Different requirements for cAMP response element binding protein in positive and negative reinforcing properties of drugs of abuse

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.