The histaminergic H1, H2, and H3 receptors of the lateral septum differentially mediate the anxiolytic-like effects of histamine on rats' defensive behaviors in the elevated plus maze and novelty-induced suppression of feeding paradigm

• We investigated the effects of histamine in two rat models of anxiety.
• Lateral septal histamine increased rats' open arm activity and reduced neophagia.
• The effects of histamine on open arm activity were reversed by an H3 antagonist.
• The effects of histamine on neophagia were reversed by H1 and H2 antagonists.
• The contribution of specific histamine receptors to anxiety is test-specific.

The neural histaminergic system is involved in a wide range of physiological processes, including anxiety. Histaminergic neurons are localized in the tuberomammillary nucleus of the posterior hypothalamus and share bidirectional connections with the lateral septum, an area well implicated in anxiety. The current study examined whether the histaminergic system of the lateral septum regulates rats' defensive behaviors in two animal models of anxiety, the elevated plus maze (EPM) and novelty-induced suppression of feeding paradigm (NISF). We found that bilateral infusions of histamine (1.0 μg and 5.0 μg) into the lateral septum selectively decreased rats' defensive behaviors in the EPM (both doses) and NISF (1.0 μg only). Follow-up studies found that pre-infusions of the H1 and H2 antagonists, pyrilamine (20 μg) and ranitidine (20 μg) respectively, reversed the anxiolytic-like effects of intra-LS histamine (1.0 μg) in the NISF but not in the EPM, while pre-infusions of the H3 antagonist ciproxifan (200 pg) attenuated the anxiolytic-like effects of intra-LS histamine in the EPM but not in the NISF. This double dissociation suggests that H1 and H2 receptors in the lateral septum, likely via a post-synaptic mechanism, mediate the anxiolytic-like effects of histamine in the NISF but not in the EPM. In contrast, lateral septal H3 receptors mediate, likely pre-synaptically, the anxiolytic-like effects of histamine in the EPM but not in the NISF. Our findings indicate that these receptors differentially contribute to rats' specific defensive behaviors in the EPM and NISF, that is, avoidance of open spaces and neophagia respectively.