The influence of the novel 5-HT1A agonist R137696 on the proximal stomach function in healthy volunteers

As fundic dysaccommodation represents one of the pathophysiological mechanisms underlying functional dyspepsia, gastric relaxant agents may serve as a new treatment of this disorder. Previous studies have suggested the involvement of 5HT1 receptors in the control of gastric tone. Our aim was to study the effect of R137696, a novel 5HT1A agonist, on fundus sensorimotor function in healthy volunteers. The effect of single oral doses (1-2 mg) R137696 was evaluated in a double-blind, placebo-controlled manner on fasting fundic volume, visceral perception, distension-evoked symptoms and fundic compliance in 21 healthy male subjects. R137696 increased the proximal stomach volumes in a dose-dependent manner. Distention-evoked symptoms or distention and discomfort threshold were not altered by R137696. A logistic regression model, characterizing the relationships between the volume and the visual analogue scale score for dyspeptic symptoms (nausea, fullness, discomfort, pain and satiety) as a sigmoidal curve, revealed that R137696 had no effect on distension-induced discomfort, fullness, pain and satiety compared to placebo. R137696 relaxes the gastric fundus in fasting conditions but has no effect on distension-evoked dyspeptic symptoms in healthy volunteers.     

Increased 5‐HT2A receptors in the temporal cortex of parkinsonian patients with visual hallucinations

Well‐formed visual hallucinations (VH) are common in patients with Parkinson's disease (PD). The pathophysiology of VH in PD is unknown but may involve structures mediating visual processing such as the inferior temporal cortex. Serotonergic type 2A (5‐HT_2A) receptors have been linked to many psychiatric disorders, including psychosis. We hypothesized that enhanced 5‐HT_2A receptor levels may be involved in VH in PD. Autoradiographic binding using [³H]‐ketanserin and spiperone, to define 5‐HT_2A receptors, was performed in 6 PD patients with VH, 6 PD patients without VH, and 5 healthy, age‐matched controls. The cerebral regions studied included the orbitofrontal cortex, inferolateral temporal cortex, motor cortex, striatum, and substantia nigra. There was a significant (45.6%) increase in the levels of [³H]‐ketanserin binding in the inferolateral temporal cortex of PD patients with VH when compared with PD patients without VH (54.3 ± 5.2 fmol/mg vs. 37.3 ± 4.3 fmol/mg, P = 0.039). Additionally, there was a significant increase in the levels of 5‐HT_2A receptors in the motor cortex of all PD patients taken as a group when compared with controls (57.8 ± 5.7 fmol/mg vs. 41.2 ± 2.6 fmol/mg, P = 0.0297). These results suggest that enhanced 5‐HT_2A‐mediated neurotransmission in the inferolateral temporal cortex, a critical structure in visual processing, might be associated with the development of VH in PD. Our results provide new insights into the pathophysiology of VH in PD and provide an anatomical basis to explain why compounds with 5‐HT_2A antagonist activity are effective at alleviating this debilitating complication. © 2010 Movement Disorder Society     

Relationship between symptom pattern, assessed by the PAGI-SYM© questionnaire, and gastric sensorimotor dysfunction in functional dyspepsia

