Inhibition of serotonergic signaling induces higher consumption of both sucrose solution and toxic baits in carpenter ants.

Biogenic amines play an important role in the regulation of appetitive responses in insects. Among them, serotonin (5-HT) regulates feeding-related processes in numerous insect species. In carpenter ants, 5-HT administration has been shown to depress feeding behavior, thus opening the possibility of using 5-HT modulation in control strategies against those species considered as pest. Here we studied if administration of a 5-HT antagonist, ketanserin, promotes feeding of a sucrose solution and a toxic bait in carpenter ants Camponotus mus. We found that 3 h after a single oral administration of ketanserin, the mass of sucrose solution consumed by carpenter ants increased significantly. A similar effect was found after a chronic administration that lasted 5 days. Yet, ketanserin did neither affect the intake rates nor the activity of the pharyngeal pump that mediates feeding dynamics. In addition, ketanserin promoted the consumption of a toxic bait based on boric acid. Our results thus show that feeding motivation and consumption of both sucrose solution and a toxic bait can be enhanced via prior administration of ketanserin. We discuss the possible mechanisms underlying these effects and conclude that understanding basic physiological and neural principles that underlie feeding motivation allows establishing more efficient control strategies for pest insects.

LSD-induced increases in social adaptation to opinions similar to one's own are associated with stimulation of serotonin receptors.

Adapting one's attitudes and behaviors to group norms is essential for successful social interaction and, thus, participation in society. Yet, despite its importance for societal and individual functioning, the underlying neuropharmacology is poorly understood. We therefore investigated its neurochemical and neural correlates in a pharmacological functional magnetic resonance imaging study. Lysergic acid diethylamide (LSD) has been shown to alter social processing and therefore provides the unique opportunity to investigate the role of the 5-HT2A receptor in social influence processing. Twenty-four healthy human volunteers received either (1) placebo + placebo, (2) placebo + LSD (100 µg), or (3) the 5-HT2A receptor antagonist ketanserin (40 mg) + LSD (100 µg) at three different occasions in a double-blind, randomized, counterbalanced, cross-over design. LSD increases social adaptation but only if the opinions of others are similar to the individual's own. These increases were associated with increased activity in the medial prefrontal cortex while participants received social feedback. Furthermore, pretreatment with the 5-HT2A antagonist ketanserin fully blocked LSD-induced changes during feedback processing, indicating a key role of the 5-HT2A system in social feedback processing. Our results highlight the crucial role of the 5-HT-system in social influence and, thus, provide important insight into the neuropharmacological basis of social cognition and behavior.

Serotonin receptors 5-HTR2A and 5-HTR2B are involved in cigarette smoke-induced airway inflammation, mucus hypersecretion and airway remodeling in mice.

BACKGROUND: Cigarette smoke plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Recently, elevated serotonin (5-HT) levels were found in the plasma of COPD patients. The role of 5-HT and its receptors in airway inflammation and remodeling induced by cigarette smoke is unclear. METHODS: BALB/c mice received the 5-HTR2A inhibitor ketanserin, the 5-HTR2B inhibitor RS-127445 or the natural 5-HTR2A/2B inhibitor quercetin intraperitoneally, then were exposed to cigarette smoke for 6 or 12 weeks. Control mice received placebo and were exposed to room air or cigarette smoke. Mice were sacrificed and bronchial alveolar lavage fluid (BALF) and lung tissue samples were collected. RESULTS: Immunohistochemistry and western blot confirmed an increase in both 5-HTR2A and 5-HTR2B expression in mouse lungs after exposure to cigarette smoke for 6 and 12 weeks. Cigarette smoke induced accumulation of macrophages and neutrophils and increased levels of inflammatory cytokines, including IL-1ß and TNF-ɑ, in BALF and lung tissue; these effects were inhibited by ketanserin, RS-127445 and quercetin. Pretreatment with 5-HT receptor antagonists suppressed the goblet cell hyperplasia induced by 6- or 12-week exposure to cigarette smoke, based on Alcian blue-periodic acid Schiff staining. After 12 weeks of cigarette smoke exposure, Masson's staining showed fibrosis surrounding the mouse airways, and inhibitor pretreatment significantly attenuated the thickening and collagen deposition around the small airways. CONCLUSIONS: Our results suggest that cigarette smoke-induced airway inflammation and small airway remodeling are partially mediated by 5-HTR2A and 5-HTR2B, which could be a new therapeutic target for airway remodeling in COPD.

