Cocaine Self-Administration: Adaptations to the Glutamatergic System and Consequences for Offspring Emotional Control

Cocaine abuse and relapse remain a major public health concern in the United States and worldwide for which there is currently no approved pharmacotherapeutic intervention. Rodent cocaine self-administration, extinction, and priming-induced reinstatement can be used to model human cocaine seeking. A growing body of evidence indicates that the transport and stabilization of calcium-permeable (CP) AMPA glutamate receptors to synapses in the accumbens, a process involving CaMKII, is associated with the reinstatement of cocaine seeking. Additional evidence indicates that the dorsal striatum contributes to aspects of cocaine addiction. Moreover, relapse to cocaine abuse has been connected to elevated levels of anxiety during withdrawal and anxiolytic agents decrease the latency for animals to self-administer cocaine. A growing body of evidence indicates that environmental information can be inherited. We have previously described a cocaine-resistance phenotype in the offspring of animals that have self-administered cocaine. The enhancement of cocaine\u27s anxiogenic effects may contribute to reduced cocaine self-administration among male cocaine-sired rats. Here, a variety of behavioral, cellular, molecular, and electrophysiological techniques are used to examine how cocaine experience directly affects the glutamatergic system in the dorsal striatum and accumbens, as well as its indirect consequences for drug-naïve offspring. Acute exposure to cocaine in drug naïve rats increased CaMKII-mediated phosphorylation of GluA1-containing AMPA receptors in the DL striatum, an effect that was not observed during cocaine priming-induced reinstatement of drug seeking. The increased phosphorylation of CaMKII and GluA1 following acute cocaine may be a compensatory mechanism in the DL striatum. Accumbens shell CP-AMPAR receptor transmission, mediated through interactions of GluA1-containing AMPARs with accessory protein SAP97, is necessary for cocaine reinstatement. Consideration of GluA1 subunit accessory proteins as potential novel targets for pharmacotherapeutic interventions in cocaine craving and addiction is warranted. Male offspring of cocaine-experienced sires exhibit baseline anxiety-like behaviors that are unaltered by subsequent cocaine exposure and dysregulation of hippocampal cellular and molecular correlates of anxiety. This identifies impairments of male offspring emotional control due to sire cocaine exposure independent of the cocaine-resistance phenotype. Collectively, these findings advance our knowledge of the direct and intergeneration effects of cocaine experience on the brain and behaviors