Human beta (1-40) and rat beta (1-42) were dissolved in three different solvents and stereotaxically injected into rat hippocampus with the contralateral side injected with control reverse sequence peptide or vehicle alone. Results at 1 week showed gross toxicity of the 35% acetonitrile solvent which was markedly enhanced by 3 nmol of beta protein but not by reverse sequence peptide. Beta peptide in water also appeared more toxic than reverse sequence, but the results were less clear cut. In contrast, 3 nmol of beta peptide in a cyclodextrin/PBS solution produced no marked short-term toxic effects. Peripheral injection of substance P failed to prevent toxicity. We conclude that solvent effects play a major role in acute beta protein neurotoxicity.