Alain Gobert

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.

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.

Agonist and antagonist actions of yohimbine as compared to fluparoxan at ?2-adrenergic receptors (AR)s, serotonin (5-HT)1A, 5-HT1B, 5-HT1D and dopamine D2 and D3 receptors. Significance for the modulation of frontocortical monoaminergic transmission and depressive states

Herein, we evaluate the interaction of the α2‐AR antagonist, yohimbine, as compared to fluparoxan, at multiple monoaminergic receptors and examine their roles in the modulation of adrenergic, dopaminergic and serotonergic transmission in freely‐moving rats. Yohimbine displays marked affinity at human (h)α2A‐, hα2B‐ and hα2C‐ARs, significant affinity for h5‐HT1A, h5‐HT1B, h5‐HT1D, and hD2 receptors and weak affinity for hD3 receptors. In [35S]GTPγS binding protocols, yohimbine exerts antagonist actions at hα2A‐AR, h5‐HT1B, h5‐HT1D, and hD2 sites, yet partial agonist actions at h5‐HT1A sites. In vivo, agonist actions of yohimbine at 5‐HT1A sites are revealed by WAY100,635‐reversible induction of hypothermia in the rat. In guinea pigs, antagonist actions of yohimbine at 5‐HT1B receptors are revealed by blockade of hypothermia evoked by the 5‐HT1B agonist, GR46,611. In distinction to yohimbine, fluparoxan shows only modest partial agonist actions at h5‐HT1A sites versus marked antagonist actions at hα2‐ARs. While fluparoxan selectively enhances hippocampal noradrenaline (NAD) turnover, yohimbine also enhances striatal dopamine (DA) turnover and suppresses striatal turnover of 5‐HT. Further, yohimbine decreases firing of serotonergic neurones in raphe nuclei, an action reversed by WAY100,635. Fluparoxan increases extracellular levels of DA and NAD, but not 5‐HT, in frontal cortex. In analogy, yohimbine enhances FCX levels of DA and NAD, yet suppresses those of 5‐HT, the latter effect being antagonized by WAY100,635. The induction by fluoxetine of FCX levels of 5‐HT, DA, and NAD is potentiated by fluparoxan. Yohimbine likewise facilitates the influence of fluoxetine upon DA and NAD levels, but not those of 5‐HT. In conclusion, the α2‐AR antagonist properties of yohimbine increase DA and NAD levels both alone and in association with fluoxetine. However, in contrast to the selective α2‐AR antagonist, fluparoxan, the 5‐HT1A agonist actions of yohimbine suppress 5‐HT levels alone and underlie its inability to augment the influence of fluoxetine upon 5‐HT levels. Synapse 35:79–95, 2000.

Potentiation of the Fluoxetine-Induced Increase in Dialysate Levels of Serotonin (5-HT) in the Frontal Cortex of Freely Moving Rats by Combined Blockade of 5-HT1A and 5-HT1B Receptors with WAY 100,635 and GR 127,935

Abstract: In this study, we examined the influence of blockade of serotonin (5‐HT)1A and/or 5‐HT1B autoreceptors on the fluoxetine‐induced increase in dialysate levels of 5‐HT as compared with dopamine (DA) and noradrenaline (NAD) in single samples of the frontal cortex (FCx) of freely moving rats. Fluoxetine (10.0 mg/kg, s.c.) elicited a twofold increase in dialysate levels of 5‐HT relative to baseline values. The selective 5‐HT1A antagonist WAY 100,635 (0.16 mg/kg, s.c.) did not influence 5‐HT release alone but doubled the influence of fluoxetine on basal levels. Similarly, the selective 5‐HT1B/1D antagonist GR 127,935 (2.5 mg/kg, s.c.) did not alter basal 5‐HT levels alone and doubled the fluoxetine‐induced increase in 5‐HT levels. Combined administration of WAY 100,635 and GR 127,935 elicited an (at least) additive rise in the fluoxetine‐induced increase in 5‐HT levels to eightfold basal values, without modifying resting 5‐HT levels. These changes were selective for 5‐HT inasmuch as the parallel (twofold) increase in DA and NAD levels provoked by fluoxetine was not potentiated. The present data demonstrate that combined blockade of 5‐HT1A and 5‐HT1B autoreceptors markedly and selectively potentiates the fluoxetine‐induced increase in dialysate levels of 5‐HT versus DA and NAD in the FCx of freely moving rats. These observations suggest that 5‐HT1A/1B antagonism may represent a novel strategy for the improvement in the therapeutic profile of 5‐HT reuptake inhibitor antidepressant agents and that 5‐HT may be primarily involved in such interactions.

