Cl. Walters et Ja. Blendy, Different requirements for cAMP response element binding protein in positive and negative reinforcing properties of drugs of abuse, J NEUROSC, 21(23), 2001, pp. 9438-9444
Addiction is a complex process that relies on the ability of an organism to
integrate positive and negative properties of drugs of abuse. Therefore, s
tudying the reinforcing as well as aversive components of drugs of abuse in
a single model system will enable us to understand the role of final commo
n mediators, such as cAMP response element-binding protein (CREB), in the a
ddiction process. To this end, we analyzed mice with a mutation in the alph
a and Delta isoforms of the CREB gene. Previously we have shown that CREBal
pha Delta mutant mice in a mixed genetic background show attenuated signs o
f physical dependence, as measured by the classic signs of withdrawal. We h
ave generated a uniform genetically stable F1 hybrid (129SvEv/C57BL/6) mous
e line harboring the CREB mutation. We have found the functional activity o
f CREB in these F1 hybrid mice to be dramatically reduced compared with the
ir wild-type littermates. These mice maintain a reduced withdrawal phenotyp
e after chronic morphine. We are now poised to examine a number of complex
behavioral phenotypes related to addiction in a well defined CREB-deficient
mouse model.
We demonstrate that the aversive properties of morphine are still present i
n CREB mutant mice despite a reduction of physical withdrawal. On the other
hand, these mice do not respond to the reinforcing properties of morphine
in a conditioned place preference paradigm. In contrast, CREB mutant mice d
emonstrate an enhanced response to the reinforcing properties of cocaine co
mpared with their wild-type controls in both conditioned place preference a
nd sensitization behaviors. These data may provide the first paradigm for d
ifferential vulnerability to various drugs of abuse.