Cécile Bétry

Lu AA21004, a novel multimodal antidepressant, produces regionally selective increases of multiple neurotransmitters—A rat microdialysis and electrophysiology study

The monoaminergic network, including serotonin (5-HT), norepinephrine (NE), and dopamine (DA) pathways, is highly interconnected and has a well-established role in mood disorders. Preclinical research suggests that 5-HT receptor subtypes, including 5-HT1A, 5-HT1B, 5-HT3, and 5-HT7 receptors as well as the 5-HT transporter (SERT), may have important roles in treating depression. This study evaluated the neuropharmacological profile of Lu AA21004, a novel multimodal antidepressant combining 5-HT3 and 5-HT7 receptor antagonism, 5-HT1B receptor partial agonism, 5-HT1A receptor agonism, and SERT inhibition in recombinant cell lines. Extracellular 5-HT, NE and DA levels were evaluated in the ventral hippocampus (vHC), medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) after acute and subchronic treatment with Lu AA21004 or escitalopram. The acute effects of LuAA21004 on NE and DA neuronal firing were also evaluated in the locus coeruleus (LC) and ventral tegmental area (VTA), respectively. Acute Lu AA21004 dose-dependently increased 5-HT in the vHC, mPFC and NAc. Maximal 5-HT levels in the vHC were higher than those in the mPFC. Furthermore, mPFC 5-HT levels were increased at low SERT occupancy levels. In the vHC and mPFC, but not the NAc, high Lu AA21004 doses increased NE and DA levels. Lu AA21004 slightly decreased LC NE neuronal firing and had no effect on VTA DA firing. Results are discussed in context of occupancy at 5-HT3, 5-HT1B and 5-HT1A receptors and SERT. In conclusion, Lu AA21004, acting via two pharmacological modalities, 5-HT receptor modulation and SERT inhibition, results in a brain region-dependent increase of multiple neurotransmitter concentrations.

The rapid recovery of 5-HT cell firing induced by the antidepressant vortioxetine involves 5-HT 3 receptor antagonism

The therapeutic effect of current antidepressant drugs appears after several weeks of treatment and a significant number of patients do not respond to treatment. Here, we report the effects of the multi-modal antidepressant vortioxetine (Lu AA21004), a 5-HT(3) and 5-HT(7) receptor antagonist, 5-HT(1B) receptor partial agonist, 5-HT(1A) receptor agonist and 5-HT transporter (SERT) inhibitor, on rat 5-HT neurotransmission. Using in vivo electrophysiological recordings in the dorsal raphe nucleus of anaesthetized rats, we assessed the acute and subchronic effects of vortioxetine and/or the selective 5-HT(3) receptor agonist, SR57227 or the selective 5-HT(1A) receptor agonist flesinoxan, on 5-HT neuronal firing activity. Using ex-vivo autoradiography, we correlated SERT occupancy and presumed 5-HT firing activity. The selective serotonin reuptake inhibitor, fluoxetine, was used as comparator. Importantly, the recovery of 5-HT neuronal firing was achieved after 1 d with vortioxetine and 14 d with fluoxetine. SR57227 delayed this recovery. In contrast, vortioxetine failed to alter the reducing action of 3 d treatment of flesinoxan. Acute dosing of vortioxetine inhibited neuronal firing activity more potently than fluoxetine. SR57227 prevented the suppressant effect of vortioxetine, but not of fluoxetine. In contrast, flesinoxan failed to modify the suppressant effect of vortioxetine acutely administered. Differently to fluoxetine, vortioxetine suppressed neuronal firing without saturating occupancy at the SERT. Vortioxetine produced a markedly faster recovery of 5-HT neuronal firing than fluoxetine. This is at least partly due to 5-HT(3) receptor antagonism of vortioxetine in association with its reduced SERT occupancy.

