Cannabinoid Receptors and Glial Response Following a Basal Forebrain Cholinergic Lesion

Abstract

The endocannabinoid system modulates learning, memory, and neuroinflammatory processes, playing a key role in neurodegeneration, including Alzheimer’s disease (AD). Previous results in a rat lesion model of AD showed modulation of endocannabinoid receptor activity in the basalo-cortical pathway following a specific lesion of basal forebrain cholinergic neurons (BFCNs), indicating that the glial neuroinflammatory response accompanying the lesion is related to endocannabinoid signaling. In this study, 7 days after the lesion, decreased astrocyte and increased microglia immunoreactivities (GFAP and Iba-1) were observed, indicating microglia-mediated neuroinflammation. Using autoradiographic studies, the density and functional coupling to G-proteins of endocannabinoid receptor subtypes were studied in tissue sections from different brain areas where microglia density increased, using CB ₁ and CB ₂ selective agonists and antagonists. In the presence of the specific CB ₁ receptor antagonist, SR141716A, [ ³H]CP55,940 binding (receptor density) was completely blocked in a dose-dependent manner, while the selective CB ₂ receptor antagonist, SR144528, inhibited binding to 25%, at best. [ ³⁵S]GTPγS autoradiography (receptor coupling to G _i/0-proteins) evoked by CP55,940 (CB ₁/CB ₂ agonist) and HU308 (more selective for CB ₂) was abolished by SR141716A in all areas, while SR144528 blocked up to 51.8% of the coupling to G _i/0-proteins evoked by CP55,940 restricted to the nucleus basalis magnocellularis. Together, these results demonstrate that there are increased microglia and decreased astrocyte immunoreactivities 1 week after a specific deletion of BFCNs, which projects to cortical areas, where the CB ₁ receptor coupling to G _i/0-proteins is upregulated. However, at the lesion site, the area with the highest neuroinflammatory response, there is also a limited contribution of CB ₂.