Jean-Michel Rivet

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.

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.

Behavioral sensitization to amphetamine is dependent on corticosteroid receptor activation

Thirty rats received 3 amphetamine injections (1.5 mg/kg, s.c.) 6 days apart and the locomotor response was measured. One day before the second injection they were adrenalectomized or sham operated. Corticosteroid replacement treatments (500 micrograms/kg, s.c.) were given every evening. Sham adrenalectomized animals exhibited behavioral sensitization to successive injections of amphetamine, which was prevented by adrenalectomy. Treatment with corticosterone or deoxycorticosterone did not reverse the effect of adrenalectomy, whereas dexamethasone completely restored and even potentiated sensitization to amphetamine. These results demonstrate that corticosteroids are necessary for sensitization of the dopaminergic system to occur and that they most probably act through the type II (or glucocorticoid) receptor subtype.

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.

Locomotor activity in relation to dopamine and noradrenaline in the nucleus accumbens, septal and frontal areas: a 6-hydroxydopamine study

Locomotor activity was automatically recorded in a circular corridor in rats treated with 6-hydroxydopamine in the ventral tegmental area (VTA), septum and frontal cortex. Control and experimental groups showed similar hyperlocomotor responses in the novel apparatus lasting 3 h. Circadian changes are described. VTA lesions resulted in increased dark activity and a large response to apomorphine compared to other lesion and control groups. Septal lesions did not affect locomotion. The frontal group showed a small increase of locomotion after apomorphine treatment that might reflect increased receptor sensitivity in cortical or subcortical areas. Together with correlations between motor activity and cortical levels of dopamine and noradrenaline these results are interpreted to support a role for dopamine, noradrenaline and the frontal cortex in modulating locomotion which is primarily mediated by VTA-accumbens-dopamine activity.

5‐HT6 receptor recruitment of mTOR as a mechanism for perturbed cognition in schizophrenia

Cognitive deficits in schizophrenia severely compromise quality of life and are poorly controlled by current antipsychotics. While 5‐HT6 receptor blockade holds special promise, molecular substrates underlying their control of cognition remain unclear. Using a proteomic strategy, we show that 5‐HT6 receptors physically interact with several proteins of the mammalian target of rapamycin (mTOR) pathway, including mTOR. Further, 5‐HT6 receptor activation increased mTOR signalling in rodent prefrontal cortex (PFC). Linking this signalling event to cognitive impairment, the mTOR inhibitor rapamycin prevented deficits in social cognition and novel object discrimination induced by 5‐HT6 agonists. In two developmental models of schizophrenia, specifically neonatal phencyclidine treatment and post‐weaning isolation rearing, the activity of mTOR was enhanced in the PFC, and rapamycin, like 5‐HT6 antagonists, reversed these cognitive deficits. These observations suggest that recruitment of mTOR by prefrontal 5‐HT6 receptors contributes to the perturbed cognition in schizophrenia, offering new vistas for its therapeutic control.

S33138 (N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1] benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenyl-acetamide), a Preferential Dopamine D3 versus D2 Receptor Antagonist and Potential Antipsychotic Agent: III. Actions in Models of Therapeutic Activity and Induction of Side Effects

