The fragile X mental retardation protein (FMRP), an RNA‐binding protein, regulates cocaine‐induced neuronal plasticity and is critical for the normal development of drug‐induced locomotor sensitization, as well as reward‐related learning in the conditioned place preference assay. However, it is unknown whether FMRP impacts behaviors that are used to more closely model substance use disorders. Utilizing a cocaine intravenous self‐administration (IVSA) assay in Fmr1 knockout (KO) and wild‐type (WT) littermate mice, we find that, despite normal acquisition and extinction learning, Fmr1 KO mice fail to make a normal upward shift in responding during dose–response testing. Later, when given access to the original acquisition dose under increasing fixed ratio (FR) schedules of reinforcement (FR1, FR3, and FR5), Fmr1 KO mice earn significantly fewer cocaine infusions than WT mice. Importantly, similar deficits are not present in operant conditioning using a palatable food reinforcer, indicating that our results do not represent broad learning or reward‐related deficits in Fmr1 KO mice. Additionally, we find an FMRP target, the activity‐regulated cytoskeleton‐associated protein (Arc), to be significantly reduced in synaptic cellular fractions prepared from the nucleus accumbens of Fmr1 KO, compared with WT, mice following operant tasks reinforced with cocaine but not food. Overall, our findings suggest that FMRP facilitates adjustments in drug self‐administration behavior that generally serve to preserve reinforcement level, and combined with our similar IVSA findings in Arc KO mice may implicate Arc, along with FMRP, in behavioral shifts that occur in drug taking when drug availability is altered.

AbstractThe fragile X mental retardation protein (FMRP), an RNA-binding protein, regulates cocaine-induced neuronal plasticity and is critical for the normal development of drug-induced locomotor sensitization, as well as reward-related learning in the conditioned place preference assay. However, it is unknown whether FMRP impacts behaviors that are used to more closely model substance use disorders. Utilizing an intravenous cocaine self-administration (IVSA) assay in Fmr1 knockout (KO) and wild type (WT) littermate mice, we find that, despite normal acquisition and extinction learning, Fmr1 KO mice fail to make a normal upward shift in responding during dose-response testing. Later, with access to the original acquisition dose under increasing schedules of reinforcement (FR1, FR3, FR5), Fmr1 KO mice earn significantly fewer cocaine infusions than WT mice. Importantly, operant conditioning with a palatable food reinforcer does not show similar deficits, indicating that our results do not stem from broad learning or reward-related deficits in Fmr1 KO mice. Additionally, we find an FMRP target, the activity-regulated cytoskeleton-associated protein (Arc), to be significantly reduced in Fmr1 KO mouse synaptic fractions from the nucleus accumbens following cocaine IVSA. Overall, our findings suggest that FMRP facilitates adjustments in drug self-administration behavior that generally serve to preserve reinforcement level, and combined with our similar IVSA findings in Arc KO mice, suggest Arc as a target of FMRP to investigate in behavioral shifts that occur when drug availability is altered.

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