Effects of delta 9-tetrahydrocannabinol on the levels of cyclic adenosine 3',5'-monophosphate in mouse brain.

The effects of intraperitoneal injections of various doses of A9-tettahydrocannabinol (A”-THC) on brain levels of cyclic adenosine 3’,5’-monophosphate (cyclic AMP) have been studied in mice. Doses of A9-THC in the range of 0.1 to 1.0 mgikg cause a 5&160 per cent elevation of cyclic AMP levels compared to controls (P < O.OOOS), while doses of A9THC in the range of 2.0 to 10.0 mg/kg cause a 3@-60 per cent depression of cyclic AMP levels (P = 0.025 to 0.0005). This pattern was obtained in whole brain, as well as in dissected samples of cortex, cerebellum and medulla. This over-all biphasic effect of THC on cyclic AMP levels correlates with known changes in biogenic amines, temperature regulation, and behavior caused by this drug. NUMEROUS investigators have demonstrated that tetrahydrocannabinol (THC) and at least one of its metabolites, 1 l-OH-THC, are the major compounds responsible for the psychomimetic action of marihuana in mammalian systems. ‘L’ 4 Although the molecular mechanism of THC action is still unknown, evidence has accumulated suggesting that the effects of Cannabis may be mediated. at least in part, by alterations in biogenic amines. Moderate doses of THC or Cannabis extracts in rodents have been reported to produce an elevation in brain levels of serotonin’ 5p19 and a depression of norepinephrine,‘b~‘7.20 5-hydroxyindole acetic acid and normetaephrine.21 In view of the importance of these biogenic amines as neurohumors affecting behavior and mood, it seems reasonable to speculate that these changes in brain amines are in some way involved in the behavioral effects of marihuana. Some biogenic amines are now thought to transmit their effects via an activation of the membrane-associated enzyme adenyl cyclase, resulting in the synthesis of cyclic adenosine 3’,5’-monophosphate (cyclic AMP).2”7 This hypothesis is based mainly on experiments in which brain slices have been incubated with norepinephrine and were subsequently found to contain increased levels of cyclic AMP, although some cell-free preparations have also been reported where adenyl cyclase activity can be stimulated by catecholamines.” Furthermore, in some experimental situations it has been possible to demonstrate that changes in neural discharge rates produced by norepinephrine can be mimicked by direct application of cyclic AMP,29 thus directly implicating cyclic AMP as a mediator of the effects of biogenic amines on nerve cells. Further support for this conclusion comes from studies which have shown that administration of dibutyryl-cyclic ,4MP directly into the brain causes a * Supported in part by Grant 5R01 DA00116 (formerly MH 21003) from the National Institute of Mental Health.