Abstract
The mechanisms by which the CB1 receptor antagonist rimonabant exerts its appetite-suppressing and energy-dissipating effects remain incompletely understood. To further explore the central pathways influenced by CB1 receptor modulation, we examined the expression of the immediate early gene c-fos in male Sprague-Dawley rats at 60, 120, and 240 minutes following intraperitoneal administration of:
- Rimonabant (10 mg/kg, CB1R antagonist)
- WIN55,212-2 (3 mg/kg, CB1R agonist)
Methods:
Perfusion-fixed brains were processed for immunohistochemistry, and c-Fos immunoreactive neuronal profiles were qualitatively assessed throughout the brain. Nine brain regions, including key hypothalamic and brainstem nuclei involved in appetite regulation, were selected for quantitative analysis.
Results:
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WIN55,212-2 (CB1R agonist) induced time-dependent increases in c-Fos immunoreactivity in the:
- Striatum
- Central nucleus of the amygdala
- Hypothalamic paraventricular nucleus (PVN)
- Arcuate nucleus (ARC)
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Rimonabant (CB1R antagonist) did not produce significant increases in c-Fos-positive nuclei in any forebrain regions.
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Both rimonabant and WIN55,212-2 significantly increased c-Fos expression in brainstem regions, including:
- Lateral parabrachial nucleus (LPBN)
- Nucleus of the solitary tract (NTS)
- Area postrema (AP)
Neuron Phenotyping in the Nucleus of the Solitary Tract (NTS):
A triple immunohistochemical staining technique was used to label c-Fos protein along with:
- Tyrosine hydroxylase (TH) (catecholaminergic neurons)
- GLP-1 (glucagon-like peptide-1)
- CART (cocaine- and amphetamine-regulated transcript)
Key Finding: Rimonabant significantly increased c-Fos expression in TH-positive (catecholaminergic) neurons within the NTS, highlighting a specific effect on ascending A2/C2 catecholaminergic neurons.
Conclusions:
These results suggest that brainstem areas, particularly the NTS, play a central role in rimonabant-induced inhibition of food intake. The activation of A2/C2 catecholaminergic neurons may be a key component of the appetite-suppressing effects of CB1 receptor blockade, providing insight into the neural circuits underlying energy balance regulation.
