Characterizing the effects of 5-HT2C receptor ligands on motor activity and feeding behaviour in 5-HT2C receptor knockout mice

5-HT_2C receptor agonists have considerable therapeutic potential, however there is little in vivo data to compare the potency and selectivity of 5-HT_2C receptor agonists. Since 5-HT_2C receptor agonists reduce locomotor activity and food intake, changes in these drug-induced behaviours in 5-HT_2C receptor knockout mice could provide a means to examine receptor selectivity in-vivo. Initially this study compared older 5-HT_2C agonists mCPP and MK212, to newer, apparently more selective compounds: Ro 60-0175, WAY161503, CP809,101 and lorcaserin (APD356) on motor activity in wild-type, and 5-HT_2C receptor knockout mice. Two 5-HT_2C receptor antagonists SB242084 and SDZ SER 082 were also examined. mCPP did not significantly alter activity in wild-type mice, but enhanced activity in knockout animals. MK212 (3 and 10 mg/kg) and Ro 60-0175 (1 and 3 mg/kg) reduced activity in wild-type but not knockout animals. At 10 mg/kg, Ro 60-0175 reduced activity in knockout animals, suggesting loss of 5-HT_2C receptor selectivity. CP809,101 and lorcaserin reduced activity in wild-type but not knockout mice. In subsequent feeding studies, Ro 60-0175 and lorcaserin reduced food intake in wild-type animals only. Selectivity of effect for mCPP was marginal. The antagonist SB242084 increased activity in wild-type animals but not in knockout mice; SB242084 did not alter feeding in either genotype. SDZ SER 082 reduced activity in both genotypes implying poor selectivity for 5-HT_2C receptors. The data demonstrate that studying food intake, and particularly motor behaviour, in the 5-HT_2C receptor knockout mouse is a useful and relatively simple approach for screening 5-HT_2C receptor ligands in vivo.     

Effect of chronic administration of selective 5-hydroxytryptamine and noradrenaline uptake inhibitors on a putative index of 5-HT2C/2B receptor function

Chronic treatment with selective 5-HT reuptake inhibitors (SSRI) are therapeutic in obsessive compulsive disorder, depression, anxiety, bulimia nervosa and migraine. In the present study the possibility that SSRI's act by desensitizing 5-HT_2C/5-HT_2B receptors was assessed using a putative in vivo model of 5-HT_2C/5-HT_2B receptor function, mCPP-induced hypolocomotion. mCPP (2,4 and 6 mg/kg i.p. 20 min pretest) reduced locomotion and rears in rats treated acutely or chronically with saline. Acute oral administration of the SSRI's fluoxetine (10 mg/kg), paroxetine (10 mg/kg), or clomipramine (70 mg/kg) or the noradrenaline reuptake inhibitor, desipramine (10 mg/kg), all 1 hr pretest, did not prevent mCPP-induced hypolocomotion. In contrast, chronic treatment with the SSRI's paroxetine and fluoxetine (both 10 mg/kg p.o. daily × 21 days), significantly attenuated the effect of mCPP (4 and 6 mg/kg i.p.) on locomotion and rears 24 hr after the last pretreatment dose. Chronic clomipramine (70 mg/kg p.o. daily × 21 days) also significantly attenuated the effect of mCPP (4 mg/kg i.p.) on rears and tended to reduce the hypolocomotor response. However, chronic treatment with desipramine, (10 mg/kg p.o.daily × 21) had no effect on any of the parameters measured. As chronic fluoxetine and paroxetine did not reduce brain mCPP levels (determined by HPLC 30 min after 4 mg/kg i.p.) the results suggest that chronic SSRI's, but not desipramine, reduce 5-HT_2C/5-HT/_2B receptor responsivity. If this occurs in man, it may mediate or contribute to their reported therapeutic efficacy in depression, anxiety, bulimia, migraine and alcoholism. It may also be of particular relevance to their unique efficacy in OCD.     

