Research reportInhibition of hippocampal acetylcholine release after acute and repeated Δ9-tetrahydrocannabinol in rats
Introduction
Δ9-Tetrahydrocannabinol (Δ9-THC), the psychoactive principle of marijuana, is known to produce impairment in learning and memory both in humans and laboratory animals 3, 4, 8, 13, 14, 16, 18. Impairment of memory processes is also produced by the synthetic cannabinoid CB1 agonists, WIN 55,212-2 {R-(+)-(2,3-dihydro-5-methyl-3-[{4-morpholinylmethyl] pyrol [1,2,3-de]1,4-benzoxazin-6-yl) (l-naphthalenyl) methanone monomethanesulfonate} and CP 55,940 {[1a,2-(r)-5-(1,1-dimethylpheptyl)-2-[5-hydroxy-2-(3-hydroxypropyl) cyclohexyl]-phenol} 18, 24and by the endogenous cannabinoid agonists, anandamide [20]and 2-AG (sn-2 arachidonylglycerol) [23]. The negative effects of the cannabinoid agonists are blocked by the cannabinoid CB1 antagonist SR 141716A, a compound that is per se able to improve memory processes in rodents 3, 24. These results indicate that the impairment in memory by Δ9-THC is mediated via CB1 receptors 19, 24and also suggest that endogenous cannabinoids play a role in cognitive processes 20, 23. Moreover, experimental evidence suggests that inhibition of cholinergic neurotransmission in the hippocampus plays an important role in cognitive alterations produced by cannabinoids [21]. Thus, cannabinoid agonists impair working memory after intrahippocampal administration [18]and inhibit long-term potentiation in hippocampal slices [5], a classic electrophysiological model for the study of learning and memory processes [1]. In addition, cannabinoid agonists reduce acetylcholine output in the hippocampus in freely moving rats [10]and [] acetylcholine release in hippocampal slices 11, 12.
The present study, using microdialysis techniques in freely moving rats, was carried out to determine whether the suppressant effect of Δ9-THC on hippocampal acetylcholine release would be modified by a repeated exposure to the drug. This problem is clinically relevant since chronic marijuana use has been claimed to produce persistent adverse effects on cognition 4, 16.
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Animals
Male Sprague–Dawley rats (225–250 g; Charles River, Calco, Lecco, Italy) were housed in groups of three per cage for at least ten days before use. Food and water were freely available and animals were maintained under an artificial 12-h/12-h light/dark cycle (lights were on from 0700 to 1900). Experiments were carried out between 0800 and 1700 h.
Microdialysis implantation and experimental procedure
Rats were anesthetised with equitensin (4 mg/kg, i.p.) and dialysis tubes (AN 69-HF, with a wet fiber outer diameter of 320 μm; Hospal-Dasco, Bologna,
Effects of a single Δ9-THC administration on hippocampal acetylcholine output
As shown in Fig. 1 the administration of Δ9-THC at the dose of 2.5, and 5 mg/kg inhibited acetylcholine release by about 25% (ANOVA main effect F1,8=3.81; post-hoc P>0.05; ANOVA main effect of repeated measures F8,36=1.37; post-hoc P>0.05) and 45% (ANOVA main effect F1,8=12.17; post-hoc P<0.05; ANOVA main effect of repeated measures F8,36=4.96; post-hoc P<0.05), respectively (Fig. 1). A higher dose of 7.5 mg/kg produced no further reduction (ANOVA main effect F1,8=5.55; post-hoc P<0.05; ANOVA
Discussion
This study confirms previous observations showing that different cannabinoid agonists inhibit acetylcholine release in the hippocampus in vivo [10]as well as in hippocampal slices 5, 11and that this effect is prevented by the CB1 receptor antagonist SR141716A. Moreover, this study shows that the inhibitory effects of Δ9-THC develops after a long delay and is a lasting response: acetylcholine concentrations were reduced about 2 h after treatment and the reduction persisted for over 3 h. The
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