J. Neurosci. 34, 8605–8611 (2014)

Voltage-gated calcium channels (VGCCs) are involved in regulating normal neurotransmission and have also been implicated in the mechanisms of plasticity and behavior that are associated with relapse to drug abuse. VGCCs are heteromeric complexes where the channel pore consists of a pore-forming subunit and ancillary subunits such as α2δ-1 that modulate channel kinetics as well as their trafficking and turnover. Repeated exposure to drugs of abuse such as ethanol and methamphetamine increase α2δ-1 expression in the cerebral cortex, and preliminary data suggest a similar upregulation with cocaine. Spencer et al. now verify α2δ-1 upregulation after cocaine self-administration and withdrawal (extinction) in the core subcompartment of the nucleus accumbens of rats, the reward center for motivationally relevant stimuli. They also found increased levels of TSP-1, an endogenous α2δ-1 ligand, suggesting that the increase in α2δ-1 is a functional one. The authors next studied an animal model of relapse, looking at drug-seeking by animals induced by drug-associated cues or drug injection. Using this model, they found that gabapentin, a pharmacological α2δ-1 antagonist that inhibits function of the channel, led to decreased cocaine-primed cocaine seeking. These results suggest that elevated α2δ-1 has a role in cocaine-reinstated drug seeking.