Cerebral metabolic responses to 5-HT2A/C receptor activation in mice with genetically modified serotonin transporter (SERT) expression

Variation in the human serotonin transporter gene (hSERT; 5-HTT) resulting in a life-long alteration in SERT function influences anxiety and the risk of developing affective disorders. The mechanisms underlying the influence of the hSERT gene on these phenotypes remain unclear but may involve altered 5-HT receptor function. Here we characterise the cerebral metabolic response to 5-HT_2A/C receptor activation in two transgenic mouse models of altered SERT function, SERT knock-out (SERT KO) and hSERT over-expressing (hSERT OE) mice, to test the hypothesis that genetically mediated variability in SERT expression alters 5-HT_2A/C function. We found that a constitutive increase in SERT expression (hSERT OE) enhanced, whereas a constitutive decrease in SERT expression (SERT KO) attenuated, 5-HT_2A/C function. Therefore, altered 5-HT_2A/C receptor functioning in response to hSERT gene variation may contribute to its influence on affective phenotypes.     

Evidence that orexin-A-evoked grooming in the rat is mediated by orexin-1 (OX1) receptors, with downstream 5-HT2C receptor involvement

RATIONALE: Orexins A and B have recently been discovered and shown to be derived from preproorexin, primarily expressed in the rat hypothalamus. Orexin-A has been ascribed a number of in vivo functions in the rat after intracerebroventricular (ICV) administration, including hyperphagia, neuroendocrine modulation and, most recently, evidence for a behavioural response characterised by an increase in grooming. OBJECTIVES: Here, we have investigated the orexin-receptor subtypes involved in the grooming response to orexin-A (3 microg, ICV) in the rat. METHODS: Male rats, habituated to clear Perspex behavioural observation boxes, were pretreated with antagonists with mixed selectivity for OX1, OX2, 5-HT2B and 5-HT2C receptor subtypes prior to the administration of orexin-A and the intense grooming response elicited by this peptide assessed. RESULTS: Pretreatment of rats with a mixed OX1/5-HT2B/2C receptor antagonist 1-(4-methylsulfanylphenyl)-3-quinolin-4-ylurea (SB-284422), revealed a significant, but incomplete, blockade of orexin-A-induced grooming. Despite the low potency of orexin-A at 5-HT2B and 5-HT2C receptors in vitro (pKi<5), studies were undertaken to determine whether downstream 5-HT2B or 5-HT2C receptors mediate in the grooming-elicited by orexin-A. Whilst the selective 5-HT2B receptor antagonist, SB-215505 (3 mg/kg, PO, 5-HT2B, pKi=8.58; OX1, pKB < 5.15) failed to effect orexin-A-induced grooming, the selective 5-HT2C receptor antagonist, SB-242084 (1 mg/kg, IP, 5-HT2C, pKi = 8.95; OX1, pKB < 5.1) potently antagonised the grooming response to this peptide. This suggested that the partial blockade of orexin-A-induced grooming obtained with SB-284422 might be attributable to its 5-HT2C and/or OX1 receptor blocking activity. However, complete blockade of orexin-A-induced grooming by the subsequently identified selective OX1 receptor antagonist 1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-yl urea hydrochloride, SB-334867-A (OX1, pKB = 7.4; OX2, pKB = 5.7), devoid of appreciable affinity for either 5-HT2B (pKi < 5.3) or 5-HT2C (pKi < 5.4) receptors, provides the first definitive evidence that a central behavioural effect of orexin-A (grooming) is mediated by OX1 receptors. CONCLUSIONS: This data suggests that orexin-A indirectly activates 5-HT2C receptors downstream from OX1 receptors to elicit grooming in the rat. The use of SB-334867-A in vivo will enable the role of OX,1 receptors within the rat central nervous system to be further characterised.     

