The 5-HT1A receptor antagonist (S)-UH-301 decreases dopamine release in the rat nucleus accumbens and striatum

Abstract

In this study we employed in vivo microdialysis to examine the effects of the selective 5-HT1A receptor antagonist (S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin [(S)-UH-301] on extracellular concentrations of dopamine (DA) and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the nucleus accumbens (NAC) and dorsal striatum of awake freely moving rats. Systemic administration of (S)-UH-301 (1.25, 2.5, 5.0 mg/kg s.c.) dose-dependently decreased extracellular concentrations of DA, DOPAC and HVA in the NAC. (S)-UH-301 (2.5 mg/kg s.c.) also decreased DA, but not DOPAC and HVA, concentrations in the striatum. Infusion of low concentrations (1, 10 microM) of (S)-UH-301 into either the NAC or the striatum did not affect DA levels, while only the highest concentration (1,000 microM) significantly decreased DA levels in both areas. Similarly, infusion of the selective 5-HT1A receptor agonist (R)-8-hydroxy-2-(di-n-propylamino)tetralin [(R)-8-OH-DPAT] only in high concentrations (100, 1,000 microM) decreased DA levels in both regions. These data suggest that (S)-UH-301 decreases DA release both in the NAC and the striatum probably indirectly via its purported DA-D2/D3 receptor agonistic properties. However, the observed inhibitory effect of (S)-UH-301 on DA release in the studied brain regions may also be explained, at least partly, by a serotonergic influence on the DA systems, acting at 5-HT1A receptor sites located elsewhere in the brain.

5-HT Modulation of Dopamine Release in Basal Ganglia in Psilocybin-Induced Psychosis in Man—A PET Study with [11C]raclopride

“…Since psilocybin also acts upon 5-HT 1A receptors (Buckholtz et al 1990;McKenna et al 1990) and stimulation of 5-HT 1A autoreceptors is expected to enhance the dopaminergic tone (Neal-Beeliveau et al 1993), one might speculate that psilocybin increases striatal dopamine release through a concomitant stimulation of both 5-HT 1A and 5-HT 2A receptors. This hypothesis is supported by the finding that 5-HT 1A agonists can facilitate dopamine release in the striatum and nucleus accumbens (Benloucif and Galloway 1991), while 5-HT 1A antagonist have been reported to inhibit dopamine release in these brain regions (Parson and Justice 1993;Boulenguez et al 1996;Nomikos et al 1996). Furthermore, recent studies in rats demonstrated that the changes in locomotor activity produced by the 5-HT 1A agonist 8-OH-DPAT (Hillegaart et al 1995) or the classic indolehallucinogen LSD were attenuated by pretreatment with the selective 5-HT 1A antagonist WAY-100,635 (Sipes and Geyer 1995;Krebs-Thomson and Geyer 1996).…”

SB-649915-B, a Novel 5-HT1A/B Autoreceptor Antagonist and Serotonin Reuptake Inhibitor, is Anxiolytic and Displays Fast Onset Activity in the Rat High Light Social Interaction Test

“…It could be postulated that an overflow technique such as microdialysis simply lacks the sensitivity to measure small changes in 5-HT, and increases in synaptic 5-HT are sufficient to mediate the observed acute anxiolytic effect. Alternatively, SSRIs and 5-HT 1A/B receptor antagonists have been shown to modulate several other neurotransmitter systems including glutamate (Marcoli et al, 1999;Schechter et al, 2002), acetylcholine (Consolo et al, 1996;Nakai et al, 1998;Koyama et al, 1999), dopamine (Boulenguez et al, 1996;Nomikos et al, 1996;Iyer and Bradberry, 1996), and noradrenaline (Hajos-Korcsok et al, 1999) which may contribute to or mediate the SB-649915-B-induced effect. However, the studies to address the effects on systems other than the 5-HT and monoaminergic (Hughes et al, 2007), have, as yet, not been performed.…”

5-HT1B receptors modulate release of [3H]dopamine from rat striatal synaptosomes

“…It was also proposed from in vivo experiments in rats that stimulation of DA release involves the activation of 5-HT 1 , 5-HT 3 and/or 5-HT 4 receptors in the striatum (Benloucif et al 1993). The participation of 5-HT 1A receptors was suggested by the fact that local infusion of the selective 5-HT 1A receptor antagonist (S)-UH-301 in awake freely moving rats decreased DA release in the nucleus accumbens and dorsal striatum (Nomikos et al 1996). Moreover, local administration of a selective serotonin reuptake inhibitor (SSRI) facilitated release of DA in the corpus striatum (Yadid et al 1994).…”