Figure 8. A schematic illustration of how stress-released orexins induce an endocannabinoid-mediated relapse for cocaine-seeking.

This scheme was illustrated by using the Biology Bundle of Motifolio PPT Drawing Toolkits (Motifolio Inc, MD) to describe what may occur in the LH and the VTA (a) before stress and (b) during stress. Right boxes are enlarged portions of synaptic events occurring in a GABAergic synapse onto a dopaminergic neuron in the VTA. During stress, LH orexin neurons are activated and release orexins. The released orexins then activate postsynaptic OX1 receptors on dopaminergic neurons in the VTA. Activation of the OX1 receptor, a G_q-protein coupled receptor, leads to PLC activation, generating DAG that is converted into 2-AG, an endocannabinoid, by DAGL. 2-AG travels retrogradely across the synapse to inhibit GABA release by activating presynaptic CB1 receptors on the GABAergic terminal. Inhibition of GABAergic synaptic neurotransmission onto dopaminergic neurons in the VTA results in activation of the mesolimbic dopaminergic circuitry, leading to a reinstatement of extinguished cocaine CPP, modelling cocaine relapse in humans. Finally, 2-AG is degraded by MAGL, which is located in GABAergic terminals. Thus, the MAGL inhibitor potentiates and prolongs orexin A-induced IPSC depression.