L-alpha-glycerylphosphorylcholine (alpha-GPC) has been proposed for the treatment of age-related cognitive disturbances. In the rat the compound prevents the learning impairment and the retrograde amnesia both induced by scopolamine and this effect appears to be correlated with an increase of hippocampal acetylcholine production and release. Since drugs ameliorating learning and memory are usually administered for long periods of time, here we investigated the effects of chronic treatment with alpha-GPC on the neurochemical parameters linked to hippocampal cholinergic transmission. The data show that an increased [3H]acetylcholine (ACh) release was detectable in rats chronically exposed to alpha-GPC and killed 3 hr after the last administration, suggesting that tolerance did not develop in these experimental conditions. An alpha-GPC-induced selective desensitization of hippocampal muscarinic M-2 receptor function was also found. This event was characterized by a decreased responsiveness of adenylate cyclase to carbachol inhibition in the absence of changes in M-2 receptor density. This effect could be relevant in view of M-2 receptor presynaptic location and function in inhibiting ACh release. In contrast with M-2 receptor, M-1 receptor density and function were not significantly changed by the treatment. The present data suggest that alpha-GPC could be proposed as a useful drug for the chronic treatment of memory deficit.