The H sub(3) receptor protean agonist proxyfan enhances the expression of fear memory in the rat

• Published in: Neuropharmacology 2005-02, Vol.48 (2), p.246-251
• Main Authors: Baldi, E, Bucherelli, C, Schunack, W, Cenni, G, Blandina, P, Passani, M B
• Format: Article
• Language: English
• ISSN: 0028-3908
• DOI: 10.1016/j.neuropharm.2004.09.009

Consolidation of fear memory requires neural changes to occur in the basolateral amygdala (BLA), including modulation of histaminergic neurotransmission. We previously demonstrated that local blockade or activation of histamine H sub(3) receptors in the BLA impaired or ameliorated, respectively, retention of fear memory. The histamine H sub(3) receptor is a G-protein-coupled receptor (GPCR) displaying high constitutive activity that regulates histamine neurons in the brain. Proxyfan is a high-affinity histamine H sub(3) receptor protean agonist exhibiting the full spectrum of pharmacological activities, from full agonist to full inverse agonist depending on the competition between constitutively active and quiescent H sub(3) receptors in a given tissue or brain region. Therefore, protean agonists are powerful tools to investigate receptor conformation and may be useful in designing specific compounds selective for the various receptor conformations. In the present study we examined the effect of post-training, systemic or intra-BLA injections of proxyfan on contextual fear memory. Rats receiving intra-BLA, bilateral injections of 1.66 ng proxyfan immediately after fear conditioning showed stronger memory for the context- footshock association, as demonstrated by longer freezing assessed at retention performed 72 hr later compared to controls. Comparable results were obtained when doses as low as 0.04 mg/kg of proxyfan were injected systemically. Hence, our results suggest that proxyfan behaves as an H sub(3) receptor agonist with a low level of constitutive activity of the H sub(3) receptor in the rat BLA.