Band 25, Heft 3 - Special Issue: 5-HT6 and 5-HT7 receptors – new therapeutic targets / Guest Editor: Alfredo Meneses

The abundant distribution of serotonin (5-HT) in different areas of the central nervous system can explain the involvement of this neurotransmitter in the regulation of several functions, such as sleep, pain, feeding, and sexual and emotional behaviors. Moreover, the serotonergic system is also involved in other more complex roles, such as cognition, including learning and memory processes. Recent studies led to the discovery of various types and subtypes of receptors differentially associated to cognitive mechanisms. 5-HT 7 is the most recently discovered receptor for 5-HT; therefore, it is also one of the least well characterized. Studies exist hypothesizing the role of 5-HT 7 on the modulation of learning and memory processes and other cognitive functions. Moreover, much attention has been devoted to the possible role of 5-HT 7 receptors in psychiatric disorders. Therefore, the aim of this review is to clarify the behavioral role of the recently discovered 5-HT 7 type receptor and highlight its involvement in the cognitive functions, with particular attention to the modulation of learning and memory processes, thus providing a basis to obtain new therapeutic agents and strategies for the treatment of cognitive disorders.

Agonists and antagonists of the 5-hydroxytryptamine (serotonin) receptor 6 (5-HT 6 ) or receptor 7 (5-HT 7 ) might improve memory and/or reverse amnesia, although the mechanisms involved are poorly understood. Hence, the current work summarizes recent reviews and findings involving these receptors. Evidence indicates that diverse 5-HT 6 receptor antagonists produce promnesic and/or antiamnesic effect in conditions, such as memory formation, age-related cognitive impairments and memory deficit in preclinical studies, as well as in diseases such as schizophrenia, Parkinson’s, and Alzheimer’s disease (AD). Memory, aging, and AD modify 5-HT 6 receptors and signaling cascades; likewise, the modulation of 5-HT 6 drugs on memory seems to be accompanied with neural changes. Moreover, 5-HT 7 receptors are localized in brain areas mediating memory, including the cortex, hippocampus (e.g., Zola-Morgan and Squire, 1993) and raphe nuclei; however, the role of these receptors on memory has yet to be fully explored. Hence, findings and reviews are summarized in this work. Evidence suggests that both 5-HT 7 receptor agonists and antagonists might have promnesic and anti-amnesic effects. These effects seem to be dependent on the basal level of performance, i.e., normal or impaired. Available evidence suggests that a potential utility of 5-HT 6 and 5-HT 7 receptor in mild-to-moderate AD patients and other memory dysfunctions as therapeutic targets.

Serotonin and its various receptors are involved in numerous brain functions and neuropsychiatric disorders. Of the 14 known serotoninergic receptors, the 5-HT 7 receptor is the most recently identified and characterized. It is closely involved in the pathogenesis of depression, anxiety, epilepsy and pain and is therefore an important target for drug therapy. It is a crucial target in neuroscience, and there is a clear need for radioligands for in vitro and in vivo visualization and quantification, first in animal models and ultimately in humans. This review focuses on the main radioligands suggested for in vitro and in vivo imaging of the 5-HT 7 receptor.

In addition to positive and negative symptoms, cognitive deficits are increasingly being recognized as a core feature of schizophrenia. Neurocognitive impairments are strongly associated with functional outcomes; thus, the treatment of cognitive impairments is of central importance. A large body of evidence suggests that the serotonin 6 (5-HT6) receptors may be potential targets for cognitive improvement. Clinical and preclinical studies have supported the notion that using 5-HT6 receptor antagonists is a promising component in the treatment of cognitive dysfunctions associated with aging and Alzheimer’s disease. However, less is known about the efficacy of this strategy in the treatment of schizophrenia-like cognitive disturbances. The purpose of this review is to summarize existing data on the effects of 5-HT6 receptor antagonists in animal experiments, utilizing tasks that assess cognitive domains that are relevant to the cognitive deficits characterizing schizophrenia. This review focuses primarily on animal models of schizophrenia that are based on the blockade of N-methyl- d -aspartate receptors; however, when relevant, data obtained in other models are also discussed. The putative procognitive actions of 5-HT6 agonists are also reviewed. Finally, the mechanisms that are putatively responsible for the procognitive effects of 5-HT6 receptor ligands are briefly discussed.

The serotonin receptor 7 (5-HT7-R) plays important functional roles in learning and memory, in regulation of mood and circadian rhythmicity. LP-211 is a new selective agonist, belonging to 1-arylpiperazine category. We report studies aimed to evaluate the modulatory effect of a subchronic regimen on behavioral/molecular parameters. At low dose [0.25 mg/kg intraperitoneally (i.p.)], LP-211 induced a 6-h anticipated wake up in adult mice (with no temporal landmark by constant light), acting as nonphotic stimulus for ‘internal clock’ resetting. In standard 12:12-h light/dark cycle, a subchronic effect (5–6 days at 0.25 mg/kg, once per day) was observed: delayed wake up, reduced peak of locomotor activity and no evidence for brain cellular proliferation after ex vivo analysis. Other studies in rats were aimed to investigate long-term effects of developmental LP-211 administration into adulthood. Subchronic LP-211 (0.125 mg/kg i.p. once per day during the prepuberal phase) reduced l -glutamate, N -methyl- d -aspartate receptor 1 and dopamine transporter within the ventral striatum. With LP-211 (0.25 mg/kg i.p. once per day during the postpuberal phase), clear reductions were observed in the immunoreactivity of serotonin transporter and dopaminergic D2 receptors in the ventral and dorsal striatum, respectively. Subchronic LP-211 in rats and mice appears to be a suitable tool for studying the role of 5-HT7-R in sleep disorders, emotional/motivational regulations, attentive processes and executive functions.

