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.