a key role in processes that control mood, cognition and motor behaviour, functions which are compromised in depression, schizophrenia and other psychiatric disorders. In this regard, there is considerable evidence that a perturbation of monoaminergic input to the FCX is involved in the pathogenesis of these states. Correspondingly, the modulation of monoaminergic transmission in the FCX and other corticolimbic structures plays an important role in the actions of antipsychotic and antidepressant agents. In order to further understand the significance of monoaminergic systems in psychiatric disorders and their treatment, it is essential to characterize mechanisms underlying their modulation. Within this framework, the present commentary focuses on our electrophysiological and dialysis analyses of the complex and reciprocal pattern of autoand heteroreceptor mediated control of dopaminergic, noradrenergic and serotonergic transmission in the FCX. The delineation of such interactions provides a framework for an interpretation of the influence of diverse classes of antidepressant agent upon extracellular levels of dopamine, noradrenaline and serotonin in FCX. Moreover, it also generates important insights into strategies for the potential improvement in the therapeutic profiles of antidepressant agents.

Anxiolytic properties of agomelatine, an antidepressant with melatoninergic and serotonergic properties: role of 5-HT2C receptor blockade.

RationaleThe novel antidepressant agent, agomelatine, behaves as an agonist at melatonin receptors and as an antagonist at serotonin (5-HT)2C receptors.ObjectivesTo determine whether, by virtue of its antagonist properties at 5-HT2C receptors, agomelatine elicits anxiolytic properties in rats.MethodsEmploying a combined neurochemical and behavioural approach, actions of agomelatine were compared to those of melatonin, the selective 5-HT2C receptor antagonist, SB243,213, and the benzodiazepine, clorazepate.ResultsIn unfamiliar pairs of rats exposed to a novel environment, agomelatine enhanced the time devoted to active social interaction, an action mimicked by clorazepate and by SB243,213. In a Vogel conflict procedure, agomelatine likewise displayed dose-dependent anxiolytic activity with a maximal effect comparable to clorazepate, and SB243,213 was similarly active in this procedure. In a plus-maze procedure in which clorazepate significantly enhanced percentage entries into open arms, agomelatine revealed only modest activity and SB243,213 was inactive. Further, like SB243,213, and in contrast to clorazepate, agomelatine did not suppress ultrasonic vocalizations emitted by rats re-exposed to an environment associated with an aversive stimulus. Whereas clorazepate reduced dialysate levels of 5-HT and noradrenaline in hippocampus and frontal cortex of freely moving rats, agomelatine did not affect extracellular levels of 5-HT and elevated those of noradrenaline. SB243,213 acted similarly to agomelatine. Melatonin, which did not modify extracellular levels of 5-HT or noradrenaline, was ineffective in all models of anxiolytic activity. Furthermore, the selective melatonin antagonist, S22153, did not modify anxiolytic properties of agomelatine in either the social interaction or the Vogel Conflict tests.ConclusionsIn contrast to melatonin, and reflecting blockade of 5-HT2C receptors, agomelatine is active in several models of anxiolytic properties in rodents. The anxiolytic profile of agomelatine differs from that of benzodiazepines from which it may also be distinguished by its contrasting influence on corticolimbic monoaminergic pathways.

N-Methyl-D-aspartate receptors as a target for improved antipsychotic agents: novel insights and clinical perspectives

RationaleActivation of “co-agonist” N-methyl-d-aspartate (NMDA) and GlycineB sites is mandatory for the operation of NMDA receptors, which play an important role in the control of mood, cognition and motor function.ObjectivesThis article outlines the complex regulation of activity at GlycineB/NMDA receptors by multiple classes of endogenous ligand. It also summarizes the evidence that a hypoactivity of GlycineB/NMDA receptors contributes to the pathogenesis of psychotic states, and that drugs which enhance activity at these sites may possess antipsychotic properties.ResultsPolymorphisms in several genes known to interact with NMDA receptors are related to an altered risk for schizophrenia, and psychotic patients display changes in levels of mRNA encoding NMDA receptors, including the NR1 subunit on which GlycineB sites are located. Schizophrenia is also associated with an overall decrease in activity of endogenous agonists at GlycineB/NMDA sites, whereas levels of endogenous antagonists are elevated. NMDA receptor “open channel blockers,” such as phencyclidine, are psychotomimetic in man and in rodents, and antipsychotic agents attenuate certain of their effects. Moreover, mice with genetically invalidated GlycineB/NMDA receptors reveal similar changes in behaviour. Finally, in initial clinical studies, GlycineB agonists and inhibitors of glycine reuptake have been found to potentiate the ability of “conventional” antipsychotics to improve negative and, albeit modestly, cognitive and positive symptoms. In contrast, therapeutic effects of clozapine are not reinforced, likely since clozapine itself enhances activity at NMDA receptors.ConclusionsReduced activity at NMDA receptors is implicated in the aetiology of schizophrenia. Correspondingly, drugs that (directly or indirectly) increase activity at GlycineB sites may be of use as adjuncts to other classes of antipsychotic agent. However, there is an urgent need for broader clinical evaluation of this possibility, and, to date, there is no evidence that stimulation of GlycineB sites alone improves psychotic states.

