[The interaction between serotonergic and cannabinoidergic modulations involved in the fear extinction]

In the amygdala, it has been demonstrated that cannabinoid CB1 receptors are particularly enriched in GABAergic axon terminals and moderately expressed on glutamatergic fibers, and involved in the fear coping strategies. In this study, we found predominant neuronal projections of serotonergic, dopaminergic and cholinergic fibers in the basolateral amygdala (BA), and CB1 receptors were frequently localized on serotonergic axons but not dopaminergic, noradrenergic or cholinergic fibers. Furthermore, extracellular release of serotonin was significantly reduced by WIN55212-2, a CB agonist, whereas dopamine concentration was not altered, indicating presynaptic serotonin release is modulated by CB1 receptors. On the other hand, alpha-methyl-5-HT, 5-HT2 receptor agonist decreased the evoked IPSC and EPSC amplitude accompanied with enhancement of paired pulse ratio and induced inward currents from the patch-clamp recording BA pyramidal neurons; these are parameters of presynaptic effect and postsynaptic localization of 5-HT2 receptors, respectively. This suppression of IPSC amplitude was completely blocked by MDL100907, a 5-HT(2A) antagonist, or AM251, a CB1 antagonist. These findings suggest that endocannabinoid is synthesized via activation of postsynaptic 5-HT(2A) receptors, and regulates not only inhibitory presynaptic GABA release but also local serotonergic transmission in the BA.