Kalirin-7 mediates cocaine-induced AMPA receptor and spine plasticity, enabling incentive sensitization.
J Neurosci
; 33(27): 11012-22, 2013 Jul 03.
Article
en En
| MEDLINE
| ID: mdl-23825406
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Cocaína
/
Receptores AMPA
/
Factores de Intercambio de Guanina Nucleótido
/
Espinas Dendríticas
/
Plasticidad Neuronal
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
J Neurosci
Año:
2013
Tipo del documento:
Article
País de afiliación:
Estados Unidos