Ž . European Journal of Pharmacology 401 2000 179–185 www.elsevier.nlrlocaterejphar Cannabinoid CB receptor agonists increase rat cortical and hippocampal 1 acetylcholine release in vivo Elio Acquas, Augusta Pisanu, Paola Marrocu, Gaetano Di Chiara ) Department of Toxicology, UniÕersity of Cagliari and Centre for Neuropharmacology, CNR, V.le A. Diaz, 182, 09126, Cagliari, Italy Received 28 February 2000; received in revised form 24 May 2000; accepted 30 May 2000 Abstract Ž Ž . w w . x Intravenous administration of the cannabinoid CB receptor agonists R- q - 2,3-Dihydro-5-methyl-3 morpholinyl methyl - 1 w x x Ž . . Ž . ŽŽ . pyrrolo 1,2,3-de -1,4-benzoxazinyl - 1-naphthalenyl methanone mesylate , WIN 55,212-2 10, 37.5, 75 and 150 mgrkg , and 6aR - Ž . w x . Ž 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 mgr . kg dose-dependently increased acetylcholine release in dialysates from the prefrontal cortex and the hippocampus of freely moving rats.  Ž . Ž . Ž . Administration of the cannabinoid receptor antagonist N- piperidin-1-yl -5- 4-chlorophenyl -1- 2,4-dichlorophenyl -4-methyl-1H- 4 Ž . pyrazole-3carboxamide HCl, SR 141716A, at a dose that per se did not affect basal acetylcholine release 2.5 mgrkg , prevented the Ž . Ž . increase of acetylcholine release by WIN 55,212-2 150 mgrkg i.v. or by HU 210 4 mgrkg i.v. in both areas. These data demonstrate that, at low i.v. doses, the synthetic cannabinoid CB receptor agonists, WIN 55,212-2 and HU 210 stimulate cortical and hippocampal 1 acetylcholine release. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Acetylcholine; Hippocampus; HU 210; Microdialysis; Cortex, prefrontal; SR 141716A; WIN 55, 212-2 1. Introduction Cholinergic projections of the basal forebrainrnucleus Ž basalis magnocellularis and of the medial septum basal . forebrain cholinergic complex to the cerebral cortex and hippocampus have long been regarded as critical for mem- Ž . ory Bartus et al., 1985 . Current views attribute to central acetylcholine a critical role in arousal and attentional Ž processes Fibiger, 1991; Robbins and Everitt, 1994; Blok- . land, 1999 . In fact, acetylcholine release in the rat frontal cortex and hippocampus is increased by presentation of Ž both unconditioned and conditioned sensory stimuli Inglis . and Fibiger, 1995; Acquas et al., 1996, 1998 and it has been suggested that increased acetylcholine neurotransmis- sion in such terminal areas strengthens the salience of motivationally relevant stimuli, thus, facilitating learning Ž and memory Robbins and Everitt, 1994; Sarter and Bruno, . 1997 . ) Corresponding author. Tel.: q 39-070-303-819; fax: q 39-070-300- 740. Ž . E-mail address: diptoss@tin.it G. Di Chiara . D 9 -tetrahydrocannabinol and synthetic agonists of cannabinoid CB receptors have been reported to reduce 1 Ž acetylcholine release in vivo from rat hippocampus Carta . Ž et al., 1998 and frontal cortex Carta et al., 1998; Gessa et . al., 1998a at doses known to inhibit spontaneous locomo- tor activity. Furthermore, in rats as well as in humans, D 9 -tetrahydrocannabinol’s amnesic effects are well-de- Ž . scribed 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 acetyl- Ž . choline neurotransmission Gessa et al., 1998a . However, cannabinoid receptor agonists may disrupt performance in a working memory task also through an acetylcholine-in- Ž . dependent mechanism Lichtman and Martin, 1996 . Intravenous administration of low doses of D 9 -tetra- hydrocannabinol and WIN 55,212-2 stimulates motor ac- tivity and dopamine release in the shell of the nucleus Ž . accumbens Tanda et al., 1997 and increases the firing Ž activity of dopamine units in the ventral tegmentum Gessa . et al., 1998b . Here, we report the effect of the cannabi- noid CB receptor agonists, WIN 55,212-2 and HU 210, 1 administered i.v. in the range doses and with the vehicle Ž which we utilized in our previous studies Tanda et al., 0014-2999r00r$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. Ž . PII: S0014-2999 00 00403-9