Serotonin and drug reward: focus on 5-HT2C receptors

Pharmacological manipulation of the 5-hydroxytryptamine (5-HT; serotonin) system has long been associated with a regulation of feeding behaviour, however, the initial part of this article reviews evidence that central 5-HT systems similarly modulate reward-related behaviours, particularly drug reward. The second part of this article considers what we believe to be strong emerging pharmacological and genetic evidence that many of these effects are mediated through 5-HT_2C receptor signalling mechanisms. Finally, we consider the potential for selective 5-HT_2C agonists as therapies for substance abuse disorders and the medical implications for different 5-HT_2C receptor isoforms generated by RNA editing.     

RU 24969-induced emesis in the cat: 5-HT1 sites other than 5-HT1A, 5-HT1B or 5-HT1c implicated

RU 24969 was administered s.c. to cats and found to elicit emesis with a maximally effective dose of 1.0 mg/kg. 5-Methoxytryptamine was found to have lower efficacy and to produce a higher incidence of non-specific effects while trifluoromethylphenylpiperizine (TFMPP) was devoid of emetic effects. The emesis elicited by 1.0 mg/kg of RU 24969 was not altered by pretreatment with phentolamine, haloperidol, yohimbine or (−)-propranolol, indicating that catecholamines played no role in this response. The emesis was prevented by metergoline and methysergide but not by ketanserin, cyproheptadine, mesulergine, ICS 205 930, methiothepin, trimethobenzamide or BMY 7378. An indirect arguments is presented that implicates a role for 5-HT_1D sites. This conclusion must remain tentative until drugs selective for this site are synthesized and tested. The emesis was also prevented by 8-hydroxy-2-(di-n-propylamine)tetralin (8-OH-DPAT), confirming that this drug has a general antiemetic effect in cats.     

[3H]Rauwolscine: an antagonist radioligand for the cloned human 5-hydroxytryptamine2B (5-HT2B) receptor

In previous reports, [³H]5-HT has been used to characterize the pharmacology of the rat and human 5-HT_2B receptors. 5-HT, the native agonist for the 5-HT_2B receptor, has a limitation in its usefulness as a radioligand since it is difficult to study the agonist low-affinity state of a G protein-coupled receptor using an agonist radioligand. When using [³H]5-HT as a radioligand, rauwolscine was determined to have relatively high affinity for the human receptor (K_i human = 14.3 ± 1.2 nM, compared to K_i rat = 35.8 ± 3.8 nM). Since no known high affinity antagonist was available as a radioligand, these studies were performed to characterize [³H]rauwolscine as a radioligand for the cloned human 5-HT_2B receptor expressed in AV12 cells. When [³H]rauwolscine was initially tested for its usefulness as a radioligand, complex competition curves were obtained. After testing several α₂-adrenergic ligands, it was determined that there was a component of [³H]rauwolscine binding in the AV12 cell that was due to the presence of an endogenous α₂-adrenergic receptor. The α₂-adrenergic ligand efaroxan was found to block [³H]rauwolscine binding to the α₂-adrenergic receptor without significantly affecting binding to the 5-HT_2B receptor and was therefore included in all subsequent studies. In saturation studies at 37° C, [³H]rauwolscine labeled a single population of binding sites, K_d = 3.75 ± 0.23 nM. In simultaneous experiments using identical tissue samples, [³H]rauwolscine labeled 783 ± 10 fmol of 5-HT_2B receptors/mg of protein, as compared to 733 ± 14 fmol of 5-HT_2B receptors/mg of protein for [³H]5-HT binding. At 0° C, where the conditions for [³H]5-HT binding should label mostly the agonist high affinity state of the human 5-HT_2B receptor, [³H]rauwolscine (B_max = 951 ± 136 fmol/ mg), again labeled significantly more receptors than [³H]5-HT (B_max = 615 ± 34 fmol/mg). The affinity of [³H]rauwolscine for the human 5-HT_2B receptor at 0° C did not change, K_d = 4.93 ± 1.27 nM, while that for [³H]5-HT increased greatly (K_d at 37° C = 7.76 ± 1.06 nM; K_d at 0° C = 0.0735 ± 0.0081 nM). When using [³H]rauwolscine as the radioligand, competition curves for antagonist structures modeled to a single binding site, while agonist competition typically resulted in curves that best fit a two site binding model. In addition, many of the compounds with antagonist structures displayed higher affinity for the 5-HT_2B receptor when [³H]rauwolscine was the radioligand. Typically, ∼ 85% of [³H]rauwolscine binding was specific binding. These studies display the usefulness of [³H]rauwolscine as an antagonist radioligand for the cloned human 5-HT_2B receptor. This should provide a good tool for the study of both the agonist high- and low-affinity states of the human cloned 5-HT_2B receptor. Received: 26 June 1997 / Accepted: 30 August 1997     

