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

1 The systemic administration of Delta(9)-tetrahydrocannabinol (2.5-7.5 mg kg(-1)) reduced hippocampal extracellular acetylcholine concentration and impaired working memory in rats. 2 Both effects were antagonized not only by the CB, 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, Delta(9)-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 mu g kg(-1)). The inhibition of hippocampal extracellular acetylcholine concentration and working memory produced by the combination of (-)-quinpirole and Delta(9)-tetrahydrocannabinol was suppressed by either SR141716A or S(-)-sulpiride. 3 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 CB1 cannabinoid receptors, and that D-2 dopamine receptor antagonists may be useful in the treatment of the cognitive deficits induced by marijuana.