A review of central 5-HT receptors and their function

The recent identification of cannabinoid receptors and their endogenous lipid ligands has triggered an exponential growth of studies exploring the endocannabinoid system and its regulatory functions in health and disease. Such studies have been greatly facilitated by the introduction of selective cannabinoid receptor antagonists and inhibitors of endocannabinoid metabolism and transport, as well as mice deficient in cannabinoid receptors or the endocannabinoid-degrading enzyme fatty acid amidohydrolase. In the past decade, the endocannabinoid system has been implicated in a growing number of physiological functions, both in the central and peripheral nervous systems and in peripheral organs. More importantly, modulating the activity of the endocannabinoid system turned out to hold therapeutic promise in a wide range of disparate diseases and pathological conditions, ranging from mood and anxiety disorders, movement disorders such as Parkinson9s and Huntington9s disease, neuropathic pain, multiple sclerosis and spinal cord injury, to cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome, and osteoporosis, to name just a few. An impediment to the development of cannabinoid medications has been the socially unacceptable psychoactive properties of plant-derived or synthetic agonists, mediated by CB 1 receptors. However, this problem does not arise when the therapeutic aim is achieved by treatment with a CB 1 receptor antagonist, such as in obesity, and may also be absent when the action of endocannabinoids is enhanced indirectly through blocking their metabolism or transport. The use of selective CB 2 receptor agonists, which lack psychoactive properties, could represent another promising avenue for certain conditions. The abuse potential of plant-derived cannabinoids may also be limited through the use of preparations with controlled composition and the careful selection of dose and route of administration. The growing number of preclinical studies and clinical trials with compounds that modulate the endocannabinoid system will probably result in novel therapeutic approaches in a number of diseases for which current treatments do not fully address the patients9 need. Here, we provide a comprehensive overview on the current state of knowledge of the endocannabinoid system as a target of pharmacotherapy.

http://www.phytecs.com/wp-content/uploads/2015/02/Pharmacol-Rev-2006-Pacher-389-462.pdf

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

https://www.cell.com/trends/pharmacological-sciences/pdf/0165-6147(94)90315-8.pdf

Current advances and trends in the treatment of depression

As our understanding of the endocannabinoids improves, so does the awareness of their complexity During pathological states, the levels of these mediators in tissues change, and their effects vary from those of protective endogenous compounds to those of dysregulated signals These observations led to the discovery of compounds that either prolong the lifespan of endocannabinoids or tone down their action for the potential future treatment of pain, affective and neurodegenerative disorders, gastrointestinal inflammation, obesity and metabolic dysfunctions, cardiovascular conditions and liver diseases When moving to the clinic, however, the pleiotropic nature of endocannabinoid functions will require careful judgement in the choice of patients and stage of the disorder for treatment

Targeting the endocannabinoid system: to enhance or reduce?

The circadian visual system.

We investigated the effect of the cannabinoid CB1 receptor antagonist, SR 141716, on indomethacin-induced small intestine inflammation and Escherichia coli lipopolysaccharide (LPS)-induced plasma TNF-α (TNF) release in comparison to the cannabinoid CB2 receptor antagonist, SR 144528, in rodents.


In rats, indomethacin induced significant ulcer formation in the small intestine; this was accompanied by an increase in tissue TNF levels and myeloperoxidase (MPO) activity. SR 141716 prevented the ulcers and the rise in TNF levels (ID50 3.3, 0.4 mg kg−1, respectively) and MPO activity. SR 144528 prevented intestinal ulcers only.


The effect of SR 141716 against indomethacin-induced ulcers and increase of plasma TNF levels after LPS was also studied in wild-type and CB1 receptor knockout mice. Indomethacin induced intestinal ulcers in mice, but not tissue TNF production and MPO activity. SR 141716 reduced the ulcers to a similar extent in wild-type and CB1 receptor knockout mice. In rats and wild-type mice, but not in CB1 receptor knockout mice, SR 141716 inhibited the LPS-induced increase in plasma TNF levels.


These findings provide evidence that the indomethacin model of intestinal lesions differs in rat and mouse and support the existence of several mechanisms for the antiulcer activity of SR141716, the most important involving the inhibition of TNF production. The potent anti-inflammatory activity of SR141716 in rodents indicated its potential therapeutic interest in chronic immune-inflammatory diseases.





