Using Kalirin conditional knockout mice to distinguish its role in dopamine receptor mediated behaviors.
BMC Neurosci
; 18(1): 45, 2017 05 23.
Article
em En
| MEDLINE
| ID: mdl-28535798
ABSTRACT
BACKGROUND:
Mice lacking Kalirin-7 (Kal7KO), a Rho GDP/GTP exchange factor, self-administer cocaine at a higher rate than wildtype mice, and show an exaggerated locomotor response to experimenter-administered cocaine. Kal7, which localizes to post-synaptic densities at glutamatergic synapses, interacts directly with the GluN2B subunit of the N-methyl-D-aspartate (NMDA; GluN) receptor. Consistent with these observations, Kal7 plays an essential role in NMDA receptor dependent long term potentiation and depression, and glutamatergic transmission plays a key role in the response to chronic cocaine. A number of genetic studies have implicated altered Kalirin expression in schizophrenia and other disorders such as Alzheimer's Disease.RESULTS:
A comparison of the effects of experimenter-administered cocaine on mice lacking all Kalirin isoforms to its effects on mice lacking only Kalirin-7 identified Kal7 as the key isoform whose deletion produces exaggerated locomotor responses to cocaine. Pretreatment of Kal7KO mice with a low dose of ifenprodil, a selective GluN2B antagonist, eliminated their enhanced locomotor response to cocaine, revealing an important role for GluN2B in this behavior. Selective knockout of Kalirin in dopamine transporter expressing neurons produced a transient enhancement of cocaine-induced locomotion, while knockout of Kalirin in Drd1a- or Drd2-dopamine receptor expressing neurons was without effect. As observed in Kalirin global knockout mice, eliminating Kalirin expression in Drd2-expressing neurons increased exploratory behavior in the elevated zero maze, an effect eliminated by pretreatment with ifenprodil.CONCLUSIONS:
The cocaine-sensitive neuronal pathways which are most sensitive to altered Kalirin function may be the pathways most dependent on GluN2B and Drd2.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Comportamento Animal
/
Receptores Dopaminérgicos
/
Fatores de Troca do Nucleotídeo Guanina
/
Locomoção
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article