Mostafa El Mansari

Functional interactions between dopamine, serotonin and norepinephrine neurons: an in-vivo electrophysiological study in rats with monoaminergic lesions

Anatomical studies have established the existence of reciprocal relationships between the main population of monoamine, serotonin (5-HT), norepinephrine (NE) and dopamine (DA) neurons in the brain. The present study was thus conducted to examine the firing activity of 5-HT and NE neurons in DA-depleted rats, as well as the firing activity of DA neurons in 5-HT- or NE-depleted rats. The selective lesion of DA neurons elicited by 6-hydroxydopamine (6-OHDA) decreased the spontaneous firing activity of dorsal raphe (DR) nucleus 5-HT neurons by 60%, thus revealing the excitatory effect of the DA input on these 5-HT neurons. In contrast, the selective lesion of 5-HT neurons produced by 5,7-dihydroxytryptamine (5,7-DHT) enhanced by 36% the firing activity of VTA DA neurons, thereby indicating an inhibitory effect of the 5-HT input on these DA neurons. With regard to the reciprocal interaction between DA and NE neurons, it was observed that the selective loss of DA neurons achieved by the intra-ventral tegmental area (VTA) injection of 6-OHDA increased the firing activity of a subset of locus coeruleus (LC) NE neurons by 47%. The selective loss of NE neurons in response to the intra-LC injection of 6-OHDA enhanced the firing activity of VTA DA neurons by 70%, demonstrating a net inhibitory role of the NE input on VTA DA neurons. These findings have important consequences for antidepressant treatments aimed at enhancing simultaneously 5-HT, NE and DA transmission. Indeed, based on the understanding of such interactions, it may be possible to develop strategies to improve the effectiveness of antidepressant drugs by preventing counter-productive negative feedback actions.

Mechanisms of action of current and potential pharmacotherapies of obsessive-compulsive disorder

A significant body of evidence documented that the orbitofrontal cortex (OFC) and the head of caudate nucleus are involved in the mediation of obsessive-compulsive disorder (OCD) symptoms. Potent serotonin (5-HT) reuptake inhibitors (SRIs) are the only antidepressant agents thus far shown to be effective in the treatment of OCD. The present review summarizes information on 5-HT release and the adaptive changes in pre- and postsynaptic 5-HT receptors sensitivity induced by SRI treatment in rat and guinea pig structures involved in OCD. It emphasizes that the time course for the occurrence of increased 5-HT release and terminal 5-HT1D desensitization is congruent with the delayed therapeutic response to SRI in OCD. In addition, a greater dose of SRI inducing a greater degree of reuptake inhibition may play an essential role in this phenomenon. This is consistent with the common clinical observation that high doses of SRIs are sometimes necessary to obtain an anti-OCD effect, and with the results of some fixed-dose double blind trials showing a dose-dependent therapeutic effect of SRIs. It is hypothesized that enhanced 5-HT release in the OFC is mediated by the activation of normosensitive postsynaptic 5-HT2-like receptors and underlies the therapeutic action of SRI in OCD. This is supported by the beneficial effect of some hallucinogens with 5-HT2 agonistic properties in obtaining a more rapid therapeutic response. Finally, based on this knowledge, new strategies aimed at producing more rapid, effective and safe anti-OCD drugs, such as a selective action on terminal 5-HT1D receptors, on 5-HT2 receptors as well as on the glutamate system, are discussed.

Serotonin and beyond: therapeutics for major depression.

The serotonin (5-HT, 5-hydroxytryptamine) system has been implicated in the pathogenesis of major depressive disorder (MDD). The case for its contribution to the therapeutic efficacy of a wide variety of antidepressant treatments is, however, much stronger. All antidepressant strategies have been shown to enhance 5-HT transmission in the brain of laboratory animals. Catecholamines, norepinephrine (NE) and dopamine (DA) can also play a pivotal role in the mechanism of action of certain antidepressant strategies. The enhancement of 5-HT transmission by selective serotonin reuptake inhibitors, which leads to a dampening of the activity of NE and DA neurons, may account in part for the low remission rate achieved with these medications and/or the residuals symptoms after remission is achieved. The functional connectivity between the 5-HT, NE and DA systems can be used to understand the mechanism of action of a wide variety of augmentation strategies in treatment-resistant MDD. Proof-of-concept studies have shown that antidepressant medications with complementary mechanisms of action on monoaminergic systems can double the remission rate achieved in a trial of standard duration. Novel approaches are also being used to treat MDD, which also appear to involve the monoaminergic system(s) to a varying extent.

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.