Keywords: Cannabinoids, CB1 receptor, TNF-α, SR141716, Rimonabant, gut, ulcers, indomethacin, cytokines, inflammation


Introduction
Cannabinoid agonists and antagonists display several pharmacological effects through interactions with at least two receptor subtypes, the cannabinoid CB1 and CB2 receptors (Howlett, 1995; Pertwee, 1997). The cannabinoid CB1 receptor subtype accounts for most of the central effects of marijuana and synthetic cannabinoid agonists. It is not only abundant in the central nervous system (Devane et al., 1988; Wilson & Nicoll, 2002), but is also present in several peripheral organs, including the gut, where it appears to modulate gastroprotection, gastrointestinal motility and secretion (Croci et al., 1998; Izzo et al., 2001; Mancinelli et al., 2001; Pertwee, 2001; Landi et al., 2002; Pinto et al., 2002).

In vitro functional evidence of prejunctional neuronal cannabinoid CB1 receptors in the human ileum longitudinal smooth muscle and colon has been provided (Croci et al., 1998; Manara et al., 2002). Cannabinoid CB1-binding sites (Pertwee, 1997) and immunoreactivity (Kulkarni-Narla & Brown, 2000) and cannabinoid CB1 transcripts have also been reported in peripheral tissues (Bouaboula et al., 1993; Galiegue et al., 1995). The cannabinoid CB2 receptor subtype is virtually absent from the brain, but largely distributed in the periphery and on the surface of immune cells, where it exerts important modulatory functions (Munro et al., 1993; Galiegue et al., 1995; Klein et al., 2000). There is substantial evidence that in different in vitro and in vivo inflammatory conditions, both endogenous and synthetic cannabinoid receptor agonists downregulate mast cells and granulocytes, and reduce cytokine release by acting mainly at cannabinoid CB2 receptors (Aloe et al., 1993; Mazzari et al., 1996; Richardson et al., 1998; Parolaro, 1999; Klein et al., 2000; Massi et al., 2000; Sacerdote et al., 2000; Smith et al., 2000,2001a; Conti et al., 2002). The importance of the cannabinoid CB1 receptor in immunological and inflammatory events is less clearly established than the cannabinoid CB2 receptor, in spite of the expression and presence of CB1 receptors on the surface of immune cells (Kaminski et al., 1992; Galiegue et al., 1995). SR 141716 (Rimonabant) is a potent and highly selective cannabinoid CB1 receptor antagonist with potential therapeutic properties in obesity (Le Fur et al., 2001); it is now widely used as a pharmacological tool to block cannabinoid CB1 receptors selectively in vitro and in vivo (Rinaldi-Carmona et al., 1994; Bouaboula et al., 1997).

The aim of this study is to investigate the role of cannabinoid CB1 receptors in inflammation and to characterize the actions of SR 141716 further in the indomethacin toxicity model in the gut. Indomethacin-induced small intestinal injury in the rat is a simple inflammatory model in which local tumor necrosis factor-α (TNF-α) tissue production is clearly involved in the early stage of the mechanism leading to the lesions (Bertrand et al., 1998; Konaka et al., 1999). We compared the effect of SR 141716 with that of the selective cannabinoid CB2 receptor antagonist, SR 144528 (Rinaldi-Carmona et al., 1998; Bouaboula et al., 1999) on indomethacin-induced intestinal ulcers, TNF-α production and myeloperoxidase (MPO) tissue activity in rats and mice. We also investigated the action of SR 141716 on plasma TNF-α levels after systemic administration of Escherichia coli lipopolysaccaride (LPS): (a) in rats, to see whether the inhibitory effect of SR141716 on local intestinal TNF-α production is not just a consequence, but rather one of the major steps in ulcer healing; (b) in wild-type and CB1-receptor knockout mice, to understand the role of cannabinoid CB1 receptors in the anti-inflammatory activity of SR141716.

A preliminary account of this study was presented at the 2002 Symposium on the cannabinoids (Croci et al., 2002).

