Abstract
The effects triggered by serotonin2C (5-hydroxytryptamin2C, 5-HT2C) receptor agonists in the brain are often subtle, and methodologies highlighting their widespread actions to account for their multiple modulatory influences on behaviors are still lacking. We report an extended analysis of a neurochemical database on monoamines obtained after the intraperitoneal administration of the preferential 5-HT2C receptor agonist WAY-163909 (0.3 and 3 mg/kg) in 29 distinct rat brain regions. We focused on the metabolite of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), the metabolites of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the index of the turnovers 5-HIAA/5-HT and DOPAC/DA. WAY-163909 increased and decreased 5-HIAA tissue levels in the amygdala and dorsolateral orbitofrontal cortex, respectively, and decreased the 5-HT turnover in the infralimbic cortex. It enhanced HVA levels in the medial orbitofrontal cortex and DOPAC levels in the amygdala. WAY-163909 increased and decreased DA turnover in the medial orbitofrontal cortex and the anterior insular cortex, respectively. The correlative analysis of the turnovers between pairs of brain regions revealed low levels of correlations across the brain but presented a distinct pattern of correlations after WAY-163909 was compared to saline-treated rats. WAY-163909, notably at 0.3 mg/kg, favored cortico-cortical and cortico-subcortical correlations of both turnovers separately, and frontal DOPAC/DA ratio with cortical and subcortical 5-HIAA/5-HT ratios at 3 mg/kg. In conclusion, the qualitative, but not the quantitative analysis shows that WAY-163909 alters the pattern of correlations across the brain, which could account for its multiple behavioral influences.
Highlights
The serotonin2C (5-hydroxytryptamin2C, 5-HT2C) receptor, a seven-transmembrane receptor coupled to several intracellular signaling pathways [1], is thought to act as a “neural rheostat regulating the intersection between vulnerability behaviors” [2]
The 5-hydroxyindoleacetic acid (5-HIAA)/5-HT and dihydroxyphenylacetic acid (DOPAC)/DA ratios, which are considered as indirect indexes of the turnover, vary across the brain, and the pattern of correlations between pairs of specific brain regions is different for the parent neurotransmitter [32,39]
We studied the effect of WAY-163909 treatment (0.3 and 3 mg/kg i.p.) on DA and 5-HT metabolism in 29 brain areas of rats and compared it with saline-treated rats (8 rats in each of the three groups; n = 24 for the entire experiment) (Figure 1)
Summary
The serotonin2C (5-hydroxytryptamin2C, 5-HT2C) receptor, a seven-transmembrane receptor coupled to several intracellular signaling pathways [1], is thought to act as a “neural rheostat regulating the intersection between vulnerability behaviors” [2]. There are numerous data reporting that the stimulation of 5-HT2C receptors alters the activity of neuronal cells in brain tissues in vitro and in vivo [1,23]. The 5-HIAA/5-HT and DOPAC/DA ratios, which are considered as indirect indexes of the turnover, vary across the brain, and the pattern of correlations between pairs of specific brain regions is different for the parent neurotransmitter [32,39]. It is, possible that the stimulation of central 5-HT2C receptors alters the metabolism of 5-HT and DA in a different way compared to the neurotransmitter itself. The analysis was done across 29 brain regions, including the cortex, basal ganglia, mesencephalon, amygdala, hippocampus, and hypothalamus
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