Kinetic analysis of [18F] altanserin bolus injection in the canine brain using PET imaging.

BACKGROUND: Currently, [18F] altanserin is the most frequently used PET-radioligand for serotonin2A (5-HT2A) receptor imaging in the human brain but has never been validated in dogs. In vivo imaging of this receptor in the canine brain could improve diagnosis and therapy of several behavioural disorders in dogs. Furthermore, since dogs are considered as a valuable animal model for human psychiatric disorders, the ability to image this receptor in dogs could help to increase our understanding of the pathophysiology of these diseases. Therefore, five healthy laboratory beagles underwent a 90-min dynamic PET scan with arterial blood sampling after [18F] altanserin bolus injection. Compartmental modelling using metabolite corrected arterial input functions was compared with reference tissue modelling with the cerebellum as reference region. RESULTS: The distribution of [18F] altanserin in the canine brain corresponded well to the distribution of 5-HT2A receptors in human and rodent studies. The kinetics could be best described by a 2-Tissue compartment (2-TC) model. All reference tissue models were highly correlated with the 2-TC model, indicating compartmental modelling can be replaced by reference tissue models to avoid arterial blood sampling. CONCLUSIONS: This study demonstrates that [18F] altanserin PET is a reliable tool to visualize and quantify the 5-HT2A receptor in the canine brain.

Role of the 5-HT2A Receptor in Self- and Other-Initiated Social Interaction in Lysergic Acid Diethylamide-Induced States: A Pharmacological fMRI Study.

Distortions of self-experience are critical symptoms of psychiatric disorders and have detrimental effects on social interactions. In light of the immense need for improved and targeted interventions for social impairments, it is important to better understand the neurochemical substrates of social interaction abilities. We therefore investigated the pharmacological and neural correlates of self- and other-initiated social interaction. In a double-blind, randomized, counterbalanced, crossover study 24 healthy human participants (18 males and 6 females) received either (1) placebo + placebo, (2) placebo + lysergic acid diethylamide (LSD; 100 µg, p.o.), or (3) ketanserin (40 mg, p.o.) + LSD (100 µg, p.o.) on three different occasions. Participants took part in an interactive task using eye-tracking and functional magnetic resonance imaging completing trials of self- and other-initiated joint and non-joint attention. Results demonstrate first, that LSD reduced activity in brain areas important for self-processing, but also social cognition; second, that change in brain activity was linked to subjective experience; and third, that LSD decreased the efficiency of establishing joint attention. Furthermore, LSD-induced effects were blocked by the serotonin 2A receptor (5-HT2AR) antagonist ketanserin, indicating that effects of LSD are attributable to 5-HT2AR stimulation. The current results demonstrate that activity in areas of the "social brain" can be modulated via the 5-HT2AR thereby pointing toward this system as a potential target for the treatment of social impairments associated with psychiatric disorders.SIGNIFICANCE STATEMENT Distortions of self-representation and, potentially related to this, dysfunctional social cognition are central hallmarks of various psychiatric disorders and critically impact disease development, progression, treatment, as well as real-world functioning. However, these deficits are insufficiently targeted by current treatment approaches. The administration of lysergic acid diethylamide (LSD) in combination with functional magnetic resonance imaging and real-time eye-tracking offers the unique opportunity to study alterations in self-experience, their relation to social cognition, and the underlying neuropharmacology. Results demonstrate that LSD alters self-experience as well as basic social cognition processing in areas of the "social brain". Furthermore, these alterations are attributable to 5-HT2A receptor stimulation, thereby pinpointing toward this receptor system in the development of pharmacotherapies for sociocognitive deficits in psychiatric disorders.

Serotonin 2A Receptor Signaling Underlies LSD-induced Alteration of the Neural Response to Dynamic Changes in Music.

