Elsevier

Brain Research Bulletin

Volume 46, Issue 6, August 1998, Pages 547-554
Brain Research Bulletin

Original Articles
Selective serotonin reuptake inhibitors reduce the spontaneous activity of dopaminergic neurons in the ventral tegmental area

https://doi.org/10.1016/S0361-9230(98)00054-9Get rights and content

Abstract

Electrophysiological techniques were used to study the effects of paroxetine, sertraline, and fluvoxamine on the basal activity of dopaminergic neurons in the ventral tegmental area (VTA) of rats. Acute i.v. administrations of paroxetine (20–1280 μg/kg), sertraline (20–1280 μg/kg), and fluvoxamine (20–1280 μg/kg) caused a slight but significant reduction in the firing rate of the VTA dopaminergic cells studied. Paroxetine produced a maximal inhibitory effect of 10 ± 11% at the cumulative dose of 160 μg/kg. Sertraline induced a dose-related inhibition of VTA dopaminergic neurons, which reached its maximum (10 ± 7%) at the cumulative dose of 1280 μg/kg. The effect of fluvoxamine on the basal firing rate of VTA dopaminergic neurons was more pronounced as compared to that of paroxetine and sertraline, in that it produced a maximal inhibition of 17 ± 12% at the cumulative dose of 1280 μg/kg. Acute i.v. injections of paroxetine (20–1280 μg/kg), sertraline (20–1280 μg/kg), and fluvoxamine (20–5120 μg/kg) caused a dose-dependent decrease in the basal firing rate of serotonergic neurons in the dorsal raphé nucleus (DRN). Paroxetine and sertraline stopped the spontaneous firing of serotonergic neurons at the cumulative dose of 1280 μg/kg, whereas fluvoxamine reached the same effect only at the cumulative dose of 5120 μg/kg. Pretreatment with the 5-HT1A receptor antagonist tertatolol (1 mg/kg, i.v.) reduced the inhibitory effects of paroxetine, fluvoxamine, and sertraline on the basal activity of serotonergic neurons in the DRN. Administration of tertatolol induced a 15-fold increase in the ED50 for fluvoxamine. The antagonistic effect of tertatolol was much less evident in blocking the inhibitory action exerted by paroxetine and sertraline on the activity of serotonergic neurons. Pretreatment with tertatolol (1 mg/kg, i.v.) potentiated the inhibitory effect of fluvoxamine on the basal activity of VTA dopaminergic neurons. Tertatolol did not affect the inhibitory action exerted by paroxetine and sertraline on these neurons. It is concluded that inhibition of the basal firing rate of dopaminergic neurons in the VTA is a common characteristic of selective serotonin reuptake inhibitors (SSRIs). The effects of SSRIs on VTA dopaminergic cell activity might be relevant for their therapeutic action and may explain the origin of the reported cases of akathisia.

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”).

References (54)

  • R.Y. Wang

    Dopaminergic neurons in the rat ventral tegmental area. I. Identification and characterization

    Brain Res. Rev.

    (1981)
  • F. Artigas et al.

    Pindolol induces a rapid improvement of depressed patients treated with serotonin reuptake inhibitors

    Arch. Gen Psychiatry

    (1994)
  • D.K. Arya

    Extrapyramidal symptoms with selective serotonin reuptake inhibitors

    Br. J. Psychiatry

    (1994)
  • D.K. Arya et al.

    Dyskinesia associated with fluvoxamine

    J. Clin. Psychopharmacol.

    (1993)
  • E.C. Azmitia et al.

    An autoradiographic analysis of the differential ascending projections of the dorsal and median raphe nuclei in the rat

    J. Comp. Neurol.

    (1978)
  • D. Baldwin et al.

    Fluoxetine, fluvoxamine and extrapyramidal tract disorders

    Int. Clin. Psychopharmacol.

    (1991)
  • P. Benfield et al.

    Fluvoxamine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness

    Drugs

    (1986)
  • P. Blier et al.

    Effectiveness of pindolol with selected antidepressant drugs in the treatment of major depression

    J. Clin. Psychopharmacol.

    (1995)
  • R.H. Bouchard et al.

    Fluoxetine and extrapyramidal side effects

    Am. J. Psychiatry

    (1989)
  • T.M. Brod

    Fluoxetine and extrapyramidal side effects

    Am. J. Psychiatry

    (1989)
  • B.S. Bunney et al.

    Dopaminergic neuronsEffects of antipsychotic drugs and amphetamine on single cell activity

    J. Pharmacol. Exp. Ther.

    (1973)
  • L. Cervo et al.

    Repeated treatment with imipramine and amitriptyline reduced the immobility of rats in the forced swimming test by enhancing dopamine mechanisms in the nucleus accumbens

    J. Pharm. Pharmacol.

    (1988)
  • Y. Chaput et al.

    Effects of a selective 5-HT reuptake blocker, citalopram, on the sensitivity of 5-HT autoreceptorselectrophysiological studies in the rat brain

    Naunyn Schmiedebergs Arch. Pharmacol.

    (1986)
  • K.A. Cunningham et al.

    The interaction of cocaine with serotonin dorsal raphé neurons. Single-unit extracellular recording sudies

    Neuropsychopharmacology

    (1990)
  • A. De Lean et al.

    Simultaneous analysis of families of sigmoidal curvesapplication to bioassay, radioligand assay, and physiological dose-response curves

    Am. J. Physiol.

    (1978)
  • S.E. Gartside et al.

    Interaction between a selective 5-HT1A receptor antagonist and SSRI in vivoEffects on 5-HT cell firing and extracellular 5-HT

    Br. J. Pharmacol.

    (1995)
  • A.A. Grace et al.

    Nigral dopamine neuronsintracellular recording and identification with L-DOPA injection and histofluorescence

    Science

    (1980)
  • Cited by (100)

    • The administration of sertraline plus naltrexone reduces ethanol consumption and motivation in a long-lasting animal model of post-traumatic stress disorder

      2021, Neuropharmacology
      Citation Excerpt :

      In addition, treatment with STR significantly up-regulated Th gene expression in the VTA. Previous studies suggested that the administration of STR increases dopamine concentrations in the NAcc (Kitaichi et al., 2010), but also reduces the spontaneous activity of dopaminergic neurons in the VTA (Di Mascio et al., 1998). Furthermore, the combination of NTX plus STR produced a similar effect than any of each drug separately.

    • Randomized, proof-of-concept trial of low dose naltrexone for patients with breakthrough symptoms of major depressive disorder on antidepressants

      2017, Journal of Affective Disorders
      Citation Excerpt :

      The pathophysiology of depression is thought to involve abnormal dopaminergic D2 receptor function, as well as abnormalities in cortico-basal ganglia reward systems (Dunlop and Nemeroff, 2007). A review by Soskin et al. (2013) notes that individuals with MDD may show reduced concentrations of homovanillic acid (HVA), a dopamine metabolite, in cerebrospinal fluid (Roy et al., 1986; Lambert et al., 2000); reduced striatal dopamine transporter density (Klimek et al., 2002); and increased D2/D3 receptor striatal binding (Di Mascio et al., 1998; Meyer et al., 2006), though not all data support these mechanisms (Parsey et al., 2001; Hirvonen et al., 2008). An additional link to depression is the observation that following successful treatment of depression with SSRIs, a D2 antagonist (sulpiride 200 mg) produced a return of depressive symptoms (Willner et al., 2005); analogous observations in an animal model of depression, reversed by tricyclic antidepressants, suggested that preventing D2 receptor desensitization was essential to effective treatment with SSRIs or SNRIs (Willner, 2002).

    View all citing articles on Scopus
    View full text