Learning and memory improvement mediated by CB1 cannabinoid receptors in animal models of cholinergic dysfunction

Abstract

The selective vulnerability of the basal forebrain cholinergic system (BFCS) is responsible for most of the clinical alterations in learning and memory processes that are characteristic of the Alzheimer¿s disease (AD). The loss of cholinergic neurons and muscarinic receptors (MR) in the nucleus basalis of Meynert has been reported in AD. The endocannabinoid system is a neuromodulator of the BFCS, but there are controversial reports regarding the cannabinoid effects in learning and memory processes.The animal models of cholinergic impairment mimick the main histopathological and behavioral effects observed in patients. The MR antagonism, e.g. using scopolamine (SCOP), is used as a model of amnesia in rodents. The intraparenchymal administration of 192-IgG-saporin (SAP) in the nucleus basalis magnocellularis eliminates cholinergic neurons leading to learning and memory deficits.Then, the present study evaluates the modulation of spatial and working memory with the Barnes Maze following a subchronic treatment with a low dose (0.5 mg/kg) of WIN55,212-2 (WIN) in both the SCOP and SAP models of learning and memory deficit. In the SCOP model, the administration of WIN protects learning and memory impairment during the probe trial, recorded as the time spent in the target quadrant (WIN + SCOP: 78 ± 13 sec vs VEH + SCOP: 45 ± 3 sec; p ¿ 0.001). A similar effect of the treatment was observed in the SAP model (SAP: 50 ± 3 sec vs SAP + WIN: 82 ± 7 sec; p ¿ 0.001). This effect was specifically mediated by CB1 receptors, since it was blocked by the co-administration of the specific CB1 antagonist, SR141716A (0.5 mg/kg) (SAP: 49 ± 3 sec vs SAP + WIN + SR: 48 ± 5 sec). However, higher doses of WIN (3 mg/kg) induced negative effects in learning and memory in control (C) rats, but positive and comparable to the lower dose in the SAP model (C: 89 ± 3 sec, C + WIN-3 mg/kg: 48 ± 3 sec; SAP: 49 ± 3; SAP + WIN-3 mg/kg: 80 ± 12 sec).The CB1 activation by low doses of the cannabinoid agonist WIN are able to block the amnesic effects induced by SCOP and also the learning and memory impairment produced by the BFCS pathway degeneration. CB1 agonists could contribute to improve the clinical symptoms of AD.