Jeon, Jongrye (St Jude Children's Research Hospital)
This technology includes a cell line to be used for the study of anti-psychotic therapies and potentially Parkinson’s disease. Activation of D1 dopamine receptors plays a critical role in many fundamental CNS processes. M4 mAChRs are coexpressed with D1 dopamine receptors in a specific subset of striatal medium spiny neurons that contain GABA as the major neurotransmitter. The present study used Cre/LoxP technology to generate mutant mice that lack M4-¬-AChRs only in D1 dopamine receptor-¬-expressing cells to investigate the physiological relevance of mAChRs in this neuronal subpopulation. A floxed mouse M4 mAChRs mutant mouse strain was created, and mated with a mouse strain expressing Cre-¬-recombinase exclusively in cells expressing the D1 dopamine receptor (D1-¬-M4-¬-KO mice). D1-¬-M4-¬-KO mice exhibited increased locomotor stimulation induced by dopamine itself or psychostimulants such as amphetamines and cocaine, suggesting that the M4 receptor may play a role as an antipsychotic agent in schizophrenia; reduced cataleptic side effects of many anti-¬psychotic drugs and possibly Parkinson’s disease; increased dopamine efflux in the nucleus accumbens, suggesting that striatal M4 receptor activity inhibits the central dopaminergic reward system that contributes to addiction, and increased behavioral sensitization, suggesting that the M4 receptor might inhibit behavioral sensitization in addiction.
Modulation of D1 dopamine receptors by M4-¬-AChR may provide therapeutic options for the increased locomotor activity associated with schizophrenia and other psychotic disorders, behavioral sensitization and modulating the reward system for psychoactive drugs (drug abuse), and overcoming the catalepsy (rigidity) associated with Parkinson’s disease.
The floxed M4 mAChR mouse may be mated with mice expressing the Cre recombinase in other specific cell types to specifically establish the role of the M4 mAChR.