A short history of the 5-HT2C receptor: from the choroid plexus to depression, obesity and addiction treatment

This paper is a personal account on the discovery and characterization of the 5-HT2C receptor (first known as the 5- HT1C receptor) over 30 years ago and how it translated into a number of unsuspected features for a G protein-coupled receptor (GPCR) and a diversity of clinical applications. The 5-HT2C receptor is one of the most intriguing members of the GPCR superfamily. Initially referred to as 5-HT1CR, the 5-HT2CR was discovered while studying the pharmacological features and the distribution of [3H]mesulergine-labelled sites, primarily in the brain using radioligand binding and slice autoradiography. Mesulergine (SDZ CU-085), was, at the time, best defined as a ligand with serotonergic and dopaminergic properties. Autoradiographic studies showed remarkably strong [3H]mesulergine-labelling to the rat choroid plexus. [3H]mesulergine-labelled sites had pharmacological properties different from, at the time, known or purported 5-HT receptors. In spite of similarities with 5-HT2 binding, the new binding site was called 5-HT1C because of its very high affinity for 5-HT itself. Within the following 10 years, the 5-HT1CR (later named 5- HT2C) was extensively characterised pharmacologically, anatomically and functionally: it was one of the first 5-HT receptors to be sequenced and cloned. The 5-HT2CR is a GPCR, with a very complex gene structure. It constitutes a rarity in theGPCR family: many 5-HT2CR variants exist, especially in humans, due to RNA editing, in addition to a few 5-HT2CR splice variants. Intense research led to therapeutically active 5-HT2C receptor ligands, both antagonists (or inverse agonists) and agonists: keeping in mind that a number of antidepressants and antipsychotics are 5- HT2CR antagonists/inverse agonists. Agomelatine, a 5-HT2CR antagonist is registered for the treatment of major depression. The agonist Lorcaserin is registered for the treatment of aspects of obesity and has further potential in addiction, especially nicotine/ smoking. There is good evidence that the 5-HT2CR is involved in spinal cord injury-induced spasms of the lower limbs, which can be treated with 5-HT2CR antagonists/inverse agonists such as cyproheptadine or SB206553. The 5-HT2CR may play a role in schizophrenia and epilepsy. Vabicaserin, a 5-HT2CR agonist has been in development for the treatment of schizophrenia and obesity, but was stopped. As is common, there is potential for further indications for 5-HT2CR ligands, as suggested by a number of preclinical and/or genome-wide association studies (GWAS) on depression, suicide, sexual dysfunction, addictions and obesity. The 5-HT2CR is clearly affected by a number of established antidepressants/antipsychotics and may be one of the culprits in antipsychotic-induced weight gain

Actions of sex steroids and corticosteroids on rabbit choroid plexus as shown by changes in transport capacity and rate of cerebrospinal fluid formation

The effect of betamethasone on choroid plexus transport and CSF formation in rabbits was studied. Following 5 days of daily treatment with betamethasone the CSF production rate was reduced by 43% as measured by ventriculo-cisternal perfusion with radioactive inulin. Accordingly, the Na(+)-K(+)-ATPase activity and the transport capacity in the choroid plexus, measured in terms of choline (10(-5) M) uptake and accumulation in vitro, decreased (in the lateral ventricles by 31% in both cases). Isolated choroid plexuses from rabbits were also used to determine uptake and accumulation of choline and the activities of various types of ATPases following pretreatment of the animals with 17-beta-oestradiol, alone or in combination with progesterone. The combined treatment reduced the choline uptake by 35% and also lowered the activity of Na(+)-K(+)-ATPase by 31% without influencing tissue wet weight. Thus, the demonstrated influences of glucocorticoids and sex steroids on the transport capacity in the choroid plexus seem to be important components in their postulated effects on intracranial hypertension

Changes in transport functions of isolated rabbit choroid plexus under the influence of oestrogen and progesterone

Isolated choroid plexuses from rabbits were used to determine uptake and accumulation of 10(-5) M radiolabelled choline (expressed as tissue/medium ratio) and the activities of various types of ATPases (based on ouabain inhibition and bicarbonate stimulation) following pre-treatment of the animals with 0.5 mg kg-1 17-beta-oestradiol, alone or in combination with 2 mg kg-1 progesterone. The combined treatment reduced the choline uptake by 35% and also lowered the activity of Na+,K+-ATPase by 31%, without influencing tissue wet weight. The reduction in HCO3-ATPase was smaller and not statistically significant. There was a tendency also for oestrogen alone to lower these activities, but only by less than 20%. The Ca2+,Mg2+-ATPase activity was not significantly affected by any of the hormones

Corticosteroid action on choroid plexus: reduction in Na+-K+-ATPase activity, choline transport capacity, and rate of CSF formation

Glucocorticoids have a well-known clinical effect on brain edema and intracranial hypertension, but the mechanism of action is still poorly understood. In the present report the effect of beta-methasone on choroid plexus transport and CSF formation was studied. Following 5 days of daily treatment with betamethasone the CSF production rate in rabbits was reduced by 43% as measured by ventriculo-cisternal perfusion with radioactive inulin. Accordingly, the transport capacity in the choroid plexus, measured in terms of choline uptake and accumulation in vitro, and the activity of Na+--K+-ATPase decreased in both rabbit (in the lateral ventricles by 31 and 31%, respectively) and rat (by 16 and 24%, respectively). Thus, the demonstrated influence of glucocorticoids on these functions of the choroid plexus seem to be important components in their therapeutic effect on intracranial hypertension

Simultaneous and continuous measurement of choroid plexus blood flow and cerebrospinal fluid production: effects of vasoactive intestinal polypeptide

Using laser-Doppler flowmetry during ventriculocisternal perfusion with inulin-[14C]carboxylic acid, choroid plexus blood flow (CPBF) and CSF production were measured simultaneously in rats during periods of 3 h. Blood flow and CSF production decreased only slightly during control experiments. The effect of vasoactive intestinal polypeptide (VIP) was studied at different concentrations of the peptide given either intraventricularly or intravenously. Intraventricular administration of VIP (10(-9) or 10(-7) M) resulted in a decrease in CSF production of up to 30%, while CPBF increased by 20%, also demonstrating that CSF production and blood flow are not directly coupled in the choroid plexus. When infused intravenously, VIP (10 or 100 pmol/kg/min) increased CPBF, an effect partly antagonized at higher concentrations owing to a VIP-induced systemic hypotension. No effect of VIP on CSF production could be seen with intravenous administration

Proton pump inhibitors act with unprecedented potencies as inhibitors of the acetylcholine biosynthesizing enzyme - A plausible missing link for their association with incidence of dementia

Introduction: Several pharmacoepidemiological studies indicate that proton pump inhibitors (PPIs) significantly increase the risk of dementia. Yet, the underlying mechanism is not known. Here, we report the discovery of an unprecedented mode of action of PPIs that explains how PPIs may increase the risk of dementia. Methods: Advanced in silico docking analyses and detailed enzymological assessments were performed on PPIs against the core-cholinergic enzyme, choline-acetyltransferase (ChAT), responsible for biosynthesis of acetylcholine (ACh). Results: This report shows compelling evidence that PPIs act as inhibitors of ChAT, with high selectivity and unprecedented potencies that lie far below their in vivo plasma and brain concentrations. Discussion: Given that accumulating evidence points at cholinergic dysfunction as a driving force of major dementia disorders, our findings mechanistically explain how prolonged use of PPIs may increase incidence of dementia. This call for restrictions for prolonged use of PPIs in elderly, and in patients with dementia or amyotrophic lateral sclerosis