Role of 5-HT1B receptors in the regulation of extracellular serotonin and dopamine in the dorsal striatum of mice

https://doi.org/10.1016/S0014-2999(03)02154-XGet rights and content

Abstract

To test the hypothesis that 5-HT1B receptors modulate serotonin (5-hydroxytryptamine, 5-HT) and dopamine release in the striatum, we used in vivo microdialysis in mice lacking 5-HT1B receptors. Local administration by reversed microdialysis of the selective 5-HT reuptake inhibitor, fluvoxamine (0.1–10 μM), concentration dependently increased 5-HT to the same extent in wildtype and in 5-HT1B knockout (KO) mice. Fluvoxamine (10 μM) increased dopamine levels similarly in both genotypes. The 5-HT releaser, fenfluramine (50 μM), increased both 5-HT and dopamine levels, but no difference was found between the genotypes. The 5-HT1B receptor agonist, 1,4-dihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-5H-pyrrolo[3,2-b]pyridin-5-one (CP-93,129), reduced 5-HT levels in the wildtype, but not in 5-HT1B KO mice. CP-93,129 at a concentration of 0.5 μM did not affect striatal dopamine outflow in either genotype, whereas dopamine outflow was increased 5-fold by 50 μM CP-93,129 in both genotypes. The CP-93,129-induced dopamine increase was not attenuated by ritanserin, a 5-HT2A/2C receptor antagonist, but was completely blocked by tetrodotoxin, demonstrating that the dopamine release was of neuronal origin. In conclusion, 5-HT1B autoreceptors are functionally present in the mouse striatum, but do not appear to play a significant role in the effects of a selective 5-HT reuptake inhibitor on extracellular 5-HT. In addition, the results in 5-HT1B knockout mice do not support a role of 5-HT1B heteroreceptors in the striatum on dopamine outflow in this brain area of mice.

Introduction

It has been well established that serotonin (5-hydroxytryptamine, 5-HT) modulates dopamine neurotransmission Soubrie et al., 1984, Bonhomme et al., 1995. The striato-nigral pathway is innervated by serotonergic afferents both at dopaminergic nerve terminals in the striatum and at dopaminergic cell bodies in the substantia nigra (Steinbusch, 1981) and neurochemical data reveal that striatal dopamine release is modulated by 5-HT neurons Benloucif and Galloway, 1991, Yadid et al., 1994, Bonhomme et al., 1995, De Deurwaerdere et al., 1995.

Anatomical data have shown that 5-HT1B receptors are abundantly present in the caudate putamen and in the substantia nigra Bruinvels et al., 1994, Sari et al., 1999. The distribution of 5-HT1B receptor mRNA suggests that this receptor is expressed predominantly on nerve terminals (Boschert et al., 1994). This is consistent with the notion that 5-HT1B receptors function as autoreceptors on 5-HT neurons and as heteroreceptors on non-5-HT neurons to control neurotransmitter release Johnson et al., 1992, Cameron and Williams, 1994, Morikawa et al., 2000. A role for 5-HT1B receptors in the modulation of dopamine release is supported by microdialysis studies in rats Benloucif et al., 1993, Galloway et al., 1993, Bentue-Ferrer et al., 1998, Ng et al., 1999, showing that 5-HT1B receptor agonists enhance dopamine release. Studying dopamine release in striatal synaptosomes of wildtype and in mice 5-HT1B knockout (KO) mice, Sarhan et al. (2000) reported that CP-93,129, a 5-HT1B receptor agonist, affected dopamine outflow in the wildtype but not in the 5-HT1B KO mice. Involvement of 5-HT1B receptors in dopamine release is also supported by other studies in 5-HT1B KO mice, showing altered dopamine neurotransmission Scearce-Levie et al., 1999, Ase et al., 2000 and increased vulnerability to dopaminergic drugs such as cocaine Lucas et al., 1997, Rocha et al., 1998.

