Cannabinoid CB₁ receptor agonists increase rat cortical and hippocampal acetylcholine release in vivo

Abstract

Intravenous administration of the cannabinoid CB₁ receptor agonists (R-(+)-[2,3-Dihydro-5-methyl-3[morpholinyl)methyl]-pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate), WIN 55,212-2 (10, 37.5, 75 and 150 μg/kg), and ((6aR)-trans-3-(1,1-Dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenzo[b,d]pyran-9-methanol), HU 210 (1 and 4 μg/kg) dose-dependently increased acetylcholine release in dialysates from the prefrontal cortex and the hippocampus of freely moving rats. Administration of the cannabinoid receptor antagonist {N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3carboxamide}HCl, SR 141716A, at a dose that per se did not affect basal acetylcholine release (2.5 μg/kg), prevented the increase of acetylcholine release by WIN 55,212-2 (150 μg/kg i.v.) or by HU 210 (4 μg/kg i.v.) in both areas. These data demonstrate that, at low i.v. doses, the synthetic cannabinoid CB₁ receptor agonists, WIN 55,212-2 and HU 210 stimulate cortical and hippocampal acetylcholine release.

Introduction

Cholinergic projections of the basal forebrain/nucleus basalis magnocellularis and of the medial septum (basal forebrain cholinergic complex) to the cerebral cortex and hippocampus have long been regarded as critical for memory (Bartus et al., 1985). Current views attribute to central acetylcholine a critical role in arousal and attentional processes Fibiger, 1991, Robbins and Everitt, 1994, Blokland, 1999. In fact, acetylcholine release in the rat frontal cortex and hippocampus is increased by presentation of both unconditioned and conditioned sensory stimuli Inglis and Fibiger, 1995, Acquas et al., 1996, Acquas et al., 1998 and it has been suggested that increased acetylcholine neurotransmission in such terminal areas strengthens the salience of motivationally relevant stimuli, thus, facilitating learning and memory Robbins and Everitt, 1994, Sarter and Bruno, 1997.

Δ⁹-tetrahydrocannabinol and synthetic agonists of cannabinoid CB₁ receptors have been reported to reduce acetylcholine release in vivo from rat hippocampus (Carta et al., 1998) and frontal cortex Carta et al., 1998, Gessa et al., 1998a at doses known to inhibit spontaneous locomotor activity. Furthermore, in rats as well as in humans, Δ⁹-tetrahydrocannabinol's amnesic effects are well-described Lichtman and Martin, 1996, Solowij et al., 1991 and it has recently been suggested that these effects of cannabinoids might be related to reductions of acetylcholine neurotransmission (Gessa et al., 1998a). However, cannabinoid receptor agonists may disrupt performance in a working memory task also through an acetylcholine-independent mechanism (Lichtman and Martin, 1996).

Intravenous administration of low doses of Δ⁹-tetrahydrocannabinol and WIN 55,212-2 stimulates motor activity and dopamine release in the shell of the nucleus accumbens (Tanda et al., 1997) and increases the firing activity of dopamine units in the ventral tegmentum (Gessa et al., 1998b). Here, we report the effect of the cannabinoid CB₁ receptor agonists, WIN 55,212-2 and HU 210, administered i.v. in the range doses and with the vehicle which we utilized in our previous studies (Tanda et al., 1997) on acetylcholine release in the rat prefrontal cortex and in the hippocampus. Furthermore, the effect of the cannabinoid CB₁ receptor antagonist, SR 141716A (Rinaldi-Carmona et al., 1994), alone and in combination with WIN 55,212-2 or HU 210, was studied.