Multiple sigma receptor subtypes have been identified in the hippocampus, yet their physiological role remains largely undefined. In the current study, we examined the role of sigma receptors in the regulation of N-methyl-D-aspartate (NMDA)-stimulated [3H]norepinephrine ([3H]NE) release from rat hippocampal slices. Both sigma agonists (+)pentazocine and BD737 inhibited stimulated norepinephrine release in a concentration-dependent manner. The sigma1 antagonist DuP 734 completely antagonized the inhibition of release by all concentrations of BD737 tested. However, DuP 734 only partially reversed inhibition of release by (+)pentazocine concentrations above 100 nM. 1,3 Di-o-tolylguanidine (DTG), but not haloperidol, antagonized BD737-mediated inhibition of release. DTG also completely antagonized inhibition of release by 100 nM (+)pentazocine yet haloperidol produced only a partial reversal. A combination of DuP 734 and haloperidol produced complete reversal of (+)pentazocine-mediated inhibition, suggesting potential involvement of multiple sigma receptor subtypes in the regulation of norepinephrine release. Both (+)pentazocine and BD737 failed to inhibit stimulated release in the presence of tetrodotoxin, suggesting that sigma receptors regulating NE release are not located on noradrenergic nerve terminals. These results suggest that sigma receptors may be a therapeutic target for disorders resulting from noradrenergic imbalance in hippocampus.