Prolonged stimulation of respiration by brain stem metabotropic glutamate receptors

Stimulation of metabotropic glutamate receptors (mGluRs) in the retrotrapezoid nucleus (RTN) of chloralose-urethan-anesthetized rats by the mGluR agonist (1S,3R)-aminocyclopentanedicarboxylic acid [(1S,3R)-ACPD; 10 nl, 1 mM] increases integrated phrenic nerve amplitude (PNA) for > 60 min. Here we ask if the mGluR antagonist (+-)-alpha-methyl-4-carboxyphenylglycine [(+-)-MCPG] can block this effect. Using multibarreled micropipettes, we first identified RTN sites that affect respiration by noting short-lived stimulation of PNA produced by brief-duration injection of glutamate (10 nl, 100 mM), a presumed ionotropic receptor response. We then injected the active or inactive isomer of (+-)-MCPG (10 nl, 10 mM) followed by (1S,3R)-ACPD or by a long-duration (60-s) injection of glutamate (10 nl, 100 mM) at the same site. Each injection location was verified anatomically. The active antagonist (+-)-MCPG itself had no significant effect on PNA, but it blocked 1) subsequent (1S,3R)-ACPD-induced PNA stimulation for 99 +/- 11 (SE) min and 2) the PNA response to 60-s glutamate injection for 66 +/- 6 min. The inactive form (-)-MCPG had no effect on (1S,3R)-ACPD-induced PNA stimulation. We conclude that 1) RTN mGluRs may be involved in respiratory control, 2) RTN mGluRs are not active in eupnea, and 3) stimulation of RTN mGluRs may require prolonged glutamate release.