5-HT1A和5-HT2A/2C受体在粉防己碱增强戊巴比妥钠睡眠中的介导作用

前期研究表明粉防己碱增强戊巴比妥钠诱导的催眠作用与5-HT系统相关。本研究采用戊巴比妥钠（45 mg/kg,i.p.）诱导的小鼠翻正反射消失和恢复实验方法,对粉防己碱与不同5-HT受体在增强戊巴比妥钠诱导睡眠中的相互作用进行了探讨。结果表明粉防己碱分别与选择性5-HT1A受体拈抗剂p-MPPI（1 mg/kg,i.p.）,选择性5-HT2A/2C受体拮抗剂ketanserin（1.5 mg/kg,i.p.）合用可以显著增强戊巴比妥钠诱导的催眠作用。选择性5-HT1A受体激动剂8-OH-DPAT（0.1 mg/kg,s.c.）或5-HT2A/2C受体激动剂DOI（0.2mg/kg,i.p.）能够显著减少戊巴比妥钠诱导的小鼠睡眠时间,而粉防己碱（60 mg/kg,i.g.）可以显著拮抗这种睡眠抑制作用。此结果提示,粉防己碱增强戊巴比妥钠诱导的催眠作用可能与5-HT1A受体和5-HT2A/2C受体有关。     

Selective labelling of 5-HT7 receptor recognition sites in rat brain using [H]5-carboxamidotryptamine

The aim of the present study was to establish a radioligand binding assay to selectively label the native 5-HT₇ receptor expressed in rat brain. In rat whole brain (minus cerebellum and striatum) homogenate, (±)-pindolol (10 μM)-insensitive [³H]5-CT ([³H]5-carboxamidotryptamine; 0.5 nM) specific binding (defined by 5-HT, 10 μM) displayed a pharmacological profile similar to the recombinant 5-HT₇ receptor, although the Hill coefficients for competition curves generated by methiothepin, ritanserin, sumatriptan, clozapine and pimozide were significantly less than unity. In homogenates of rat hypothalamus, (±)-pindolol (10 μM)-insensitive [³H]5-CT recognition sites also resembled, pharmacologically, the 5-HT₇ receptor, although pimozide still generated Hill coefficients significantly less than unity. Subsequent studies were performed in the additional presence of WAY100635 (100 nM) to prevent [³H]5-CT binding to residual, possibly, 5-HT_1A sites. Competition for this [³H]5-CT binding indicated the labelling in whole rat brain homogenate of a homogenous population of sites with the pharmacological profile of the 5-HT₇ receptor. Saturation studies also indicated that (±)-pindolol (10 μM)/WAY 100635 (100 nM)-insensitive [³H]5-CT binding to homogenates of whole rat brain was saturable and to an apparently homogenous population of sites which were labelled with nanomolar affinity (B_max=33.2±0.7 fmol mg⁻¹ protein, pK_d=8.78±0.05, mean±S.E.M., n=3). The development of this 5-HT₇ receptor binding assay will aid investigation of the rat native 5-HT₇ receptor.     

