5-HT1A Antagonist Research Articles

Denial of food to the hungry rat: A novel paradigm for induction and evaluation of anger-like emotion

BackgroundAnger is one of the primary emotions that profoundly impacts our daily life. Although the neural basis of anger needs to be explored on high priority, the field has not sufficiently advanced, perhaps due to the lack of a suitable animal model. New methodWe fabricated arenas in which the hungry rat can see and smell food but can not consume it. These animals seemed hyperactive and we monitored the (a) motor activity to access food, (b) biting behaviour, (c) blood pressure, heart rate and nor-epinephrine (NE) in plasma, (d) 5-HT and its metabolite in CSF, (e) effect of diazepam, 5-HT agonist, and antagonist on the behaviour, and (f) expression of immediate early gene in discrete areas of the brain. ResultsThe fasted animal frantically tries to acquire food. It engages in intense biting of the separator plate; the behaviour was considered as an expression of anger-like emotion. These behaviours were attenuated following pre-treatment with diazepam, fluoxetine (both ip) or 5-HT1A receptor agonist (icv), but potentiated by 5-HT1A antagonist (icv). Concomitantly, an increase in the blood pressure, heart rate and NE in plasma, but a decrease in 5-HT and 5-HIAA in the CSF was noted. The animals showed activation of neuronal c-Fos in different brain areas compared to fasted or refed controls. Comparison with existing methodsA novel animal paradigm for assessment of anger. ConclusionsThe protocol enables us to generate and evaluate anger-like responses in rat and permits insights into the neurological basis of anger.

M208. MEASURES OF COGNITION AND SOCIAL FUNCTIONING IN SCHIZOPHRENIA PATIENTS RECEIVING SEP-363856

BackgroundSEP-363856 is a novel trace amine associated receptor-1 (TAAR1)/5-HT1A agonist with no dopamine-D2/5-HT2A antagonist activity. SEP-363856 showed significant antipsychotic efficacy in patients with schizophrenia, and a safety and tolerability profile similar to placebo and consistent with a non-D2 mechanism of action. Here, we examined measures of cognition and social functioning in schizophrenia patients receiving SEP-363856.MethodsPatients aged 18–40 years with an acute exacerbation of schizophrenia were randomized, double-blind (DB), to 4-weeks of flexible-dose treatment with once daily SEP-363856 (N=120; 50 or 75 mg) or placebo (N=125). Patients (N=156) entering a subsequent 26-week open-label (OL) extension study were evaluated utilizing the Cogstate Brief Battery, administered at DB baseline and week 4, and OL baseline and weeks 12 and 26. Standardized z-scores were calculated for the Cogstate composite and subscale tasks (Detection task, Identification task, One Card Learning task, One Back task). The University of California San Diego Performance Based Skills Assessment (UPSA-B) scale was assessed at the same time-points, as were the following psychiatric scales: Positive and Negative Syndrome Scale (PANSS), the Brief Negative Symptom Scale (BNSS), the Montgomery–Åsberg Depression Rating Scale (MADRS), the Clinical Global Impression Scale, severity scale (CGI-S), and the Pittsburgh Sleep Quality Index global score (PSQI-global). Pearson correlation analyses were performed between DB baseline to Week 26 change in Cogstate composite and subscale scores and Week 26 change in the psychiatric scale scores.ResultsSmall improvements, from DB baseline to Week 26, were observed in standardized scores on the Cogstate composite (+0.29), Identification task (+0.19), Detection task (+0.28); One Card learning task (+0.33); and One Back task (+0.33). Improvement from OL baseline at Week 26 was also observed on the mean [SD] UPSA-B total score (+6.2 [11.6]). At DB baseline, there were no correlations between CogState composite score and individual test scores with any of the psychiatric scales. Week 26 improvement in the following Cogstate composite and subscale tasks were correlated with Week 26 improvement in the following psychiatric scale scores: Cogstate composite score (PANSS total, r=-0.26; BNSS total, r=-0.31; CGI-S, r=-0.30; MADRS total, r=-0.23; PSQI-global, r=-0.23); Identification task (PANSS total, r=-0.30; BNSS total, r=-0.30), Detection task (BNSS total, r=-0.30; CGI-S, r=-0.28; PSQI-global, r=-0.23); One Card learning task (MADRS total, r=-0.29); and One Back task (PANSS total, r=-0.26).DiscussionDuring 6-months of open-label extension treatment with SEP-363856, improvement in overall functioning was observed on the UPSA-B scale; and small but consistent improvement in cognition was noted in the Cogstate composite and subscale task scores. Endpoint reduction in the severity of schizophrenia-related symptomatology (eg, on the PANSS, BNSS, MADRS, insomnia) were associated with modest correlations, in the range of 0.2 to 0.3, in cognitive performance as measured by the Cogstate composite and subscale task scores.