Abstract The patient assessment of upper gastrointestinal symptom severity index (PAGI‐SYM) questionnaire was recently developed and validated for the evaluation of therapeutic responsiveness in functional dyspepsia (FD). Functional dyspepsia is a heterogeneous disorder, with different pathophysiological mechanisms underlying the symptom pattern. The relationship between PAGI‐SYM scores and putative pathophysiological mechanisms has not been studied. The aim of this study was to evaluate the relationship between PAGI‐SYM subscales and gastric emptying, gastric sensitivity and gastric accommodation in FD. A total of 161 consecutive FD patients underwent Helicobacter pylori (HP), gastric barostat and standardized gastric emptying testing (n = 126), and completed the PAGI‐SYM questionnaire. Relationships between scores for the six subscales (heartburn/regurgitation, nausea/vomiting, fullness/satiety, bloating, upper abdominal pain, lower abdominal pain) and gastric function were analysed using Pearson’s linear correlation, multiple regression analysis, chi‐square and Student’s t‐tests. Gastric emptying was significantly correlated with scores for heartburn/regurgitation (r = 0.26), nausea/vomiting (r = 0.19), fullness/satiety (r = 0.20), bloating (r = 0.21) and lower abdominal pain (r = 0.22; all P < 0.05). Patients with delayed emptying had significantly higher scores for each of these subscales (all P < 0.05). Discomfort volume during gastric distension was significantly correlated with scores for fullness/satiety (r = ?0.27), bloating (r = ?0.23), heartburn/regurgitation (r = ?0.21), and upper abdominal pain (r = ?0.20). Patients with hypersensitivity to distension had significantly higher scores for fullness/satiety (P < 0.05). At different cut‐off levels of symptom severities, consistent associations were found between fullness/satiety and gastric discomfort volume, between preprandial volumes and upper abdominal pain, compliance and upper abdominal pain, and between bloating and gastric discomfort volume. Multiple regression analysis revealed that gastric emptying rate contributed significantly to models for the severity of these subscales. The importance of discomfort volume disappeared in favour of gender when sex was included in the model. No significant correlations were found with HP status or with gastric accommodation. PAGI‐SYM scores are mainly correlated with gastric emptying rate and with gastric hypersensitivity. Multivariate analysis suggests that the questionnaire may be useful in the evaluation of gastroprokinetics. Its role in the evaluation of drugs that alter gastric sensitivity is less clear.     

Influence of tegaserod on proximal gastric tone and on the perception of gastric distention in functional dyspepsia

Background Abnormalities in gastric sensorimotor function (hypersensitivity to distention and impaired meal accommodation) have been implicated in the pathophysiology of functional dyspepsia (FD). To study the effect of the 5‐HT₄ agonist tegaserod on sensitivity to gastric distention and gastric accommodation in FD. Methods Thirty FD patients (7 males, mean age 42 ± 2 years) underwent a gastric barostat study on two separate occasions, 2 weeks apart, after 5 days of pretreatment with placebo or tegaserod 6 mg b.i.d. in a double‐blind randomized order. After introduction of the barostat bag, graded isobaric distentions (2 mmHg increments/2 min) were performed to determine gastric compliance and sensitivity to distention. Subsequently, the pressure level was set at intra‐abdominal pressure [minimal distending pressure (MDP)] + 2 mmHg for 90 min, with administration of a liquid meal (200 mL; 300 kcal) after 30 min. Key Results Tegaserod had no influence on MDP (7.9 ± 0.4 vs 7.4 ± 0.4 mmHg) or fasting gastric compliance (44 ± 10 vs 61 ± 6 mL mmHg^?1) and on fasting thresholds for first perception (3.6 ± 0.4 vs 4.2 ± 0.2 mmHg above MDP) or discomfort (9.9 ± 0.7 vs 10.5 ± 0.5 mmHg above MDP). Tegaserod did not alter intra‐balloon volumes before and after the meal [respectively 146 ± 14 vs 120 ± 11 and 297 ± 28 vs 283 ± 29 mL, not significant (NS)], or the amplitude of the meal‐induced gastric relaxation (151 ± 23 vs 162 ± 23 mL, NS). In the subgroup with normal gastric emptying (n = 22), tegaserod significantly enhanced meal‐induced accommodation (126 ± 23 vs 175 ± 29 mL, anova P < 0.001). Conclusions & Inferences Tegaserod does not alter gastric sensorimotor function in FD patients as a group. In the subgroup with normal gastric emptying, tegaserod 6 mg b.i.d enhanced gastric accommodation.     