Distinct functional profiles of aripiprazole and olanzapine at RNA edited human 5-HT2C receptor isoforms

In this study we have functionally characterized aripiprazole (OPC-14597; 7-(4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butyloxy-3,4-dihydro-2-(1H)-quinolinone), the prototype of a new generation antipsychotic drug termed dopamine-serotonin-system stabilizer, in cells expressing 5-hydroxytryptamine2 (5-HT2) receptor subtypes in comparison with olanzapine. In Chinese hamster ovary (CHO) cells stably expressing 5-HT2 receptors, aripiprazole displayed a dual agonist/antagonist profile for 5-HT2C receptor (VNI isoform) mediated calcium signaling (EC50 1070 nM, IC50 281 nM). It exhibited no appreciable 5-HT2A or 5-HT2B agonism, whereas it antagonized 5-HT-stimulated calcium increase at either 5-HT2A or 5-HT2B receptor expressed in CHO cells (IC50s of 369 and 0.46 nM, respectively). In comparison, olanzapine was devoid of agonism but was an antagonist at all three subtypes, with a potency rank order of 5-HT2A (IC50, 2.5 nM)>5-HT2B (47 nM)>5-HT2C (69 nM). In human embryonic kidney (HEK) cells transiently expressing 5-HT2C receptor isoforms, aripiprazole exhibited full agonism at the unedited INI, but partial agonism at the partially edited VNI and fully edited VSV isoforms (EC50s of 571, 1086 and 2099 nM, respectively). A partial antagonism was also observed for aripiprazole at the two edited isoforms (IC50s of 1138 and 1000 nM, respectively). In contrast, while lacking agonist activity at the VNI and VSV, olanzapine showed inverse agonism at the INI isoform (IC50 594 nM), reaching a maximal attenuation of 20%. In addition, olanzapine was a full antagonist at all three isoforms, with a rank order of potency of VNI (IC50, 79 nM)>VSV (101 nM)>INI (3856 nM). The modest 5-HT2A antagonism and 5-HT2C partial agonism, along with reported D2 and 5-HT1A partial agonism, may allow aripiprazole to stabilize the disturbed dopamine-serotonin interplay in schizophrenia with a moderate yet adequate pharmacological intervention. 5-HT2C agonism may also underlie the minimal weight gain seen with aripiprazole.     

Correlation between 5-HT7 receptor affinity and protection against sound-induced seizures in DBA/2J mice

Audiogenic seizures can be induced in DBA/2J mice following intense auditory stimulation. A number of neurotransmitters, including 5-hydroxytryptamine (5-HT), are believed to be involved in mediating this effect since it has been shown previously that depletion of 5-HT or blockade of 5-HT receptors protects DBA/2J mice from these audiogenic seizures. The present study was undertaken to determine whether antagonism of the newly identified 5-HT₇ receptor may protect DBA/2J mice from audiogenic seizures by attempting to correlate in vivo potency of compounds with their affinity at the 5-HT₇ receptor. All compounds used in the correlation were shown to be antagonists at the 5-HT₇ receptor and a statistically significant correlation was observed between 5-HT₇ affinity and doses for half-maximal response (ED₅₀) for protection of DBA/2J mice from sound-induced seizures (r = 0.80; P < 0.05). No significant correlation was observed between in vivo activity and affinity at either 5-HT_1A, 5-HT_2A or 5-HT_2C receptors. It is also unlikely that interactions between the 5-ht₅ receptor will protect DBA/2J mice from audiogenic seizures since metergoline and mesulergine which are both active in this in vivo model have no affinity for the 5-ht₅ receptor. There are similarities between the pharmacology of the 5-HT₇ receptor and that of the 5-HT_1A receptor, however the correlation between the in vivo potency in DBA/2J mice and 5-HT_1A affinity was not significant. Furthermore, the 5-HT_1A receptor antagonist WAY 100135 did not protect DBA/2J mice from audiogenic seizures at doses that antagonise 5-HT_1A receptor-mediated effects in mice. These data suggest that antagonism of 5-HT₇ receptors may protect against audiogenic seizures in DBA/2J mice although a definitive conclusion must await studies with selective 5-HT₇ antagonists. Received: 20 March 1997 / Accepted: 10 August 1997     

