Figure 3.

Summary of drug-induced disruptions of eCB-mediated long-term plasticity in the VTA and NAc. a, b, Although the specific mechanism differs by brain region, eCB-LTD induction under normal conditions is primarily governed by activity-dependent release of eCBs from the postsynaptic cell and CB1 receptor stimulation on active afferents. a, Within the VTA, eCB-LTDi at GABAergic synapses permits adaptive dopamine cell firing, and induction involves additional coordination between presynaptic (e.g., D2 dopamine receptors) and postsynaptic (e.g., Group I mGluRs) metabotropic receptors. b, Control over accumbal glutamate release from cortical and limbic afferents through the induction of eCB-LTDe relies on activation of postsynaptic metabotropic receptors (e.g., mGluR5) and release of calcium from intracellular stores. c, d, Following exposure to drugs of abuse, such as THC or cocaine, parallel disturbances in eCB-LTD mechanisms that normally provide inhibitory control over VTA dopamine neuron activity and curb excitation of NAc MSNs instead promote activation of reward circuitry. c, Drug exposure facilitates the induction of eCB-LTDi in the VTA, removing GABA-mediated inhibition of dopamine neurons and enhancing their excitability. d, Drug-induced loss of eCB-LTDe at glutamatergic synapses in the NAc prevents control over excitation of MSNs.