Tetanus-induced heterosynaptic depression in the hippocampus is a key cellular mechanism in neural networks

Current antidepressants are clinically effective only after several weeks of administration. Here, we show that serotonin(4) (5-HT(4)) agonists reduce immobility in the forced swimming test, displaying an antidepressant potential. Moreover, a 3 day regimen with such compounds modifies rat brain parameters considered to be key markers of antidepressant action, but that are observed only after 2-3 week treatments with classical molecules: desensitization of 5-HT(1A) autoreceptors, increased tonus on hippocampal postsynaptic 5-HT(1A) receptors, and enhanced phosphorylation of the CREB protein and neurogenesis in the hippocampus. In contrast, a 3 day treatment with the SSRI citalopram remains devoid of any effect on these parameters. Finally, a 3 day regimen with the 5-HT(4) agonist RS 67333 was sufficient to reduce both the hyperlocomotion induced by olfactory bulbectomy and the diminution of sucrose intake consecutive to a chronic mild stress. These findings point out 5-HT(4) receptor agonists as a putative class of antidepressants with a rapid onset of action.

We report here the first direct functional evidence of an increase in the tonic activation of postsynaptic 5-HT1A receptors by antidepressant treatments. Because 5-HT1A receptor activation hyperpolarizes and inhibits CA3 pyramidal neurons in the dorsal hippocampus, we determined, using in vivo extracellular recording, whether the selective 5-HT1A receptor antagonist WAY 100635 could disinhibit these neurons. Unexpectedly, no disinhibition could be detected in controls. However, after long-term treatment with the tricyclic antidepressant imipramine, the selective 5-HT reuptake inhibitor paroxetine, the reversible monoamine oxidase-A inhibitor befloxatone, the alpha2-adrenergic antagonist mirtazapine, or the 5-HT1A receptor agonist gepirone or multiple electroconvulsive shock (ECS) administration, WAY 100635 markedly increased (60-200%) the firing activity of CA3 pyramidal neurons. Such a disinhibition was absent in rats treated with the nonantidepressant drug chlorpromazine, in rats receiving only one ECS, or in rats receiving multiple ECSs in combination with an intrahippocampal pertussis toxin treatment to inactivate Gi/o-coupled 5-HT1A receptors. These data indicate that such antidepressant treatments, acting on entirely different primary targets, might alleviate depression by enhancing the tonic activation of forebrain postsynaptic 5-HT1A receptors.

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The present study was undertaken to compare the acute and long-term effects of escitalopram and citalopram on rat brain 5-HT neurotransmission, using electrophysiological techniques. In hippocampus, after 2 weeks of treatment with escitalopram (10 mg/kg/day, s.c.) or citalopram (20 mg/kg/day, s.c.), the administration of the selective 5-HT 1A receptor antagonist WAY-100,635 (20-100 mg/kg, i.v.) dose-dependently induced a similar increase in the firing activity of dorsal hippocampus CA 3 pyramidal neurons, thus revealing direct functional evidence of an enhanced tonic activation of postsynaptic 5-HT 1A receptors. In dorsal raphe nucleus, escitalopram was four times more potent than citalopram in suppressing the firing activity of presumed 5-HT neurons (ED 50 ¼ 58 and 254 mg/kg, i.v., respectively). Interestingly, the suppressant effect of escitalopram (100 mg/kg, i.v.) was significantly prevented, but not reversed by R-citalopram (250 mg/kg, i.v.). Sustained administration of escitalopram and citalopram significantly decreased the spontaneous firing activity of presumed 5-HT neurons. This firing activity returned to control rate after 2 weeks in rats treated with escitalopram, but only after 3 weeks using citalopram, and was associated with a desensitization of somatodendritic 5-HT 1A autoreceptors. These results suggest that the time course of the gradual return of presumed 5-HT neuronal firing activity, which was reported to account for the delayed effect of SSRI on 5-HT transmission, is congruent with the earlier onset of action of escitalopram vs citalopram in validated animal models of depression and anxiety.

