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

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Abstract
The systemic administration of Δ9‐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 CB1 cannabinoid receptor antagonist SR141716A (0.5 mg kg−1, i.p.) but also unexpectedly by the D2 dopamine receptor antagonist S(−)‐sulpiride (5, 10 and 25 mg kg−1, i.p.). Conversely, Δ9‐tetrahydrocannabinol‐induced memory impairment and inhibition of hippocampal extracellular acetylcholine concentration were potentiated by the subcutaneous administration of the D2 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 Δ9‐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 D2 dopamine and CB1 cannabinoid receptors, and that D2 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