Inhibition of TARP γ-8 Bound AMPARs in Cocaine Use Disorder

In 2022, 1.4 million people were diagnosed with cocaine use disorder (CUD). Repeated cocaine administration upregulates expression of the GluA1 AMPA receptor (AMPAR) subunit in the nucleus accumbens (NAC). The transmembrane AMPAR regulatory protein γ-8 (TARP γ-8) binds to the GluA1 or GluA2 subunit of AMPARs and regulates synapses in NAC projecting regions. This study investigates the role of TARP γ-8 in CUD. TARP γ-8 wild-type and knockout mice were habituated to i.p. injections and locomotor sessions before measuring behavioral sensitization to cocaine (10 mg/kg). After withdrawal, mice received a cocaine challenge and locomotion was measured. RT-PCR was performed to evaluate gene expression changes in various brain regions in the reward circuit. TARP γ-8 knockout mice showed blunted induction and expression of locomotor behavioral sensitization to cocaine. After the cocaine challenge, wild-type animals demonstrated an increase in GluA2 in the prefrontal cortex (PFC) and of TARP γ-8 in the NAC, and a decrease of DRD2 in the PFC. The preclinical efficacy of JNJ-5551118 (JNJ-5), a negative modulator of AMPARs containing TARP γ-8, was also investigated to compare pharmacological and genetic inhibition of TARP γ-8 in the context of cocaine induced brain changes. An additional group of wild-type mice were subjected to cocaine behavioral sensitization as described above. After withdrawal, mice orally received vehicle or JNJ-5 before a cocaine challenge, and locomotion was measured. JNJ-5 did not blunt expression as seen in TARP γ-8 knockouts. Following the conclusion of behavioral sensitization, these mice were given saline or cocaine and placed in startle chambers to assess the interaction of cocaine and TARP γ-8 inhibition on the sensory gating response via a prepulse inhibition test. High cocaine dose disrupted PPI at 74 and 78 decibels, whereas low cocaine dose showed a trending decrease in PPI. This study demonstrates TARP γ-8 is interacting with cocaine to alter neuroplasticity in the context of both genetics and pharmacology.