5-HT receptors expressed throughout the human body are targets for established therapeutics and various drugs in development. Their diversity of structure and function reflects the important role 5-HT receptors play in physiologic and pathophysiological processes. The present review offers a framework for the official receptor nomenclature and a detailed understanding of each of the 14 5-HT receptor subtypes, their roles in the systems of the body, and, where appropriate, the (potential) utility of therapeutics targeting these receptors. SIGNIFICANCE STATEMENT: This review provides a comprehensive account of the classification and function of 5-hydroxytryptamine receptors, including how they are targeted for therapeutic benefit.

International Union of Basic and Clinical Pharmacology. CX. Classification of Receptors for 5-hydroxytryptamine; Pharmacology and Function

Improving cognition in schizophrenia with antipsychotics that elicit neurogenesis through 5-HT(1A) receptor activation.

Diverse neuropsychiatric disorders present dysfunctional memory and no effective treatment exits for them; likely as result of the absence of neural markers associated to memory. Neurotransmitter systems and signaling pathways have been implicated in memory and dysfunctional memory; however, their role is poorly understood. Hence, neural markers and cerebral functions and dysfunctions are revised. To our knowledge no previous systematic works have been published addressing these issues. The interactions among behavioral tasks, control groups and molecular changes and/or pharmacological effects are mentioned. Neurotransmitter receptors and signaling pathways, during normal and abnormally functioning memory with an emphasis on the behavioral aspects of memory are revised. With focus on serotonin, since as it is a well characterized neurotransmitter, with multiple pharmacological tools, and well characterized downstream signaling in mammals' species. 5-HT1A, 5-HT4, 5-HT5, 5-HT6, and 5-HT7 receptors as well as SERT (serotonin transporter) seem to be useful neural markers and/or therapeutic targets. Certainly, if the mentioned evidence is replicated, then the translatability from preclinical and clinical studies to neural changes might be confirmed. Hypothesis and theories might provide appropriate limits and perspectives of evidence.

/pdf/serotonin-neural-markers-and-memory-4wqtj2t3cb.pdf

Serotonin, neural markers, and memory

Notwithstanding tremendous research efforts, the cause of Alzheimer's disease (AD) remains elusive and there is no curative treatment. The cholinergic hypothesis presented 35 years ago was the first major evidence-based hypothesis on the etiology of AD. It proposed that the depletion of brain acetylcholine was a primary cause of cognitive decline in advanced age and AD. It relied on a series of observations obtained in aged animals, elderly, and AD patients that pointed to dysfunctions of cholinergic basal forebrain, similarities between cognitive impairments induced by anticholinergic drugs and those found in advanced age and AD, and beneficial effects of drugs stimulating cholinergic activity. This review revisits these major results to show how this hypothesis provided the drive for the development of anticholinesterase inhibitor-based therapies of AD, the almost exclusively approved treatment in use despite transient and modest efficacy. New ideas for improving cholinergic therapies are also compared and discussed in light of the current revival of the cholinergic hypothesis on the basis of two sets of evidence from new animal models and refined imagery techniques in humans. First, human and animal studies agree in detecting signs of cholinergic dysfunctions much earlier than initially believed. Second, alterations of the cholinergic system are deeply intertwined with its reactive responses, providing the brain with efficient compensatory mechanisms to delay the conversion into AD. Active research in this field should provide new insight into development of multitherapies incorporating cholinergic manipulation, as well as early biomarkers of AD enabling earlier diagnostics. This is of prime importance to counteract a disease that is now recognized to start early in adult life.

/pdf/a-second-wind-for-the-cholinergic-system-in-alzheimer-s-8kmjcurgvw.pdf

A second wind for the cholinergic system in Alzheimer's therapy.

Role of 5-HT1A Receptors in Learning and Memory

Background and Purpose

Pattern separation, that is, the formation of distinct representations from similar inputs, is an important hippocampal process implicated in cognitive domains like episodic memory. A deficit in pattern separation could lead to memory impairments in several psychiatric and neurological disorders. Hence, mechanisms by which pattern separation can be increased are of potential therapeutic interest.



Experimental approach

5-HT1A receptors are involved in spatial memory. Herein we tested the ‘biased’ 5-HT1A receptor agonists F15599, which preferentially activates post-synaptic heteroreceptors, and F13714, which preferentially activates raphe-located autoreceptors, in rats in a novel spatial task assessing pattern separation, the object pattern separation (OPS) task.



Key Results

The acetylcholinesterase inhibitor donepezil, which served as a positive control, significantly improved spatial pattern separation at a dose of 1 mg·kg−1, p.o. F15599 increased pattern separation at 0.04 mg·kg−1, i.p., while F13714 decreased pattern separation at 0.0025 mg·kg−1, i.p. The selective 5-HT1A receptor antagonist WAY-100635 (0.63 mg·kg−1, s.c.) counteracted the effects of both agonists. These data suggest that acute preferential activation of post-synaptic 5-HT1A heteroreceptors improves spatial pattern separation, whereas acute preferential activation of raphe-located 5-HT1A autoreceptors impairs performance.



Conclusions and Implications

We successfully established and validated a novel, simple and robust OPS task and observed a diverging profile of response with ‘biased’ 5-HT1A receptor agonists based on their targeting of receptors in distinct brain regions. Our data suggest that the post-synaptic 5-HT1A receptor consists of a potential novel molecular target to improve pattern separation performance.

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/bph.13071

R Schreiber

Papers

Divergent effects of the ‘biased’ 5-HT1A receptor agonists F15599 and F13714 in a novel object pattern separation task