The effect of intracerebroventricular (icv) injection of A beta 25-35 and/or intraperitoneal (ip) application of the L-type calcium channel (VDCC) blockers verapamil or diltiazem were examined in vivo. To by-pass possible systemic actions of these agents, their effects on long-term potentiation (LTP) in the CA1 region of the in vitro hippocampal slice preparation were also examined. Application of A beta 25-35 (10 nmol in 5 microl, i.c.v.) significantly impaired LTP in vivo, as did IP injection of verapamil (1 or 10 mg/kg) or diltiazem (1 or 10 mg/kg). In the in vitro slice preparation, LTP was also depressed by prior application of A beta 25-35 (500 nmol), verapamil (20 microM), or diltiazem (50 microM). Combined application of A beta 25-35 and verapamil in either the in vivo or in vitro preparation resulted in a significant reversal of the LTP depression observed in the presence of either agent alone. However, co-application of diltiazem and A beta 25-35 failed to attenuate the depression of LTP observed in the presence of either agent alone in vivo or in vitro. Since LTP is a cellular correlate of memory and A beta is known to be involved in Alzheimer's disease (AD), these results indicate that verapamil, a phenylalkylamine, may be useful in the treatment of cognitive deficits associated with AD.