Serotonin (5‐HT) regulates neurite outgrowth through 5‐HT1A and 5‐HT7 receptors in cultured hippocampal neurons

Serotonin (5‐HT) production and expression of 5‐HT receptors (5‐HTRs) occur early during prenatal development. Recent evidence suggests that, in addition to its classical role as a neurotransmitter, 5‐HT regulates neuronal connectivity during mammalian development by modulating cell migration and neuronal cytoarchitecture. Given the variety of 5‐HTRs, researchers have had difficulty clarifying the specific role of each receptor subtype in brain development. Signalling mediated by the G‐protein‐coupled 5‐HT_1AR and 5‐HT₇R, however, has been associated with neuronal plasticity. Thus, we hypothesized that 5‐HT promotes neurite outgrowth through 5‐HT_1AR and 5‐HT₇R. The involvement of 5‐HT_1AR and 5‐HT₇R in the morphology of rat hippocampal neurons was evaluated by treating primary cultures at 2 days in vitro with 5‐HT and specific antagonists for 5‐HT_1AR and 5‐HT₇R (WAY‐100635 and SB269970, respectively). The stimulation of hippocampal neurons with 100 nM 5‐HT for 24 hr produced no effect on either the number or the length of primary neurites. Nonetheless, after 5HT₇R was blocked, the addition of 5‐HT increased the number of primary neurites, suggesting that 5HT₇R could inhibit neuritogenesis. In contrast, 5‐HT induced secondary neurite outgrowth, an effect inhibited by 1 μM WAY‐100635 or SB269970. These results suggest that both serotonergic receptors participate in secondary neurite outgrowth. We conclude that 5‐HT_1AR and 5‐HT₇R regulate neuronal morphology in primary hippocampal cultures by promoting secondary neurite outgrowth. © 2014 Wiley Periodicals, Inc.     

A phase 2a,randomized, double‐blind 28‐day study of TZP‐102 a ghrelin receptor agonist for diabetic gastroparesis

Background Gastroparesis causes significant morbidity and treatment options are limited. TZP‐102 a novel, macrocyclic, selective, oral ghrelin receptor agonist, was evaluated in a randomized, double‐blind, placebo‐controlled trial in patients with diabetic gastroparesis. Methods A total of 92 outpatients were randomized to once‐daily administrations of 10‐mg (n = 22), 20‐mg (n = 21), 40‐mg (n = 23) TZP‐102 or placebo (n = 26). The primary endpoint was the change from baseline in gastric half‐emptying time (T_½) utilizing ¹³C‐breath test methodology and secondary endpoints included symptom improvement using patient‐reported gastroparesis symptom scores (PAGI‐SYM questionnaire) and patient and physician overall treatment evaluations (OTE). Key Results Gastric T½ changes were not statistically significant between TZP‐102 and placebo after 28 days of treatment at any dose. Clinical improvements (?1.0 to ?1.4 point mean decrease in symptom severity) occurred in the Gastroparesis Cardinal Symptom Index (GCSI) component of the PAGI‐SYM, which was significant vs placebo for all TZP‐102 doses combined. Improvements became evident after 1 week of treatment. Significantly, more patients given TZP‐102 (any dose) had a 50% reduction in baseline GCSI score (28.8%vs 7.7% placebo). Safety profiles were similar across groups. All TZP‐102 doses were well‐tolerated with no adverse cardiac, weight, or glucose control outcomes. Conclusions & Inferences TZP‐102 for 28 days, at doses of 10–40 mg once daily, was well‐tolerated and resulted in a reduction in symptoms of gastroparesis. The lack of correlation between symptom improvement and gastric emptying change is consistent with previous studies in diabetic gastroparesis, and emphasizes the value of patient‐defined outcomes in determining therapeutic benefit.     

5‐HT2A receptor blockade and 5‐HT2C receptor activation interact to reduce cocaine hyperlocomotion and fos protein expression in the caudate‐putamen