In contrast to clinically available antipsychotics, the novel benzopyranopyrrolidine derivative, S33138 (N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenyl-acetamide), behaves as a preferential antagonist of D3 versus D2 receptors and does not interact with histamine H1 and muscarinic receptors. In contrast to haloperidol, clozapine, olanzapine, and risperidone, S33138 (0.16–2.5 mg/kg s.c.) did not disrupt performance in passive-avoidance and five-choice serial reaction time procedures. Furthermore, upon either systemic administration (0.04–2.5 mg/kg s.c.) or introduction into the frontal cortex (0.04–0.63 μg/side), S33138 potently attenuated the perturbation of social recognition by scopolamine or a prolonged intersession delay. Over a comparable and low-dose range, S33138 (0.04–0.63 mg/kg s.c.) elevated dialysis levels of acetylcholine in the frontal cortex of freely moving rats. At higher doses (2.5–10.0 mg/kg s.c.), S33138 also increased frontocortical levels of histamine, whereas monoamines, glutamate, glycine, and GABA were unaffected. By analogy to the other antipsychotics, S33138 (0.63–10.0 mg/kg s.c.) inhibited conditioned avoidance responses in rats, apomorphine-induced climbing in mice, and hyperlocomotion elicited by amphetamine, cocaine, dizocilpine, ketamine, and phencyclidine in rats. S33138 (0.16–2.5 mg/kg s.c.) also blocked the reduction of prepulse inhibition elicited by apomorphine. In comparison with the above actions, only “high” doses of S33138 (10.0–40.0 mg/kg s.c.) elicited catalepsy. To summarize, reflecting preferential blockade of D3 versus D2 receptors, S33138 preserves and/or enhances cognitive function, increases frontocortical cholinergic transmission, and is active in models of antipsychotic properties at doses well below those inducing catalepsy. In comparison with clinically available agents, S33138 displays, thus, a distinctive and promising profile of potential antipsychotic properties.

Buspirone Enhances Duloxetine‐ and Fluoxetine‐Induced Increases in Dialysate Levels of Dopamine and Noradrenaline, but Not Serotonin, in the Frontal Cortex of Freely Moving Rats

Abstract: A serotonin (5‐HT)1A receptor partial agonist, buspirone, potentiates the clinical antidepressant properties of 5‐HT reuptake inhibitors (SSRIs). Herein, we examined the interaction of buspirone with two SSRIs, duloxetine and fluoxetine, on extra‐cellular levels of 5‐HT, dopamine (DA), and noradrenaline (NAD) in single dialysate samples of freely moving rats. Duloxetine (5.0 mg/kg, s.c.) and fluoxetine (10.0 mg/kg, s.c.) increased dialysate levels of DA (65 and 60% vs. basal values, respectively), NAD (400 and 90%, respectively), and 5‐HT (130 and 110%, respectively) in the frontal cortex (FCX). Buspirone (2.5 mg/kg, s.c.) similarly elevated levels of DA (100%) and NAD (160%) but reduced those of 5‐HT (−50%). Administered with buspirone, the ability of duloxetine and fluoxetine to increase 5‐HT levels was transiently inhibited (over 60 min), although by the end of sampling (180 min) their actions were fully expressed. In contrast, buspirone markedly and synergistically facilitated the elevation in DA levels elicited by duloxetine (550%) and fluoxetine (240%). Furthermore, buspirone potentiated the induction of NAD levels by duloxetine (750%) and fluoxetine (350%). These data suggest that a reinforcement in the influence of SSRIs on DA and, possibly, NAD but not 5‐HT release in FCX may contribute to their increased antidepressant activity in the presence of buspirone. More generally, they support the hypothesis that a reinforcement in dopaminergic transmission in the FCX contributes to the actions of SSRIs and other antidepressant drugs.

Dopamine D3 (auto) receptors inhibit dopamine release in the frontal cortex of freely moving rats in vivo.

Abstract: In freely moving rats, the novel, selective dopamine (DA) D3 receptor agonist PD 128,907 dose‐dependently [effective dose (ED25) = 0.07 mg/kg, s.c.] reduced dialysate levels of DA in the frontal cortex, a structure innervated by the ventral tegmental area (VTA). This action of PD 128,907 (0.16 mg/kg, s.c.) was abolished by a selective DA D3 receptor antagonist S 14297 (1.25 mg/kg, s.c.), which alone did not modify levels of DA. In contrast to S 14297, its inactive distomer, S 17777, did not modify the actions of PD 128,907. In addition, PD 128,907 dose‐dependently and potently inhibited the firing rate of VTA‐localized neurons in anesthetized rats (ED50 = 0.001 mg/kg, i.v.). S 14297, but not S 17777, completely reversed the actions of PD 128,907 (0.005 mg/kg, i.v.) with a 50% inhibitory dose of 0.03 mg/kg, i.v. and did not itself significantly modify the firing rate. In conclusion, these data provide the first direct evidence that DA D3 (auto)receptors modulate (inhibit) the release of DA in the frontal cortex.