Abstract
Lorcaserin is a preferential serotonin2C receptor (5-HT2CR) agonist effective to treat obesity that has also recently been proposed to treat addiction and epilepsy. Central dopamine (DA) mechanisms are likely involved in the lorcaserin mechanism of action, but other monoamines 5-HT and noradrenaline (NA) contents or their interaction with DA might account for its effects. Here we showed that lorcaserin at 3, but not 0.3 mg/kg enhanced 5-HT content in the insular cortex, the core of the nucleus accumbens, and ventral hypothalamus. Without affecting the metabolite 5-hydroxy indole acetic acid, lorcaserin reduced the indirect index of 5-HT turnover in the hippocampus, substantia nigra, and habenula. Lorcaserin at 3 mg/kg increased NA content in the orbitofrontal cortex, the central amygdala (also at 0.3 mg/kg), the ventral hypothalamus, and the shell of the nucleus accumbens. A correlative analysis of the tissue contents between pairs of brain regions revealed that 0.3 mg/kg lorcaserin enhanced the number of correlations for 5-HT, its metabolism, and NA to a lower extent. The correlation profiles were very different between saline, 0.3 and 3 mg/kg lorcaserin. Lorcaserin enhanced the correlations established between NA or 5-HT at 0.3 and 3 mg/kg and reduced the number of correlations established between the index of the turnover for DA and 5-HT. These results show that lorcaserin modulates the biochemistry of NA and 5-HT systems in a subset of brain regions. Qualitatively, they reveal, oppositely to the DA changes, that lorcaserin at 0.3, but not 3 mg/kg, enhanced the number of correlations of 5-HT content between brain regions.
Highlights
Lorcaserin is a preferential serotonin2C receptor (5-HT2CR) agonist that was approved for the treatment of obesity in 2012 (Voigt and Fink, 2015; Greenway et al, 2016; Bohula et al, 2018) but recently withdrawn from clinical use because of long term studies suggesting an increased risk of cancer with its use
We report that lorcaserin caused a few quantitative modifications of NA and 5-HT contents across the rat brain, with the main effects being seen in the central nucleus of the amygdala (CE) and the ventral hypothalamus (vHY) for both the neurotransmitter systems
These results further confirm that Serotonin2C receptors (5-HT2CR) activation exerts widespread effects in the brain (Chagraoui et al, 2019; Whitestone et al, 2019; De Deurwaerdere et al, 2020a) and suggests that the effects on NA and 5-HT systems play a role in lorcaserin effects
Summary
Lorcaserin is a preferential serotonin2C receptor (5-HT2CR) agonist that was approved for the treatment of obesity in 2012 (Voigt and Fink, 2015; Greenway et al, 2016; Bohula et al, 2018) but recently withdrawn from clinical use because of long term studies suggesting an increased risk of cancer with its use (https://www.fda.gov/drugs/drug-safety-and-availability/ fdarequests-withdrawal-weight-loss-drug-belviq-belviqxrlorcaserin-market). The 5-HT neurons in the dorsal raphe nucleus (DR) (Boothman et al, 2006; Queree et al, 2009), and noradrenaline (NA) neurons in the locus coeruleus (LC) (Gobert et al, 2000; Dekeyne et al, 2008) These findings suggest that 5-HT2CR agonists could modulate these two systems either locally or through distal actions in various brain regions and participate in the subtle differences reported between 5-HT2CR agonists. Using postmortem analysis of monoamine tissue contents in a broad number of brain areas, it was found that the preferential 5-HT2CR agonist WAY-163909 poorly altered monoamines content quantitatively, but induced changes in the pattern of correlations between pairs of brain regions for monoamines, monoamine metabolism, between monoamines, and between their metabolism (Chagraoui et al, 2019; Whitestone et al, 2019). We studied the profile of correlations between the neurotransmitters, including DA or between DOPAC/DA and 5-HIAA/5-HT ratios
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