Cannabinoid Receptors and Glial Response Following a Basal Forebrain Cholinergic Lesion

[Image: see text] 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, [(3)H]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. [(35)S]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).