TY - JOUR
T1 - Elevated cholecystokininergic tone constitutes an important molecular/neuronal mechanism for the expression of anxiety in the mouse
AU - Chen, Qian
AU - Nakajima, Akira
AU - Meacham, Corbin
AU - Tang, Ya Ping
PY - 2006/3/7
Y1 - 2006/3/7
N2 - Cholecystokinin (CCK), one of the most abundant neuropeptides in the brain, plays an important role in anxiogenesis through the activation of CCK receptor-2 (CCKR-2). Accumulating evidence, however, has suggested this role depends on endogenous CCKergic "tone," which is largely determined by the expression level of the CCKR-2. Using the tTA tetO-inducible transgenic (tg) approach, we show here that overexpression of the CCKR-2 in neurons of the forebrain significantly increases CCKR-2 binding capacity in tg mice compared with their littermate controls. Interestingly, these tg mice consistently exhibit increased fear responses, which are generally interpreted as anxiety-like behaviors in the rodent, in a battery of behavioral tests, which represented conflict situations or delivered stress to the subjects. The inhibition of transgene expression with doxycycline treatment completely diminished both increased receptor-binding activity and all behavioral phenotypes. Furthermore, treatment of tg mice with diazepam significantly attenuated these anxiety-like behaviors. Our results directly demonstrate that the elevated CCKergic tone via overexpression of the CCKR-2 in the brain may constitute an underlying molecular/neuronal mechanism for the expression of anxiety. In addition, our study has validated a robust genetic anxiety model in the mouse in terms of their face, constructive, and predictive validity.
AB - Cholecystokinin (CCK), one of the most abundant neuropeptides in the brain, plays an important role in anxiogenesis through the activation of CCK receptor-2 (CCKR-2). Accumulating evidence, however, has suggested this role depends on endogenous CCKergic "tone," which is largely determined by the expression level of the CCKR-2. Using the tTA tetO-inducible transgenic (tg) approach, we show here that overexpression of the CCKR-2 in neurons of the forebrain significantly increases CCKR-2 binding capacity in tg mice compared with their littermate controls. Interestingly, these tg mice consistently exhibit increased fear responses, which are generally interpreted as anxiety-like behaviors in the rodent, in a battery of behavioral tests, which represented conflict situations or delivered stress to the subjects. The inhibition of transgene expression with doxycycline treatment completely diminished both increased receptor-binding activity and all behavioral phenotypes. Furthermore, treatment of tg mice with diazepam significantly attenuated these anxiety-like behaviors. Our results directly demonstrate that the elevated CCKergic tone via overexpression of the CCKR-2 in the brain may constitute an underlying molecular/neuronal mechanism for the expression of anxiety. In addition, our study has validated a robust genetic anxiety model in the mouse in terms of their face, constructive, and predictive validity.
KW - Behaviors
KW - Transgenic mouse
UR - http://www.scopus.com/inward/record.url?scp=33644868458&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33644868458&partnerID=8YFLogxK
U2 - 10.1073/pnas.0505407103
DO - 10.1073/pnas.0505407103
M3 - Article
C2 - 16537459
AN - SCOPUS:33644868458
SN - 0027-8424
VL - 103
SP - 3881
EP - 3886
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 10
ER -