The serotonin 7 (5-HT 7 ) receptor was the last serotonin receptor subtype to be discovered in 1993. This receptor system has been implicated in several central nervous system (CNS) functions, including circadian rhythm, rapid eye movement sleep, thermoregulation, nociception, memory and neuropsychiatric symptoms and pathologies, such as anxiety, depression and schizophrenia. In 1999, medicinal chemistry efforts led to the identification of SB-269970, which became the gold standard selective 5-HT 7 receptor antagonist, and later of various selective agonists such as AS-19, LP-44, LP-12, LP-211 and E-55888. In this review, we summarize the preclinical pharmacological studies performed using these agonists, highlighting their strengths and weaknesses. The data indicate that 5-HT 7 receptor agonists can have neuroprotective effects against N -methyl- d -aspartate-induced toxicity, modulate neuronal plasticity in rats, enhance morphine-induced antinociception and alleviate hyperalgesia consecutive to nerve lesion in neuropathic animals.

The 5-HT 6 receptor (5-HT 6 R) is one of the most recently discovered serotonin receptors and has received much attention after observations showing its procognition properties. Indeed, 5-HT 6 R appears to be a promising target to treat cognitive decline, particularly via its modulatory function of cholinergic and glutamatergic systems. 5-HT 6 Rs are present mostly in the central nervous system, in brain structures known to be particularly involved in memory. Growing evidence suggests that blockade of 5-HT 6 R can not only improve memory processes in adult rodents but also reverse age-related and pharmacologically induced deficits. 5-HT 6 R blockade could also have a beneficial effect on neuronal plasticity. Regarding these findings, several 5-HT 6 R antagonists are currently going through clinical trials. This review provides an overview of the major findings arguing in favour of a role for 5-HT 6 R antagonists in developing treatment for cognitive disorders related to ageing and neurodegenerative diseases.

Different approaches have been followed to characterize the role of 5-hydroxytryptamine (serotonin) receptor 7 (5-HT7) in the regulation of sleep-wake behavior: (1) 5-HT7 receptor knockout mice spend less time in rapid eye movement sleep than their wild-type counterparts, mainly during the light period. In contrast, there is no difference between the genotypes in time spent in wakefulness or slow-wave sleep. (2) Systemic administration of the selective 5-HT7 receptor agonist LP-211 significantly increased wakefulness (time spent awake) and reduced rapid eye movement sleep in the rat. Direct infusion of LP-211 into the dorsal raphe nucleus, locus coeruleus nucleus, basal forebrain (horizontal limb of the diagonal band of Broca), or laterodorsal tegmental nucleus also produced a decrease in rapid eye movement sleep. Additionally, microinjection of the 5-HT7 receptor agonist into the basal forebrain augmented the time animals remained awake. Local injection of the 5-HT7 receptor agonist LP-44 into the dorsal raphe nucleus also suppressed rapid eye movement sleep in the rat. (3) A similar reduction of rapid eye movement sleep has been described following intraperitoneal injection of the selective 5-HT7 receptor antagonists SB-269970 and SB-656104 in the rat and oral administration of the 5-HT7 receptor antagonist NJ-18038683 to rat and man. Local microinjection of SB-269970 into the dorsal raphe nucleus and basal forebrain also induced a decrease in rapid eye movement sleep in the rat. This tends to suggest that the on-off (activation/blockade), two-state ligand-receptor interaction model is not tenable for the 5-HT7 receptor.

A hyperactive hypothalamic-pituitary-adrenal (HPA) axis is a common feature of stress-related disorders, and the brain serotonin (5-HT) system plays a major role in HPA axis modulation. Glucocorticoids and stress profoundly affect the 5-HT system so it is possible that alterations of endocrine 5-HT mechanisms may underlie HPA axis overdrive in stress-related diseases. Available evidence suggests a role of 5-HT 1A , 5-HT 2A/2C and 5-HT 7 receptors in HPA system activation, and pharmacological blockade of 5-HT 7 receptors produces a fast-acting antidepressant-like action and shortens the onset of antidepressant-like effects of various classes of antidepressants. The mechanisms involved in this effect have not been elucidated, but recent findings suggest a role of 5-HT 7 receptors in the development of HPA axis overdrive as a result of chronic stress. Remarkably, clinical findings have shown an association between corticosteroid-producing adenomas and expression of ectopic 5-HT 7 receptors in corticosteroid-producing adrenocortical cells. These observations might therefore reveal an endocrine mechanism for the antidepressant-like action of 5-HT 7 receptor blockers, possibly through normalization of HPA axis function. If such a preliminary hypothesis is confirmed, the potential therapeutic usefulness of 5-HT 7 receptor antagonists could extend beyond depression to include other diseases, the pathophysiology of which has been associated with chronic stress and HPA axis dysregulation.

5-Hydroxytryptamine (5-HT, serotonin) subtype 6 receptor (5-HT 6 receptor, 5-HT 6 R) belongs to a 5-HT subclass of a relatively wide G protein-coupled receptor (GPCR) family. Accumulated biological data indicate that 5-HT 6 R antagonists and agonists have a great potential for the treatment of neuropathological disorders, such as Parkinson’s disease, Alzheimer’s disease, and schizophrenia. A number of painstaking efforts have been made toward the design of novel 5-HT 6 R ligands; however, there are still no drugs that successfully passed all the clinical trials and entered the market, except for several multimodal ligands. Novel active molecules are strongly needed to progress this development forward. The in silico drug design has some benefits compared with the other rough approaches in terms of thoroughness and predictive accuracy; therefore, it can be effectively used as a solid foundation for the design of novel 5-HT 6 R ligands with high potency and selectivity. Here, we provide an overview of the reported computational approaches to the design of novel 5-HT 6 R ligands.