Effects of chronic Delta(9)-tetrahydrocannabinol treatment on hippocampal extracellular acetylcholine concentration and alternation performance in the T-maze

Delta (9)-Tetrahydrocannabinol (Delta (9)-THC), the psychoactive ingredient of cannabis sativa, reduces both extracellular hippocampal acetylcholine c oncentration and correct alternation tasks in the T-maze. The principal aim of this study was to determine whether a chronic Delta (9 )-THC treatment would induce tolerance both to the reduction of extracellul ar hippocampal acetylcholine concentration and memory deficit produced by t he drug. Our results show that a chronic Delta (9)-THC treatment (5 mg/kg, i.p., twi ce daily for two weeks) did not produce tolerance to the inhibitory effects induced by the drug. Moreover, no strict temporal correlation between the two Delta (9)-THC effects was observed: the inhibition in extracellular ace tylcholine concentration appeared only 80 min after treatment, while the re duction of correct alternation tasks in the T-maze began after 20 min. The cognitive and cholinergic effects induced by a chronic Delta (9)-THC treatm ent were completely blocked by the CB1 cannabinoid receptor antagonist SR 1 41716A, indicating an involvement of CB1 cannabinoid receptors in the persi stent negative effects induced by the drug. These findings confirm the proposition that CB1 cannabinoid receptors media te the negative effects induced by Delta (9)-THC both on hippocampal extrac ellular acetylcholine concentration and correct alternation tasks in the T- maze, and they indicate that these effects may be differentiated. However, the major outcome of this work is the demonstration that no tolerance to th e two inhibitory effects develops after a chronic Delta (9)-THC treatment. (C) 2001 Published by Elsevier Science Ltd.