Role of the stress response and the endocannabinoid system in Δ9-tetrahydrocannabinol (THC)-induced nausea.

Dysregulation of the endocannabinoid (eCB) system by high doses of Δ9-tetrahydrocannabinol (THC) is hypothesized to generate a dysfunctional hypothalamic-pituitary-adrenal (HPA) axis contributing to cannabinoid hyperemesis syndrome (CHS). Using the conditioned gaping model of nausea, we aimed to determine if pre-treatments that interfere with stress, or an anti-emetic drug, interfere with THC-induced nausea in male rats. The corticotropin-releasing hormone (CRH) antagonist, antalarmin, was given to inhibit the HPA axis during conditioning. Since eCBs inhibit stress, MJN110 (which elevates 2-arachidonylglycerol (2-AG)) and URB597 (which elevates anandamide (AEA)) were also tested. Propranolol (β-adrenergic antagonist) and WAY-100635 (5-HT1A antagonist) attenuate HPA activation by cannabinoids and, therefore, were assessed. In humans, CHS symptoms are not alleviated by anti-emetic drugs, such as ondansetron (5-HT3 antagonist); however, benzodiazepines are effective. Therefore, ondansetron and chlordiazepoxide were tested. To determine if HPA activation by THC is dose-dependent, corticosterone (CORT) was analyzed from serum of rats treated with 0.0, 0.5, or 10mg/kg THC. Antalarmin (10 and 20mg/kg), MJN110 (10mg/kg), URB597 (0.3mg/kg), propranolol (2.5 and 5mg/kg), WAY-100635 (0.5mg/kg), and chlordiazepoxide (5mg/kg) interfered with THC-induced conditioned gaping, but the anti-emetic ondansetron (0.1 and 0.01mg/kg) did not. THC produced significantly higher CORT levels at 10mg/kg than at 0.0 and 0.5mg/kg THC. Treatments that interfere with the stress response also inhibit THC-induced conditioned gaping, but a typical anti-emetic drug does not, supporting the hypothesis that THC-induced nausea, and CHS, is a result of a dysregulated stress response.

Depressive-like state sensitizes 5-HT1A and 5-HT1B auto-receptors in the dorsal raphe nucleus sub-system

Dorsal raphe (DR) and median raphe (MR) 5-HT neurons are two distinct sub-systems known to be regulated by 5-HT1A and 5-HT1B auto-receptors. Whether the auto-receptors in each sub-system are functionally altered in depressive-like state remains unknown. The present study is aimed to study a specific circuit (DR-ventral hippocampus and MR-dorsal hippocampus) within each sub-system to investigate changes in receptor sensitivity in the pathogenesis of depression. A mouse model of depression was developed through the social defeat paradigm, and was then treated with fluoxetine (FLX). 5-HT1A auto-receptor in the neuronal cell body (DR or MR) and 5-HT1B auto-receptor in the axonal terminal (ventral or dorsal hippocampus) were directly targeted by local perfusion of antagonists (5-HT1A: WAY100635; 5-HT1B: GR127935) through reverse microdialysis. Time courses of dialysate 5-HT measured at the axonal terminal were subsequently determined for each circuit. At baseline, 5-HT1A and 5-HT1B antagonists dose-dependently increased dialysate 5-HT, with sub-circuit specificity. In the depressive-like state, greater increases in dialysate 5-HT were observed only in the DR-ventral hippocampus circuit following local delivery of both antagonists, which were then fully restored following the FLX treatment. In contrast, no changes were observed in the MR-dorsal hippocampus circuit. Our results demonstrate differential changes in sensitivities of 5-HT1A and 5-HT1B auto-receptors in the DR-ventral hippocampus and MR-dorsal hippocampus circuits. 5-HT1A and 5-HT1B auto-receptors in the DR-ventral hippocampus circuit are sensitized in the depressive-like state. Taken together, these results suggest that the DR sub-system maybe the neural substrate mediating depressive phenotypes.

