The role of the serotonin receptor subtypes 5-HT(1A) and 5-HT(7) and its interaction in emotional learning and memory

Serotonin [5-hydroxytryptamine (5-HT)] is a multifunctional neurotransmitter innervating cortical and limbic areas involved in cognition and emotional regulation. Dysregulation of serotonergic transmission is associated with emotional and cognitive deficits in psychiatric patients and animal models. Drugs targeting the 5-HT system are widely used to treat mood disorders and anxiety-like behaviors. Among the fourteen 5-HT receptor (5-HTR) subtypes, the 5-HT(1A)R and 5-HT(7)R are associated with the development of anxiety, depression and cognitive function linked to mechanisms of emotional learning and memory. In rodents fear conditioning and passive avoidance (PA) are associative learning paradigms to study emotional memory. This review assesses the role of 5-HT(1A)R and 5-HT(7)R as well as their interplay at the molecular, neurochemical and behavioral level. Activation of postsynaptic 5-HT(1A)Rs impairs emotional memory through attenuation of neuronal activity, whereas presynaptic 5-HT(1A)R activation reduces 5-HT release and exerts pro-cognitive effects on PA retention. Antagonism of the 5-HT(1A)R facilitates memory retention possibly via 5-HT(7)R activation and evidence is provided that 5HT(7)R can facilitate emotional memory upon reduced 5-HT(1A)R transmission. These findings highlight the differential role of these 5-HTRs in cognitive/emotional domains of behavior. Moreover, the results indicate that tonic and phasic 5-HT release can exert different and potentially opposing effects on emotional memory, depending on the states of 5-HT(1A)Rs and 5-HT(7)Rs and their interaction. Consequently, individual differences due to genetic and/or epigenetic mechanisms play an essential role for the responsiveness to drug treatment, e.g., by SSRIs which increase intrasynaptic 5-HT levels thereby activating multiple pre- and postsynaptic 5-HTR subtypes.