Amnesia induced by β-amyloid fragments is counteracted by cannabinoid CB₁ receptor blockade

Abstract

Administration of drugs activating cannabinoid CB₁ receptors in the brain induces memory deficit in rodents, and blockade of these receptors may restore memory capacity in these animals. Central administration of β-amyloid or β-amyloid fragments may also lead to memory disturbances. This study was undertaken to study the involvement of cannabinoid CB₁ receptors in amnesia induced by β-amyloid fragments in mice tested in a step-through passive avoidance paradigm. Pre-training intracerebroventricular (i.c.v.) injection of β-amyloid fragments, β-amyloid peptide-(25–35) (4, 8 or 16 nmol/mouse) or β-amyloid peptide-(1–42) (200, 400, 800 pmol/mouse) 7 days prior to the learning trial reduced in a dose-dependent manner the retention of passive avoidance response. This effect was observed in two retention tests, 1 and 7 days after the learning trial. The two β-amyloid fragments showed similar potency in reducing retention of passive avoidance behavior. This effect was counteracted by a single intraperitoneal (i.p.) injection of the cannabinoid CB₁ receptor antagonist, N-(piperidin-l-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A, 1 mg/kg), made 30 min prior to the second retention test. The injection of SR141716A per se did not affect memory capacity of mice. The i.c.v. administration of β-amyloid peptide-(25–35) (8 nmol/mouse) or of β-amyloid peptide-(1–42) (400 pmol/mouse) made 30 min prior to the learning trial failed to affect the retention capacity of mice as measured 1 and 7 days later. Also, the i.p. injection of SR 141716A (1 mg/kg) made 30 min prior to the learning trial did not influence the behavioral response of mice injected with β-amyloid peptide-(25–35) (8 nmol/mouse) or of β-amyloid peptide-(1–42) (400 pmol/mouse) 7 days prior to the learning trial. These results show that β-amyloid fragments induce a dose-dependent memory deficit. Their effect on memory retention depends upon the time of administration and seems to involve cannabinoid CB₁ receptors in the brain.

Introduction

The pathogenesis of Alzheimer's disease includes, among others, factors such as oxidative stress, inflammation and deficit of the brain cholinergic system Whitehouse et al., 1981, Mountjoy et al., 1984, Yamamoto and Hirano, 1985, Behl, 1999, McGeer and McGeer, 1999, Lyness et al., 2003. There is evidence that intracerebroventricular (i.c.v.) infusion of β-amyloid causes brain dysfunctions similar to those of Alzheimer's disease, as evidenced by neurodegeneration and impairment of learning and memory in rodents Kowall et al., 1991, Flood et al., 1994, Nitta et al., 1994, Nitta et al., 1997, Giovannelli et al., 1995, Maurice et al., 1996, Yamada et al., 1998. However, the mechanisms of neurotoxic effects of β-amyloid in vivo are not fully understood yet Clemens and Stephenson, 1992, Podlisny et al., 1993, Winkler et al., 1994, Fukuchi et al., 1996. Neuronal degeneration induced by β-amyloid affects subcortical nuclei modulating various physiological processes and behaviors, such as arousal and sleep, attention and vigilance, mood and aggression, pain and sensory reactivity, learning and memory (Lyness et al., 2003). Various neurotransmitters are involved in synaptic connections of these nuclei, including acetylcholine, norepinephrine, dopamine and serotonin Curcio and Kemper, 1984, Yamamoto and Hirano, 1985. Neuronal degeneration, particularly of the cholinergic neuronal system, is usually accompanied by cognitive dysfunction Whitehouse et al., 1981, Mountjoy et al., 1984.

Several drugs may induce memory alterations in rodents. Recent studies have demonstrated that marijuana or its active ingredient Δ⁹-tetrahydrocannabinol impairs learning and memory processes in rats, mice Heyser et al., 1993, Terranova et al., 1996, Brodkin and Moerschbaecher, 1997, Jentsch et al., 1997, Nava et al., 2000, non-human primates (Evans, 1992) and humans Miller, 1983, Chait and Perry, 1994, Heishman et al., 1997. These effects seem to be mediated by cannabinoid CB₁ receptors. In fact, activation of cannabinoid CB₁ receptor by the selective agonist anandamide decreases acetylcholine cerebral levels and causes cognitive impairment Lichtman et al., 1995, Lichtman and Martin, 1996, Mallet and Beninger, 1998. Administration of the selective cannabinoid CB₁ receptor antagonist SR141716A antagonizes the cognitive impairment induced by cannabinoids Lichtman and Martin, 1996, Carta et al., 1998, Gessa et al., 1997, Nava et al., 2000. Thus, there is a connection between the amnesic effect induced by β-amyloid and the cannabinoid receptor system.

The present study was aimed at investigating in detail the amnesic effects of β-amyloid fragments and the possible involvement of cannabinoid CB₁ receptors in these effects. In particular, the influence of time of administration in relation to memory processes (consolidation and retrieval) has been evaluated.