Classic psychedelic drugs (serotonin 2A, or 5HT2A, receptor agonists) have notable effects on music listening. In the current report, blood oxygen level-dependent (BOLD) signal was collected during music listening in 25 healthy adults after administration of placebo, lysergic acid diethylamide (LSD), and LSD pretreated with the 5HT2A antagonist ketanserin, to investigate the role of 5HT2A receptor signaling in the neural response to the time-varying tonal structure of music. Tonality-tracking analysis of BOLD data revealed that 5HT2A receptor signaling alters the neural response to music in brain regions supporting basic and higher-level musical and auditory processing, and areas involved in memory, emotion, and self-referential processing. This suggests a critical role of 5HT2A receptor signaling in supporting the neural tracking of dynamic tonal structure in music, as well as in supporting the associated increases in emotionality, connectedness, and meaningfulness in response to music that are commonly observed after the administration of LSD and other psychedelics. Together, these findings inform the neuropsychopharmacology of music perception and cognition, meaningful music listening experiences, and altered perception of music during psychedelic experiences.

Methoxetamine produces rapid and sustained antidepressant effects probably via glutamatergic and serotonergic mechanisms.

Depression afflicts around 16% of the world's population, making it one of the leading causes of disease burden worldwide. Despite a number of antidepressants available today, the delayed onset time and low remission rate of these treatments are still a major challenge. The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has shown to produce rapid and sustained antidepressant effects and has paved the way for a new generation of glutamate-based antidepressants. Methoxetamine (MXE) is a ketamine analogue that acts as an NMDA receptor antagonist and a serotonin reuptake inhibitor. However, no studies have evaluated the antidepressant effects of MXE. Here, we assessed whether MXE produces antidepressant effects and explored possible mechanisms underlying its effects. Mice were treated with MXE (2.5, 5, or 10 mg/kg) and their behavior was evaluated 30 min and 24 h later in an array of behavioral experiments used for screening antidepressant drugs. A separate group of mice were treated with NBQX, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist, or ketanserin, a 5HT2 receptor antagonist, before MXE (5 mg/kg) administration in the forced swimming test (FST). We also investigated the effect of MXE on glutamatergic- and serotonergic-related genes in the mouse hippocampus using quantitative real-time PCR. MXE produced antidepressant effects 30 min after treatment that persisted for 24 h. Both NBQX and ketanserin blocked the antidepressant effects of MXE in the FST. MXE also altered hippocampal glutamatergic- and serotonergic gene expressions. These results suggest that MXE has rapid and sustained antidepressant effects, possibly mediated by the glutamatergic and serotonergic system.

Berberine produces antidepressant-like effects in ovariectomized mice.

Berberine has been reports to have antidepressant-like effects. However, it is seldom known whether berberine produces antidepressant-like effects in ovariectomized mice, which exhibit depressive-like responses. To examine the antidepressant-like effects of berberine in ovariectomized mice, behavioral tests were conducted, including the forced swimming test and the open field test. To elucidate the mechanisms, levels of BDNF, phosphorylated CREB and phosphorylated eEF2 were analyzed by western blotting, and c-Fos induction was examined by immunohistochemistry. In the forced swimming test, berberine decreased the immobility time in a dose-dependent manner, reversing the depressive-like effect observed in ovariectomized mice, and this effect was blocked by the 5-HT2 antagonist ketanserin. In addition, western blotting indicated that BDNF and peEF2 in the hippocampus, but not pCREB/CREB in the frontal cortex, were affected by berberine treatment. Furthermore, immunohistochemistry demonstrated that the reduction in c-Fos induced by ovariectomy were greater after berberine treatment. Ketanserin also antagonized the effect of berberine on the c-Fos expression. Our findings suggest that berberine exerts antidepressant-like effects in ovariectomized mice, and 5-HT2 receptor activation may be partially related to the antidepressant-like effects of the berberine by BDNF-CREB and eEF2 pathways.

Involvement of serotonin 2A receptor activation in modulating medial prefrontal cortex and amygdala neuronal activation during novelty-exposure.