Role of 5-HT3 Receptors in the Antidepressant Response

Serotonin (5-HT)3 receptors are the only ligand-gated ion channel of the 5-HT receptors family. They are present both in the peripheral and central nervous system and are localized in several areas involved in mood regulation (e.g., hippocampus or prefrontal cortex). Moreover, they are involved in regulation of neurotransmitter systems implicated in the pathophysiology of major depression (e.g., dopamine or GABA). Clinical and preclinical studies have suggested that 5-HT3 receptors may be a relevant target in the treatment of affective disorders. 5-HT3 receptor agonists seem to counteract the effects of antidepressants in non-clinical models, whereas 5-HT3 receptor antagonists, such as ondansetron, present antidepressant-like activities. In addition, several antidepressants, such as mirtazapine, also target 5-HT3 receptors. In this review, we will report major advances in the research of 5-HT3 receptors roles in neuropsychiatric disorders, with special emphasis on mood and anxiety disorders.

Bifeprunox and aripiprazole suppress in vivo VTA dopaminergic neuronal activity via D2 and not D3 dopamine autoreceptor activation.

Bifeprunox and aripiprazole are two novel antipsychotics presenting partial agonistic activity for the D(2) and D(3) dopamine (DA) receptors. Using in vivo electrophysiological paradigms in anaesthetized rats, we have previously shown that both drugs independently inhibit the spontaneous firing and bursting activity of ventral tegmental area (VTA) dopaminergic neurons and partially reverse the suppressing effect of the full DA receptor agonist apomorphine. Moreover, we have also shown that the D(2/3) receptor antagonist haloperidol prevents the inhibitory effects of these antipsychotics, confirming their partial D(2)-like agonistic activities [L. Dahan, H. Husum, O. Mnie-Filali, J. Arnt, P. Hertel, N. Haddjeri, Effects of bifeprunox and aripiprazole on rat serotonin and dopamine neuronal activity and anxiolytic behaviour, J. Psychopharmacol. (2009)]. In the present electrophysiological study, selective antagonists of D(2) and D(3) receptors were used to further characterize the inhibitory role of bifeprunox and aripiprazole on the D(2) and D(3) receptors in vivo. Administration of bifeprunox (250 microg/kg, i.v.) or aripiprazole (300 microg/kg, i.v.) reduced the firing activity of VTA DA neurons by 40-50%. The bursting activity was reduced by 95% and 77% by bifeprunox and aripiprazole, respectively. Systemic administration of the preferential D(3) receptor antagonist GR218,231 (200 microg/kg, i.v.) did not modify the inhibitory effect of bifeprunox or aripiprazole, either on the firing or on the bursting activity. On the other hand, the preferential D(2) receptor antagonist L741,626 (500 microg/kg, i.v.) completely blocked the inhibitory effect of both bifeprunox and aripiprazole on the VTA DA neuronal activity. The present study shows that bifeprunox and aripiprazole behave as partial D(2), but not D(3), receptor agonists in vivo, inhibiting the firing activity (preferentially the phasic activity) of VTA DA cells.

Synergistic antidepressant-like action of gaboxadol and escitalopram

According to current theories on the etiopathogenesis and pathophysiology of depression, both GABAergic and monoaminergic transmitter systems are perturbed. Consequently, the present study addressed the putative antidepressant action of the sedative-hypnotic GABAA receptor agonist, gaboxadol, separately and in combination with the selective serotonin reuptake inhibitor (SSRI) escitalopram. The rat chronic mild stress model was used to test the chronic antidepressant properties of gaboxadol in this depression model. Sucrose intake used as a read-out on anhedonic-like behavior indicated that the drug response rate for gaboxadol (5 mg/kg/day, i.p.) was similar to that measured for escitalopram (5 mg/kg/day, i.p.), however, the rate increased when the two drugs were co-administered, suggesting a synergistic action. Using in vivo electrophysiological recordings in dorsal raphe nucleus (DRN) of anesthetised rats, the present results showed that one week treatment with gaboxadol (5 mg/kg/day, i.p.) or with escitalopram (5 mg/kg/day, i.p.), followed by a 24 h washout period, did not affect DRN 5-HT neuronal firing per se, but in rats treated with both drugs for one week, the firing rate of DRN 5-HT neurons was significantly increased. Immunohistochemical estimations of cell proliferation in the hippocampal dentate gyrus did not reveal any effect of gaboxadol on chronic mild stressed rats, indicating that neurogenesis per se is not systematically associated with recovery from anhedonic-like behavior. Taken together, our data reveal for the first time an antidepressant action of gaboxadol and indicate a synergistic mechanism, regarding rapid onset of action and efficacy, when co-administered with escitalopram.