Role of alpha7 nicotinic acetylcholine receptors in the pressor response to intracerebroventricular injection of choline: blockade by amyloid peptide Abeta1-42.

Abstract

Systemic blood pressure and cardiac function have long been known to be under the control of central autonomic and hormonal pathways that, in part, use cholinergic neural systems. Recently choline, a precursor and product of acetylcholine metabolism, has been shown to serve as a selective endogenous agonist for the alpha7 subtype of the nicotinic acetylcholine receptor (alpha7nAChR). This receptor subtype mediates several responses to nicotine in animals, most notably, neuroprotection and enhanced cognition. The purpose of this study was to determine whether the cardiovascular changes induced by central injection of choline in rats also were mediated by alpha7nAChRs. Moreover, we sought to determine whether these cardiovascular changes to choline could be blocked by central pretreatment with amyloid beta peptide (1-42) (Abeta1-42), a neurotoxic component of cerebral amyloid that is known to bind with high affinity to alpha7nAChRs. Central, i.c.v. injection of choline (50, 100, or 150 microg) produced dose-dependent (10-15-min duration) pressor response of up to about 20 mm Hg. The most consistent change in heart rate included a brief increase (up to 40 beats/min) that lasted 2 to 3 min, followed by a prolonged decrease averaging 50 beats/min that lasted up to 30 min. Pretreatment (i.c.v.) with the selective alpha7nAChR antagonists alpha-bungarotoxin and methyllycaconitine significantly inhibited the pressor and heart rate responses to subsequent injection of choline. Pretreatment with the non-alpha7-preferring antagonist dihydro-beta-erythroidin was not effective. These findings suggested that the cardiovascular response to i.c.v. injection of choline was mediated at least in part through alpha7nAChRs. Pretreatment (30 min) with low doses (1-100 pmol) of amyloid peptide Abeta1-42 (but not with Abeta40-1) administered by the i.c.v. route significantly inhibited the choline-induced blood pressure increase as well as the choline-induced decrease in heart rate.