title: Kalirin-7 mediates cocaine-induced AMPA receptor and spine plasticity, enabling incentive sensitization.
abstract: It is well established that behavioral sensitization to cocaine is accompanied by increased spine density and AMPA receptor (AMPAR) transmission in the nucleus accumbens (NAc), but two major questions remain unanswered. Are these adaptations mechanistically coupled? And, given that they can be dissociated from locomotor sensitization, what is their functional significance? We tested the hypothesis that the guanine-nucleotide exchange factor Kalirin-7 (Kal-7) couples cocaine-induced AMPAR and spine upregulation and that these adaptations underlie sensitization of cocaine's incentive-motivational properties-the properties that make it "wanted." Rats received eight daily injections of saline or cocaine. On withdrawal day 14, we found that Kal-7 levels and activation of its downstream effectors Rac-1 and PAK were increased in the NAc of cocaine-sensitized rats. Furthermore, AMPAR surface expression and spine density were increased, as expected. To determine whether these changes require Kal-7, a lentiviral vector expressing Kal-7 shRNA was injected into the NAc core before cocaine exposure. Knocking down Kal-7 abolished the AMPAR and spine upregulation normally seen during cocaine withdrawal. Despite the absence of these adaptations, rats with reduced Kal-7 levels developed locomotor sensitization. However, incentive sensitization, which was assessed by how rapidly rats learned to self-administer a threshold dose of cocaine, was severely impaired. These results identify a signaling pathway coordinating AMPAR and spine upregulation during cocaine withdrawal, demonstrate that locomotor and incentive sensitization involve divergent mechanisms, and link enhanced excitatory transmission in the NAc to incentive sensitization.
authors.affiliation: Department of Neuroscience, The Chicago Medical School at Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064, USA.
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Wang
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cahill
authors.forename: Craig T
authors.initials: CT
authors.lastname: Werner
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Christoffel
authors.forename: Sam A
authors.initials: SA
authors.lastname: Golden
authors.forename: Zhong
authors.initials: Z
authors.lastname: Xie
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Loweth
authors.forename: Michela
authors.initials: M
authors.lastname: Marinelli
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Russo
authors.forename: Peter
authors.initials: P
authors.lastname: Penzes
authors.forename: Marina E
authors.initials: ME
authors.lastname: Wolf
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism*; D055785:Gene Knockdown Techniques / Q000379:methods; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D012646:Self Administration; D013375:Substance Withdrawal Syndrome / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C102365:Kalrn protein, rat; D018091:Receptors, AMPA; D003042:Cocaine