Hyperdopaminergia and altered locomotor activity in GABAB1-deficient mice

GABA(B1)(-/-) mice, which are devoid of functional GABA(B) receptors, consistently exhibit marked hyperlocomotion when exposed to a novel environment. Telemetry recordings now revealed that, in a familiar environment, GABA(B1)(-/-) mice display an altered pattern of circadian activity but no hyperlocomotion. This indicates that hyperlocomotion is only triggered when GABA(B1)(-/-) mice are aroused by novelty. In microdialysis experiments, GABA(B1)(-/-) mice exhibited a 2-fold increased extracellular level of dopamine in the striatum. Following (D)-amphetamine administration, GABA(B1)(-/-) mice released less dopamine than wild-type mice, indicative of a reduced cytoplasmic dopamine pool. The hyperdopaminergic state of GABA(B1)(-/-) mice is accompanied by molecular changes, including reduced levels of tyrosine ohydroxylase mRNA, D-1 receptor binding-sites and Ser40 phosphorylation of tyrosine hydroxylase. Tyrosine hydroxylase activity, tissue dopamine content and dopamine metabolism do not appear to be measurably altered. Pharmacological and electrophysiological experiments support that the hyperdopaminergic state of GABA(B1)(-/-) mice is not severe enough to inactivate dopamine D-2 receptors and to disrupt D-2-mediated feedback inhibition of tyrosine hydroxylase activity. The data support that loss of GABA(B) activity results in a sustained moderate hyperdopaminergic state, which is phenotypically revealed by contextual hyperlocomotor activity. Importantly, the presence of an inhibitory GABA tone on the dopaminergic system mediated by GABA(B) receptors provides an opportunity for therapeutic intervention.