New 5-HT2C receptor agonists

While there is evidence for the involvement of different serotonin (5hydroxytryptamine; 5-HT) receptors in the regulation of food intake and body weight maintenance, the data supporting the role of the 5-HT_2C receptor are especially strong. This information has elevated 5-HT_2C receptor activation into one of the most competitive research areas for antiobesity therapy, a therapeutic area with few (if any) safe, effective pharmacological agents available. Varying amounts of evidence also exist to support the use of 5-HT_2C agonists for the pharmacological treatment of several other conditions, including anxiety, depression, obsessive–compulsive disorder, sexual dysfunction, epilepsy, urinary incontinence and hot flushes. The therapeutic potential of 5-HT_2C receptor modulation has spawned a successful search for 5-HT_2C receptor agonists. This review will focus on recent patent applications through August 2003 that describe compounds that have agonist activity at the 5-HT_2C receptor, and should be complementary to previous Expert Opinion discussions on the 5-HT_2C receptor [1-7].     

Chromium treatment decreases the sensitivity of 5-HT<Subscript>2A</Subscript> receptors

RATIONALE: Recent case series suggest that chromium picolinate in doses of 400 microg daily may have antidepressant properties, perhaps through increasing the peripheral availability of tryptophan for brain serotonin (5-HT) synthesis. OBJECTIVES: To determine the effects of chromium treatment on plasma tryptophan availability and on brain 5-HT function in human and animal models. METHODS: We studied the effects of short-term chromium supplementation on plasma concentrations of tryptophan and other large neutral amino acids. Brain 5-HT function was assessed by measuring the corticosterone/cortisol response to the 5-HT precursor, 5-hydroxytryptophan (5-HTP), a response believed to be mediated via indirect activation of 5-HT(2A) receptors. RESULTS: In rats, chromium increased peripheral and central tryptophan availability and elevated brain 5-HT content. Changes in peripheral tryptophan availability were not seen in humans but in both rats and humans, chromium lowered the cortisol response to challenge with 5-HTP. CONCLUSIONS: Chromium can modify brain 5-HT function in humans and animals, perhaps by altering the sensitivity of central 5-HT(2A) receptors.     

Mechanism of tolerance development to 2,5-dimethoxy-4-iodoamphetamine in rats: down-regulation of the 5-HT2A, but not 5-HT2C, receptor

  Rationale: Defining the mechanism of tolerance development to hallucinogenic drugs will help to explain their mechanism of action. Objectives: The present study was conducted to determine first, if tolerance develops to the discriminative stimulus (DS) properties of the hallucinogen, 2,5 dimethoxy-4-iodo-amphetamine (DOI) and second, the mechanism mediating tolerance. Methods: Rats were trained to discriminate 0.75 mg/kg DOI from saline on a concurrent VI-30-min schedule of reinforcement with a 15-min time-out for incorrect responses. To evaluate tolerance development, rats were assigned to one of four groups and treated with either chronic saline or chronic DOI. Prior to chronic treatment, two groups were tested for choice behavior following vehicle administration while the remaining two groups were tested following the administration of 0.375 mg/kg DOI. One group from each pre-test condition was injected with either saline or DOI (1 mg/kg) for 8 days. Twenty-four hours after the last chronic injection the pre-test treatments were replicated. Using receptor autoradiography, the density of 5-HT_2A and 5-HT_2C receptors was measured in independent groups of rats that had received identical treatment conditions. Results: Animals receiving chronic DOI showed a 60% decrease in DOI lever responding (from 100% to 40%) when tested on 0.375 mg/kg DOI, while animals receiving chronic saline showed no change in percent choice (100%) on the DOI lever. Significant changes in binding were observed in 5-HT_2A receptors but not 5-HT_2C receptors. The results of tests with antagonists were consistent with the changes in binding. Conclusions: These results suggest that behavioral tolerance to DOI reflects neuroadaptive changes in 5-HT_2A receptors. Received: 17 July 1998 / Final version: 19 January 1999     

