Project 8H: The CRF system and methamphetamine sensitization

Andrey E. Ryabinin, Ph.D., Principal Investigator

Recent research in animal models implicates the corticotropin releasing factor (CRF) peptide system in the mechanisms of psychostimulant addiction. These studies suggest that CRF receptors could be important targets for development of therapeutics to treat methamphetamine (meth) addiction.

The CRF peptide system is complex, consisting of two main types of receptors -- CRF1 and CRF2 -- and four endogenous ligands: CRF, urocortin 1 (Ucn1), urocortin 2 (Ucn2) and urocortin 3 (Ucn3).

Since many brain regions are innervated by several of these endogenous ligands and often contain both receptors, the contribution of individual components of the CRF system to addiction is difficult to resolve using only pharmacological approaches.

Knockout (KO) mice, deficient in components of the CRF system, provide a novel approach that can complement pharmacological studies and clarify the role of components of the CRF system in addiction-related behaviors. These KO mice have previously been used to study the contribution of CRF1 and CRF2 receptors to alcohol intake and sensitization, but have not been used for studies of other drugs of abuse.

The phenomenon of behavioral sensitization is thought to underlie several aspects of drug addiction.  We hypothesize that sensitization to repeated meth administration involves CRF1 receptor-mediated mechanisms, and, perhaps to a lesser degree, CRF2 receptors and Ucn1 peptide. 

The specific aim of this proposal is to address this hypothesis using CRF1 KO, CRF2 KO and Ucn1 KO mice. KO mice and their wildtype and hetrozygous littermates will be tested for locomotor activity following  repeated administration of 1 or 2 mg/kg of meth.

The resultant data will be important for understanding the critical roles of specific components of the CRF system in meth sensitization, and could provide the basis for future development of pharmacotherapies to treat meth addiction.