D₂ dopamine receptors enable Δ⁹‐tetrahydrocannabinol induced memory impairment and reduction of hippocampal extracellular acetylcholine concentration

Abstract

The systemic administration of Δ 9 ‐tetrahydrocannabinol (2.5–7.5 mg kg −1 ) reduced hippocampal extracellular acetylcholine concentration and impaired working memory in rats. Both effects were antagonized not only by the CB 1 cannabinoid receptor antagonist SR141716A (0.5 mg kg −1 , i.p.) but also unexpectedly by the D 2 dopamine receptor antagonist S(−)‐sulpiride (5, 10 and 25 mg kg −1 , i.p.). Conversely, Δ 9 ‐tetrahydrocannabinol‐induced memory impairment and inhibition of hippocampal extracellular acetylcholine concentration were potentiated by the subcutaneous administration of the D 2 dopamine receptor agonist (−)‐quinpirole (25 and 500 μg kg −1 ). The inhibition of hippocampal extracellular acetylcholine concentration and working memory produced by the combination of (−)‐quinpirole and Δ 9 ‐tetrahydrocannabinol was suppressed by either SR141716A or S(−)‐sulpiride. Our findings suggest that impairment of working memory and inhibition of hippocampal extracellular acetylcholine concentration are mediated by the concomitant activation of D 2 dopamine and CB 1 cannabinoid receptors, and that D 2 dopamine receptor antagonists may be useful in the treatment of the cognitive deficits induced by marijuana. British Journal of Pharmacology (2000) 130 , 1201–1210; doi: 10.1038/sj.bjp.0703413