Selective blockade of dopamine D3 versus D2 receptors enhances frontocortical cholinergic transmission and social memory in rats: a parallel neurochemical and behavioural analysis

Though dopaminergic mechanisms modulate cholinergic transmission and cognitive function, the significance of specific receptor subtypes remains uncertain. Here, we examined the roles of dopamine D3 versus D2 receptors. By analogy with tacrine (0.16–2.5 mg/kg, s.c.), the selective D3 receptor antagonists, S33084 (0.01–0.63) and SB277,011 (0.63–40.0), elicited dose‐dependent, pronounced and sustained elevations in dialysis levels of acetylcholine (ACh) in the frontal cortex, but not the hippocampus, of freely‐moving rats. The actions of these antagonists were stereospecifically mimicked by (+)S14297 (1.25), whereas its inactive distomer, (–)S17777, was ineffective. The preferential D2 receptor antagonist, L741,626 (10.0), failed to modify levels of ACh. S33084 (0.01–0.63) and SB277,011 (0.16–2.5) also mimicked tacrine (0.04–0.63) by dose‐dependently attenuating the deleterious influence of scopolamine (1.25) upon social memory (recognition by an adult rat of a juvenile conspecific). Further, (+)S14297 (1.25) versus (–)S17777 stereospecifically blocked the action of scopolamine. Using an intersession interval of 120 min (spontaneous loss of recognition), S33084 (0.04–0.63), SB277,011 (0.16–10.0) and (+)S14297 (0.63–10.0) likewise mimicked tacrine (0.16–2.5) in enhancing social memory. In contrast, L741,626 (0.16–10.0) displayed amnesic properties. In conclusion, selective blockade of D3 receptors facilitates frontocortical cholinergic transmission and improves social memory in rats. These data support the pertinence of D3 receptors as a target for treatment of disorders in which cognitive function is compromised.

Anxiolytic Properties of the Selective, Non-peptidergic CRF1 Antagonists, CP154,526 and DMP695 ☆: A Comparison to Other Classes of Anxiolytic Agent

The selective, non-peptidergic corticotropin-releasing factor (CRF)1 receptor antagonists, CP154,526 and DMP695, dose-dependently increased punished responses of rats in a Vogel conflict test and enhanced social interaction (SI) of rats in an unfamiliar environment. They were, however, inactive in a plus-maze procedure and failed to reduce ultrasonic vocalizations (USV) associated with an aversive environment. In contrast, the benzodiazepine, chlordiazepoxide, was effective in all these procedures. Further, the serotonin (5-HT)1A agonist, flesinoxan, was active in each paradigm (except the plus-maze) while the 5-HT2C antagonist, SB242,084, was effective in the SI and Vogel but not the plus-maze and USV procedures. In contrast to chlordiazepoxide, flesinoxan and SB242,084, CP154,526 did not modify dialysate levels of 5-HT, norepinephrine (NE) and dopamine (DA) in the frontal cortex (FCX) of freely moving rats. In conclusion, CP154,526 and DMP695 possess a common and distinctive profile of anxiolytic action expressed in the absence of an intrinsic influence upon monoamine release.

α2‐Adrenergic Receptor Blockade Markedly Potentiates Duloxetine‐ and Fluoxetine‐Induced Increases in Noradrenaline, Dopamine, and Serotonin Levels in the Frontal Cortex of Freely Moving Rats

