CB 1 cannabinoid receptors (CB 1 Rs) are attractive therapeutic targets for numerous central nervous system disorders. However, clinical application of cannabinoid ligands has been hampered owing to their adverse on-target effects. Ligand-biased signaling from, and allosteric modulation of, CB 1 Rs offer pharmacological approaches that may enable the development of improved CB 1 R drugs, through modulation of only therapeutically desirable CB 1 R signaling pathways. There is growing evidence that CB 1 Rs are subject to ligand-biased signaling and allosterism. Therefore, in the present study, we quantified ligand-biased signaling and allosteric modulation at CB 1 Rs. Cannabinoid agonists displayed distinct biased signaling profiles at CB 1 Rs. For instance, whereas 2-arachidonylglycerol and WIN55,212-2 [(R)- (1) [5-chloro-3-ethyl-1H-indole-2-carboxylic acid [2-(4-piperidin-1-yl-phenyl)ethyl]amide] displayed biased allosteric effects by blocking cAMP inhibition mediated by all cannabinoid ligands tested, at the same time having little or no effect on ERK1/2 phosphorylation mediated by a subset of these ligands. Org27569 also displayed negative binding cooperativity with [however, it had minimal effects on binding of cannabinoid agonists. Furthermore, we highlight the need to validate the reported allosteric effects of the endogenous ligands lipoxin A4 and pregnenolone at CB 1 Rs. Pregnenolone but not lipoxin A4 displaced [ 3 H]SR141716A, but there was no functional interaction between either of these ligands and cannabinoid agonists. This study demonstrates an approach to validating and quantifying ligand-biased signaling and allosteric modulation at CB 1 Rs, revealing ligand-biased "fingerprints" that may ultimately allow the development of improved CB 1 R-targeted therapies.

Cannabidiol, a nonpsychoactive constituent of the Cannabis sativa plant, has been reported to act as an agonist of the vanilloid 1 channel in the transient receptor potential family (TRPV1) and also to inhibit the hydrolysis and cellular uptake of the endogenous cannabinoid anandamide. Cannabidiol has also been reported to have potential as an antipsychotic. We investigated the effect of cannabidiol on sensorimotor gating deficits in mice induced by the noncompetitive NMDA receptor antagonist, MK-801. Sensorimotor gating is deficient in psychotic disorders such as schizophrenia and may be reliably measured by prepulse inhibition (PPI) of the startle response in rodents and humans. MK-801 (0.3-1 mg/kg i.p.) dose dependently disrupted PPI while cannabidiol (1-15 mg/kg i.p.), when administered with vehicle, had no effect on PPI. Cannabidiol (5 mg/kg i.p.) successfully reversed disruptions in PPI induced by MK-801 (1 mg/kg i.p.), as did the atypical antipsychotic clozapine (4 mg/kg i.p.). Pretreatment with capsazepine (20 mg/kg i.p.) prevented the reversal of MK-801-induced disruption of PPI by cannabidiol, providing preliminary evidence that TRPV1 receptors are involved in the reversal of MK-801-induced sensorimotor gating deficits by cannabidiol.

Cannabis is one of the most widely used illicit drugs among adolescents, and most users first experiment with it in adolescence. Adolescence is a critical phase for brain development, characterized by neuronal maturation and rearrangement processes, such as myelination, synaptic pruning and dendritic plasticity. The endocannabinoid system plays an important role in fundamental brain developmental processes such as neuronal cell proliferation, migration and differentiation. Therefore changes in endocannabinoid activity during this specific developmental phase, induced by the psychoactive component of marijuana, D 9 -tetrahydrocannabinol, might lead to subtle but lasting neurobiological changes that can affect brain functions and behaviour. In this review, we outline recent research into the endocannabinoid system focusing on the relationships between adolescent exposure to cannabinoids and increased risk for certain neuropsychiatric diseases such as schizophrenia, as highlighted by both human and animal studies. Particular emphasis will be given to the possible mechanisms by which adolescent cannabis consumption could render a person more susceptible to developing psychoses such as schizophrenia.

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1. The present study was undertaken to investigate the effect of Delta9-tetrahydrocannabinol (Delta9-THC) and possible serotoninergic involvement on the extracellular level of dopamine (DA) in the striatum using microdialysis in conscious, freely-moving rats. 2. A dose-dependent increase in striatal DA release occurred after i.v. administration of 0.5 - 5 mg kg-1 Delta9-THC when compared with vehicle (n=5 - 8, P<0.05). Maximum increases, ranging from 42.1+/-5. 4% to 97.4+/-5.9% (means+/-s.e.mean) of basal levels occurred 20 min after Delta9-THC. This effect was abolished by pretreatment with the cannabinoid CB1 receptor antagonist, SR 141716 (2.5 mg kg-1 i.p.). 3. Pretreatment with fluoxetine (10 mg kg-1 i.p.) abolished the Delta9-THC-induced DA release. Fluoxetine 10 mg kg-1 i.p. administered 40 min after Delta9-THC had no significant effect on Delta9-THC-induced DA release. However, fluoxetine perfused locally into the striatum by adding it to the microdialysis perfusion fluid (10 microM) 40 min after Delta9-THC significantly potentiated the Delta9-THC-induced DA release (n=6 - 8, P<0.05). 4. These results suggest that DA release induced by Delta9-THC is modulated by serotoninergic changes induced by fluoxetine, the effect of which depends on the time of its administration relative to that of Delta9-THC. Fluoxetine induces an acute increase in extracellular 5-HT through reuptake inhibition, which can activate autoreceptors which may decrease serotoninergic neuronal activity. This may be the reason fluoxetine pretreatment abolished the Delta9-THC-induced DA release. The potentiation of Delta9-THC-induced DA release by fluoxetine perfusion added 40 min after Delta9-THC may be due to an acute increase in 5-HT produced by reuptake inhibition.

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