Increased Tonic Activation of Rat Forebrain 5-HT1A Receptors by Lithium Addition to Antidepressant Treatments

Abstract

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-HTAlthough the physiopathology of major depression is not fully defined, there is a growing body of evidence suggesting the implication of the serotonin (5-HT) system in the therapeutic effect of antidepressant treatments (Heninger and Charney 1987;Price et al. 1990a;Van Praag et al. 1990;Cummings 1993;Blier and de Montigny 1994;Maes and Meltzer 1995). For example, it has been shown that long-term tricyclic antidepressant (TCA) treatment and repeated electroconvulsive shock (ECS) administration lead to enhanced 5-HT neurotransmission via sensitization of the postsynaptic 5-HT 1A receptors (de Montigny and Aghajanian 1978;de Montigny 1984;Welner et al. 1989;Nowak and Dulinski 1991;Stockmeier et al. 1992). Long-term treatment with either monoamine oxidase inhibitors (MAOIs) or selective 5-HT reuptake inhibitors (SSRIs) results in a desensitization of the somatodendritic 5-HT 1A autoreceptor of 5-HT neurons in the dorsal raphe nucleus, thereby allowing their firing rate to recover in Received May 14, 1999; revised October 18, 1999; accepted October 19, 1999. N EUROPSYCHOPHARMACOLOGY 2000 -VOL . 22 , NO . 4 5-HT Transmission and Lithium Addition 347 the presence of the drugs Chaput et al. 1986). In addition, long-term SSRI treatment also desensitizes terminal 5-HT 1B autoreceptors; whereas, longterm MAOI treatment desensitizes terminal ␣ 2 -adrenergic heteroreceptors located on 5-HT terminals (Blier and Bouchard 1994;Mongeau et al. 1994). The desensitization of the latter two receptors is thought to contribute to a greater release of 5-HT following SSRI and MAOI administration. Long-term treatment with the antidepressant mirtazapine, an ␣ 2 -adrenoceptor antagonist, increases 5-HT neurotransmission as a result of a sustained increase in the firing activity of 5-HT neurons in the presence of the decreased function of ␣ 2 -adrenergic heteroreceptors located on 5-HT terminals ). Finally, long-term treatment with 5-HT 1A receptor agonists, such as gepirone, desensitizes the 5-HT 1A autoreceptor on 5-HT neurons, but not the postsynaptic 5-HT 1A receptors located on CA 3 pyramidal neurons .Recently, novel direct evidence of an enhanced 5-HT neurotransmission by antidepressant treatments has been provided (Haddjeri et al. 1998a). This study showed that long-term treatment with either the TCA imipramine, the SSRI paroxetine, the selective and reversible MAO-A inhbitor befloxatone, the ␣ 2 -adrenergic antagonist mirtazapine, the 5-HT 1A receptor agonist gepirone, as well as repeated ECS administration, enhanced the tonic activation of postsynaptic 5-HT 1A receptors in the dorsal hippocampus, as put into evidence by the enhanced disinhibition produced by the acute administration of the selective 5-HT 1A receptor antagonist WAY 100635 (Haddjeri et al. 1998a). Furthermore, no disinhibi...

Partial Dopamine D2/Serotonin 5-HT1A Receptor Agonists as New Therapeutic Agents~!2009-12-17~!2010-04-07~!2010-07-20~!

“…Second, there is evidence that neurogenesis, which is a crucial phenomenon in the antidepressant action, can be mediated via 5-HT 1A receptor activation [132,133]. These results support the hypothesis that an enhancement of 5-HT 1A neurotransmission underlies the antidepressant response [134][135][136][137]. Partial 5-HT 1A receptor agonists present high affinity (similar to the endogenous ligand) for the 5-HT 1A receptors, but a relatively low efficacy.…”

Effect of acute and chronic lamotrigine on basal and stimulated extracellular 5‐hydroxytryptamine and dopamine in the hippocampus of the freely moving rat

“…However, the observations by Vinod & Subhash (2002) that 7-day treatment with LTG downregulates cortical, but not hippocampal, 5-HT 1A receptors illustrate that such changes do occur. An alteration of 5-HT 1A receptor density by LTG at the level of the raphe nuclei would have a profound effect on serotonergic transmission, as appears to be the case for at least some antidepressant and mood stabilising drugs such as lithium (Haddjeri et al, 2000). Similar arguments may also apply to the effects of LTG on extracellular DA also but a resolution to these speculations is beyond the scope of the present study.…”

Chronic Lithium Administration to Rats Selectively Modifies 5-HT2A/2C Receptor-Mediated Brain Signaling Via Arachidonic Acid

“…Chronic lithium is reported to increase the 5-HT concentration in the serotonergic synaptic cleft by reducing 5-HT 1 density, particularly the density of presynaptic 5-HT 1B receptors, but it does not appear to affect 5-HT 2A/ 2C receptor density (Friedman and Wang, 1988;Goodwin, 1989;Haddjeri et al, 2000;Januel et al, 2002;Massot et al, 1999;Mizuta and Segawa, 1988;Redrobe and Bourin, 1999). As 5-HT 1B receptors depress presynaptic 5-HT release, lithium's elevation of k* for AA in auditory and visual areas may result from derepressed 5-HT release, elevated 5-HT in the cleft, or an increased 5-HT 2A/2C -mediated activation of PLA 2 (Januel et al, 2002;Redrobe and Bourin, 1999).…”