There appears to have been an increase in use of the extremely potent synthetic cannabinoids JWH-122 and JWH-210. Acute toxic symptoms associated with their use are also reported after intake of high doses of cannabis, but agitation, seizures, hypertension, emesis and hypokalaemia seem to be characteristic to the synthetic cannabinoids, which are high-affinity and high-efficacy agonists of the CB(1) receptor. Thus, these effects are due probably to a strong CB(1) receptor stimulation.

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It was shown recently that Delta9-tetrahydrocannabinol, like several other drugs eliciting euphoria, stimulates dopaminergic neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens. The aim of the present work was to clarify the mechanism of this stimulatory effect. Our hypothesis was that cannabinoids depress the GABAergic inhibition of dopaminergic neurons in the VTA. Electrophysiological properties of VTA neurons in rat coronal midbrain slices were studied with the patch-clamp technique. GABA(A) receptor-mediated inhibitory postsynaptic currents (IPSCs) were evoked by electrical stimulation in the vicinity of the recorded neurons. The amplitude of IPSCs was depressed by the synthetic mixed CB1/CB2 cannabinoid receptor agonist WIN55212-2 (10(-6) and 10(-5) m). The CB1 cannabinoid receptor antagonist SR141716A (10(-6) m) prevented the inhibition produced by WIN55212-2 (10(-5) m). Two observations showed that IPSCs were depressed with a presynaptic mechanism. WIN55212-2 (10(-5) m) did not change the amplitude of miniature IPSCs recorded in the presence of tetrodotoxin. Currents evoked by pressure ejection of muscimol from a pipette were also not changed by WIN55212-2 (10(-5) m). The results indicate that activation of CB1 cannabinoid receptors inhibits GABAergic neurotransmission in the VTA with a presynaptic mechanism. Depression of the GABAergic inhibitory input of dopaminergic neurons would increase their firing rate in vivo. Accordingly, dopamine release in the projection region of VTA neurons, the nucleus accumbens, would also increase.

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Endocannabinoids acting on CB 1 cannabinoid receptors are involved in short-and long-term depression of synaptic transmission. The aim of the present study was to determine which endocannabinoid, anandamide or 2-arachidonoylglycerol (2-AG), is involved in depolarization-induced suppression of inhibition (DSI) in the cerebellar cortex, which is the most widely studied form of short-term depression. Depolarization of Purkinje cells in the mouse cerebellum led to an increase in intracellular calcium concentration and to suppression of the inhibitory input to these neurons (i.e. DSI occurred). Orlistat and RHC80267, two blockers of sn-1-diacylglycerol lipase, the enzyme catalysing 2-AG formation, abolished DSI by acting downstream of calcium influx. In contrast, DSI occurred also in the presence of a phospholipase C inhibitor. Intact operation of the calcium-dependent messengers calmodulin and Ca 2+ -calmodulin-dependent protein kinase II were necessary for DSI. DSI was potentiated by an inhibitor of the main 2-AG-degrading enzyme, monoacylglycerol lipase. Interference with the anandamide metabolizing enzyme, fatty acid amide hydrolase, did not modify DSI. Thus, three kinds of observations identified 2-AG as the endocannabinoid involved in DSI in the mouse cerebellum: DSI was abolished by diacylglycerol lipase inhibitors; DSI was potentiated by a monoglyceride lipase inhibitor; and DSI was not changed by an inhibitor of fatty acid amide hydrolase. Further experiments indicated that 2-AG is the endocannabinoid mediating short-term retrograde signalling also at other synapses: orlistat abolished DSI in the rat cerebellum, DSI in the mouse substantia nigra pars reticulata and depolarization-induced suppression of excitation in the mouse cerebellum.

Our data indicate that beta-adrenergic EAD share a common ionic mechanism with DAD in terms of cellular Ca2+ overload and spontaneous SR Ca2+ release. beta-Adrenergic EAD consist of two phases: (1) a conditional phase coinciding with the onset of an early aftercontraction, often followed by (2) an EAD upstroke. A Ca2(+)-activated membrane current, probably I Na-Ca, is necessary at least for the initiation of these EAD.

1 The aim of the present study was to analyse the cardiovascular actions of the synthetic CB 1 /CB 2 cannabinoid receptor agonist WIN55212-2, and speci®cally to determine its sites of action on sympathetic cardiovascular regulation. 2 Pithed rabbits in which the sympathetic out¯ow was continuously stimulated electrically or which received a pressor infusion of noradrenaline were used to study peripheral prejunctional and direct vascular eects, respectively. For studying eects on brain stem cardiovascular regulatory centres, drugs were administered into the cisterna cerebellomedullaris in conscious rabbits. Overall cardiovascular eects of the cannabinoid were studied in conscious rabbits with intravenous drug administration. 3 In pithed rabbits in which the sympathetic out¯ow was continuously electrically stimulated, intravenous injection of WIN55212-2 (5, 50 and 500 mg kg 71 ) markedly reduced blood pressure, the spillover of noradrenaline into plasma and the plasma noradrenaline concentration, and these eects were antagonized by the CB 1 cannabinoid receptor-selective antagonist SR141716A. The hypotensive and the sympathoinhibitory eect of WIN55212-2 was shared by CP55940, another mixed CB 1 /CB 2 cannabinoid receptor agonist, but not by WIN55212-3, the enantiomer of WIN55212-2, which lacks anity for cannabinoid binding sites. WIN55212-2 had no eect on vascular tone established by infusion of noradrenaline in pithed rabbits. 4 Intracisternal application of WIN55212-2 (0.1, 1 and 10 mg kg 71 ) in conscious rabbits increased blood pressure and the plasma noradrenaline concentration and elicited bradycardia; this latter eect was antagonized by atropine. 5 In conscious animals, intravenous injection of WIN55212-2 (5 and 50 mg kg 71 ) caused bradycardia, slight hypotension, no change in the plasma noradrenaline concentration, and an increase in renal sympathetic nerve ®ring. The highest dose of WIN55212-2 (500 mg kg 71) elicited hypotension and tachycardia, and sympathetic nerve activity and the plasma noradrenaline concentration declined. 6 The results obtained in pithed rabbits indicate that activation of CB 1 cannabinoid receptors leads to marked peripheral prejunctional inhibition of noradrenaline release from postganglionic sympathetic axons. Intracisternal application of WIN55212-2 uncovered two eects on brain stem cardiovascular centres: sympathoexcitation and activation of cardiac vagal ®bres. The highest dose of systemically administered WIN55212-2 produced central sympathoinhibition; the primary site of this action is not known.