Design, Synthesis, and Biological Evaluation of New Peripheral 5HT2A Antagonists for Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent worldwide, causing serious liver complications, including nonalcoholic steatohepatitis. Recent findings suggest that peripheral serotonin (5-hydroxytryptamine, 5HT) regulates energy homeostasis, including hepatic lipid metabolism. More specifically, liver-specific 5HT2A knockout mice exhibit alleviated hepatic lipid accumulation and hepatic steatosis. Here, structural modifications of pimavanserin (CNS drug), a 5HT2A antagonist approved for Parkinson's disease, led us to synthesize new peripherally acting 5HT2A antagonists. Among the synthesized compounds, compound 14a showed good in vitro activity, good liver microsomal stability, 5HT subtype selectivity, and no significant inhibition of CYP and hERG. The in vitro and in vivo blood-brain barrier permeability study proved that 14a acts peripherally. Compound 14a decreased the liver weight and hepatic lipid accumulation in high-fat-diet-induced obesity mice. Our study suggests new therapeutic possibilities for peripheral 5HT2A antagonists in NAFLD.

Current Treatment Options and Emerging Agents for Schizophrenia.

The currently available antipsychotics mostly treat the positive symptoms of schizophrenia and have at least one adverse effect as a potential liability. Encouraging data suggest potential efficacy for a variety of new agents for the treatment of total symptoms and/or specific symptom domains of schizophrenia. Mechanisms of action that are under investigation include dopamine D3 antagonism/serotonin 5-HT1A partial agonism; combined dopamine, serotonin, and glutamate modulation; phosphodiesterase 10A inhibition; trace amine-associated receptor-1 (TAAR1) agonism plus 5-HT1A agonism; 5-HT2A inverse agonism; sigma-2/5-HT2A antagonism; D-amino acid oxidase (DAAO) inhibition; glycine transporter-1 inhibition; vesicular monoamine transporter-2 antagonism; mu opioid antagonism added to olanzapine; and novel long-acting injectable antipsychotic formulations. It is hoped that ongoing and recently completed trials for agents with known and/or novel mechanisms of action will lead to approved treatments that effectively target the various symptom domains of schizophrenia, minimize the risk for a broad range of clinically relevant adverse effects, and improve functional outcomes for patients. Some novel treatments have already received approval for use in patients with schizophrenia. This brief report discusses recently approved novel agents and potential new treatment options for schizophrenia that are being investigated.

Blast‐induced Traumatic Brain Injury Elicits Sociability Deficits and Aggressive Behaviors Coinciding with Transient Variations in CNS 5‐HT Levels and 5‐HT2A Hypersensitivity

Traumatic brain injury (TBI) is a leading cause of mortality and morbidity. In the United States alone, TBI accounts for 2.8 million emergency department visits and an economic cost of nearly $80 billion annually. The lack of any FDA‐approved therapies for treatment of acute or chronic symptoms of TBI necessitates the identification and characterization of novel drug targets. TBI often results in the generation of neuropsychiatric disorders including major depressive disorder (MDD), anxiety, aggression, and social withdrawal within the first 12 months following injury, disorders linked to altered serotonin (5‐HT) signaling. Currently, the effects of TBI on physiologic function of the 5‐HT signaling system within the CNS are poorly understood. We hypothesize that TBI drives the formation of aberrant behavioral states linked to neuropsychiatric disorders through alterations of normal, physiologic 5‐HT signaling. To test this hypothesis, adult, wild type C57Bl/6J mice were subjected to a single, blast‐induced TBI or sham treatment, followed by behavioral and/or molecular analyses 0–30 days post‐injury (dpi). High performance liquid chromatography (HPLC) revealed a time‐dependent increase and subsequent decrease in total 5‐HT and 5HIAA levels within the dorsal raphe nucleus (DRN) 10 and 30 dpi, respectively. No effect of TBI on 5‐HT levels was found in prefrontal cortex (PFC) or somatosensory cortex (SSC), areas of high 5‐HT innervation. Using the tube test for social dominance, time‐dependent alterations in DRN 5‐HT levels were found to correlate with altered social dominance behavior. TBI resulted in decreased social dominance/aversion 10 dpi, but an increase in dominance behavior 30 dpi. Using the Crawley Three Chamber Sociability Assay, TBI‐induced decreases in sociability were observed 10 dpi, an effect not present at 30 dpi. To investigate alterations in 5‐HT receptor pharmacology associated with TBI, 5‐HT2A receptor sensitivity was determined using DOI‐induced head twitch response (HTR) assays. TBI rapidly increased 5‐HT2A receptor sensitivity, effects persisting for 10 dpi. TBI‐elicited increases in DOI‐induced HTR were attenuated by administration of the 5‐HT2A antagonist M100907, indicating a dependence on intact 5‐HT2A receptor signaling. [3H]Ketanserin receptor binding studies revealed an increase in cortical 5‐HT2A receptor binding at 3 and 10 dpi. Collectively, these data provide evidence that TBI elicits time‐dependent alterations in the 5‐HT architecture of the CNS, effects that coincide with altered social function. A more thorough understanding of specifically how neurotrauma alters 5‐HT signaling will allow for the informed clinical utilization of available 5‐HT‐oriented pharmacotherapies and may provide drug discovery targets for TBI‐elicited neuropsychiatric sequelae.Support or Funding InformationStudies were supported by the Brain & Behavior Research Foundation, PhRMA Foundation, and the University of Cincinnati