The medial prefrontal cortex (PFC) plays a major role in executive function by exerting a top-down control onto subcortical areas. Novelty-induced frontal cortex activation is 5-HT2A receptor (5-HT2AR) dependent. Here, we further investigated how blockade of 5-HT2ARs in mice exposed to a novel open-field arena affects medial PFC activation and basolateral amygdala (BLA) reactivity. We used c-Fos immunoreactivity (IR) as a marker of neuronal activation and stereological quantification for obtaining the total number of c-Fos-IR neurons as a measure of regional activation. We further examined the impact of 5-HT2AR blockade on the striatal-projecting BLA neurons. Systemic administration of ketanserin (0.5mg/kg) prior to novel open-field exposure resulted in reduced total numbers of c-Fos-IR cells in dorsomedial PFC areas and the BLA. Moreover, there was a positive correlation between the relative time spent in the centre of the open-field and BLA c-Fos-IR in the ketanserin-treated animals. Unilateral medial PFC lesions blocked this effect, ascertaining an involvement of this frontal cortex area. On the other hand, medial PFC lesioning exacerbated the more anxiogenic-like behaviour of the ketanserin-treated animals, upholding its involvement in modulating averseness. Ketanserin did not affect the number of activated striatal-projecting BLA neurons (measured by number of Cholera Toxin b (CTb) retrograde labelled neurons also being c-Fos-IR) following CTb injection in the ventral striatum. These results support a role of 5-HT2AR activation in modulating mPFC and BLA activation during exposure to a novel environment, which may be interrelated. Conversely, 5-HT2AR blockade does not seem to affect the amygdala-striatal projection.

Distinct effect of 5-HT1A and 5-HT2A receptors in the medial nucleus of the amygdala on tonic immobility behavior.

The tonic immobility (TI) response is an innate fear behavior associated with intensely dangerous situations, exhibited by many species of invertebrate and vertebrate animals. In humans, it is possible that TI predicts the severity of posttraumatic stress disorder symptoms. This behavioral response is initiated and sustained by the stimulation of various groups of neurons distributed in the telencephalon, diencephalon and brainstem. Previous research has found the highest Fos-IR in the posteroventral part of the medial nucleus of the amygdala (MEA) during TI behavior; however, the neurotransmission of this amygdaloid region involved in the modulation of this innate fear behavior still needs to be clarified. Considering that a major drug class used for the treatment of psychopathology is based on serotonin (5-HT) neurotransmission, we investigated the effects of serotonergic receptor activation in the MEA on the duration of TI. The results indicate that the activation of the 5HT1A receptors or the blocking of the 5HT2 receptors of the MEA can promote a reduction in fear and/or anxiety, consequently decreasing TI duration in guinea pigs. In contrast, blocking the 5HT1A receptors or activating the 5HT2 receptors in this amygdalar region increased the TI duration, suggesting an increase in fear and/or anxiety. These alterations do not appear to be due to a modification of spontaneous motor activity, which might non-specifically affect TI duration. Thus, these results suggest a distinct role of the 5HT receptors in the MEA in innate fear modulation.

Effects of ketanserin on microcirculatory alterations in septic shock: An open-label pilot study.

INTRODUCTION: Microcirculatory alterations in sepsis are associated with increased morbidity and mortality. These alterations occur despite macrohemodynamic resuscitation. Alternative pro-microcirculatory strategies, including vasodilatory drugs, have been suggested to improve capillary blood flow. Ketanserin, a serotonin receptor antagonist, is an attractive candidate because of its vasodilatory, antithrombotic, and anti-inflammatory effects. METHODS: This is an open-label pilot study on the effect of ketanserin administration on microcirculatory alterations in septic shock, defined as microvascular flow index (MFI)≤2.5 after a strict macrohemodynamic resuscitation protocol. Sidestream dark-field imaging was applied to assess the microcirculation. A stepwise incremental dose regiment was applied until an MFI>2.9, the primary end point, was reached. RESULTS: Ten patients (Acute Physiology and Chronic Health Evaluation IV scores of 115 [100-136]) were included. Baseline MFI was 1.71 (1.31-2.32) and was significantly increasing to 2.96 (2.54-3.00; P=.021) during the ketanserin infusion. The total ketanserin dose was 0.09 (0.08-0.13) mg/kg per patient in 60 (30-60) minutes. In 3 patients (30%), the ketanserin infusion was discontinued due to refractory hypotension. CONCLUSION: An improvement in microcirculatory perfusion was observed during ketanserin administration in patients with septic shock after macrohemodynamic resuscitation. This finding needs further exploration in a placebo-controlled setting.

Tramadol and Tramadol+Caffeine Synergism in the Rat Formalin Test Are Mediated by Central Opioid and Serotonergic Mechanisms.

