Distinct modulatory roles of sigma receptor subtypes on glutamatergic responses in the dorsal hippocampus

Sigma ligands have been previously shown to modulate the N-methyl-D-aspartate (NMDA) response in the dorsal hippocampus, such that low doses of sigma agonists dose-dependently potentiate the response. Recent studies with the sigma ligand 4-IBP found it to act differently from the sigma ligands (+)-pentazocine and DTG in the modulation of 5-HT firing activity in the dorsal raphe nucleus (DRN), as its effects were not blocked by the sigma antagonists which reversed those of (+)-pentazocine or DTG. Thus, this study set out to characterize 4-IBP's action at sigma receptors using the hippocampal paradigm of sigma ligand activity. Interestingly, we found that in 50% of the neurons recorded, 4-IBP (20 microg/kg i.v.) produced a potentiation of both NMDA- and quisqualate (QUIS)-induced responses. In the other 50% of neurons, 4-IBP produced an attenuation of both QUIS and NMDA responses. The sigma1 antagonist NE-100 blocked the reduction induced by 4-IBP, while the nonselective sigma antagonist haloperidol blocked all responses induced by 4-IBP. These data suggest that, in this model, 4-IBP may be acting as an agonist or inverse agonist of sigma receptors. Furthermore, the initial responses to NMDA and QUIS were higher in the group in which 4-IBP induced an attenuation of the firing activity. This suggests a modulatory role for 4-IBP on glutamatergic neurotransmission in the hippocampus, which appears to involve two distinct pathways, mediated by different sigma1 receptor subtypes, an NE-100 and haloperidol-sensitive sigma1 receptor, and an NE-100-insensitive, haloperidol-sensitive sigma1 receptor. This modulatory role has implications for disorders that involve glutamatergic transmission in the hippocampus.