In silico identification of novel 5-HT2A antagonists supported with ligand- and target-based drug design methodologies

A wide range of neuropsychological disorders is caused by serotonin 5-HT2A receptor (5-HT2AR) malfunction. Therefore, this receptor had been frequently used as target in CNS drug research. To design novel potent 5-HT2AR antagonists, we have combined ligand-based and target-based approaches. This study was performed on wide range of structurally diverse antagonists that were divided into three different clusters: clozapine, ziprasidone, and ChEMBL240876 derivatives. By performing the 50 ns long molecular dynamic simulations with each cluster representative in complex with 5-HT2A receptor, we have obtained virtually bioactive conformations of the ligands and three different antagonist-bound, inactive, conformations of the 5-HT2AR. These three 5-HT2AR conformations were further used for docking studies and generation of the bioactive conformations of the data set ligands in each cluster. Subsequently, selected conformers were used for 3D-Quantitative Structure Activity Relationship (3D-QSAR) modelling and pharmacophore analysis. The reliability and predictive power of the created model was assessed using an external test set compounds and showed reasonable external predictability. Statistically significant variables were used to define the most important structural features required for 5-HT2A antagonistic activity. Conclusions obtained from performed ligand-based (3D-QSAR) and target-based (molecular docking and molecular dynamics) methods were compiled and used as guidelines for rational drug design of novel 5-HT2AR antagonists. Communicated by Ramaswamy H. Sarma

Fictive Scratching Patterns in Brain Cortex-Ablated, Midcollicular Decerebrate, and Spinal Cats.

Background: The spinal cord’s central pattern generators (CPGs) have been explained by the symmetrical half-center hypothesis, the bursts generator, computational models, and more recently by connectome circuits. Asymmetrical models, at odds with the half-center paradigm, are composed of extensor and flexor CPG modules. Other models include not only flexor and extensor motoneurons but also motoneuron pools controlling biarticular muscles. It is unknown whether a preferred model can explain some particularities that fictive scratching (FS) in the cat presents. The first aim of this study was to investigate FS patterns considering the aiming and the rhythmic periods, and second, to examine the effects of serotonin (5HT) on and segmental inputs to FS.Methods: The experiments were carried out first in brain cortex-ablated cats (BCAC), then spinalized (SC), and for the midcollicular (MCC) preparation. Subjects were immobilized and the peripheral nerves were used to elicit the Monosynaptic reflex (MR), to modify the scratching patterns and for electroneurogram recordings.Results: In BCAC, FS was produced by pinna stimulation and, in some cases, by serotonin. The scratching aiming phase (AP) initiates with the activation of either flexor or extensor motoneurons. Serotonin application during the AP produced simultaneous extensor and flexor bursts. Furthermore, WAY 100635 (5HT1A antagonist) produced a brief burst in the tibialis anterior (TA) nerve, followed by a reduction in its electroneurogram (ENG), while the soleus ENG remained silent. In SC, rhythmic phase (RP) activity was recorded in the soleus motoneurons. Serotonin or WAY produced FS bouts. The electrical stimulation of Ia afferent fibers produced heteronymous MRes waxing and waning during the scratch cycle. In MCC, FS began with flexor activity. Electrical stimulation of either deep peroneus (DP) or superficial peroneus (SP) nerves increased the duration of the TA electroneurogram. Medial gastrocnemius (MG) stretching or MG nerve electrical stimulation produced a reduction in the TA electroneurogram and an initial MG extensor burst. MRes waxed and waned during the scratch cycle.Conclusion: Descending pathways and segmental afferent fibers, as well as 5-HT and WAY, can change the FS pattern. To our understanding, the half-center hypothesis is the most suitable for explaining the AP in MCC.