Both the 5‐HT_2A receptor (R) antagonist M100907 and the 5‐HT_2CR agonist MK212 attenuate cocaine‐induced dopamine release and hyperlocomotion. This study examined whether these drugs interact to reduce cocaine hyperlocomotion and Fos expression in the striatum and prefrontal cortex. We first determined from dose‐effect functions a low dose of both M100907 and MK212 that failed to alter cocaine (15 mg/kg, i.p.) hyperlocomotion. Subsequently, we examined whether these subthreshold doses given together would attenuate cocaine hyperlocomotion, consistent with a 5‐HT_2A/5‐HT_2CR interaction. Separate groups of rats received two sequential drug injections 5 min apart immediately before a 1‐h locomotion test as follows: (1) saline + saline, (2) saline + cocaine, (3) 0.025 mg/kg M100907 + cocaine, (4) 0.125 mg/kg MK212 + cocaine, or (5) cocktail combination of 0.025 mg/kg M100907 and 0.125 mg/kg MK212 + cocaine. Brains were extracted for Fos immunohistochemistry 90 min after the second injection. We next examined the effects of 0.025 mg/kg M100907 and 0.125 mg/kg MK212, alone and in combination, on spontaneous locomotor activity. While neither drug given alone produced any effects, the M100907/MK212 cocktail attenuated cocaine hyperlocomotion as well as cocaine‐induced Fos expression in the dorsolateral caudate‐putamen (CPu), but had no effect on spontaneous locomotion. The findings suggest that 5‐HT_2ARs and 5‐HT_2CRs interact to attenuate cocaine hyperlocomotion and Fos expression in the CPu, and that the CPu is a potential locus of the interactive effects between these 5‐HT₂R subtypes on behavior. Further research investigating combined 5‐HT_2AR antagonism and 5‐HT_2CR agonism as a treatment for cocaine dependence is warranted. Synapse, 2012. © 2012 Wiley Periodicals, Inc.     

Effect of a hallucinogenic serotonin 5‐HT2A receptor agonist on visually guided,hippocampal‐dependent spatial cognition in C57BL/6J mice

By acting on serotonin 5‐HT_2A receptors (5‐HT_2ARs), serotonergic psychedelic drugs induce perceptual and visual hallucinations by increasing neuronal excitability and altering visual‐evoked neuronal responses. The present study was designed to examine whether the perceptual alterations induced by a serotonergic psychedelic drug would affect the integrity of hippocampal‐dependent, visually guided spatial cognition. phenylalkylamine hallucinogen TCB‐2 is a selective agonist of 5‐HT_2ARs. Mice received TCB‐2 (1.0 mg kg⁻¹, i.p.), and spatial behaviors and hippocampal electrophysiological responses were measured with water maze tasks and in vivo single‐unit recording, respectively. TCB‐2 did not affect visual cue approach behavior in the visible platform water maze, but increased the latency of trained mice to initiate goal‐directed swimming during a probe test in the hidden platform Morris water maze, which could be prevented by 5‐HT_2AR antagonist MDL 11,939. Interestingly, TCB‐2 did not affect the efficiency of the swim path or the proper use of distal visual cues during the probe test. Hippocampal place cell activity is considered to represent spatial and context‐specific episodic memory. Systemic TCB‐2 did not affect previously established place fields of CA1 neurons in mice exploring a familiar environment, or the remapping of place cells when the mice explored a novel environment. However, TCB‐2 impaired the long‐term stability of place fields for the novel environment initially encoded under the influence of TCB‐2, which could be prevented by 5‐HT_2AR antagonist MDL 11,939. Our data indicate that hallucinogenic 5‐HT_2AR agonist delays the initiation of spatial search behavior, but does not impair the use of visual cues to guide goal‐directed spatial behavior. Moreover, activation of 5‐HT_2ARs does not impair the coding and retrieval of spatial information, but impairs the long‐term stability of new formed place fields of CA1 neurons. © 2017 Wiley Periodicals, Inc.     

Acute social defeat does not alter cerebral 5‐HT2A receptor binding in male Wistar rats

It has been hypothesized that effects of uncontrollable stress on serotonin receptor expression contribute to the etiology of stress‐related disorders like depression. While the serotonin‐2A receptors (5‐HT_2AR) are thought to be important in this context, only few studies examined effects of stress on this receptor subtype. In this study, we therefore assessed acute and long‐term changes in 5HT_2AR binding after social defeat stress in rats. Male Wistar rats were subjected to social defeat by placing them in the home cage of an aggressive, dominant Long Evans rat. Acute social defeat suppressed growth, but did not affect anxiety‐like behavior in an open field test. A positron emission tomography scan with the 5‐HT_2AR tracer [¹¹C]MDL 100907 1 day and 3 weeks after defeat did not show significant changes in receptor binding. To verify these results, [³H]MDL 100907 binding assays were performed in homogenates of prefrontal cortex and hippocampus, which also did not indicate any changes in B_max or K_d. These findings do not support the hypothesis that changes in 5‐HT_2AR function are a vital mechanism through which uncontrollable stress contributes to stress‐related pathologies such as depression. It remains to be determined whether effects of stress on 5HT_2AR binding depend on the nature of the stressor or on the characteristics of the rat strain. Synapse, 2014. © 2014 Wiley Periodicals, Inc.     

