Low dose anandamide affects food intake, cognitive function, neurotransmitter and corticosterone levels in diet-restricted mice

Abstract

This investigation reports the possible role of the endocannabinoid anandamide on modulating the behavioral and neurochemical consequences of semi-starvation. We studied the effect of very low dose anandamide (0.001 mg/kg) administration on food intake, cognitive function and catecholaminergic and serotonergic pathways in two murine brain areas concerned with appetite (hypothalamus) and learning (hippocampus), and the peripheral corticosterone response to the stress of 40% diet restriction. Anandamide-treated mice consumed 44% more food (P<0.05) during 1 week of 2.5-h feeding each day. In the hypothalamus, there were significantly increased concentrations of norepinephrine (P<0.01), dopamine (P<0.05) and 5-hydroxytryptamine (5-HT) (P<0.001). In the hippocampus, anandamide increased significantly norepinephrine and dopamine, but decreased 5-HT (all at P<0.001). Diet restriction was accompanied in both areas by a significant decrease in all neurotransmitter concentrations that were partially restored by anandamide for dopamine and 5-HT, but not for norepinephrine. In animals on diet restriction, anandamide significantly improved impaired maze performance. Norepinephrine turnover and plasma corticosterone levels were also raised significantly by anandamide. The fact that low dose anandamide improved food intake, cognitive function and reversed some of the neurotransmitter changes caused by diet restriction, might have implications for the treatment of cachexia associated with acquired immunodeficiency syndrome (AIDS) and cancer, for mood changes sometimes associated with dieting, and in the extreme case, of patients with anorexia.

Introduction

Anandamide is an endogenous lipid substance isolated in 1992 from porcine brain and the first natural ligand binding to the endogenous cannabinoid receptor (Devane et al., 1992). It produces some effects similar to Δ⁹-tetrahydrocannabinol, both in vivo and in vitro Devane et al., 1992, Fride and Mechoulam, 1993, Onaivi et al., 1996. Both Δ⁹-tetrahydrocannabinol and anandamide bind to the cannabinoid receptor, and Δ⁹-tetrahydrocannabinol is used to increase appetite in acquired immunodeficiency syndrome (AIDS) patients (Mechoulam et al., 1998). Anandamide produces bi-phasic dose responses in both behavior and neuro-biochemistry Fride, 1995, Fride and Mechoulam, 1993, Fride et al., 1995, Sulcova et al., 1998. Thus, at low doses, it stimulated ambulation and rearing, as well as gut motility in the open field situation, decreased the rate of immobility on ring standing, and analgesia on a hot plate; it also stimulated aggressive behavior in timid mice and phagocytosis by mouse leukocytes. At high doses, opposite effects of inhibition were observed (Sulcova et al., 1998).

The stimulating effect of a low dose of anandamide (0.001 mg/kg) on appetite and behavior might have possible therapeutic potential for dealing with mood changes sometimes experienced following dieting, and also in anorexic patients (Berry, 1999). We therefore evaluated its effects on food intake; and on cognitive function, brain neurotransmitters and plasma corticosterone concentration in a model of diet restriction in mice (Avraham et al., 1996).