Both serotonin (5-HT) and dopamine (DA) neurotransmitters play a key role in modulating synaptic transmission in the central nervous system. Such 5-HT- and DA-mediated modulatory activity has been shown to influence a wide variety of cerebral functions, both of an instrumental and cognitive nature. Some brain regions strongly involved in cognition such as the prefrontal cortex, hippocampal formation and corpus striatum, are densely innervated by serotonergic and dopaminergic afferents proceeding from the raphe complex and the mesocorticolimbic or nigrostriatal systems, respectively. Learning and memory are strongly modulated by 5-HT and DA neurotransmitter activity, and in some cases they interact interdependently to sustain the psychobiological organization of these cognitive processes. Learning and memory, at least in part, depend on short- or long-lasting synaptic modifications, mainly occurring at dendritic spines. Indeed, the modulatory influence of 5-HT and DA at the synaptic level may affect the codification of mnemonic information on such spines. In fact, several experimental models of neurotransmitter activity have identified a close association between a 5-HT-DA imbalance and cytoarchitectonic changes underlying learning and memory impairment.