Characterizing cellular mechanisms of cocaine-evoked synaptic plasticity in the nucleus accumbens

Abstract

Repeated exposure to drugs of abuse alters the structure and function of neural circuits mediating reward, generating maladaptive plasticity in circuits critical for motivated behavior. Within mesocorticolimbic dopamine circuitry, repeated exposure to cocaine induces progressive alterations in AMPAR-mediated glutamatergic synaptic transmission. During abstinence from cocaine treatment, AMPAR signaling is potentiated at synapses on nucleus accumbens (NAc) medium spiny neurons (MSNs), promoting a state of heightened synaptic excitability. Re-exposure to cocaine during abstinence, however, reverses and depotentiates enhanced AMPAR signaling, demonstrating that cocaine bidirectionally alters excitatory synaptic transmission in the NAc. Understanding the neurobiological mechanisms underlying drug-induced synaptic adaptations in the NAc could provide targets for developing strategies to reverse or offset maladaptive processes driving long-lasting vulnerability to relapse. However, the detailed cellular signaling mechanisms mediating cocaine-evoked plasticity have not been well-characterized. Using pharmacological approaches in combination with patch-clamp recordings in the NAc, we investigated the role of candidate signaling factors that mediate adaptive synaptic plasticity in the striatum. Among these, activation of group I metabotropic receptors (mGluR1/5) play a prominent role in synaptic depression at excitatory synapses, and furthermore are implicated in models of relapse to drug-seeking. Consistent with this, we found that activation of mGluR5 is necessary for cocaine-induced depotentiation of AMPAR signaling in the NAc. Downstream of mGluR1/5 receptors, mobilization of endogenous cannabinoids (eCBs) is an important factor modulating excitatory synaptic strength. Dopamine receptors in the striatum also broadly modulate synaptic transmission at glutamatergic terminals on MSNs, and are critically engaged by drugs of abuse. Both dopamine and eCB signaling were necessary factors in the induction of cocaine-induced synaptic plasticity in the NAc, suggesting that these neuromodulators may modify the responsiveness of MSNs to alterations in glutamatergic input induced by cocaine. Finally, we examined plasticity at synapses on specific MSN cell subpopulations, demonstrating that specific dopamine receptors on distinct cell types promote specific modifications in AMPAR synaptic function following cocaine experience. These neuromodulatory signaling mechanisms may serve to gate the induction of plasticity at glutamatergic afferents on NAc MSNs by converging on common factors that control the sensitivity of MSNs to excitatory input, ultimately driving addiction-related behavior.