Eight experiments compared and contrasted the effects of serotonin release and depletion on performance by rats in two tests of memory. Most experiments (Experiments 1-5) examined the effects of the serotonergic releasing/depleting agent p-chloroamphetamine on passive avoidance performance. Additional experiments explored p-chloroamphetamine's effects on retention performance by animals trained in an 8-arm radial maze (Experiment 6), and the effects of dorsal raphe nucleus lesions on passive avoidance in animals treated with (Experiment 8) or not treated with (Experiment 7) p-chloroamphetamine. In general, acute increases in serotonin release produced consistent and extensive retention performance deficits in both passive avoidance and radial arm maze. Results from an ancillary control experiment indicated that the p-chloroamphetamine-induced passive avoidance impairment was not related to drug-induced alterations in pain sensitivity. Other experiments ruled out the possibility that p-chloroamphetamine was disrupting passive avoidance retention performance by affecting post-trial consolidation processes, producing state-dependent retention, having direct effects at postsynaptic receptors, or indirectly by affecting non-serotonergic neurotransmitter systems. Depletion of serotonin resulting from either the long-term residual effects of p-chloroamphetamine or lesions of the dorsal raphe nucleus failed to alter passive avoidance retention scores although it produced extensive depletion (45-85%) of serotonin and 5-hydroxyindoleacetic acid in the cortex and hippocampus. These data contribute to the growing body of literature indicating an important role of serotonin in cognitive processes by demonstrating that excessive release, but not depletion, of serotonin produces profound retention performance impairment.