Effects of combined 5-HT2A and cannabinoid receptor modulation on a schizophrenia-related prepulse inhibition deficit in mice.

Prepulse inhibition of the startle reflex (PPI) is disrupted in several psychiatric disorders including schizophrenia. Understanding PPI pharmacology may help elucidate the pathophysiology of these disorders and lead to better treatments. Given the advantages of multi-target approaches for complex mental illnesses treatment, we have investigated the interaction between receptors known to modulate PPI (5-HT1A and 5-HT2A) and the neuromodulatory endocannabinoid system. To investigate serotonin and cannabinoid receptor (CBR) co-modulation in a model of PPI disruption relevant to schizophrenia METHODS: Male Swiss mice were pretreated with WIN 55,212-2 (CBR agonist), rimonabant (CB1R inverse agonist), 8-OH-DPAT (5-HT1A/7 agonist), and volinanserin (5-HT2A antagonist) or with a combination of a cannabinoid and a serotonergic drug. PPI disruption was induced by acute administration of MK-801. WIN 55,212-2 and rimonabant did not change PPI nor block MK-801-induced deficits. 8-OH-DPAT increased PPI in control mice and, in a higher dose, inhibited MK-801-induced impairments. Volinanserin also increased PPI in control and MK-801-treated mice, presenting an inverted U-shaped dose-response curve. Co-administration of either cannabinoid ligand with 8-OH-DPAT did not change PPI; however, the combination of volinanserin with rimonabant increased PPI in both control and MK-801-exposed mice. WIN 55,212-2 and rimonabant had similar effects in PPI. Moreover, serotonin and cannabinoid receptors interact to modulate PPI. While co-modulation of CBR and 5-HT1A receptors did not change PPI, a beneficial effect of 5-HT2A and CB1R antagonist combination was detected, possibly mediated through potentiation of 5-HT2A blockade effects by concomitant CB1R blockade.

P.106 Induction of aggregation by tau seeding in tauP301S-PS19 transgenic mice

Acute ethanol (EtOH) consumption exerts a biphasic effect on behavior and increases serotonin levels in the brain. However, the molecular mechanisms underlying alcohol-mediated behavioral responses still remain to be fully elucidated. Here, we investigate pharmacologically the involvement of the serotonergic pathway on acute EtOH-induced behavioral changes in zebrafish. We exposed zebrafish to 0.25, 0.5, 1.0% (v/v) EtOH for 1 h and analyzed the effects on aggression, anxiety-like behaviors, and locomotion. EtOH concentrations that changed behavioral responses were selected to the subsequent experiments. As a pharmacological approach, we used pCPA (inhibitor of tryptophan hydroxylase), WAY100135 (5-HT1A antagonist), buspirone (5-HT1A agonist), CGS12066A and CGS12066B (5-HT1B antagonist and agonist, respectively), ketanserin (5-HT2A antagonist) and (±)-DOI hydrochloride (5-HT2A agonist). All serotonergic receptors tested modulated aggression, with a key role of 5-HT2A in aggressive behavior following 0.25% EtOH exposure. Because CGS12066B mimicked 0.5% EtOH anxiolysis, which was antagonized by CGS12066A, we hypothesized that anxiolytic-like responses are possibly mediated by 5-HT1B receptors. Conversely, the depressant effects of EtOH are probably not related with direct changes on serotonergic pathway. Overall, our novel findings demonstrate a role of the serotonergic system in modulating the behavioral effects of EtOH in zebrafish. These data also reinforce the growing utility of zebrafish models in alcohol research and help elucidate the neurobiological mechanisms underlying alcohol abuse and associated complex behavioral phenotypes.

Serotonin 5-HT1A and 5-HT1B receptors co-mediate the RU 24969-induced locomotor activity of male and female preweanling rats

