The 5HT_1B receptor agonist, CP‐93129, inhibits [³H]‐GABA release from rat globus pallidus slices and reverses akinesia following intrapallidal injection in the reserpine‐treated rat

Abstract

1 This study examined whether activation of 5HT 1B receptors in the rodent globus pallidus (GP) could reduce GABA release in vitro and reverse reserpine-induced akinesia in vivo. 2 Microdissected slices of GP from male Sprague Dawley rats (300 ± 350 g) were preloaded with [ 3 H]-GABA. During subsequent superfusion, 4 min fractions were collected for analysis of release. The eects of the 5HT 1B receptor agonist, 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one (CP-93129), on 25 mM KCl-evoked release were examined using a standard dual stimulation paradigm. 3 Male Sprague Dawley rats (270 ± 290 g), stereotaxically cannulated above the GP, were rendered akinetic by injection of reserpine (5 mg kg 71 s.c.). Eighteen hours later, the rotational behaviour induced by unilateral injection of CP-93129 was examined. 4 CP-93129 (0.6 ± 16.2 mM) produced a concentration-dependent inhibition of 25 mM KCl-evoked [ 3 H]-GABA release reaching a maximum inhibition of 52.5+4.5%. The eect of a submaximal concentration of CP-93129 (5.4 mM) was fully inhibited by the 5HT 1B receptor antagonist, isamoltane (10 mM). 5 Following intrapallidal injection, CP-93129 (30 ± 330 nmol in 0.5 ml) produced a dose-dependent increase in net contraversive rotations reaching a maximum of 197+32 rotations in 240 min at 330 nmol. Pre-treatment with isamoltane (10 nmol in 1 ml) inhibited the eects of a submaximal dose of CP-93129 (220 nmol) by 84+6%. 6 These data suggest that at least some 5HT 1B receptor function as heteroreceptors in the GP, reducing the release of GABA. Moreover, CP-93129-mediated activation of these receptors in the GP provides relief of akinesia in the reserpine-treated rat model of PD.

Serotonin Modulates Pallidal Neuronal Activity in the Awake Monkey

“…5-HT 1B receptors are the most commonly suggested presynaptic receptors that mediate suppression of GABA release in rat GPe and other areas of the brain (Pickard et al, 1999;Chadha et al, 2000;Matsuoka et al, 2004). This, together with the present results that 5-CT (which is not only a 5-HT 1A but also 5-HT 1B agonist) suppressed the inhibition, suggested the possibility that 5-HT 1B receptors mediate the suppression of the inhibition in GPe and GPi.…”

“…A 5-HT 1B receptor agonist inhibited 3 H-GABA release from rat GPe slices (Chadha et al, 2000), and activation of presynaptic 5-HT 1B receptors suppresses GABAergic inhibition in other brain areas (Pickard et al, 1999;Matsuoka et al, 2004).…”

5-HT1B Receptor-Mediated Serotoninergic Modulation of Methylphenidate-Induced Locomotor Activation in Rats

“…5-HT 1B receptors are mostly found presynaptically, in nerve terminals of serotoninergic neurons (autoreceptors) and non-serotoninergic neurons (heteroreceptors), and they are highly expressed in the basal ganglia, particularly in the terminals of the GABAergic striatal efferent neurons, that is globus pallidus, ventral pallidum, substantia nigra pars reticulata, and entopeduncular nucleus, where their stimulation inhibits GABA release (Bruinvels et al, 1993;Chadha et al, 2000;Sari, 2004). Therefore, the 5-HT 1B receptormediated serotoninergic modulation of methylphenidateinduced locomotor activation demonstrated in the present study most probably involves 5-HT 1B receptors localized in the striatal projecting areas.…”

Analysis of the Role of the 5-HT1B Receptor in Spatial and Aversive Learning in the Rat

“…In addition, this receptor also has a postsynaptic localization as a heteroreceptor, which allows for potential multiple interactions with several neurotransmitter systems. Thus, studies in vitro have given circumstantial evidence that the 5-HT 1B receptor may regulate the release of acetylcholine (BolanosJiménez et al, 1994;, glutamate (Li and Bayliss, 1998), GABA (Chadha et al, 2000), and dopamine (Sarhan et al, 2000). In the context of this study, the possibility that the 5-HT 1B receptor could regulate the terminal transmitter release of acetylcholine in vivo is of special interest.…”