Enhanced effect of dopaminergic stimulation on prepulse inhibition in mice deficient in the alpha subunit of G_z

Rationale: G_z is a member of the G_i G protein family associated with dopamine D2-like receptors; however, its functions remain relatively unknown. The aim of the present study was to investigate prepulse inhibition (PPI) of acoustic startle, locomotor hyperactivity and dopamine D2 receptor binding in mice deficient in the α subunit of G_z. Methods: We used automated startle boxes to assess startle and PPI after treatment with saline, amphetamine, apomorphine or MK-801. We used photocell cages to quantitate locomotor activity after amphetamine treatment. Dopamine D2 receptor density was determined by autoradiography. Results: Startle responses and baseline PPI were not different between the Gα_z knockout mice and wild-type controls (average PPI 46±4 vs 49±3%, respectively). Amphetamine treatment caused a marked disruption of PPI in Gα_z knockouts (average PPI 22±2%), but less so in controls (average PPI 42±3%). Similar genotype-dependent responses were seen after apomorphine treatment (average PPI 23±3% vs 40±3%), but not after MK-801 treatment (average PPI 29±5 vs 33±2%). Amphetamine-induced locomotor hyperactivity was greater in Gα_z knockouts than in controls. There was no difference in the density of dopamine D2 receptors in nucleus accumbens. Conclusions: Mice deficient in the α subunit of G_z show enhanced sensitivity to the disruption of PPI and locomotor hyperactivity caused by dopaminergic stimulation. These results suggest a possible role for G_z in neuropsychiatric illnesses with presumed dopaminergic hyperactivity, such as schizophrenia.