The serotonin (5-HT) 1A/1B agonist RU 24969 robustly increases the locomotor activity of adult male rats and mice; however, studies using selective antagonists alternately report that 5-HT1A, 5-HT1B, or both receptor types mediate RU 24969's locomotor activating effects. The purpose of the present study was to extend these past findings by administering a selective 5-HT1 agonist and/or antagonists to male and female preweanling rats. This age group was tested because younger rats often exhibit psychopharmacological responses that are quantitatively or qualitatively different from adult rats. In a series of experiments, male and female preweanling rats were pretreated with vehicle, the 5-HT1A antagonist WAY 100635 (0.5, 1, 5, or 10 mg/kg), or the 5-HT1B antagonists NAS-181 (5 or 10 mg/kg) or SB 216641 (5 or 10 mg/kg) 30 min before assessment of locomotor activity. Rats were injected with saline or RU 24969 immediately prior to testing. Results showed that RU 24969 (0.625, 1.25, 2.5, or 5 mg/kg) significantly increased the locomotor activity of both male and female preweanling rats (no sex differences were apparent). Antagonism of either the 5-HT1A or the 5-HT1B receptor was sufficient to significantly reduce the locomotor activity of RU 24969-treated preweanling rats. Unexpectedly, NAS-181 did not act as a silent receptor antagonist, as both doses of NAS-181 significantly increased the locomotor activity of saline-treated preweanling rats. In sum, the present results show that both the 5-HT1A and 5-HT1B receptor systems mediate locomotion during the late preweanling period, and this mediation does not vary according to sex.

Biphasic Effect of Buspirone on the H-Reflex in Acute Spinal Decerebrated Mice

Pharmacological treatment facilitating locomotor expression will also have some effects on reflex expression through the modulation of spinal circuitry. Buspirone, a partial serotonin receptor agonist (5-HT1A), was recently shown to facilitate and even trigger locomotor movements in mice after complete spinal lesion (Tx). Here, we studied its effect on the H-reflex after acute Tx in adult mice. To avoid possible impacts of anesthetics on H-reflex depression, experiments were performed after decerebration in un-anesthetized mice (N = 20). The H-reflex in plantar muscles of the hind paw was recorded after tibial nerve stimulation 2 h after Tx at the 8th thoracic vertebrae and was compared before and every 10 min after buspirone (8 mg/kg, i.p.) for 60 min (N = 8). Frequency-dependent depression (FDD) of the H-reflex was assessed before and 60 min after buspirone. Before buspirone, a stable H-reflex could be elicited in acute spinal mice and FDD of the H-reflex was observed at 5 and 10 Hz relative to 0.2 Hz, FDD was still present 60 min after buspirone. Early after buspirone, the H-reflex was significantly decreased to 69% of pre-treatment, it then increased significantly 30–60 min after treatment, reaching 170% 60 min after injection. This effect was not observed in a control group (saline, N = 5) and was blocked when a 5-HT1A antagonist (NAD-299) was administered with buspirone (N = 7). Altogether results suggest that the reported pro-locomotor effect of buspirone occurs at a time where there is a 5-HT1A receptors mediated reflex depression followed by a second phase marked by enhancement of reflex excitability.

Role of the serotonergic system in ethanol-induced aggression and anxiety: A pharmacological approach using the zebrafish model

Acute ethanol (EtOH) consumption exerts a biphasic effect on behavior and increases serotonin levels in the brain. However, the molecular mechanisms underlying alcohol-mediated behavioral responses still remain to be fully elucidated. Here, we investigate pharmacologically the involvement of the serotonergic pathway on acute EtOH-induced behavioral changes in zebrafish. We exposed zebrafish to 0.25, 0.5, 1.0% (v/v) EtOH for 1 h and analyzed the effects on aggression, anxiety-like behaviors, and locomotion. EtOH concentrations that changed behavioral responses were selected to the subsequent experiments. As a pharmacological approach, we used pCPA (inhibitor of tryptophan hydroxylase), WAY100135 (5-HT1A antagonist), buspirone (5-HT1A agonist), CGS12066A and CGS12066B (5-HT1B antagonist and agonist, respectively), ketanserin (5-HT2A antagonist) and (±)-DOI hydrochloride (5-HT2A agonist). All serotonergic receptors tested modulated aggression, with a key role of 5-HT2A in aggressive behavior following 0.25% EtOH exposure. Because CGS12066B mimicked 0.5% EtOH anxiolysis, which was antagonized by CGS12066A, we hypothesized that anxiolytic-like responses are possibly mediated by 5-HT1B receptors. Conversely, the depressant effects of EtOH are probably not related with direct changes on serotonergic pathway. Overall, our novel findings demonstrate a role of the serotonergic system in modulating the behavioral effects of EtOH in zebrafish. These data also reinforce the growing utility of zebrafish models in alcohol research and help elucidate the neurobiological mechanisms underlying alcohol abuse and associated complex behavioral phenotypes.

Investigating serotonergic contributions to cognitive effort allocation, attention, and impulsive action in female rats.

