The role of the serotonin receptor subtypes 5-HT1A and 5-HT7 and its interaction in emotional learning and memory

Abstract

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-HT1AR and 5-HT7R 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-HT1AR and 5-HT7R as well as their interplay at the molecular, neurochemical and behavioral level. Activation of postsynaptic 5-HT1ARs impairs emotional memory through attenuation of neuronal activity, whereas presynaptic 5-HT1AR activation reduces 5-HT release and exerts pro-cognitive effects on PA retention. Antagonism of the 5-HT1AR facilitates memory retention possibly via 5-HT7R activation and evidence is provided that 5HT7R can facilitate emotional memory upon reduced 5-HT1AR 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-HT1ARs and 5-HT7Rs 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.

Serotonin differentially modulates excitatory and inhibitory synaptic inputs to putative sleep-promoting neurons of the ventrolateral preoptic nucleus

“…Indeed, deciphering the effects of serotonin (5-hydroxytryptamine, or 5-HT) on sleep is a complex matter, especially since this monoamine neurotransmitter plays major roles in several physiological functions including appetite, gastrointestinal motility, thermoregulation, nociception, emotion and cognition (Artigas, 2015;Berger et al, 2009;Stiedl et al, 2015). Moreover, 5-HT effects are mediated by a wide family of receptors that are classified into seven main receptor subtypes, designated 5-HT 1e7 .…”

Marmoset Serotonin 5-HT1AReceptor Mapping with a Biased Agonist PET Probe18F-F13714: Comparison with an Antagonist Tracer18F-MPPF in Awake and Anesthetized States

“…Agonist PET probes would also be desirable when assessing the association between 5-HT 1A receptors and behavioral phenotypes. The involvement of the 5-HT 1A receptor in various aspects of cognition, depression, and anxiety has been amply demonstrated (Harder and Ridley, 2000; Gingrich and Hen, 2001; Albert et al, 2014; Stiedl et al, 2015), but a human database of 5-HT 1A receptor binding by PET with an antagonist probe 11 C-WAY100635 showed high between-subject variability and failed to find any correlations with personality variables (Rabiner et al, 2002), while several studies reported an association with anxious or aggressive traits in smaller sample sizes (Tauscher et al, 2001; Parsey et al, 2002). …”

Lurasidone for major depressive disorder with mixed features and anxiety: a post-hoc analysis of a randomized, placebo-controlled study

“…31,[58][59][60][61][62] The observed reduction in anxiety associated with pharmacologic inhibition, or receptor inactivation using knockout mouse models, suggests that both the 5-HT 1A and 5-HT 7 receptors may mediate anxiety symptoms and behaviors. 58,62 Previous studies have reported that the presence of prominent anxiety in MDD was associated with increased illness severity and functional impairment.…”