Because 5-HT1B receptors function both as autoreceptors on 5-HT nerve terminals to reduce 5-HT levels in the striatum Abellan et al., 2000, Knobelman et al., 2000 and as postsynaptic receptors, studies on the effects of a 5-HT1B receptor agonist on dopamine should take in account the effects of both receptor subtypes. In mice lacking 5-HT1B receptors, augmented 5-HT levels can be expected when 5-HT levels are increased by a 5-HT reuptake inhibitor. However, in 5-HT1B KO mice, no changes in striatal 5-HT levels were observed upon systemic administration of a 5-HT reuptake inhibitor (Knobelman et al., 2001), although activation of 5-HT1A autoreceptors may have limited the contribution of 5-HT1B autoreceptors.

The aim of the present study was to further explore the role of serotonergic intervention on striatal 5-HT and dopamine release. To this end, 5-HT and dopamine release was evaluated in wildtype mice with mice lacking 5-HT1B receptors using in vivo microdialysis.

Section snippets

Animals

In this study, male wildtype and 5-HT1B KO mice on a 129/SV genetic background were tested. The mice were housed eight per cage, kept on a 12-h light–dark cycle (6 a.m. on, 6 p.m. off) at constant room temperature (22±2 °C), controlled humidity (40–60%) and free access to food and water. At the time of the experiments, the mice were aged between 12 and 16 weeks with body weights between 25 and 35 g. The mice were bred in separate homozygous lines in the animal facilities, GDL, Utrecht, The

Basal levels

Basal levels of extracellular 5-HT and dopamine levels in the dorsal striatum were not different between wildtype and 5-HT1B KO mice. Basal 5-HT levels were 4.0±0.3 fmol/sample in wildtype (n=51) and 5.0±0.6 fmol/sample in 5-HT1B KO mice (n=45). Basal dopamine levels were 181.3±14.6 fmol/sample in wildtype (n=51) and 183.1±15.9 fmol/sample in 5-HT1B KO mice (n=45).

Effects of fluvoxamine and CP-93,129 on 5-HT outflow

Local administration of fluvoxamine into the striatum increased 5-HT levels concentration dependently as shown in Fig. 1. Three

Discussion

Consistently with other studies, we found no difference in basal extracellular levels of 5-HT and dopamine in the dorsal striatum of wildtype and those in 5-HT1B KO mice Knobelman et al., 2001, Shippenberg et al., 2000. This suggests that, either 5-HT1B receptors do not affect 5-HT and dopamine release in the striatum under basal conditions, or that compensatory effects may have taken place during neurodevelopment.

No genotype difference was found for the effects on 5-HT levels following local

References (38)

  • P. Soubrie et al.

    Functional aspects of serotonin transmission in the basal ganglia: a review and an in vivo approach using the push–pull cannula technique

    Neuroscience

    (1984)
  • H.W. Steinbusch

    Distribution of serotonin-immunoreactivity in the central nervous system of the rat-cell bodies and terminals

    Neuroscience

    (1981)
  • K. Thorre et al.

    5-HT4 receptor involvement in the serotonin-enhanced dopamine efflux from the substantia nigra of the freely moving rat: a microdialysis study

    Brain Res.

    (1998)
  • Q. Yan et al.

    Activation of 5-HT(1B/1D) receptors in the mesolimbic dopamine system increases dopamine release from the nucleus accumbens: a microdialysis study

    Eur. J. Pharmacol.

    (2001)
  • A.R. Ase et al.

    Altered serotonin and dopamine metabolism in the CNS of serotonin 5-HT(1A) or 5-HT(1B) receptor knockout mice

    J. Neurochem.

    (2000)
  • S. Benloucif et al.

    Serotonin-facilitated dopamine release in vivo: pharmacological characterization

    J. Pharmacol. Exp. Ther.

    (1993)
  • D.L. Cameron et al.

    Cocaine inhibits GABA release in the VTA through endogenous 5-HT

    J. Neurosci.

    (1994)
  • P. De Deurwaerdere et al.

    d-Fenfluramine increases striatal extracellular dopamine in vivo independently of serotonergic terminals or dopamine uptake sites

    J. Neurochem.

    (1995)
  • L. De Groote et al.