Individuals must frequently evaluate whether it is worth allocating cognitive effort for desired outcomes. Motivational deficits are a common feature of psychiatric illness such as major depression. Selective serotonin reuptake inhibitors are commonly used to treat this disorder, yet some data suggest these compounds are ineffective at treating amotivation, and may even exacerbate it. Here we used the rodent Cognitive Effort Task (rCET) to assess serotonergic (5-hydroxytryptamine, 5-HT) contributions to decision-making with cognitive effort costs. The rCET is a modified version of the 5-choice serial reaction time task, a well-validated test of visuospatial attention and impulse control. At the start of each rCET trial, rats chose one of two levers, which set the difficulty of an attentional challenge, namely the localization of a visual stimulus illuminated for 0.2 or 1 s on hard versus easy trials. Successful completion of hard trials was rewarded with double the sugar pellets. Twenty-four female Long-Evans rats were trained on the rCET and systemically administered the 5-HT1A agonist 8-OH-DPAT, the 5-HT2A antagonist M100907, the 5-HT2C agonist Ro-60-0175, as well as the 5-HT2C antagonist SB 242, 084. 5-HT2A antagonism dose-dependently reduced premature responding, while 5-HT2C antagonism had the opposite effect. 8-OH-DPAT impaired accuracy of target detection at higher doses, while Ro-60-0175 dose-dependently improved accuracy on difficult trials. However, none of the drugs affected the rats' choice of the harder option. When considered with existing work evaluating decision-making with physical effort costs, it appears that serotonergic signalling plays a minor role in guiding effort allocation.

Performance evaluation of a MIP for the MISPE-LC determination of p-[18F]MPPF and a potential metabolite in human plasma

Within the family of serotonin (5-HT) receptors, the 5-HT1A subtype is particularly interesting as it may be involved in various physiological processes or psychological disorders. The p-[18F]MPPF, a highly selective 5-HT1A antagonist, is used for in vivo studies in human or animal by means of positron emission tomography (PET) [1].In order to selectively extract p-[18F]MPPF and its main metabolites from plasma, molecularly imprinted polymer (MIP) was prepared against these compounds by using the p-MPPF as template. For the control of the selectivity, non-imprinted polymer (NIP) was also synthesized without template. The MIP sorbent, packed in disposable extraction cartridges (DECs), was then evaluated as molecularly imprinted solid-phase extraction (MISPE) prior to the LC determination. The conditions of extraction were evaluated in order to obtain the highest selective retention of the p-[18F]MPPF and its metabolites on this MIP. The MIP selectivity was exploited in the loading and washing steps by adjusting the pH of plasma samples at a suitable value and by selecting mixtures for the washing step to limit the contribution of non-specific interactions. Other important parameters involved in the conditioning and elution steps were also studied. Finally, a pre-validation was carried out with optimal extraction conditions to demonstrate the performance of this MISPE-LC method as a generic method in the context of evaluation of new MISPE for p-[18F]MPPF and its potential for metabolites extraction from human plasma.

Dopaminergic neuroprotective effects of rotigotine via 5-HT1A receptors: Possibly involvement of metallothionein expression in astrocytes

Astrocytes exert neuroprotective effects through production of antioxidant molecules and neurotrophic factors. A recent study showed that stimulation of astrocyte serotonin 1A (5-HT1A) receptors promotes astrocyte proliferation and upregulation of the antioxidant molecules metallothionein (MT)-1,2, which protect dopaminergic neurons against oxidative stress. Rotigotine, an anti-parkinsonian drug, can bind to dopamine and 5-HT1A receptors. In this study, we examined neuroprotective effects of rotigotine in models of Parkinson’s disease and involvement of astrocyte 5-HT1A receptors in neuroprotective effects of rotigotine against dopaminergic neurodegeneration. Rotigotine increased the number of astrocytes and MT-1,2 expression in cultured astrocytes. Pretreatment with conditioned media from rotigotine-treated astrocytes significantly inhibited 6-hydroxydopamine (6-OHDA)-induced dopaminergic neurotoxicity. These effects were completely blocked by a 5-HT1A antagonist or MT-1,2 specific antibody. Subcutaneous administration of rotigotine increased MT-1,2 expression in striatal astrocytes and prevented reduction of dopaminergic neurons in the substantia nigra of a 6-OHDA-lesioned mouse model of Parkinson’s disease. These effects were blocked by co-administration with a 5-HT1A antagonist. These results suggest that rotigotine exerts neuroprotective effects through upregulation of MT expression in astrocytes by targeting 5-HT1A receptors. Our findings provide a possible therapeutic application of rotigotine to prevent dopaminergic neurodegeneration in Parkinson’s disease.

