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Major depressive disorder (MDD) is a common psychiatric disorder that often features impairments in cognitive function, and these cognitive symptoms can be important determinants of functional ability. Vortioxetine is a multimodal antidepressant that may improve some aspects of cognitive function in patients with MDD, including attention, processing speed, executive function, and memory. However, the cause of these effects is unclear, and there are several competing theories on the underlying mechanism, notably including regionally-selective downstream enhancement of glutamate neurotransmission and increased acetylcholine (ACh) neurotransmission. The current work sought to evaluate the ACh hypothesis by examining vortioxetine’s ability to reverse scopolamine-induced impairments in rodent tests of memory and attention. Additionally, vortioxetine’s effects on hippocampal extracellular ACh levels were examined alongside studies of vortioxetine’s pharmacokinetic profile. We found that acute vortioxetine reversed scopolamine-induced impairments in social and object recognition memory, but did not alter scopolamine-induced impairments in attention. Acute vortioxetine also induced a modest and short-lived increase in hippocampal ACh levels. However, this short-term effect is at variance with vortioxetine’s moderately long brain half life (5.1 hours). Interestingly, subchronic vortioxetine treatment failed to reverse scopolamine-induced social recognition memory deficits and had no effects on basal hippocampal ACh levels. These data suggest that vortioxetine has some effects on memory that could be mediated through cholinergic neurotransmission, however these effects are modest and only seen under acute dosing conditions. These limitations may argue against cholinergic mechanisms being the primary mediator of vortioxetine′s cognitive effects, which are observed under chronic dosing conditions in patients with MDD.

With a lifetime prevalence of more than 16 worldwide, major depressive disorder is one of the most common psychiatric disorders. Only one third of patients experience a complete therapeutic improvement with the use of current antidepressant drugs, with a therapeutic effect appearing only after several weeks of treatment. Hence, a better understanding of the mechanisms of action of current antidepressant treatments is needed to ultimately identify new targets and enhance beneficial effects. Given the intimate relationships between astrocytes and neurons at synapses and the ability of astrocytes to “sense” neuronal communication and release gliotransmitters, an attractive hypothesis is emerging stating that the effects of antidepressants on brain function could be, at least in part, mediated by direct influences of astrocytes on neuronal networks. This review aims at highlighting the involvement of astrocytes and gliotransmission in the antidepressant effects of both non- and pharmacological therapies.

Serotonin (5-HT) exerts its diverse physiological and pharmacological effects through the activation of multiple receptor subtypes. One of the newest members of this family is the 5-HT7 receptor. Increasing investigations on this receptor are currently undertaken to highlight its physiological and physiopathological significance. With the development of selective 5-HT7 receptor ligands, preclinical studies have started to elucidate the functions of this receptor subtype in more details. Hence, growing body of evidence suggests that the 5-HT7 receptor is involved in biological processes such as circadian rhythm and thermoregulation, in addition to disorders in which disturbances of the latter are considered to be an important contributing factor. Moreover, preclinical data support the use of 5-HT7 receptor antagonism as a promising mechanism for the treatment of several dysfunctions such as cognitive deficits and, importantly, have also unveiled anxiolytic and antidepressant-like properties. In this review, we will report major advances in the discovery of 5-HT7 receptor roles, with special emphasis on the potential application of their antagonists as novel anxiolytic and antidepressant drugs.

The serotonin (5-HT) transporter (SERT) is implicated in numerous neuropsychiatric disorders including major depression and represents the main target for antidepressants, especially for the selective serotonin reuptake inhibitors (SSRIs). A recently developed SSRI has the particularity to enhance its own reuptake inhibitory activity via the allosteric modulation of SERT. In this review, the SSRI escitalopram, the (S)-enantiomer of the SSRI citalopram, is exemplified in order to illustrate such an allosteric regulation of SERT and to depict putative biochemical mechanisms involving changes in SERT proteins conformations and/or their cellular distribution that could be linked to this antidepressant specificity. Insights into the physiological mechanisms by which SERT is regulated will increase not only our understanding of pathologic processes underlying affective disorders, but can also lead to the development of new strategies to treat these devastating illnesses.