Antidepressant-like responses to the combined sigma and 5-HT1A receptor agonist OPC-14523

The antidepressant-like activity of a novel compound, OPC-14523, was investigated in comparison with the conventional antidepressants, fluoxetine and imipramine. OPC-14523 bound with nanomolar affinities to sigma receptors (IC₅₀=47–56 nM), the 5-HT_1A receptor (IC₅₀=2.3 nM), and the 5-HT transporter (IC₅₀=80 nM). OPC-14523 inhibited the in vitro reuptake of ³H-5-HT (IC₅₀=27 nM), but it showed very weak inhibitory activity on ³H-NE and ³H-DA reuptake. OPC-14523 did not inhibit MAO A or B activities or muscarinic receptors. A single oral administration of OPC-14523 produced a marked antidepressant-like effect in the forced swimming test (FST) with rats (ED₅₀=27 mg/kg) and mice (ED₅₀=20 mg/kg) without affecting the general locomotor activity. In contrast, fluoxetine and imipramine each required at least four days of repeated dosing to show this activity. The acute activity of OPC-14523 was blocked by pretreatment with the sigma receptor antagonist NE-100 or the selective 5-HT_1A receptor antagonist WAY-100635. The induction of flat body posture by OPC-14523 was blocked by the selective 5-HT_1A receptor antagonist NAN-190, and forebrain 5-HT biosynthesis was attenuated by OPC-14523 at behaviorally effective doses. In contrast, OPC-14523, unlike fluoxetine, failed to inhibit 5-HT reuptake at oral doses below 100 mg/kg. Thus, the acute antidepressant-like action of OPC-14523 is achieved by the combined stimulation of sigma and 5-HT_1A receptors without inhibition of 5-HT reuptake in vivo.     

Ritanserin antagonism of m-chlorophenylpiperazine effects in neuroleptic-free schizophrenics patients: support for serotonin-2 receptor modulation of schizophrenia symptoms

RATIONALE: Serotonin-2 (5-HT(2)) receptor antagonism has been hypothesized to have antipsychotic activity. However, there has been limited evidence directly linking 5-HT(2) receptor antagonism to symptom control in schizophrenic patients. Objectives: In order to test this hypothesis this study evaluated the capacity of pretreatment with the 5-HT(2) receptor antagonist ritanserin to attenuate the effects of the 5-HT agonist, m-chlorophenylpiperazine (mCPP). METHODS: Twenty-two male inpatients who met DSM-III-R criteria for schizophrenia or schizoaffective disorder completed 4 test days during which 10 mg ritanserin or matched placebo was administered orally 50 min prior to the intravenous infusion of 0.1 mg/kg mCPP or saline. The test days were conducted in a randomized order under double-blind conditions. RESULTS: mCPP mildly and transiently increased positive symptoms and behavioral activation but not negative symptoms, as assessed by the Brief Psychiatric Rating Scale. mCPP also raised plasma prolactin and cortisol levels. All of these effects were attenuated by ritanserin pretreatment. CONCLUSIONS: These data support a contribution of 5-HT(2) receptor stimulation to symptom exacerbation in schizophrenic patients and a role for 5-HT(2) receptor antagonism in the prevention of this effect.     

