Lorcaserin Alters Serotonin and Noradrenaline Tissue Content and Their Interaction With Dopamine in the Rat Brain

Abstract

Lorcaserin is a preferential serotonin2C receptor (5-HT_2CR) 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.

Keywords: amygdala; brain; correlation; cortex; electrochemical detection; high-pressure liquid chromatography; monoamines; nucleus accumbens.

Figure 1

Photomicrograph represents the brain regions sampled. Tissue samples were taken from the left and right cerebral hemispheres in a cryostat. Cortical areas: medial (MO), lateral (LO) and dorsolateral (DLO) orbitofrontal cortex, motor cortex (M2), prelimbic (PL), and infralimbic (IL) cortices, anterior cingulate cortex (aCg), posterior cingulate cortex (pCg), anterior insular cortex (ains), posterior insular cortex (pins), mediodorsal thalamus (MD), dorsal and ventral part of the hippocampus (dHP and vHP), basolateral nucleus (BLA) and central nucleus (CE), nucleus accumbens (shell and core), ventromedial striatum (VMS), ventrolateral striatum (VLS), dorsomedial striatum (DMS), dorsolateral striatum (DLS), entopeduncular nucleus (EPN), subthalamic nucleus (STN), habenula (Hb), dorsal and ventral parts of the hypothalamus (dHY and vHY), substantia nigra (SN), ventral tegmental area (VTA), dorsal raphe nucleus (DR); median raphe nucleus (MR). Two punched tissue in each side were taken from the M2, dHP, vHP regions to be able to measure the concentrations of monoamines (mostly DA and metabolites).

Figure 2

Effect of lorcaserin on 5-HT, 5-HIAA and 5-HIAA/5-HT ratio across the brain. Upper, middle, and lower panels correspond to 5-HT (A), 5-HIAA (B) tissue content and 5-HIAA/5-HT ratio (C), respectively. The left, medial, and right bars of histogram correspond to saline-, lorcaserin 0.3 mg/kg, and 3 mg/kg treated rats, respectively. The results correspond to the mean ± SEM of monoamine content (pg/mg tissue) in the 30 different rat brain regions. Lorcaserin has been intraperitoneally administered and the tissue values correspond to 45 min after the administration. The effects of lorcaserin have been compared to saline-treated rats using a one-way ANOVA (see Table 1 for the number of observations). *p < 0.05, **p < 0.01 with respect to the saline group; °p < 0.05, ^oop < 0.01 with respect to the other group of lorcaserin (PLSD’s test).

Figure 3

Effect of lorcaserin on NA tissue content across the brain. The left, medial, and right bars of histogram correspond to saline (first column), lorcaserin 0.3 mg/kg (second column), and 3 mg/kg (third column) treated rats, respectively. The results correspond to the mean ± SEM of monoamine content (pg/mg tissue) in the 30 different rat brain regions. Lorcaserin has been intraperitoneally administered and the tissue values correspond to 45 min after the administration. The effects of lorcaserin have been compared to saline-treated rats using a one-way ANOVA (see Table 1 for the number of observations and ANOVAs). *p < 0.05, **p < 0.01, ***p < 0.001 with respect to the saline group; °p < 0.05 with respect to the other group of Lorcaserin (PLSD’s test).

Figure 4

Correlative analysis of 5-HT content across rat brain regions. Representation of the range of Pearson’s R values for each linear regression of 5-HT (A), 5-HIAA (B) tissue contents (pg/mg) as well as 5-HIAA/5-HT ratio (C) between the 30 brain areas in saline (first column), lorcaserin 0.3 mg/kg (second column), and 3 mg/kg (third column) treated rats. The three insets at the level of 5-HT report one linear regression between the 5-HT content in PL and IL cortices of the animals (n = 10 animals/group) for the three groups. It shows that the 5-HT content in these two brain regions correlates in the lorcaserin 0.3 mg/kg group. These results are reported in the matrix of correlations as indicated by the arrow. Colored boxes correspond to the existence of a correlation between the two parameters (yellow to red, positive; blue, negative) considered after correction for multiple comparisons.

Figure 5

Correlative analysis of NA content across rat brain regions. Representation of the range of Pearson’s R values for each linear regression of NA tissues content (pg/mg) between the 30 brain areas in saline (first column), lorcaserin 0.3 mg/kg (second column), and 3 mg/kg (third column) treated rats. Colored boxes correspond to the existence of a correlation between the two parameters (yellow to red, positive; blue, negative) considered after correction for multiple comparisons.

Figure 6

Correlative analysis of monoamine content across rat brain regions. Representation of the range of Pearson’s r values for each linear regression of NA with 5-HT contents (first row), NA with DA contents (second row), DA with 5-HT contents (third row), and the DOPAC/DA and 5-HIAA/5-HT ratios (last row) between the 30 brain areas in saline (first column), lorcaserin 0.3 mg/kg (second column) and 3 mg/kg (third column) treated rats. Colored boxes correspond to the existence of a correlation between the two parameters (yellow to red, positive; blue, negative) considered after correction for multiple comparisons.