This study examined the long-term effects of the antidepressant escitalopram on rat serotonin (5-HT) neuronal activity and hippocampal neuroplasticity. In the dorsal raphe nucleus, a 2-week treatment with escitalopram (10 mgkgday, subcutaneous) did not modify the firing activity of 5-HT neurons, whereas a cotreatment with R-citalopram (20 mgkgday, subcutaneous) decreased it. In the dentate gyrus of dorsal hippocampus, escitalopram increased significantly (57) the number of de novocells and this was prevented by a cotreatment with R-citalopram. The present results support the role of the allosteric modulation of the 5-HT transporter in the regulation of the recovery of 5-HT neuronal activity and long-lasting hippocampal cellular plasticity induced by escitalopram, two adaptive changes presumably associated with the antidepressant response.

The development of conventional antidepressants has been largely based on the hypothesis of monoaminergic dysfunctions and focuses particularly on the serotonin 5-hydroxytryptamine (5-HT) system. Hence, various classes of antidepressant treatments enhance 5-HT neurotransmission with a time course consistent with their delayed therapeutic effect. This delayed onset appears to be associated with the gradual development of specific adaptive changes of functional 5-HT receptors. However, recent theories suggest that major depressive disorders may be associated with impairments of functional plasticity and cellular flexibility. This review discusses several physiological mechanisms by which 5-HT function and hippocampal neuroplasticity are regulated. Knowledge of these long-term adaptations will increase not only our understanding of pathological processes underlying affective disorders, but could also lead to the development of new strategies to treat these devastating illnesses.

Several observations indicate that 5-HT1Areceptors found on a long neuronal feedback loop, originating from the medial prefrontal cortex, regulate 5-HT neuronal firing. In the present study, the muscarinic (M) receptor antagonists atropine and scopolamine as well as the M2 receptor antagonist AF-DX 116, but not the preferential M1 receptor antagonist pirenzepine, reduced the suppressant effect of the 5-HT1Areceptor agonist 8-OH-DPAT on the spontaneous firing activity of rat dorsal raphe 5-HT neurons. Moreover, AF-64A-induced lesions of cholinergic neurons directly in the medial prefrontal cortex and after its i.c.v. injection attenuated the effect of 8-OH-DPAT. Finally, the NMDA receptor antagonist () MK-801 and the GABABreceptor antagonist SCH-50911, but not the GABAAreceptor antagonist (−) bicuculline, dampened the latter response. The present study unveiled a key role for the cholinergic and GABAergic systems in the feedback inhibition of dorsal raphe 5-HT neurons.

Substance P antagonists have been proposed to be a new class of antidepressants. The present study aimed to determine the effect of the selective non-peptide rat neurokinin-1 (NK1) receptor antagonists WIN 51,708 and CP-96,345 on the firing activity of rat dorsal raphe serotonin (5-HT) and locus coeruleus noradrenaline (NA) neurons. While WIN51,708 (2 mg/kg, i.v.) and CP-96,345 (0.15 mg/kg, i.v.) did not modify the firing activity of 5-HT and NA neurons, both antagonists attenuated the suppressant effect of the α2-adrenoceptor agonist clonidine on the firing activity of both types of neurons. In contrast, the responsiveness of 5-HT neurons to the i.v. administration of the 5-HT autoreceptor agonist LSD and the 5-HT1Areceptor agonist 8-OH-DPAT remained unchanged. These findings suggest that NK1receptor antagonists affect markedly the NA system via an attenuation of the function of α2-adrenoceptors on the cell body of NA neurons and, consequently, may also modulate 5-HT neurotransmission.