Different analgesic combinations with caffeine have shown this drug to be capable of increasing the analgesic effect. Many combinations with nonsteroidal anti-inflammatory drugs (NSAIDs) have been carried out, but, in regard to opioids, only combinations with morphine and tramadol have been reported. The antinociceptive synergism mechanism of these combinations is not well understood. The purpose of the present study was to determine the participation of spinal and supraspinal opioidergic and serotonergic systems in the synergic effect of the tramadol+caffeine combination in the rat formalin test. At the supraspinal level, the opioid antagonist, naloxone, completely reversed the effect of the drug combination, whereas ketanserin, a 5-HT2 receptor antagonist, inhibited the effect by 60%; however, ondansetron, a 5-HT3 receptor antagonist, did not alter the combination effect. When the antagonists were intrathecally administered, there was a significant reduction in all tramadol-caffeine combination effects. With respect to tramadol alone, there was significant participation of the opioid system at the supraspinal level, whereas it was the serotonergic system that participated at the spinal level by means of the two receptors studied. In conclusion, the tramadol+caffeine combination synergically activated the opioid and serotonergic systems at the supraspinal level, as well as at the spinal level, to produce the antinociception.

Dressings and topical agents for arterial leg ulcers.

BACKGROUND: It is estimated that people in industrialised countries have a 1% chance of suffering from a leg ulcer at some time in their life. The majority of leg ulcers are associated with circulation problems; poor blood return in the veins causes venous ulcers (around 70% of ulcers) and poor blood supply to the legs causes arterial ulcers (around 22% of ulcers). Treatment of arterial leg ulcers is directed towards correcting the poor arterial blood supply, for example by correcting arterial blockages (either surgically or pharmaceutically). If the blood supply has been restored, these arterial ulcers can heal following principles of good wound care. Dressings and topical agents make up a part of good wound care for arterial ulcers but there are many products available and it is unclear what impact these have on ulcer healing. This is an update of a review first published in 2003. OBJECTIVES: To determine whether topical agents and wound dressings affect healing in arterial ulcers. To compare healing rates, patient-centred outcomes and costs between wound dressings and topical agents. SEARCH METHODS: For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched November 2014) and The Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library) (2014, Issue 10). SELECTION CRITERIA: Randomised controlled trials (RCTs), or controlled clinical trials (CCTs) evaluating dressings and topical agents in the treatment of arterial leg ulcers were eligible for inclusion. The participants had to have ulcers that were described as arterial, and the time to healing, proportion completely healed, or rate of reduction in ulcer area had to be reported. All wound dressings and topical agents were eligible for inclusion in this review. DATA COLLECTION AND ANALYSIS: The two review authors independently extracted information on the participants' characteristics, the interventions, and outcomes using a standardised data extraction form. Disagreements between the review authors were resolved through discussion. MAIN RESULTS: One trial met the inclusion criteria, which was a small trial that compared 2% ketanserin ointment in polyethylene glycol (PEG) with vehicle alone (PEG) control, changed twice a day in 40 participants with arterial leg ulcers. The overall quality of the evidence was low with a single small included study which showed inadequate reporting of the results and had too short a follow-up time (eight weeks) to be able to capture sufficient healing events to allow comparisons to be made. In addition, the study was of low methodological quality. The majority of the 'risk of bias' domains received an 'unclear' risk rating as very little information was provided in the text on the methods of the study. The trial demonstrated increased wound healing in the ketanserin group, compared with the control group, but the trial was too small and had too short a follow-up period (eight weeks) to be able to determine whether there was any difference in healing rates. It should also be noted that ketanserin is not licensed in all countries for use in humans. AUTHORS' CONCLUSIONS: There is insufficient evidence to determine whether the choice of topical agent or dressing affects the healing of arterial leg ulcers.

Effects of a combination of ketanserin and propranolol on inflammatory hyperalgesia in rats.