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1038/sj.bjp.0705412

Role of cannabinoid CB1 receptors and tumor necrosis factor‐α in the gut and systemic anti‐inflammatory activity of SR 141716 (Rimonabant) in rodents

In the rat brain, the presynaptic 5-hydroxytrypt-amine (5-HT) autoreceptors located on 5-HT terminals correspond to the 5-HT1B subtype. The presence of a 5-HT receptor probably located on 5-HT nerve endings and modulating transmitter release in the human neocortex has been reported, but its detailed pharmacological characterization is not yet available. On the other hand, receptor binding and autoradiographic results indicate that the 5-HT1B receptor subtype is not present in the human brain. We, therefore, studied the modulation of the electrically evoked release of [3H]5-HT by various 5-HT receptor agonists and antagonists in preloaded slices of human neocortex obtained from 18 patients undergoing neurosurgery. The nonselective 5-HT1A/1B/1D receptor agonist 5-carboxamidotryptamine produced a potent inhibition (70% at 0.03 μM) of the electrically evoked release of [3H]5-HT which was blocked by 5-HT receptor antagonists with the following relative order of potency: methiothepin > metergoline = methysergide > propranolol. The selective 5-HT1A receptor agonist 8-hydroxy-2–(di-n-propylamino)tetralin at 0.1 μM did not modify the electrically evoked release of [3H]5-HT. The 5-MT1A/1B receptor agonist RU 24969 was 10 times more potent at inhibiting [3H]5-HT overflow in the rat frontal cortex than in the human neocortex. The potent 5-HT1B receptor antagonist cyanopindolol did not modify the 5-carboxamidotryptamine-induced inhibition of the electrically evoked release of [3H]5-HT in slices of the human neocortex, but produced by itself a small inhibition of [3H]5-HT overflow. The α2-adrenoceptor antagonist yohimbine, which possesses affinity for the 5-HT1D receptor subtype, decreased the release of [3H]5-HT, but only in the presence of the selective α2-adrenoceptor antagonist idazoxan, which by itself increased significantly [3H]5-HT overflow. Taken together, these results support the view that the 5-HT receptor modulating the electrically evoked release of [3H]5-HT in slices of the human neocortex could be of the 5-HT1D subtype. Moreover, preliminary results obtained with idazoxan confirm the existence of a presynaptic α2-adrenoceptor modulating the release of [3H]5-HT in the human neocortex. These α2-heteroreceptors could exert a tonic inhibitory modulation on 5-HT neurotransmission in the human neocortex.

Characterization of the 5-Hydroxytryptamine Receptor Modulating the Release of 5-[3H]Hydroxytryptamine in Slices of the Human Neocortex

The high-affinity binding sites for [3H]-imipramine (IMI) present in human platelets are associated with the neuronal uptake system for 5HT. It was recently demonstrated that previous antidepressant therapy with drugs which inhibit 5HT uptake could down-regulate [3H]-IMI binding and that this effect could persist up to 1 month after the end of treatment. We therefore re-examined the reported differences inB
 max of [3H]-IMI binding in platelets between control and depressed untreated patients, to evaluate the residual influence of previous antidepressant medication. The saturation characteristics of [3H]-IMI binding were compared in platelets from 17 depressed patients care-fully selected according to previous antidepressant therapy and washout period, who were closely matched, for age and sex, with a group of control healthy volunteers. The results reveal a significant decrease by 47% in theB
 max of [3H]-IMI binding in platelets of untreated depressed patients when compared with controls. There was no significant modification ofK
 d values for platelet [3H]-IMI binding between the depressed and the control groups. Our results support the view that platelet [3H]-IMI binding is a useful tool as a biological marker in depression.

Reduced Bmax of [3H]-imipramine binding to platelets of depressed patients free of previous medication with 5HT uptake inhibitors

Lack of seasonal variation in platelet [3H]imipramine binding in humans.

Changes in [3H]5-HT uptake and [3H]imipramine binding in platelets after chlorimipramine in healthy volunteers. Comparison with maprotiline and amineptine.

Anne-Marie Galzin

Papers

Role of cannabinoid CB1 receptors and tumor necrosis factor‐α in the gut and systemic anti‐inflammatory activity of SR 141716 (Rimonabant) in rodents

Characterization of the 5-Hydroxytryptamine Receptor Modulating the Release of 5-[3H]Hydroxytryptamine in Slices of the Human Neocortex

Reduced Bmax of [3H]-imipramine binding to platelets of depressed patients free of previous medication with 5HT uptake inhibitors

Lack of seasonal variation in platelet [3H]imipramine binding in humans.

Changes in [3H]5-HT uptake and [3H]imipramine binding in platelets after chlorimipramine in healthy volunteers. Comparison with maprotiline and amineptine.