The dopamine D-2, but not D-3 or D-4, receptor subtype is essential for the disruption of prepulse inhibition produced by amphetamine in mice

Brain dopamine (DA) systems are involved in the modulation of the sensorimo tor gating phenomenon known as prepulse inhibition (PPI). The class of D2-l ike receptors, including the D2, D3, and D4 receptor subtypes, have all bee n implicated in the control of PPI via studies of DA agonists and antagonis ts in rats. Nevertheless, the functional relevance of each receptor subtype remains unclear because these ligands are not specific. To determine the r elevance of each receptor subtype, we used genetically altered strains of " knock-out" mice lacking the DA D2, D3, or D4 receptors. We tested the effec ts of each knock-out on both the phenotypic expression of PPI and the disru ption of PPI produced by the indirect DA agonist d-amphetamine (AMPH). No p henotypic differences in PPI were observed at baseline. AMPH significantly disrupted PPI in the D2 (+/+) mice but had no effect in the D2 (-/-) mice. After AMPH treatment, both DA D3 and D4 receptor (+/+) and (-/-) mice had s ignificant disruptions in PPI. These findings indicate that the AMPH-induce d disruption of PPI is mediated via the DA D2 receptor and not the D3 or D4 receptor subtypes. Uncovering the neural mechanisms involved in PPI will f urther our understanding of the substrates of sensorimotor gating and could lead to better therapeutics to treat gating disorders, such as schizophren ia.