Inflammation of the hind limb as a model of unilateral, localized pain: influence on multiple opioid systems in the spinal cord of the rat

Inoculation of the right hind paw with Mycobacterium butyricum rapidly led to swelling and inflammation. The afflicted limb showed an enhanced sensitivity to noxious pressure (hyperalgesia) and a reduced sensitivity to noxious heat 24 h following treatment. Both naloxone and MR 2266 (which has greater activity at kappa-opioid receptors) further increased the sensitivity to pressure (that is, potentiated the hyperalgesia) but did not affect the response to heat. They did not affect the response of the uninflamed paw. At 1 week, only MR 2266 was effective. At both 24 h and 1 week, the inflamed paw showed pronounced supersensitivity to the antinociceptive action of morphine against noxious pressure. At both 24 h and (to a greater extent) 1 week, a rise in levels of immunoreactive (ir)-dynorphin (DYN) was seen in the ipsilateral dorsal horn of the lumbar spinal cord. There was no alteration in the contralateral dorsal horn or in either ventral horn. Furthermore, levels of ir-met-enkephalin (ME) and ir-leu-enkephalin (LE) were unaffected. There was no difference in the density of mu-, delta- or kappa-binding sites in any part of the lumbar cord, at either 24 h or 1 week, between ipsilateral and contralateral tissue. By 3 and 5 weeks postinoculation, the symptoms had spread to the contralateral hind limb and ir-DYN was elevated in the contralateral dorsal horn and the ipsilateral ventral horn. At 5 weeks, levels of ir-ME and ir-LE also were increased in the ipsilateral and contralateral dorsal horns, but not in the contralateral ventral horn. Furthermore, levels of ir-DYN were increased in the cervico-thoracic spinal cord, and rats displayed adrenal hypertrophy and a rise in plasma levels of ir-beta-endorphin (beta-EP). These data indicate: (1) Peripheral inflammation localized to a single limb selectively modifies levels of ir-DYN in ipsilateral dorsal horn. The effect is specific to DYN as compared to ME and LE. The density of mu-, delta-, or kappa-receptors in the lumbar spinal cord is unmodified. (2) The altered response to opioid agonists and antagonists shown by rats with an inflamed limb may be selective to the injured tissue. (3) Alterations in opioid systems associated with unilateral hind limb inflammation may not be exclusively chronic in nature: they appear very rapidly (within 24 h) of the induction of pain. With time, the contralateral limb becomes affected and, eventually, the effects resemble those seen with generalized polyarthritis.

Signaling at G-protein-coupled serotonin receptors: recent advances and future research directions

The broadly distributed monoaminergic neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) exerts its actions via 14 classes of receptor. With the exception of 5-HT3 receptors, which gate a cation-permeable ion channel, all 5-HT receptors are coupled to G proteins. The core features of transduction via 5-HT receptors are well established, but much still remains to be learned, in particular, with regard to native populations in the brain. In this article, we survey the current knowledge of cellular signaling at G-protein-coupled 5-HT receptors and focus on several novel (and surprising) insights that have emerged over the past few years. We also highlight several promising directions for future research that should improve the understanding of serotonin signaling and ultimately permit its therapeutic exploitation in the control of central nervous system disorders. In view of the diversity of transduction mechanisms engaged by 5-HT, much of this discussion is relevant to other classes of G-protein-coupled receptors.