Modulation of anxiety by μ-opioid receptors of the lateral septal region in mice

Morphine and opiates are known to exert anxiolytic effects, probably by interacting with the GABAergic system. The lateral septum (LS), mainly constituted of GABA neurons, exhibits high densities of μ-opiate receptors and could thus represent one the brain sites where opiates interact with GABAergic transmission to modulate anxiety. We examined the effects of intra-LS morphine injections on measures of anxiety using the elevated plus-maze and hole-board tests. Fos imaging was used to identify neural circuits involved in anxiety modulation. Unilateral intra-LS morphine (100 or 500 ng/100 nl) decreased open-arm exploration in the plus-maze and reduced head-dipping frequency in the hole-board, an anxiogenic-like effect associated with decreased Fos expression in the ventral LS, the dorsal hippocampus and the anterior hypothalamus. Anatomical specificity was assessed by injecting morphine into the medial septum, which failed to produce anxiogenesis. Pre-injection of the μ-opioid receptor antagonist naloxonazine (100 ng/100 nl) into LS reversed morphine-induced anxiogenesis and the associated pattern of Fos expression, indicating a specific recruitment of μ-opioid receptors by morphine. Surprisingly, bilateral morphine injections (20 to 500 ng/100 nl) were not found anxiogenic, perhaps due to their stimulant effect. Taken together, these results suggest that LS μ-opioid receptors participate to the modulation of anxiety.