Pain management is still challenging in clinic as current analgesics either are not very effective or produce serious adverse effects. This study aimed to examine if old drugs could display the new use and to develop a novel therapy for inflammatory pain. Injection of carrageenan in hindpaw evoked hyperalgesia detected by noxious heat stimulation. Intraplantar (i.pl.) injection of the 5-HT1A receptor antagonist WAY-100635 increased paw withdrawal latency (PWL) above normal level (hypoalgesia) during the late phase of carrageenan-evoked inflammation. The hypoalgesia was completely abolished by systemic injection of naloxone chloride and naloxone methiodide. Moreover, i.pl. injection of a combination of WAY-100635 and ketanserin, a 5-HT2A receptor antagonist, at their minimal doses attenuated hyperalgesia in the late phase of carrageenan-evoked inflammation. Subcutaneous (s.c.) injection of both ketanserin and propranolol dose-dependently inhibited carrageenan-evoked hyperalgesia. The treatment with a combination of ketanserin and propranolol by s.c. injection abolished carrageenan-evoked hyperalgesia at the doses, at which the drugs failed to alter the hypersensitivity when they were given alone. Furthermore, the combination of ketanserin and propranolol was also effective in relieving arthritic hyperalgesia and muscle pain at a minimal dose. The present study suggests that the activation of 5-HT1A receptors suppressed naloxone-reversible antinociception contributing to the maintenance of inflammatory pain, and that the concomitant blockade of 5-HT1A and 5-HT2A receptors in the periphery produced synergistic effects on inflammatory hyperalgesia. It is proposed that the combination of ketanserin and propranolol injected s.c. could be a promising therapy for relieving inflammatory pain with minimal side effects.

[Effect of agonists and antagonists of 5-HT2 receptors on rats with different choice of reinforcement value].

The influence of drugs, agonist (DOI) and antagonist (ketanserin) ofserotonin receptors 5-HT2 on the behavior of rats tested by the method of choice to the value of reinforcement was investigated. Depending on their preferences in food reinforcement rats were divided into self-control (choosing more valuable, delayed reinforcement) and impulsive (low value, immediate reinforcement) groops. An hour before the test animals were administrated i.p. DOI and ketanserin at a dose of 0.2 mg/kg. Evaluated parameters of rat behavior: number of clicks on a particular pedal, the latencies and the number of omitted responses. The administration of ketanserin resulted in a statistically significant decrease in the choice of low-value immediate reinforcement of impulsive rats, and did not statistically significant alter the behavior of self-control animals. After the administration of DOI no statistically significant changes in the choice of reinforcement were observed in the groups of impulsive and self-control rats. But the study of the effect this drug in tote without division into typological groups the decreasing in impulsivity was revealed. In some cases DOI reduced the number of missing responses, and ketanserin--reduced the latency of response.

[Behavioral effects during the local activation and blockade of serotonin and dopamine receptors in the frontal cortex in cats in the model with a choice of reinforcements of different value].

In the model with a choice of reinforcements of different value animals were able to "impulsive" and "self-controlled" behavior with an equal probability. Five adult cats were tested. A local application of agonists of 5-HT(1A) and 5-HT(2A/C) receptors (8-OH-DPAT, DOI) in the frontal cortex have resulted in a significant decrease of the "impulsive" reactions and an increase of omissions. The administration of antagonists of 5-HT(2A/C) receptors (ketanserin) and D1/D2 receptors (SCH 23390, raclopride) have impaired the "impulsive" behavior. However the combined administration of agonists/antagonists of 5-HT(2A/C) receptors and antagonists of D1/D2 receptors have not shown the significant changes in behavior as compared with control experiments. The data showed the realization of the optimal behavior with the "impulsive" and "self-controled" reactions in ambivalent animals requires the involvement of both dopaminergic and serotoninergic systems for the regulation of the activity of neurons in frontal cortex areas.

Neuronal serotonin regulates growth of the intestinal mucosa in mice.

BACKGROUND & AIMS: The enteric abundance of serotonin (5-HT), its ability to promote proliferation of neural precursors, and reports that 5-HT antagonists affect crypt epithelial proliferation led us to investigate whether 5-HT affects growth and maintenance of the intestinal mucosa in mice. METHODS: cMice that lack the serotonin re-uptake transporter (SERTKO mice) and wild-type mice were given injections of selective serotonin re-uptake inhibitors (gain-of-function models). We also analyzed mice that lack tryptophan hydroxylase-1 (TPH1KO mice, which lack mucosal but not neuronal 5-HT) and mice deficient in tryptophan hydroxylase-2 (TPH2KO mice, which lack neuronal but not mucosal 5-HT) (loss-of-function models). Wild-type and SERTKO mice were given ketanserin (an antagonist of the 5-HT receptor, 5-HT(2A)) or scopolamine (an antagonist of the muscarinic receptor). 5-HT(2A) receptors and choline acetyltransferase were localized by immunocytochemical analysis. RESULTS: Growth of the mucosa and proliferation of mucosal cells were significantly greater in SERTKO mice and in mice given selective serotonin re-uptake inhibitors than in wild-type mice, but were diminished in TPH2KO (but not in TPH1KO) mice. Ketanserin and scopolamine each prevented the ability of SERT knockout or inhibition to increase mucosal growth and proliferation. Cholinergic submucosal neurons reacted with antibodies against 5-HT(2A). CONCLUSIONS: 5-HT promotes growth and turnover of the intestinal mucosal epithelium. Surprisingly, these processes appear to be mediated by neuronal, rather than mucosal, 5-HT. The 5-HT(2A) receptor activates cholinergic neurons, which provide a muscarinic innervation to epithelial effectors.