Increased levels of 5‐HT1A receptor binding in ventral visual pathways in Parkinson's disease

Visual hallucinations are common in advanced Parkinson's disease (PD). The pathophysiology of visual hallucinations may involve enhanced serotonergic neurotransmission. The atypical antipsychotics clozapine and quetiapine, which have affinity for 5‐HT_2A and 5‐HT_1A receptors, are effective against visual hallucinations in PD. 5‐HT_2A receptors are increased in ventral visual pathways in PD patients with visual hallucinations, and we hypothesized that 5‐HT_1A receptors were also involved in visual hallucinations in PD. Autoradiographic binding using [³H]‐WAY‐100,635 and NAN‐190 was performed in brain sections from 6 PD patients with visual hallucinations, 6 PD patients without visual hallucinations, and 5 age‐matched controls. All PD subjects had been treated with L ‐dopa. Brain areas studied were the orbitofrontal, inferolateral temporal, and motor cortices, as well as the striatum, globus pallidus, substantia nigra, and thalamus. 5‐HT_1A‐binding levels were dramatically increased in the ventral visual pathways of all PD patients compared with controls (0 vs 11 and 0 vs 100 nmol/mg, respectively; both P < .05). There was no significant difference in 5‐HT_1A‐binding levels in PD patients with visual hallucinations compared with PD patients without visual hallucinations or with controls in any of the brain areas studied (P > .05). Gross abnormalities in 5‐HT_1A levels in ventral visual areas occurred in all PD patients exposed to L ‐dopa. However, as there was no difference in 5‐HT_1A‐binding levels between hallucinators and nonhallucinators, alterations in 5‐HT_1A receptor levels may not contribute specifically to visual hallucinations in PD. However, the discrete anatomical distribution of rises to the ventral visual areas suggests some role in predisposing to visual hallucinations. © 2012 Movement Disorder Society     

The 5‐HT4 receptor levels in hippocampus correlates inversely with memory test performance in humans

The cerebral serotonin (5‐HT) system is involved in cognitive functions such as memory and learning and animal studies have repeatedly shown that stimulation of the 5‐HT type 4 receptor (5‐HT₄R) facilitates memory and learning and further that the 5‐HT₄R modulates cellular memory processes in hippocampus. However, any associations between memory functions and the expression of the 5‐HT₄R in the human hippocampus have not been investigated. Using positron emission tomography with the tracer [¹¹C]SB207145 and Reys Auditory Verbal Learning Test we aimed to examine the individual variation of the 5‐HT4R binding in hippocampus in relation to memory acquisition and consolidation in healthy young volunteers. We found significant, negative associations between the immediate recall scores and left and right hippocampal BP_ND, (p = 0.009 and p = 0.010 respectively) and between the right hippocampal BP_ND and delayed recall (p = 0.014). These findings provide evidence that the 5‐HT₄R is associated with memory functions in the human hippocampus and potentially pharmacological stimulation of the receptor may improve episodic memory. Hum Brain Mapp 34:3066–3074, 2013. © 2012 Wiley Periodicals, Inc.     

A 5‐HT4‐receptor activation‐induced neural plasticity enhances in vivo reconstructs of enteric nerve circuit insult

