The chakragati mouse: a mouse model for rapid in vivo screening of antipsychotic drug candidates.
The chakragati (ckr) mouse is a serendipitously discovered insertional transgenic mutant that exhibits circling and hyperactivity. Studies of social behavior, sensorimotor gating and ventricular anatomy suggest that the ckr mouse models aspects of schizophrenia. The underlying genetic and neurodevelopmental mechanisms remain to be elucidated but appear to result in a hemispheric asymmetry in striatal D(2)-like dopamine receptors. The circling is inhibited by administration of antipsychotic drugs and so lends itself to in vivo prospective screening for novel molecules with antipsychotic-like activity. Using the ckr mouse we have applied an in vivo first approach to screening for antipsychotic drug candidates. This offers the advantage of early indication of central nervous system bioavailability and potential toxicological concerns. Additionally, in vivo first screening in the ckr mouse is not biased by any particular neurotransmitter hypothesis of the disease, and so has the potential to identify compounds modifying the behavioral output by novel mechanisms of interaction with the underlying brain circuitry. Thus, in contrast to the classical strategy of hypothesis-driven in vitro screening for drugs fitting a "receptor model" of the disease, the ckr mouse screen has greater potential to identify lead molecules for a new generation antipsychotics with novel mechanisms of action.
Dawe
Gavin S
GS
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Ratty
Anil K
AK
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D051379:Mice; D008822:Mice, Transgenic; D012083:Renin / Q000235:genetics; D012559:Schizophrenia / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology
D014150:Antipsychotic Agents; D012083:Renin