Calcium-permeable AMPA receptors contribute to the accelerated development of enhanced motivation for cocaine in female rats

RATIONALE: The telescoping effect, where females progress more rapidly than males from initial drug use to developing a substance use disorder, is a widely cited sex/gender difference, yet its molecular basis remains unknown. OBJECTIVES: To test whether calcium-permeable AMPA receptors (CP-AMPARs) in the nucleus accumbens (NAc) contribute to the development of enhanced motivation for cocaine, a defining feature of addiction, which emerges earlier in females than in males. METHODS: Motivation for cocaine was measured under a progressive-ratio schedule before and after extended-access self-administration (4 trials/h, 24 h/day, 10 days) and a 7-day abstinence period. During abstinence, females received SYN119 (0 or 10 mg/kg) to block, and males received JNJ16259685 (0 or 5 mg/kg) to enhance, NAc CP-AMPAR recruitment, consistent with a hypothesis-driven, sex-informed design. After stable motivation was established, intra-NAc infusions of the CP-AMPAR antagonist naspm (40 µg/side) were administered. RESULTS: Females, but not males, developed enhanced cocaine motivation after 7 days of abstinence, replicating the telescoping effect. This effect was persistently blocked by SYN in females and reproduced in males by JNJ treatment for over three weeks. Subsequently, intra-NAc naspm reduced motivation in JNJ-treated males, but not SYN-treated females, supporting a role for CP-AMPARs in the development of an enhanced motivation for cocaine. CONCLUSION: These findings suggest that CP-AMPAR recruitment in the NAc, a mechanism classically linked to the incubation of cocaine craving, may also contribute to abstinence-dependent increases in drug motivation that emerge earlier in females.