Noradrenergic Augmentation of Escitalopram Response by Risperidone: Electrophysiologic Studies in the Rat Brain

BACKGROUND Atypical antipsychotic drugs have been used in depressed patients not responding adequately to the selective serotonin reuptake inhibitors (SSRIs). The aim of the current study was to investigate putative mechanisms of the beneficial effect of atypical antipsychotic drugs during their co-administration with SSRIs. In previous electrophysiological studies, it was found that SSRIs decrease, while atypical antipsychotics increase, norepinephrine neuronal firing. Thus, the resistance to SSRIs could be explained, at least in part, by the SSRI-induced decrease of norepinephrine neuronal firing activity, and the beneficial effect of atypical antipsychotic drugs could be explained by the reversal of the above-mentioned suppression of firing. METHODS Rats were administered the SSRI escitalopram and the atypical antipsychotic drug risperidone. Norepinephrine neuronal activity was determined using in vivo electrophysiology. RESULTS Subacute and long-term escitalopram decreased, while risperidone co-administered with escitalopram increased, norepinephrine neuronal firing. Attempts at reversing the escitalopram-induced decrease of firing with various selective antagonists revealed that the serotonin-2A receptor antagonistic property of risperidone may mediate the pronoradrenergic action of atypical antipsychotics in the presence of serotonin reuptake inhibition. CONCLUSIONS Risperidone reverses escitalopram-induced inhibition of norepinephrine neuronal activity by a mechanism involving serotonin-2A receptors. This reversal may explain the beneficial effect of atypical antipsychotics in treatment-resistant depression.

Electrophysiological and neurochemical effects of long-term vagus nerve stimulation on the rat monoaminergic systems

Vagus nerve stimulation (VNS) is an adjunctive treatment for resistant epilepsy and depression. Electrophysiological recordings in the rat brain have already shown that chronic VNS increases norepinephrine (NE) neuronal firing activity and, subsequently, that of serotonin (5-HT) neurons through an activation of their excitatory α1-adrenoceptors. Long-term VNS was shown to increase the tonic activation of post-synaptic 5-HT1A receptors in the hippocampus. This study was aimed at examining the effect of VNS on extracellular 5-HT, NE and dopamine (DA) levels in different brain areas using in vivo microdialysis, on NE transmission in the hippocampus, and DA neuronal firing activity using electrophysiology. Rats were implanted with a VNS device and stimulated for 14 d with standard parameters used in treatment-resistant depression (0.25 mA, 20 Hz, 500 μs, 30 s on-5 min off). The results of the present study revealed that 2-wk VNS significantly increased extracellular NE levels in the prefrontal cortex and the hippocampus and enhanced the tonic activation of post-synaptic α2-adrenoceptors on pyramidal neurons. The electrophysiological experiments revealed a significant decrease in ventral tegmental area DA neuronal firing rate after long-term VNS; extracellular DA levels were nevertheless increased in the prefrontal cortex and nucleus accumbens. Chronic VNS significantly increased extracellular 5-HT levels in the dorsal raphe but not in the hippocampus and prefrontal cortex. In conclusion, the effect of VNS in increasing the transmission of monoaminergic systems targeted in the treatment of resistant depression should be involved, at least in part, in its antidepressant properties observed in patients not responding to many antidepressant strategies.

SUSTAINED ADMINISTRATION OF BUPROPION ALTERS THE NEURONAL ACTIVITY OF SEROTONIN, NOREPINEPHRINE BUT NOT DOPAMINE NEURONS IN THE RAT BRAIN

Bupropion is widely used in the treatment of depression. There are, however, limited data on its long-term effects on monoaminergic neurons and therefore the mechanism of its delayed onset of action is at present not well understood. The present study was conducted to examine the effects of prolonged bupropion administration on the firing activity of dorsal raphe nucleus (DRN), locus coeruleus (LC), and ventral tegmental area (VTA) neurons. Spontaneously firing neurons were recorded extracellularly in rats anesthetized with chloral hydrate. Bupropion (30 mg/kg/day) was administered using subcutaneously implanted minipumps. In the DRN, the firing rate of serotonin (5-HT) neurons was significantly increased after 2, 7 and 14 days of administration. The suppressant effect of LSD was significantly diminished after the two-day regimen, indicating a desensitization of 5-HT1A autoreceptors. In the LC, the firing rate of norepinephrine (NE) neurons was significantly attenuated after a 2-day regimen, but recovered progressively over 14 days of administration. The suppressant effect of clonidine on NE neuronal firing was significantly attenuated in rats treated with bupropion for 14 days, indicating a desensitization of alpha2-adrenoceptors. In the VTA, neither 2 nor 14 days of bupropion administration altered the firing and burst activity of dopamine neurons. These results indicate that bupropion, unlike 5-HT reuptake inhibitors, promptly increased 5-HT neuronal activity, due to early desensitization of the 5-HT1A autoreceptor. The gradual recovery of neuronal firing of NE neurons, due to the desensitization of alpha2-adrenoceptors, in the presence of the sustained increase in 5-HT neuronal firing, may explain in part the delayed onset of action of bupropion in major depression.

