Histamine H-3 receptor-mediated impairment of contextual fear conditioningand in-vivo inhibition of cholinergic transmission in the rat basolateral amygdala

We investigated the effects of agents acting at histamine receptors on both , spontaneous release of ACh from the basolateral amygdala (BLA) of freely moving rats, and fear conditioning. Extensive evidence suggests that the ef fects of histamine on cognition might be explained by the modulation of cho linergic systems. Using the microdialysis technique in freely moving rats, we demonstrated that perfusion of the BLA with histaminergic compounds modu lates the spontaneous release of ACh. The addition of 100 mm KCl to the per fusion medium strongly stimulated ACh release, whereas, 0.5 muM tetrodotoxi n (TTX) inhibited spontaneous ACh release by more than 50%. Histaminergic H -3 antagonists (ciproxifan, clobenpropit and thioperamide), directly admini stered to the BLA, decreased ACh spontaneous release, an effect fully antag onized by the simultaneous perfusion of the BLA with cimetidine, an H-2 ant agonist, Local administration of cimetidine alone increased ACh spontaneous release slightly, but significantly. Conversely, the administration of H-1 antagonists failed to alter ACh spontaneous release. Rats receiving intra- BLA, bilateral injections of the H-3 antagonists at doses similar to those inhibiting ACh spontaneous release, immediately after contextual fear condi tioning, showed memory consolidation impairment of contextual fear conditio ning. Post-training, bilateral injections of 50 mug scopolamine also had an adverse effect on memory retention, These observations provide the first e vidence that histamine receptors are involved in the modulation of choliner gic tone in the amygdala and in the consolidation of fear conditioning.