Background It was recently reported that some 5‐HT₄‐receptor agonists increased neuronal numbers and length of neurites in enteric neurons developing in vitro from immunoselected neural crest‐derived precursors. We aimed to explore a novel approach in vivo to reconstruct the enteric neural circuitry that mediates a fundamental distal gut reflex. Methods The neural circuit insult was performed in guinea pigs by rectal transection and subsequent end‐to‐end one layer anastomosis. A 5‐HT₄‐receptor agonist, mosapride citrate (10–100 μmol L^?1) (applied for a patent) was applied locally at the anastomotic site. Key Results Mosapride promoted the regeneration of the neural circuit in the impaired myenteric plexus and the recovery of the defecation reflex in the distal gut. Furthermore, mosapride generated neurofilament (NF)‐, 5‐HT₄‐receptor‐ and 5‐bromo‐2′‐deoxyuridine (BrdU)‐positive cells and surprisingly formed neural network in the newly formed granulation tissue at the anastomotic site 2 weeks after enteric nerve circuit insult. Possible neural stem cell markers, anti‐distal less homeobox 2 (DLX2)‐ and p75‐positive and NF‐positive cells increased during the same time period. All actions by mosapride were inhibited by the specific 5‐HT₄‐receptor antagonist, GR113808 (10 μmol L^?1). Conclusions & Inferences These results indicate that activation of enteric neural 5‐HT₄‐receptors promotes reconstruction of an enteric neural circuit leading to the recovery of the defecation reflex in the distal gut, and that this reconstruction involves possibly neural stem cells. These findings indicate that treatment with 5‐HT₄ agonists could be a novel therapy for generating new enteric neurons to rescue aganglionic gut disorders.     

Similar serotonin‐2A receptor binding in rats with different coping styles or levels of aggression

Individual differences in coping style emerge as a function of underlying variability in the activation of a mesocorticolimbic brain circuitry. Particularly serotonin seems to play an important role. For this reason, we assessed serotonin‐2A receptor (5‐HT_2AR) binding in the brain of rats with different coping styles. We compared proactive and reactive males of two rat strains, Wild‐type Groningen (WTG) and Roman high‐ and low avoidance (RHA, RLA). 5‐HT_2AR binding in (pre)frontal cortex (FC) and hippocampus was investigated using a radiolabeled antagonist ([³H]MDL‐100907) and agonist ([³H]Cimbi‐36) in binding assays. No differences in 5‐HT_2AR binding were observed in male animals with different coping styles. [³H]MDL‐100907 displayed a higher specific‐to‐nonspecific binding ratio than [³H]Cimbi‐36. Our findings suggest that in these particular rat strains, 5‐HT_2AR binding is not an important molecular marker for coping style. Because neither an antagonist nor an agonist tracer showed any binding differences, it is unlikely that the affinity state of the 5‐HT_2AR is co‐varying with levels of aggression or active avoidance in WTG, RHA and RLA. Synapse, 69:226–232, 2015 . © 2015 Wiley Periodicals, Inc.     

l‐Stepholidine‐induced excitation of dopamine neurons in rat ventral tegmental area is associated with its 5‐HT1A receptor partial agonistic activity

Rationale: l‐Stepholidine (l‐SPD), a tetrahydroprotoberberine alkaloid, possesses a pharmacological profile of a D₁/5‐HT_1A agonist and a D₂ antagonist. This unique pharmacological profile makes it a promising novel antipsychotic candidate. Preliminary clinical trials and animal experiments suggest that l‐SPD improves both positive and negative symptoms of schizophrenia without producing significant extrapyramidal side effects. To further explore the antipsychotic mechanisms of the drug, we studied the effects of l‐SPD on the activity of dopamine (DA) neurons in the ventral tegmental area (VTA) using in vivo single‐unit recording technique in rats. Result: We found that l‐SPD increased VTA DA neurons firing rate and induced slow oscillation in firing pattern. Moreover, l‐SPD, not clozapine, reversed d‐amphetamine‐induced inhibition which induced an excitation of VTA DA neurons. Furthermore, our data indicated that the excitatory effect of l‐SPD is associated with its partial agonistic action for the 5‐HT_1A receptor since the 5‐HT_1A receptor antagonist WAY100635 could block the l‐SPD‐induced excitatory effect. However, activation of 5‐HT_1A receptor alone by specific agonist (±)‐8‐Hydroxy‐2‐(dipropylamino) tetralin (8‐OH‐DPAT) was insufficient to elicit excitation of VTA DA neurons, but the excitation of 8‐OH‐DPAT on VTA DA neurons was elicited in the presence of D₂‐like receptors antagonist raclopride. Collectively, these results indicate that l‐SPD excited VTA DA neurons requiring its D₂‐like receptors antagonistic activity and 5‐HT_1A receptor agonistic activity. Conclusion: The present data demonstrate that D₂ receptor antagonist/5‐HT_1A receptor agonistic dual properties modulate dopaminergic transmission in a unique pattern that may underlie the different therapeutic responses between l‐SPD and other atypical antipsychotic drugs. Synapse, 2010. © 2010 Wiley‐Liss, Inc.     

