title: Locomotor conditioning by amphetamine requires cyclin-dependent kinase 5 signaling in the nucleus accumbens.
abstract: Intermittent systemic exposure to psychostimulants leads to several forms of long-lasting behavioral plasticity including nonassociative sensitization and associative conditioning. In the nucleus accumbens (NAcc), the protein serine/threonine kinase cyclin-dependent kinase 5 (Cdk5) and its phosphorylation target, the guanine-nucleotide exchange factor kalirin-7 (Kal7), may contribute to the neuroadaptations underlying the formation of conditioned associations. Pharmacological inhibition of Cdk5 in the NAcc prevents the increases in dendritic spine density normally observed in this site following repeated cocaine. Mice lacking the Kal7 gene display similar effects. As increases in spine density may relate to the formation of associative memories and both Cdk5 and Kal7 regulate the generation of spines following repeated drug exposure, we hypothesized that either inhibiting Cdk5 or preventing its phosphorylation of Kal7 in the NAcc may prevent the induction of drug conditioning. In the present experiments, blockade in rats of NAcc Cdk5 activity with roscovitine (40 nmol/0.5 μl/side) prior to each of 4 injections of amphetamine (1.5 mg/kg; i.p.) prevented the accrual of contextual locomotor conditioning but spared the induction of locomotor sensitization as revealed on tests conducted one week later. Similarly, transient viral expression in the NAcc exclusively during amphetamine exposure of a threonine-alanine mutant form of Kal7 [mKal7(T1590A)] that is not phosphorylated by Cdk5 also prevented the accrual of contextual conditioning and spared the induction of sensitization. These results indicate that signaling via Cdk5 and Kal7 in the NAcc is necessary for the formation of context-drug associations, potentially through the modulation of dendritic spine dynamics in this site.
authors.affiliation: Committee on Neurobiology, The University of Chicago, Chicago, IL, USA.
authors.forename: Bryan F
authors.initials: BF
authors.lastname: Singer
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL, USA.
authors.forename: Nichole M
authors.initials: NM
authors.lastname: Neugebauer
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Forneris
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL, USA.
authors.forename: Kelli R
authors.initials: KR
authors.lastname: Rodvelt
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL, USA.
authors.forename: Dongdong
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL, USA.
authors.forename: Nancy
authors.initials: N
authors.lastname: Bubula
authors.affiliation: Committee on Neurobiology, The University of Chicago, Chicago, IL, USA; Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, IL, USA. Electronic address: pvezina@yoda.bsd.uchicago.edu.
authors.forename: Paul
authors.initials: P
authors.lastname: Vezina
mesh_terms: D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects* / Q000502:physiology; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009154:Mutation; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000502:physiology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D000077546:Roscovitine; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000697:Central Nervous System Stimulants; D020662:Guanine Nucleotide Exchange Factors; C102365:Kalrn protein, rat; D047428:Protein Kinase Inhibitors; D011687:Purines; D000077546:Roscovitine; D000661:Amphetamine; D051360:Cyclin-Dependent Kinase 5; C495907:Cdk5 protein, rat
keywords: Conditioning; Dendritic spines; Learning; Memory; Psychostimulants; Roscovitine; Sensitization