5-HT receptors in human and animal cerebrovasculature

doi:10.1016/0165-6147(91)90583-E

Trends in Pharmacological Sciences

Volume 12, 1991, Pages 310-315

https://doi.org/10.1016/0165-6147(91)90583-E Get rights and content

Abstract

5-HT has been implicated in the pathogenesis of cerebral arterial vasospasm following subarachnoid haemorrhage and in the aetiology of migraine. Within the cerebrovasculature, 5-HT possesses a complex action dependent on the type of 5-HT receptors present. In this review, Andrew Parsons analyses the evidence demonstrating contractile and relaxant 5-HT receptors within different areas of the cerebrovasculature, and examines differences between human and animal cerebral arteries. The extensive regional and species differences are important considerations for the development of future therapeutic agents in cerebrovascular disease.

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Cited by (67)

Central 5-HT receptors and their function; present and future
2020, Neuropharmacology
Citation Excerpt :
At the macro-level, 5-HT receptors are widely distributed, with specific brain regions having distinct complements of 5-HT receptor subtypes: for instance, cortical and limbic areas - 5-HT1A, 5-HT2A/C, 5-HT3, 5-HT4, 5-HT6; basal ganglia - 5-HT1B, 5-HT2A/C, 5-HT4, 5-HT6; mesolimbic pathways - 5-HT1B, 5-HT2A/C, 5-HT4 receptors; hypothalamus (eg. paraventricular and arcuate nuclei) - 5-HT2C; suprachiasmatic nucleus - 5-HT7; trigeminal nucleus - 5-HT1B/D/F; dorsal vagal complex (encompassing the area postrema and nucleus tractus solitarus, and dorsal motor nucleus of the vagus nerve) - 5-HT3. The majority of data favour 5-HT receptors being principally expressed by neurons; evidence that they are expressed by non-neural cells is often conflicting with the possible exception of cells of the cerebrovasculature, especially as in the case of the 5-HT1B receptor (Parsons, 1991; Riad et al., 1998). In particular, the literature describing the expression of 5-HT receptor subtypes by glial cells is controversial and incomplete.
Since our review of central 5-HT receptors and their function twenty years ago, no new 5-HT receptor has been discovered and there is little evidence that this situation will change in the near future. Nevertheless, over this time significant progress has been made in our understanding of the properties of these receptors and in the clinical translation of this information, and some of these developments are highlighted herein. Such highlights include extensive mapping of 5-HT receptors in both animal and human brain, culminating in readily-accessible brain atlases of 5-HT receptor distribution, as well as emerging data on how 5-HT receptors are distributed within complex neural circuits. Also, a range of important pharmacological and genetic tools have been developed that allow selective 5-HT receptor manipulation, in cells through to whole organism models. Moreover, unexpected complexity in 5-HT receptor function has been identified including agonist-dependent signalling that goes beyond the pharmacology of canonical 5-HT receptor signalling pathways set down in the 1980s and 1990s. This new knowledge of 5-HT signalling has been extended by the discovery of combined signalling of 5-HT and co-released neurotransmitters, especially glutamate. Another important advance has been the progression of a large number of 5-HT ligands through to experimental medicine studies and clinical trials, and some such agents have already become prescribed therapeutic drugs. Much more needs to be discovered and understood by 5-HT neuropharmacologists, not least how the diverse signalling effects of so many 5-HT receptor types interact with complex neural circuits to generate neurophysiological changes which ultimately lead to altered cognitions and behaviour.
This article is part of the special issue entitled ‘Serotonin Research: Crossing Scales and Boundaries’.
5-Hydroxytryptophan: A precursor of serotonin influences regional blood-brain barrier breakdown, cerebral blood flow, brain edema formation, and neuropathology
2019, International Review of Neurobiology
Citation Excerpt :
