The effect of chronic lead exposure on calmodulin regulated cAMP metabolism in rat brain, was investigated in the present study. Lead was observed to activate calmodulin, both in vivo and in vitro and thus mimic calcium in its actions. Lead had a biphasic effect on the activity of calmodulin dependent cAMP phosphodiesterase, i.e. at lower concentrations lead activated the enzyme and at higher concentrations inhibited it. In vivo lead exposure resulted in stimulation of the soluble cAMP phosphodiesterase activity. Adenylyl cyclase activity was significantly inhibited in calmodulin rich and depleted synaptic plasma membranes following in vitro and in vivo lead exposure. The activity of forskolin and dopamine stimulated adenylyl cyclase was also similarly inhibited by lead ions. The results were further substantiated by the decreased intracellular levels of cAMP in brain of lead treated animals. Our observations suggest, cAMP messenger system to be a target candidate in lead neurotoxicity.