药物发现新靶点--5-HT2C受体

5-羟色胺(5-HT或serotonin)是中枢神经系统及外周神经系统的重要神经递质。近年来，越来越多的研究结果表明，5-HT2c受体亚型与多种疾病的病理机制相关，有望成为有潜力的药物靶点。综述了5-HT2c受体亚型的结构、体内分布、信号转导以及它与肥胖、成瘾性和癫痫的作用机制之间的关系。     

A PET study of brain 5-HT2 receptors and their correlation with platelet 5-HT2 receptors in healthy humans

RATIONALE: Platelets share many properties with brain serotonergic neurons such as active 5-hydroxytryptamine (5-HT) transport, 5-HT2 receptors, and mitochondrial monoamine oxidase. OBJECTIVES: We measured brain 5-HT2 receptors and platelet 5-HT2 receptors in healthy volunteers to determine if there was any correlation between the two measures. METHODS: Ten healthy volunteers with no lifetime history of psychiatric illness or family history in first-degree relatives were recruited. 5-HT2 receptor binding was determined for each subject with positron emission tomography and [18F]setoperone scan in the brain and with 3H-LSD binding in platelets. RESULTS: We found no significant correlation between 5-HT2 binding potential (BP) in platelets (Bmax/Kd) and a semiquantitative estimate of 5-HT2 BP in frontal, parietal, and temporal cortical regions. SPM voxel based analysis also showed no significant correlation between the 5-HT2 BP in platelets and in the brains of the study subjects. CONCLUSIONS: Brain 5-HT2 receptor binding was not significantly correlated to platelet 3H-LSD binding in healthy subjects. This raises questions about the validity of generalizing findings from platelet studies to 5-HT neurons in the brain.     

The potential use of selective 5-HT2C agonists in treating obesity

Activation of central 5-HT_2C receptors as a strategy for appetite suppression and weight control is supported by animal pharmacology and human clinical studies. Considerable evidence comes from the weight-loss effects of fenfluramine, a non-selective 5-HT_2C agonist. Advances in molecular pharmacology have led to an understanding of the effects of 5-HT_2C receptor activation on food intake and satiety, in addition to providing insight into the causes of cardiac valvular insufficiency and pulmonary hypertension associated with the use of fenfluramine. However, clinically validated animal models of drug-induced disease and knowledge of the molecular mechanisms of these safety issues is lacking. For this reason, the development of selective 5-HT_2C agonists for the treatment of obesity has remained a challenge.     

The receptor mechanisms underlying the disruptive effects of haloperidol and clozapine on rat maternal behavior: A double dissociation between dopamine D2 and 5-HT2A/2C receptors

Many antipsychotic drugs disrupt active components of maternal behavior such as pup approach, pup retrieval and nest building at clinically relevant doses in postpartum female rats. However, the neurochemical mechanisms underlying such a disruptive effect remain to be determined. This study examined the neurochemical mechanisms that mediate the disruptive effects of haloperidol (a typical antipsychotic) and clozapine (an atypical antipsychotic) on rat maternal behavior. Postpartum rats were administered with haloperidol (0.2 mg/kg, sc) or clozapine (10.0 mg/kg, sc) together with either vehicle (saline or water), quinpirole (a selective dopamine D₂/D₃ agonist, 0.5 or 1.0 mg/kg, sc), or 2,5-dimethoxy-4-iodo-amphetamine (DOI, a selective 5-HT_2A/2C agonist, 1.0 or 2.5 mg/kg, sc), and their maternal behaviors were tested at different time points before and after drug administration. Haloperidol and clozapine treatment disrupted pup approach, pup retrieval, pup licking and nest building. Pretreatment of quinpirole, but not DOI, dose-dependently reversed the haloperidol-induced disruptions. In contrast, pretreatment of DOI, but not quinpirole, dose-dependently reversed the clozapine-induced disruptions. Quinpirole pretreatment even exacerbated the clozapine-induced disruption of pup retrieval and nest building. These findings suggest a double dissociation mechanism underlying the disruption of haloperidol and clozapine on rat maternal behavior. Specifically, haloperidol disrupts maternal behavior primarily by blocking dopamine D₂ receptors, whereas clozapine exerts its disruptive effect primarily by blocking the 5-HT_2A/2C receptors. Our findings also suggest that 5-HT receptors are involved in the mediation of rat maternal behavior.