Abstract: Evidence exists that a reinforcement in monoaminergic transmission in the frontal cortex (FCX) is associated with antidepressant (AD) properties. Herein, we examined whether blockade of α2‐adrenergic receptors modified the influence of monoamine reuptake inhibitors on FCX levels of serotonin (5‐HT), noradrenaline (NAD), and dopamine (DA). The selective α2‐adrenergic receptor agonist S 18616 (0.16 mg/kg, s.c.) suppressed extracellular levels of NAD, DA, and 5‐HT (by 100, 51, and 63%, respectively) in single dialysates of FCX of freely moving rats. In contrast, the selective α2‐adrenergic receptor antagonists atipamezole (0.16 mg/kg, s.c.) and 1‐(2‐pyrimidinyl)piperazine (1‐PP; 2.5 mg/kg, s.c.) increased levels of NAD (by 180 and 185%, respectively) and DA (by 130 and 90%, respectively), without affecting 5‐HT levels. Duloxetine (5.0 mg/kg, s.c.), a mixed inhibitor of 5‐HT and NAD reuptake, and fluoxetine (10.0 mg/kg, s.c.), a selective 5‐HT reuptake inhibitor, both increased levels of 5‐HT (by 150 and 120%, respectively), NAD (by 400 and 100%, respectively), and DA (by 115 and 55%, respectively). Atipamezole (0.16 mg/kg, s.c.) markedly potentiated the influence of duloxetine and fluoxetine on levels of 5‐HT (by 250 and 330%, respectively), NAD (by 1,030 and 215%, respectively), and DA (by 370 and 170%, respectively). 1‐PP similarly potentiated the influence of duloxetine on 5‐HT, NAD, and DA levels (by 290, 1,320, and 600%, respectively). These data demonstrate that α2‐adrenergic receptors tonically inhibit NAD and DA and phasically inhibit 5‐HT release in the FCX and that blockade of α2‐adrenergic receptors strikingly potentiates the increase in FCX levels of 5‐HT, NAD, and DA elicited by reuptake inhibitors. Concomitant α2‐adrenergic receptor antagonism and inhibition of monoamine uptake may thus provide a mechanism allowing for a marked increase in the efficacy of AD agents.

Modulation of Dialysate Levels of Dopamine, Noradrenaline, and Serotonin (5-HT) in the Frontal Cortex of Freely-Moving Rats by (-)-Pindolol Alone and in Association with 5-HT Reuptake Inhibitors: Comparative Roles of β-Adrenergic, 5-HT1A, and 5-HT1B Receptors

(-)-Pindolol, which possesses significant affinity for 5-HT1A, 5-HT1B, and β1/2-adrenergic receptors (AR)s, dose-dependently increased extracellular levels of dopamine (DA) and noradrenaline (NAD) versus 5-HT, in dialysates of the frontal cortex (FCX), but not accumbens and striatum, of freely-moving rats. In distinction, the preferential β1-AR antagonist, betaxolol, and the preferential β2-AR antagonist, ICI118,551, did not increase basal levels of DA, NAD, or 5-HT. Further, they both dose-dependently and markedly blunted the influence of (-)-pindolol upon DA and NAD levels. The selective 5-HT1A receptor antagonist, WAY100,635, slightly attenuated the (-)-pindolol-induced increase in DA and NAD levels, while the selective 5-HT1B antagonist, SB224,289, was ineffective. These data suggest that (-)-pindolol facilitates frontocortical dopaminergic (and adrenergic) transmission primarily by activation of β1/2-ARs and, to a lesser degree, by stimulation of 5-HT1A receptors, whereas 5-HT1B receptors are not involved. (-)-Pindolol potentiated the increase in FCX levels of 5-HT elicited by the 5-HT reuptake inhibitors, fluoxetine and duloxetine, and also enhanced their ability to elevate FCX levels of DA—though not of NAD. In contrast to (-)-pindolol, betaxolol and ICI118,551 did not affect the actions of fluoxetine, whereas both WAY100,635 and SB224,289 potentiated the increase in levels of 5-HT—but not DA or NAD levels—elicited by fluoxetine. In conclusion, (-)-pindolol modulates, both alone and together with 5-HT reuptake inhibitors, dopaminergic, adrenergic, and serotonergic transmission in the FCX via a complex pattern of actions at β1/2-ARs, 5-HT1A, and 5-HT1B receptors. These findings have important implications for clinical studies of the influence of (-)-pindolol upon the actions of antidepressant agents.

Selective blockade of neurokinin (NK)(1) receptors facilitates the activity of adrenergic pathways projecting to frontal cortex and dorsal hippocampus in rats.

The selective NK1 receptor antagonist, GR205,171 (2.5–40.0 mg/kg, i.p.), dose‐dependently elevated dialysate levels of noradrenaline (NA), but not serotonin (5‐HT), in the frontal cortex of freely moving rats. This action was exerted stereospecifically inasmuch as its less active isomer, GR226,206, was ineffective. In the dorsal hippocampus, GR205,171 (but not GR226,206) also significantly increased dialysate levels of NA, whereas levels of 5‐HT were unaffected. Further, in anaesthetized rats, GR205,171 dose‐dependently (1.0–4.0 mg/kg, i.v.) increased the firing rate of adrenergic perikarya in the locus coeruleus. In contrast, their activity was not modified by GR226,206. These findings indicate that selective blockade of NK1 receptors enhances the activity of ascending adrenergic pathways in rats. Adrenergic mechanisms may, thus, be involved in the potential antidepressant and other functional properties of NK1 receptor antagonists.