Original ArticlesSelective serotonin reuptake inhibitors reduce the spontaneous activity of dopaminergic neurons in the ventral tegmental area
Introduction
Several studies have shown that both the substantia nigra, pars compacta (SNc) and the ventral tegmental area (VTA) are innervated by serotonin (5-hydroxytryptamine, 5-HT)-containing axon terminals originating in the midbrain raphé nuclei 7, 40, 43, 52. Electrophysiological experiments have shown that 5-HT inhibits the spontaneous activity of dopaminergic neurons in the VTA by acting through the 5-HT2C/2B receptor subtype [47]. Mixed 5-HT2C/2B receptor agonists, such as trifluoromethylphenylpiperazine (TFMPP) and m-chlorophenylpiperazine (mCPP) only weakly inhibited SNc dopaminergic cell activity [30], therefore, suggesting a less relevant role of 5-HT in the control of nigral dopamine (DA)-containing neurons. Prisco and Esposito [46] have shown that fluoxetine and citalopram, two selective 5-HT (serotonin) reuptake inhibitors (SSRIs), inhibit the activity of dopaminergic cells in the VTA but not in the SNc. The effect of fluoxetine on VTA dopaminergic neurons was mediated through an enhancement of 5-HT neurotransmission, in that it was abolished by selective lesions of 5-HT neurons by the neurotoxin 5,7-dihydroxytryptamine [46]. Moreover, pretreatment with mesulergine, a 5-HT2C/2B antagonist, blocked the inhibitory effect of fluoxetine, therefore, indicating an involvement of this receptor subtype in fluoxetine’s action [46]. It has been proposed that the effect of fluoxetine on the mesolimbic dopaminergic system might be relevant for its therapeutic action and it might explain the pathophysiology of the reported cases of akathisia 36, 46. On the basis of these evidences, it is conceivable that other SSRIs such as paroxetine, sertraline, and fluvoxamine would affect mesolimbic dopaminergic function. It is now well established that paroxetine, sertraline, and fluvoxamine are effective drugs in the treatment of depression 9, 41, 48. Although their clinical profile is similar to that of fluoxetine, they differ in the incidence of side effects in that only fluoxetine is associated with a high incidence of insomnia, nervousness, restlessness, and anxiety [49]. In addition, fluoxetine and paroxetine have been reported to cause extrapyramidal side effects in a limited number of patients 5, 11, 12, 18, 38, 53, and only a few cases of akathisia with fluvoxamine and sertraline have been described to date 5, 8, 35, 44. It is, therefore, of interest to evaluate the effects of paroxetine, sertraline, and fluvoxamine on the activity of dopaminergic neurons in the VTA and the SNc.
Because paroxetine, sertraline, and fluvoxamine do not affect DA reuptake or show any appreciable binding to DA receptors 9, 41, 48, it is conceivable that they would affect dopaminergic function indirectly by enhancing serotonergic transmission. As a consequence of their ability to block 5-HT reuptake, SSRIs inhibit the firing rate of serotonergic neurons in the midbrain raphé nuclei 17, 19, 22, 25. The reduced impulse flow of 5-HT-containing neurons induced by SSRIs attenuates their ability to increase the synaptic levels of 5-HT in terminal regions of the serotonergic system 2, 25, 26, 27, 28. Pretreatment with 5-HT1A receptor antagonists markedly enhances the effect of SSRIs in increasing extracellular 5-HT in forebrain areas 22, 26, 28. Therefore, it is conceivable that pretreatment with the 5-HT1A receptor antagonist tertatolol [45] would potentiate the effect of paroxetine, sertraline, and fluvoxamine on dopaminergic neurons in the VTA.
In the present study, single-cell recording techniques were used to assess the effects of paroxetine, sertraline, and fluvoxamine on the electrical activity of dopaminergic neurons in the VTA, the SNc, and on 5-HT-containing neurons in the dorsal raphé nucleus (DRN). These three SSRIs were administered alone and in combination with tertatolol.
Section snippets
Surgical and recording procedures
Male Sprague-Dawley rats (Consorzio Mario Negri Sud, Italy) weighing 250–350 g were anesthetized with chloral hydrate (400 mg/kg, i.p.) and mounted on a stereotaxic instrument (SR-6, Narishige, Japan). Supplemental doses of anesthetic were administered via a lateral tail vein cannula. Throughout the experiment the animals’ body temperatures were maintained at 36–37°C by a thermostatically regulated heating pad. Procedures involving animals and their care were conducted in conformity with the
Effects of 5-HT reuptake inhibitors on the basal activity of dopaminergic neurons in the VTA
Intravenous administration of paroxetine caused a small but significant reduction in the firing rate of the VTA dopaminergic cells studied. The typical effect of paroxetine is represented in Fig. 1a. Overall, paroxetine (n = 16) produced a maximal inhibitory effect of 10 ± 11% at the cumulative dose of 160 μg/kg; administration of higher doses of the drug did not cause further inhibition of dopaminergic cell activity (Fig. 1b). The entity of response to paroxetine was variable in that it
Discussion
The present study shows that acute administration of paroxetine, sertraline, and fluvoxamine inhibits the basal firing rate of dopaminergic neurons in the VTA, which is the nucleus of origin of the mesolimbic system [39]. Interestingly, the effects of these three drugs appear to be selective in that they do not affect the activity of nigrostriatal dopaminergic neurons (data not shown). These data confirm and extend previous findings showing that fluoxetine and citalopram are capable of
Acknowledgements
This work was supported by the Italian National Research Council (Convenzione C.N.R. - Consorzio Mario Negri Sud). M.D.M. is a recipient of a fellowship from the Centro di Formazione e Studi per il Mezzogiorno (FORMEZ, Progetto Speciale “Ricerca Scientifica e Applicata nel Mezzogiorno”).
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