The effect of 5-HT1A receptor antagonist on reward-based decision-making.

When choosing the best action from several alternatives, we compare each value that depends on the balance between benefit and cost. Previous studies have shown that animals and humans with low brain serotonin (5-HT) level tend to choose smaller immediate reward. We used a decision-making schedule task to investigate whether 5-HT1A receptor is responsible for the decisions related to reward. In this task, the monkeys chose either of two different alternatives that were comprised of 1-4 drops of liquid reward (benefit) and 1-4 repeats of a color discrimination trial (workload cost), then executed the chosen schedule. By the administration of 5-HT1A antagonist, WAY100635, the choice tendency did not change, however, the sensitivity to the amount of reward in the schedule part was diminished. The 5-HT1A could have a role in maintaining reward value to keep track with the promised reward rather than modulating workload discounting of reward value.

Enhancing the efficacy of 5-HT uptake inhibitors in the treatment of attention deficit hyperactivity disorder

Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common childhood behavioural disorders, the frontline treatments for which are drugs with abuse potential. As a consequence, there is an urgent need to develop non addictive drug treatments with equivalent efficacy. Preclinical evidence suggests that selective serotonin uptake inhibitors (SSRIs) are likely to be effective in ADHD, however clinical reports suggest that SSRIs are of limited therapeutic value for the treatment of ADHD. We propose that this disconnect can be explained by the pattern of drug administration in existing clinical trials (administration for short periods of time, or intermittently) leading to inadequate control of the autoregulatory processes which control 5-HT release, most notably at the level of inhibitory 5-HT1A somatodendritic autoreceptors. These autoreceptors reduce the firing rate of 5-HT neurons (limiting release) unless they are desensitised by a long term, frequent pattern of drug administration. As such, we argue that the participants in earlier trials were not administered SSRIs in a manner which realises any potential benefits of targeting 5-HT in the pharmacotherapy of ADHD. In light of this, we hypothesise that there may be under-researched potential to exploit 5-HT transmission therapeutically in ADHD, either through changing the administration regime, or by pharmacological means. Recent pharmacological research has successfully potentiated the effects of SSRIs in acute animal preparations by antagonising inhibitory 5-HT1A autoreceptors prior to the administration of the SSRI fluoxetine. We suggest that combination therapies linking SSRIs and 5-HT1A antagonists are a potential way forward in the development of efficacious non-addictive pharmacotherapies for ADHD.

Role of prefrontal cortical 5-HT2A receptors and serotonin transporter in the behavioral deficits in post-pubertal rats following neonatal lesion of the ventral hippocampus

Neonatal ventral hippocampal-lesioned (NVHL) rats have been shown to display neurochemical and behavioral abnormalities at adulthood, analogous to some of those seen in schizophrenia. Serotonergic neurotransmission is implicated the pathophysiology and treatment of schizophrenia. In this study, we evaluated possible role of serotonergic transmission is the behaviors of NVHL-lesioned rats. Bilateral lesions to the ventral hippocampus (VH) in rat pups were made using the excitotoxin ibotenic acid. We investigated 5-HT2A-receptor and SERT binding sites in cortical and subcortical areas in post-pubertal NVHL and sham-lesioned rats, using quantitative receptor autoradiography. We compared a 5-HT-dependent behavior in NVHL and sham animals, the wet-dog shake response (WDSr) to a 5-HT2A receptor agonist DOI. In addition, we studied prepulse inhibition (PPI) of startle responses in NVHL and Sham-lesioned animals treated with antipsychotic drugs haloperidol, risperidone and clozapine and 5-HT2A antagonists ketanserin or MDL100907. The WDSr elicited by DOI was enhanced in post-pubertal NVHL rats compared to sham-lesioned controls. Moreover, post-pubertal NVHL rats exhibited PPI deficits which was reversed by atypical antipsychotics, ketanserin and MDL100907. A significant increase in 5-HT2A-like receptor binding was observed in the medial prefrontal cortex (mPFC) in post-pubertal NVHL rats without any significant change in the striatum and ventral pallidum. A significant increase in SERT-like binding was also observed in the mPFC and striatum of NVHL rats at pre-pubertal period; however, at post-pubertal age, the binding remained elevated in mPFC only. These data suggest that increased prefrontal cortical 5-HT transmission may play a role in the behavioral deficits observed in this neurodevelopmental model of schizophrenia.