Postnatal serotonin type 2 receptor blockade prevents the emergence of anxiety behavior, dysregulated stress-induced immediate early gene responses, and specific transcriptional changes that arise following early life stress.

BACKGROUND: Early life adverse experience contributes to an enhanced vulnerability for adult psychopathology. Recent evidence indicates that serotonin type 2 (5-HT(2)) receptor function, implicated in the pathophysiology of mood and anxiety disorders, is significantly enhanced in the maternal separation model of early life stress. We examined whether postnatal 5-HT(2) receptor blockade would prevent the consequences of maternal separation on anxiety behavior and dysregulated gene expression. METHODS: Control and maternally separated litters received treatment with the 5-HT(2) receptor antagonist, ketanserin, or vehicle during postnatal life and were examined for effects on adult anxiety behavior, adult stress-induced immediate early gene expression responses, and transcriptional changes within the prefrontal cortex during postnatal life and in adulthood. RESULTS: Treatment with ketanserin during postnatal life blocked the long-lasting effects of maternal separation on anxiety behavior in the open field test and the elevated plus maze. Further, the dysregulated adult stress-induced expression pattern of the immediate early gene, Arc, observed in maternally separated animals was also prevented by postnatal ketanserin treatment. Ketanserin treatment normalized the alterations in the expression of specific genes in the prefrontal cortex of maternally separated animals, including changes in serotonin type 2A receptor messenger RNA expression during postnatal life and in genes associated with G-protein signaling in adulthood. CONCLUSIONS: Postnatal treatment with the 5-HT(2) receptor antagonist, ketanserin, blocked specific consequences of maternal separation, including anxiety behavior and dysregulated gene expression in the prefrontal cortex. Our results suggest that enhanced 5-HT(2) receptor function may contribute to the emergence of anxiety behavior and perturbed stress responses following early life stress.

Blockade of 5-HT(2) receptors in the periaqueductal grey matter (PAG) abolishes the anxiolytic-like effect of 5-HT(1A) receptor antagonism in the median raphe nucleus in mice.

Several lines of evidence support the involvement of serotonergic (5-HT) neurons of the median raphe nucleus (MRN) in anxiety-like behaviour. In this context, it is known that blockade of 5-HT(1A) somatodendritic autoreceptors in the midbrain raphe nuclei increases the firing rate of these neurons, disinhibiting 5-HT release in postsynaptic target areas such as amygdala, hippocampus and periaqueductal grey matter (PAG). However, while activation of 5-HT(1A) or 5-HT(2) receptors in forebrain targets such as the amygdala or hippocampus enhances anxiety-like behaviours in rodents, stimulation of both receptor subtypes in the midbrain PAG markedly reduces anxiety-like behaviour. In view of these findings, the present study investigated whether the anti-anxiety effects induced by pharmacological disinhibition of 5-HT neurons in the MRN are attenuated by the blockade of 5-HT(2) receptors within the PAG. Mice received combined intra-PAG injection with ketanserin (10 nmol/0.1 µl), a 5-HT(2) receptor antagonist, followed by intra-MRN injection of WAY-100635 (5.6 nmol/0.1 µl), a highly selective 5-HT(1A) receptor antagonist. They were then individually exposed to the elevated plus-maze (EPM), with the videotaped behavioural sessions subsequently scored for both conventional and ethological measures. The results confirmed that intra-MRN infusion of WAY100635 reduces behavioural indices of anxiety without significantly altering general activity measures, and further showed that this effect was completely blocked by intra-PAG pretreatment with an intrinsically-inactive dose of ketanserin. Together, these results suggest that 5HT(2) receptor populations located within the midbrain PAG play a significant role in the reduction of anxiety observed following disinhibition of 5-HT neurons in the MRN.