Repeated cocaine exposure causes persistent, maladaptive alterations in brain and behavior, and hope for effective therapeutics lies in understanding these processes. We describe here an essential role for fragile X mental retardation protein (FMRP), an RNA-binding protein and regulator of dendritic protein synthesis, in cocaine conditioned place preference, behavioral sensitization, and motor stereotypy. Cocaine reward deficits in FMRP-deficient mice stem from elevated mGluR5 (or GRM5) function, similar to a subset of fragile X symptoms, and do not extend tonatural reward. We find that FMRP functions inthe adult nucleus accumbens (NAc), a critical addiction-related brain region, to mediate behavioral sensitization but not cocaine reward. FMRP-deficient mice also exhibit several abnormalities in NAc medium spiny neurons, including reduced presynaptic function and premature changes in dendritic morphology and glutamatergic neurotransmission following repeated cocaine treatment. Together, our findings reveal FMRP as a critical mediator of cocaine-induced behavioral and synaptic plasticity.
Bibliographical noteFunding Information:
The authors thank Marissa Baumgardner, Lindsey Williams, Dr. Julia Wilkerson, Sarah Jenevein, Dr. Seth Hays, and Katie Schaukowitch for technical assistance; Ami Pettersen and Lauren Peca for behavioral assistance; and Dr. David Nelson for generously sharing the floxed Fmr1 conditional KO mouse line. We thank Dr. Rachel Penrod for insightful comments on the written manuscript. L.N.S. was supported by fellowships from the National Institute on Drug Abuse (NIDA) (T32 DA007290 and F32 DA027265) and the FRAXA Research Foundation. We also acknowledge the generous support of the Simons Foundation (Simons Foundation Autism Research Initiative grant to C.W.C. and K.M.H.), NIDA (DA008277, DA027664, and DA030590 to C.W.C. and DA019666, R21DA033457, and K02DA035459 to M.J.T.), and the National Institute of Neurological Disorders and Stroke (NS062158 to M.J.T.).