Thus, in this study the influence of 5-HTP on regional CBF was also investigated. Finally, to find out the receptor-mediated effect of serotonin on BBB function, brain edema and cellular injuries, several drugs modifying serotonin receptor or serotonin induced signal transduction mechanisms on the endothelial cell vesicular transports were also analyzed (Anon, 1989; Burnstock, 1985; MacKenzie & Scatton, 1987; Parsons, 1991; Saxena, Bom, & Verdouw, 1989; Wiernsperger, 1990). A brief description on our findings on 5-HT-induced neurotoxicity is discussed below.
5-Hydroxytryptophan (5-HTP), a precursor of serotonin, is therapeutically used for several psychiatric disorders such as anxiety and depression in the clinic. However, severe side effects, including abnormal mental functions, behavioral disturbances and intolerance are associated with this treatment. 5-HTP-induced elevation of plasma and brain serotonin levels may affect blood-brain barrier (BBB) breakdown, edema formation and regional cerebral blood flow (CBF) disturbances. Breakdown of BBB to serum proteins leads to vasogenic brain edema formation and cellular injuries. However, 5-HTP-neurotoxicity is still not well known. In this investigations 5-HTP induced elevation of endogenous plasma and brain serotonin levels and its effect on BBB breakdown, edema formation neuronal injuries was examined in a rat model. Furthermore, potential role of oxidative stress and nitric oxide (NO) was evaluated. In addition, several neurochemical agents such as p-CPA (5-HT synthesis inhibitor) indomethacin (prostaglandin synthase inhibitor), diazepam (ant stress drug), cyproheptadine, ketanserin (5-HT2 receptor antagonists) and vinblastine (inhibitor of microtubule function) were examined on 5-HT neurotoxicity. Our observations suggest that 4 h after 5-HTP administrations, the endogenous serotonin levels increased by fourfold (150 mg/kg) in the plasma and brain associated with profound hyperthermia (+ 3.86 ± 0.24 °C, oxidative stress and NO upregulation. Breakdown of the BBB to Evans blue albumin (EBA) in 8 brain regions and to ^[131]Iodine in 14 brain regions was observed. The CBF exhibited marked reduction in all the brain regions examined. Brain edema and cellular injuries are present in the areas associated with BBB disruption. Drug treatments reduced the BBB breakdown, edema formation NO production and brain pathology. These observations are the first to point out that 5-HTP-neurotoxicity caused by BBB breakdown, edema formation and NO production is instrumental in causing adverse mental and behavioral abnormalities, not reported earlier.
Nonhuman Primate Models of Drug and Alcohol Addiction
2012, Nonhuman Primates in Biomedical Research: Diseases: Second Edition
The dorsal raphe nucleus and serotonin: implications for neuroplasticity linked to major depression and Alzheimer's disease
2008, Progress in Brain Research
Citation Excerpt :
Such changes could include loss of serotonergic DRN neurons, which would lead to decreased serotonergic innervation of DRN target areas of the forebrain. Interestingly, serotonergic fibres surround major cerebral arteries and pial microvessels (Chan-Palay, 1976) and play a potent vasoconstrictor role (Parsons, 1991) while depression strongly correlates with abnormal rCBF (Soares and Mann, 1997; Drevets, 2001; Mayberg, 2003). The role of rCBF in depression is supported by studies, which show that some antidepressant treatments normalize blood flow in specific areas in depressive patients (Drevets, 2000; Mayberg, 2003; Zobel et al., 2005).
The dorsal raphe nucleus (DRN) is a heterogeneous brainstem nucleus located in the midbrain and pons. Via widespread projections, which target a multitude of brain areas, its neurons utilize many transmitters to control various physiological functions, including learning, memory and affect. Accordingly, the DRN has been strongly associated with brain dysfunction, especially mood disorders such as depression, but also Alzheimer's disease. The DRN's most abundant transmitter, serotonin, has received the most attention in studies on both normal brain function and disease, and lately its involvement in the regulation of neuroplasticity has been under particular scrutiny. This chapter begins with a systematic overview of what we currently know about the anatomy of the DRN and its neurons, including their ascending projections. It continues with a review of the transmitters of the DRN, followed by a discussion on the connection between the DRN and neuroplasticity. Special emphasis is put on serotonin and its central role in neuroplasticity, which is proving to be of high priority in unraveling the full picture of the cellular mechanisms and their interconnections in the etiology of major depression and Alzheimer's disease.