Current antidepressants still display unsatisfactory efficacy and a delayed onset of therapeutic action. Here we show that the pharmacological blockade of serotonin 7 (5-HT 7 ) receptors produced a faster antidepressant-like response than the commonly prescribed antidepressant fluoxetine. In the rat, the selective 5-HT 7 receptor antagonist SB-269970 counteracted the anxiogenic-like effect of fluoxetine in the open field and exerted an antidepressant-like effect in the forced swim test. In vivo, 5-HT 7 receptors negatively regulate the firing activity of dorsal raphe 5-HT neurons and become desensitized after long-term administration of fluoxetine. In contrast with fluoxetine, a 1-week treatment with SB-269970 did not alter 5-HT firing activity but desensitized cell body 5-HT autoreceptors, enhanced the hippocampal cell proliferation, and counteracted the depressive-like behavior in olfactory bulbectomized rats. Finally, unlike fluoxetine, early-life administration of SB-269970, did not induce anxious/depressive-like behaviors in adulthood. Together, these findings indicate that the 5-HT 7 receptor antagonists may represent a new class of antidepressants with faster therapeutic action.

1 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 vivo extracellular unitary recordings and microiontophoresis in anaesthetized rats. To this end, the potent and selective 5-HT 1A receptor antagonist WAY 100635 (N-{2-[4(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)cyclohexanecarboxamide trihydroxychloride) was used. 2 In the dorsal hippocampus, both local (by microiontophoresis, 20 nA) and systemic (100 mg kg 71 , i.v.) administration of WAY 100635 antagonized the suppressant e ect of microiontophorecticallyapplied 5-HT on the ®ring activity of CA 3 pyramidal neurones, indicating its antagonistic e ect on postsynaptic 5-HT 1A receptors. 3 WAY 100635 and 5-HT failed to modify the spontaneous ®ring activity of LC NA neurones when applied by microiontophoresis. However, the intravenous injection of WAY 100635 (100 mg kg 71 ) readily suppressed the spontaneous ®ring activity of LC NA neurones. 4 The lesion of 5-HT neurones with the neurotoxin 5,7-dihydroxytryptamine increased the spontaneous ®ring activity of LC NA neurones and abolished the suppressant e ect of WAY 100635 on the ®ring activity of LC NA neurones. 5 In order to determine the nature of the 5-HT receptor subtypes mediating the suppressant e ect of WAY 100635 on NA neurone ®ring activity, several 5-HT receptor antagonists were used. The selective 5-HT 3 receptor antagonist BRL 46470A (10 and 100 mg kg 71 , i.v.), the 5-HT 1D receptor antagonist GR 127935 (100 mg kg 71 , i.v.) and the 5-HT 1A/1B receptor antagonist (7)-pindolol (15 mg kg 71 , i.p.) did not prevent the suppressant e ect of WAY 100635 on the ®ring activity of LC NA neurones. However, the suppressant e ect of WAY 100635 was prevented by the non-selective 5-HT receptor antagonists spiperone (1 mg kg 71 , i.v.) and metergoline (1 mg kg 71 , i.v.), by the 5-HT 2 receptor antagonist ritanserin (500 mg kg 71 , i.v.). It was also prevented by the 5-HT 1A receptor/a 1D -adrenoceptor antagonist BMY 7378 (1 mg kg 71 , i.v.) and by the a 1 -adrenoceptor antagonist prazosin (100 mg kg 71 , i.v.). 6 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 ®ring activity and the suppressant e ect of WAY 100635 on the ®ring activity of NA neurones was abolished by this lesion. However, the location of the 5-HT 1A receptors involved in this complex circuitry remains to be elucidated. It is concluded that the suppressant e ect of WAY 100635 on the ®ring activity of LC NA neurones is due to an enhancement of the function of 5-HT neurones via a presynaptic 5-HT 1A receptor. In contrast, the postsynaptic 5-HT receptor mediating this e ect of WAY 100635 on NA neurones appears to be of the 5-HT 2A subtype.

The findings from binding, neurochemical, and neurophysiological studies may provide a mechanistic rationale for the clinical difference observed with escitalopram compared to other antidepressant therapies.