Abnormalities in the function of the central nervous system exist in phosphate depletion (PD). It is possible that this is due to an adverse effect of PD on the metabolism of neurotransmitters, such as norepinephrine (NE), in brain synaptosomes. We examined the effects of PD, produced by restriction of dietary phosphate intake on NE metabolism of brain synaptosomes. Synaptosomes from PD rats had significantly reduced NE content, uptake and release, elevated Km, but normal Vmax of tyrosine hydroxylase, normal Km and Vmax of monoamine oxidase, elevated resting levels of cytosolic calcium ([Ca2+]i), higher A[Ca2+]i in response to KC1, higher A[Ca2+]i/basal [Ca2+]i ratio, lower ATP content and reduced activity of Na+-K+-ATPase as compared to synaptosomes from pair-weighed rats. Treatment of PD rats with verapamil corrected all the synaptosomal derangements except for the elevated Km of tyrosine hydroxylase and NE content. Verapamil did not affect the metabolism of PW rats. The data demonstrate that PD causes significant derangements in NE metabolism of brain synaptosomes. Observations in the present study and in others indicate that these derangements in NE metabolism are due to the PD-induced abnormalities in the homeostasis of synaptosomal [Ca2+]i, ATP and phospholipids and in the activities of Na+-K+-ATPase and Ca2+-ATPase.