The present study was undertaken to determine whether lithium addition to long-term treatment with different classes of antidepressant drugs could induce a greater effect on the serotonin (5-HT) system than the drugs given alone. Because 5-HT1Areceptor activation hyperpolarizes and inhibits the firing activity of CA3pyramidal neurons in the dorsal hippocampus, the degree of disinhibition produced by the selective 5-HT1Areceptor antagonist WAY 100635 was determined using in vivo extracellular recordings. In controls, as well as in rats receiving a lithium diet for 3 days, the administration of WAY 100635 (25-100 μg/kg, IV) did not modify the firing activity of dorsal hippocampus CA3pyramidal neurons. When the tricyclic antidepressant imipramine (10 mg/kg/day, SC), the monoamine oxidase inhibitor tranylcypromine (2.5 mg/kg/day, SC) and the selective 5-HT reuptake inhibitor paroxetine (10 mg/kg/day, SC) were administered alone for 21 days, a dose of 50 μg/kg of WAY 100635 was needed to increase significantly the firing activity of these neurons. On the other hand, WAY 100635, at a dose of only 25 μg/kg, increased significantly the firing rate of CA3pyramidal neurons in rats receiving both a long-term antidepressant treatment and a short-term lithium diet. It is concluded that the addition of lithium to antidepressant treatments produced a greater disinhibition of dorsal hippocampus CA3pyramidal neurons than any treatments given alone. The present results support the notion that the addition of lithium to antidepressants may produce a therapeutic response in treatment-resistant depression by enhancing 5-HT neurotransmission.

La dopamine (DA) joue un rôle primordial dans la régulation de nombreux aspects circadiens et physiologiques de la rétine chez l’adulte et au cours du développement. En particulier, la DA agit sur divers types cellulaires en reconfigurant leurs synapses électriques/chimiques. De plus, les cellules ganglionnaires à mélanopsine (ipRGCs) participent via la DA à la plasticité des ondes cholinergiques dans la rétine néonatale. Cependant, l’implication de la DA dans la mise en place de l’horloge rétinienne reste à élucider.

The aim of the present study was to investigate the putative modulation of locus coeruleus (LC) noradrenergic (NA) neurones by the 5‐hydroxytryptaminergic (5‐HT) system by use of in vivoextracellular unitary recordings and microiontophoresis in anaesthetized rats. To this end, the potent and selective 5‐HT1Areceptor antagonist WAY 100635 (N‐{2‐[4(2‐methoxyphenyl)‐1‐piperazinyl]ethyl}‐N‐(2‐pyridinyl)cyclohexanecarboxamide trihydroxychloride) was used.In the dorsal hippocampus, both local (by microiontophoresis, 20 nA) and systemic (100 μg kg−1, i.v.) administration of WAY 100635 antagonized the suppressant effect of microiontophorectically‐applied 5‐HT on the firing activity of CA3pyramidal neurones, indicating its antagonistic effect on postsynaptic 5‐HT1Areceptors.WAY 100635 and 5‐HT failed to modify the spontaneous firing activity of LC NA neurones when applied by microiontophoresis. However, the intravenous injection of WAY 100635 (100 μg kg−1) readily suppressed the spontaneous firing activity of LC NA neurones.The lesion of 5‐HT neurones with the neurotoxin 5,7‐dihydroxytryptamine increased the spontaneous firing activity of LC NA neurones and abolished the suppressant effect of WAY 100635 on the firing activity of LC NA neurones.In order to determine the nature of the 5‐HT receptor subtypes mediating the suppressant effect of WAY 100635 on NA neurone firing activity, several 5‐HT receptor antagonists were used. The selective 5‐HT3receptor antagonist BRL 46470A (10 and 100 μg kg−1, i.v.), the 5‐HT1Dreceptor antagonist GR 127935 (100 μg kg−1, i.v.) and the 5‐HT1A/1Breceptor antagonist (−)‐pindolol (15 mg kg−1, i.p.) did not prevent the suppressant effect of WAY 100635 on the firing activity of LC NA neurones. However, the suppressant effect of WAY 100635 was prevented by the non‐selective 5‐HT receptor antagonists spiperone (1 mg kg−1, i.v.) and metergoline (1 mg kg−1, i.v.), by the 5‐HT2receptor antagonist ritanserin (500 μg kg−1, i.v.). It was also prevented by the 5‐HT1Areceptor/α1D‐adrenoceptor antagonist BMY 7378 (1 mg kg−1, i.v.) and by the α1‐adrenoceptor antagonist prazosin (100 μg kg−1, i.v.).These data support the notion that the 5‐HT system tonically modulates NA neurotransmission since the lesion of 5‐HT neurones enhanced the LC NA neurones firing activity and the suppressant effect of WAY 100635 on the firing activity of NA neurones was abolished by this lesion. However, the location of the 5‐HT1Areceptors involved in this complex circuitry remains to be elucidated. It is concluded that the suppressant effect of WAY 100635 on the firing activity of LC NA neurones is due to an enhancement of the function of 5‐HT neurones via a presynaptic 5‐HT1Areceptor. In contrast, the postsynaptic 5‐HT receptor mediating this effect of WAY 100635 on NA neurones appears to be of the 5‐HT2Asubtype.