Electrophysiological characterization of the effects of asenapine at 5-HT1A, 5-HT2A, α2-adrenergic and D2 receptors in the rat brain

Asenapine is a psychopharmacologic agent being developed for schizophrenia and bipolar disorder. This study electrophysiologically characterized the in vivo effects of asenapine at dorsal raphe nucleus (DRN) and hippocampus serotonin-1A (5-HT(1A)), ventral tegmental area D(2), locus coeruleus 5-HT(2A,) and alpha(2)-adrenergic receptors in anesthetized rats. Asenapine displayed potent antagonistic activity at alpha(2)-adrenoceptors (ED(50), 85+/-2 microg/kg), 5-HT(2A) (ED(50), 75+/-2 microg/kg) and D(2) receptors (ED(50), 40+/-2 microg/kg) as evidenced by its reversal of clonidine-, DOI-, and apomorphine-induced inhibition of norepinephrine and dopamine neurons. In contrast, asenapine acted as a partial agonist at 5-HT(1A) receptors in DRN and hippocampus, as indicated by blockade of its inhibitory effect on neuronal firing by the 5-HT(1A) antagonist WAY 100635 and the partial inhibition of the suppressant action of 5-HT when co-applied by microiontophoresis. These results confirm that asenapine displays potent antagonistic activity at 5-HT(2A), D(2), alpha(2)-adrenergic receptors and provide evidence to support its 5-HT(1A) partial agonistic activity.

Effects of acute and sustained administration of the catecholamine reuptake inhibitor nomifensine on the firing activity of monoaminergic neurons.

Nomifensine potently inhibits the reuptake of norepinephrine and dopamine in vitro. It is one of few antidepressants with marked potency to block dopamine reuptake that has ever been used clinically. Acute and sustained administration of nomifensine was investigated on the firing of monoaminergic neurons to understand its mechanism of action. In vivo extracellular recordings of locus coeruleus, ventral tegmental area and dorsal raphe nucleus neurons were obtained from male Sprague-Dawley rats. The intravenous injection of nomifensine in the locus coeruleus and ventral tegmental area yielded ED50 values of 40 ± 1 and 450 ± 41 μg/kg, respectively, suggesting that nomifensine directly acted upon dopamine and norepinephrine neurons, since these values are proportional to its affinities for norepinephrine and dopamine transporters. There was no effect on 5-HT neurons. Nomifensine (5 mg/kg/day, subcutaneous, using minipumps) potently and significantly inhibited dopamine neuronal firing in the ventral tegmental area after 2 days, with recovery to normal after the 14-day treatment due to D2 autoreceptor desensitization. Norepinephrine neuronal firing in the locus coeruleus was significantly decreased after 2 and 14 days. A significant increase in dorsal raphe nucleus 5-HT neuronal firing was seen after a two-day regimen, and remained elevated after 14 days. Desensitization of the 5-HT1A receptor on 5-HT neurons of the dorsal raphe nucleus occurred after two days of nomifensine administration. Nomifensine likely treated depression by acting on dopamine, norepinephrine and 5-HT neurons, highlighting the importance of the functional connectivity between these three monoaminergic systems.

Acute Effects of Brexpiprazole on Serotonin, Dopamine, and Norepinephrine Systems: An In Vivo Electrophysiologic Characterization

Brexpiprazole, a compound sharing structural molecular characteristics with aripiprazole, is currently under investigation for the treatment of schizophrenia and depression. Using electrophysiologic techniques, the present study assessed the in vivo action of brexpiprazole on serotonin (5-HT) receptor subtypes 5-HT1A, 5-HT1B, and 5-HT2A; dopamine (DA) D2 autoreceptors, and α1- and α2-adrenergic receptors. In addition, the effects on 5-HT1A autoreceptors in the dorsal raphe nucleus (DRN) and D2 autoreceptors in the ventral tegmental area (VTA) were compared with those of aripiprazole, an agent in wide clinical use. In the DRN, brexpiprazole completely inhibited the firing of 5-HT neurons via 5-HT1A agonism and was more potent than aripiprazole (ED50 = 230 and 700 μg/kg, respectively). In the locus coeruleus, brexpiprazole reversed the inhibitory effect of the preferential 5-HT2A receptor agonist DOI (2,5-dimethoxy-4-iodoamphetamine) on norepinephrine neuronal firing (ED50 = 110 μg/kg), demonstrating 5-HT2A antagonistic action. Brexpiprazole reversed the inhibitory effect of the DA agonist apomorphine on VTA DA neurons (ED50 = 61 μg/kg), whereas it was ineffective when administered alone, indicating partial agonistic action on D2 receptors. Compared with aripiprazole, which significantly inhibited the firing activity of VTA DA neurons, brexpiprazole displayed less efficacy at D2 receptors. In the hippocampus, brexpiprazole acted as a full agonist at 5-HT1A receptors on pyramidal neurons. Furthermore, it increased 5-HT release by terminal α2-adrenergic heteroceptor but not 5-HT1B autoreceptor antagonism. In the lateral geniculate nucleus, brexpiprazole displayed α1B-adrenoceptor antagonistic action. Taken together, these results provide insight into the in vivo action of brexpiprazole on monoamine targets relevant in the treatment of depression and schizophrenia.