    Extracellular serotonin in the prefrontal cortex is limited through terminal 5-HT1B autoreceptors: a microdialysis study in knockout mice

    Psychopharmacology

    (2002)

    • Cited by (27)

    • Synergistic effect of serotonin 1A and serotonin 1B/D receptor agonists in the treatment of L-DOPA-induced dyskinesia in 6-hydroxydopamine-lesioned rats

      2022, Experimental Neurology
      Citation Excerpt :

      This is hypothesized to be mediated either through activation of pre-synaptic 5-HT1A auto-receptors or by off-target activities on DA receptors (Bartoszyk et al., 2004; Hamik et al., 1990; Kula et al., 1994; Le Foll et al., 2016). Since 5-HT1B receptors have been shown to impact neurotransmitter release in the striatum (Ase et al., 2001; De Groote et al., 2003; Sarhan et al., 2000), the therapeutic index limitations from 5-HT1A agonism might be overcome by combining lower and safe doses with a simultaneous effect coming from 5-HT1B agonists acting at the same presynaptic terminals. Compatible with this concept, studies in animal models demonstrate that a combination of 5-HT1A and 5-HT1B agonism is effective at reducing LID and can act synergistically to provide better treatment than drugs acting on only one of the receptors (Bezard et al., 2013; Carta et al., 2007; Ghiglieri et al., 2016; Muñoz et al., 2008).

    • Modulation of Kalirin-7 expression by hippocampal CA1 5-HT <inf>1B</inf> receptors in spatial memory consolidation

      2019, Behavioural Brain Research
      Citation Excerpt :

      Compared with CP93129 treatment, GR55562 infusion significantly increased the GluA2/3 expression in the hippocampus (p < 0.0001). 5-HT1BR has been shown to regulate the release of serotonin, GABA, acetylcholine, dopamine, glutamate and other neurotransmitters [31–36]. Our previous study demonstrated that endogenous serotonin through activation of 5-HT1BRs enhances excitatory synaptic transmission at TA-CA1 synapses, which have been implicated in spatial recognition tasks and for long-term consolidation of spatial memory [17].

    • Serotonergic modulation of the activity of mesencephalic dopaminergic systems: Therapeutic implications

      2017, Progress in Neurobiology
      Citation Excerpt :

      It is noteworthy that (−) pindolol, applied at 10 μM, prevents the inhibition of nigral 5-HT release elicited by 5-HT1B receptor agonists, as expected from the activation of terminal 5-HT1B receptors (Thorre et al., 1998), but does not modify 5-HT- or CP 93129 (10 μM)-stimulated DA release in the striatum and the SN (Bonhomme et al., 1995; Thorre et al., 1998). Therefore, it is not surprising that the increase in striatal DA release induced by CP 93129 persists in 5-HT1B receptor knockout mice (De Groote et al., 2003). Also, the co-application of 5-HT-moduline (1.25 mM), a neuropeptide influencing 5-HT1B receptor activity, and CP93129 (100 μM or 500 μM) elicits strong effects on DA release that are independent of one another (Bentue-Ferrer et al., 1998).

    • CB1 cannabinoid receptor-mediated aggressive behavior

      2013, Neuropharmacology
      Citation Excerpt :

      Interestingly, under conditions that may lead to an escalation of aggression, such as consumption of moderate doses of alcohol or maternal aggression, a 5-HT1Br agonist has been shown to further increase levels of aggressive behavior when infused into the medial prefrontal cortex (Faccidomo et al., 2008) or the medial septal area (De Almeida and Lucion, 1997). Microdialysis studies have shown that both systemic and intra-raphe administration of 5-HT1Br agonists decrease extracellular levels of 5-HT in the forebrain areas (Adell et al., 2001; De Groote et al., 2003). These data suggest that inhibition of 5-HT release by 5-HT1Br agonists is mediated by 5-HT1 autoreceptors.

    • Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission

      2007, Pharmacology and Therapeutics

    • Effect of antidepressant drugs on 6-OHDA-treated mice in the FST

      2007, European Neuropsychopharmacology
    View all citing articles on Scopus
    View full text
    Copyright © 2003 Elsevier B.V. All rights reserved.