Influence of Serotonin on the Blood-Brain and the Blood-Spinal Cord Barriers
2004, Blood-Spinal Cord and Brain Barriers in Health and Disease
The role of serotonin on the blood–brain barrier (BBB) and the blood–spinal cord barrier (BSCB) is not well known. Serotonin concentration is very high in the central nervous system (CNS), and several serotonergic receptors are present in the cerebral vessels. Elevation of plasma and tissue serotonin occurs under a wide variety of neurological and psychiatric conditions. The functional significance of these findings is still unclear. Based on serotonin infusion experiments in animal models, new data suggest that the amine can induce BBB and BSCB disruption. This effect of serotonin is mediated via serotonergic receptors. These findings are clinically relevant, as breakdown of microvascular permeability leads to edema formation and neurodegeneration. Thus, drugs modifying serotonergic transmission and/or specific serotonin receptors could be useful for the treatment of several neurological diseases in which the BBB or BSCB is compromised.
Mechanisms of blockade by the novel migraine prophylactic agent, dotarizine, of various brain and peripheral vessel contractility
2001, European Journal of Pharmacology
The novel antimigraineur, dotarizine, inhibited 5-HT (5 hydroxytryptamine)-evoked contractions of rabbit vertebral, aorta, femoral and mesenteric arteries, with IC₅₀s of 1.35, 1.40, 0.52 and 1.09 μM, respectively. Flunarizine had little effect on these contractions, while ketanserin was more potent (IC₅₀s of 0.17 μM for vertebral, 0.22 μM for aorta, 0.05 μM for femoral and 0.03 μM for mesenteric arteries). At 10 μM, dotarizine caused 40% blockade of K⁺-evoked contractions of rabbit aorta, and 70% inhibition of 5-HT-evoked responses; these values were 30% and 20% for 10 μM flunarizine. Contractions of rabbit aorta elicited by noradrenaline, angiotensin II or prostaglandin F_2α were not affected by 10 μM dotarizine or flunarizine. Ketanserin shifted to the right, in parallel, the concentration–response curves for 5-HT in rabbit aorta; however, dotarizine caused a non-competitive type of blockade, increasing the maximum 5-HT contraction at 30 nM and decreasing it at 3 and 30 μM. K⁺-evoked contractions of rabbit aorta were halved by 3 μM dotarizine in a voltage-independent manner; flunarizine caused a delayed-type, non-reversible post-drug blockade, and exhibited some voltage-dependence. Blockade by nifedipine was voltage-dependent and fully reversible. Ca²⁺-evoked contractions of depolarised bovine middle cerebral arteries were blocked by 1–3 μM dotarizine in a non-surmountable manner. Contraction of these vessels evoked by electrical stimulation was blocked 50% and 70% by 1 and 3 μM dotarizine, respectively. Dotarizine (1–3 μM) also inhibited to a similar extent the K⁺-evoked [³H]noradrenaline release from cultured rat sympathetic neurones. These data suggest that the mechanism of blockade by dotarizine of cerebral vessels contractility has three components: (i) presynaptic inhibition of noradrenaline release; (ii) blockade of postsynaptic vascular 5-HT receptors; (iii) blockade of Ca²⁺entry into the vascular smooth muscle cell cytosol. The compound does not affect the vascular receptors for noradrenaline, angiotensin II or prostaglandin F_2α.

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¹: Present address: SmithKline Beecham Pharmaceuticals, The Frythe, Welwyn, Herts., UK.

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Trends in Pharmacological Sciences

TIPS review5-HT receptors in human and animal cerebrovasculature

Abstract

Neuropharmacology

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Brain Res.

Eur. J. Pharmacol.

J. Cereb. Blood Flow Metab.

Circ. Res.

J. Neurosurg.

Naunyn-Schmied. Arch. Pharmacol.

J. Neurosci.

Br. J. Pharmacol.

Circ. Res.

Naunyn-Schmied. Arch. Pharmacol.

Naunyn-Schmied. Arch. Pharmacol.

J. Pharmacol. Exp. Ther.

J. Pharmacol. Exp. Ther.

J. Pharmacol. Exp. Ther.

Br. J. Pharmacol.

Int. J. Microcirc. Clin. Exp.

Acta Physiol. Scand.

Br. J. Pharmacol.

J. Pharmacol. Exp. Ther.

TIPS review
5-HT receptors in human and animal cerebrovasculature