The role of 5-HT1A receptors in learning and memory

The ascending serotonin (5-HT) neurons innervate the cerebral cortex, hippocampus, septum and amygdala, all representing brain regions associated with various domains of cognition. The 5-HT innervation is diffuse and extensively arborized with few synaptic contacts, which indicates that 5-HT can affect a large number of neurons in a paracrine mode. Serotonin signaling is mediated by 14 receptor subtypes with different functional and transductional properties. The 5-HT1A subtype is of particular interest, since it is one of the main mediators of the action of 5-HT. Moreover, the 5-HT1A receptor regulates the activity of 5-HT neurons via autoreceptors, and it regulates the function of several neurotransmitter systems via postsynaptic receptors (heteroreceptors).This review assesses the pharmacological and genetic evidence that implicates the 5-HT1A receptor in learning and memory. The 5-HT1A receptors are in the position to influence the activity of glutamatergic, cholinergic and possibly GABAergic neurons in the cerebral cortex, hippocampus and in the septohippocampal projection, thereby affecting declarative and non-declarative memory functions. Moreover, the 5-HT1A receptor regulates several transduction mechanisms such as kinases and immediate early genes implicated in memory formation. Based on studies in rodents the stimulation of 5-HT1A receptors generally produces learning impairments by interfering with memory-encoding mechanisms. In contrast, antagonists of 5-HT1A receptors facilitate certain types of memory by enhancing hippocampal/cortical cholinergic and/or glutamatergic neurotransmission. Some data also support a potential role for the 5-HT1A receptor in memory consolidation. Available results also implicate the 5-HT1A receptor in the retrieval of aversive or emotional memories, supporting an involvement in reconsolidation. The contribution of 5-HT1A receptors in cognitive impairments in various psychiatric disorders is still unclear. However, there is evidence that 5-HT1A receptors may play differential roles in normal brain function and in psychopathological states. Taken together, the evidence indicates that the 5-HT1A receptor is a target for novel therapeutic advances in several neuropsychiatric disorders characterized by various cognitive deficits.