In the rat dorsal hippocampus and dorsal raphe nucleus, the microiontophoretic application of ergotamine and 5-HT suppressed the firing activity of CA3pyramidal neurons and 5-HT neurons, an effect antagonized by selective 5-HT1Areceptor antagonists. Co-application of ergotamine prevented the inhibitory action of 5-HT on the firing activity of CA3pyramidal neurons but not of 5-HT neurons, indicating that ergotamine acted as a partial 5-HT1Areceptor agonist in the dorsal hippocampus and as a full agonist at 5-HT1Aautoreceptors. Ergotamine decreased, in a concentration-dependent manner, the electrically evoked release of [3H]5-HT in preloaded rat and guinea pig hypothalamus slices; this effect was prevented by the nonselective 5-HT receptor antagonist methiothepin but not by the selective 5-HT1B/1Dreceptor antagonist GR 127935 or the α2-adrenoceptor antagonist idazoxan. Although body temperature in humans remained unchanged following inhaled ergotamine, in the rat, subcutaneously injected ergotamine produced a hypothermia that was prevented by a pretreatment with the 5-HT1A/1Breceptor/β-adrenoceptor antagonist pindolol. Finally in humans, ergotamine did not alter prolactin or adrenocorticotropic hormone levels, but increased growth hormone level, which was prevented by pindolol. Cortisol level was increased in humans by ergotamine, but this enhancement was unaltered by pindolol. In conclusion, the present results suggest that ergotamine acted in the rat brain as a 5-HT1Areceptor agonist and as an agonist of terminal 5-HT autoreceptor of a yet undefined subtype. In humans, ergotamine also displayed some 5-HT1Areceptor activity but, probably because of lack of receptor selectivity, it did not present the same profile as other 5-HT1Areceptor agonists.

The aim of the present study was to investigate a putative modulation of rat 5-HT system by the muscarinic receptor antagonist atropine using in-vivo electrophysiological and behavioural techniques. In the dorsal raphe nucleus, administration of atropine (1 mg/kg i.v.) prevented the suppressant effect of the selective serotonin reuptake inhibitor paroxetine (0.5 mg/kg i.v.) on the spontaneous firing activity of 5-HT neurons, suggesting that atropine could induce an attenuation of somatodendritic 5-HT1A autoreceptors responsiveness. The 5-HT1A receptor agonist 8-OH-DPAT decreased both immobility in the forced swim test and the body core temperature. Pre-treatment with atropine (5 and 10 mg/kg i.p.) enhanced antidepressant-like effect of 8-OH-DPAT (1 mg/kg s.c.) and reduced 8-OH-DPAT (0.1 mg/kg s.c.)-induced hypothermia. In conclusion, the present study reports a functional role of muscarinic receptors in the modulation of pre- and post-synaptic 5-HT1A receptors mediated responses.