Hyperactivity and dopamine D1 receptor activation in mice lacking girk2 channels

Rationale: G-protein-coupled inwardly rectifying potassium channels (GIRKs) regulate synaptic transmission and neuronal firing rates. Co-localization of GIRK2 channels and dopamine receptors in the mesolimbic system suggests a role in regulation of motor activity. Objectives: To explore the role of GIRK channels in the regulation of motor behavior. Methods: GIRK2 null mutant mice (knockout) were used. Locomotor activity in a mildly stressful situation was conducted either in a circular open field with video tracking or in standard mouse cages equipped with infrared sensors. Drugs were injected intraperitoneally or subcutaneously. Results: GIRK2 knockout mice demonstrated a transient "hyperactive" behavioral phenotype with initially higher motor activity and slower habituation in a novel situation. increased levels of spontaneous locomotor activity during dark phase in their home cages, and impaired habituation in the open-field test. After habituation, GIRK2 knockout mice showed higher motor activity, which was inhibited by the D-1 receptor antagonist SCH 23390 and was more sensitive to the activating effects of the D-1 receptor partial agonist SKF 38393. In a novel environment (open-field) only the highest dose of SKF38393 used (20 mg/kg) produced significant activation, perhaps due to a ceiling effect in GIRK2 knockout mice. SCH 23390 inhibited the basal activity levels of mice of both genotypes. Conclusions: Activation of the dopamine D-1 receptor in a stressful environment may be stronger in GIRK2 deficient mice. and this modified function of D-1 receptors may cause the transient hyperactive behavioral phenotype of these mice.