Betahistine increases ACh release from the cortex, but not histamine release from the nucleus basalis magnocellularis of freely-moving rats

Histaminergic perikarya are found exclusively in the tuberomammillary nucleus of the posterior hypothalamus from where they project to all parts of the brain [1]. Histaminergic efferents to the basal forebrain modulate the activity of the nucleus basalis magnocellularis (NBM) neurons [2], which provide cholinergic innervation to the cortex, and play a pivotal role in learning and memory processes [3]. Indeed, intra-NBM administration of H3 antagonists increased cortical ACh release; this effect was blocked by H1 antagonists [4]. Likely, blockade of H3 autoreceptors released endogenous histamine that impacted on postsynaptic H1 receptors. This modulation seems functionally relevant, as H3 receptor blockade in the NBM improves place recognition memory [5], and H1 receptor stimulation ameliorates time-dependent deterioration in memory in a rat object recognition test [6]. Betahistine acts both as a partial histamine H1 receptor agonist, and as a histamine H3 receptor antagonist [7] and the current study focuses on the effects of betahistine upon NBM-cortical cholinergic neurons.