Altered sensitivities to morphine and cocaine in scaffold protein tamalin knockout mice.
Tamalin is a scaffold protein that interacts with metabotropic glutamate receptors and the kinase-deficient neurotrophin TrkCT1 receptor and forms a protein complex with multiple protein-trafficking and intracellular signaling molecules. In culture, tamalin promotes intracellular trafficking of group 1 metabotropic glutamate receptors through its interaction with guanine nucleotide exchange factor cytohesins and causes actin reorganization and membrane ruffling via the TrkCT1/cytohesin-2 signaling mechanism. However, how tamalin serves its physiological function in vivo has remained elusive. In this study, we generated tamalin knockout (Tam(-/-) KO) mice and investigated behavioral alterations resulting from their deficiency in functional tamalin. Targeted deletion of functional tamalin altered neither the overall brain architecture nor the general behavior of the mice under ordinary conditions. However, Tam(-/-) KO mice showed a decrease in sensitivity to acute morphine-induced hyperlocomotion and morphine analgesic effects in the hot-plate test. Furthermore, tamalin deficiency impaired the ability of the animals to show conditioned place preference after repeated morphine administration and to display locomotor sensitization by chronic cocaine treatment. Upon in vivo microdialysis analysis of the nucleus accumbens, Tam(-/-) KO and wild-type mice showed no genotypic differences in their response patterns of extracellular dopamine and glutamate before or after morphine administration. These results demonstrate that the tamalin scaffold protein plays a unique role in both acute and adaptive behavioral responses to morphine and cocaine and could regulate common neural substrates implicated in drugs of abuse.
Ogawa
Masaaki
M
Department of Systems Biology, Osaka Bioscience Institute, Suita, Osaka 565-0874, Japan.
Miyakawa
Tsuyoshi
T
Nakamura
Kenji
K
Kitano
Jun
J
Furushima
Kenryo
K
Kiyonari
Hiroshi
H
Nakayama
Rika
R
Nakao
Kazuki
K
Moriyoshi
Koki
K
Nakanishi
Shigetada
S
D000698:Analgesia / Q000379:methods*; D000818:Animals; D016739:Behavior, Addictive / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics*; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D003433:Crosses, Genetic; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000378:metabolism; D006579:Heterozygote; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D008124:Locomotion / Q000187:drug effects* / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C523888:tamalin protein, mouse; D018698:Glutamic Acid; D009020:Morphine; D003042:Cocaine; D004298:Dopamine