Intracerebral administration of metabotropic glutamate receptor agonists disrupts prepulse inhibition of acoustic startle in Sprague-Dawley rats

The functional role of striatal metabotropic glutamate receptors (mGluRs) was examined by measuring prepulse inhibition (PPI) of an acoustic startle response following the intracerebral administration of selective agonists in male Sprague-Dawley rats prepared with bilateral cannulae aimed at either the nucleus accumbens or dorsal striatum. mGluR subtypes (1-8) are classed in three groups based on sequence homology, signal transduction mechanism and pharmacology. Intra-accumbens IS,3R-ACPD, an agonist at group 1 and 2 mGluRs (0.5-1.0 micromol/2 microl), caused a dose-dependent loss of PPI. The effect of 1S,3R-ACPD was diminished when injected into dorsal striatum. Intra-accumbens infusion of the group 1 selective agonist 3,5-DHPG (1 micromol) and the group 2 selective agonist L-CCG-I (100 nmol) also led to statistically significant disruptions of PPI, while the group 3 selective agonist L-AP4 (0.4-1.0 micromol) had no significant effect. Although the group 1/2 mGluR antagonist (+) MCPG (0.5 micromol) had no significant effect of its own on PPI, co-administration with IS,3R-ACPD (1 micromol) blocked ACPD-induced loss of PPI. In addition, pretreatment (30 min) with haloperidol (0.3 mg/kg IP) attenuated the PPI disruption induced by 1 micromol 1S,3R-ACPD, suggesting dopamine may play a role in mGluR agonist induced loss of PPI. These results support a role for group 1 and group 2 mGluRs in the nucleus accumbens in the regulation of PPI, a measure of sensory gating. As PPI is abnormal in some patient populations, such as Huntington's and schizophrenia, mGluRs may have potential as novel therapeutic targets for these diseases.