A double‐blind,placebo‐controlled study of prucalopride in elderly patients with chronic constipation

Background Constipation affects up to 50% of the elderly; this study evaluates the efficacy, safety, and tolerability of the selective 5‐HT₄ agonist prucalopride in chronically constipated elderly patients. Methods Three hundred chronic constipation patients aged ≥65 years were randomized to prucalopride (1, 2, or 4 mg once daily) or placebo for 4 weeks. The primary endpoint was the percentage of patients with ≥3 spontaneous complete bowel movements (SCBM) per week. Secondary endpoints included the percentage with an increase of ≥1 SCBM per week, BM frequency, constipation‐related symptoms, quality of life (QoL), safety, and tolerability. Key Results More patients achieved ≥3 SCBM per week with prucalopride than with placebo. This difference was largest and significant during the first week of 4 mg prucalopride (P ≤ 0.05). Significantly more patients in each prucalopride group achieved an increase of ≥1 SCBM per week from baseline vs placebo (e.g. 60% with 1 mg prucalopride vs 34% with placebo at week 4; P ≤ 0.05). More patients had improvement in PAC‐QOL satisfaction score of ≥1 with 1 mg prucalopride than with placebo (P ≤ 0.05); the same was true for PAC‐SYM stool symptoms (1 and 4 mg prucalopride; P ≤ 0.05). Treatment‐emergent adverse events were similar between groups: the most frequently reported with prucalopride were headache and gastrointestinal events. There were no clinically significant differences between prucalopride and placebo for vital signs, laboratory assessments, or ECG variables. Conclusions & Inferences Prucalopride, in the dose‐range tested (1–4 mg once daily), has beneficial effects on bowel movements, symptoms, and QoL, and is safe and well‐tolerated in elderly patients with chronic constipation.     

Serotonin‐2C receptor agonists decrease potassium‐stimulated GABA release in the nucleus accumbens

The serotonin 5‐HT_2C receptor has shown promise in vivo as a pharmacotherapeutic target for alcoholism. For example, recently, a novel 4‐phenyl‐2‐N,N‐dimethylaminotetralin (PAT) drug candidate, that demonstrates 5‐HT_2C receptor agonist activity together with 5‐HT_2A/2B receptor inverse agonist activity, was shown to reduce operant responding for ethanol after peripheral administration to rats. Previous studies have shown that the 5‐HT_2C receptor is found throughout the mesoaccumbens pathway and that 5‐HT_2C receptor agonism causes activation of ventral tegmental area (VTA) GABA neurons. It is unknown what effect 5‐HT_2C receptor modulation has on GABA release in the nucleus accumbens core (NAcc). To this end, microdialysis coupled to capillary electrophoresis with laser‐induced fluorescence was used to quantify extracellular neurotransmitter concentrations in the NAcc under basal and after potassium stimulation conditions, in response to PAT analogs and other 5‐HT_2C receptor modulators administered by reverse dialysis to rats. 5‐HT_2C receptor agonists specifically attenuated stimulated GABA release in the NAcc while 5‐HT_2C antagonists or inverse agonists had no effect. Agents with activity at 5‐HT_2A receptors had no effect on GABA release. Thus, in contrast to results reported for the VTA, current results suggest 5‐HT_2C receptor agonists decrease stimulated GABA release in the NAcc, and provide a possible mechanism of action for 5HT_2C‐mediated negative modulation of ethanol self‐administration. Synapse 69:78–85, 2015. © 2014 Wiley Periodicals, Inc.     

Brain‐derived neurotrophic factor expression is increased in the hippocampus of 5‐HT2C receptor knockout mice

Several studies have suggested a close interaction between serotonin (5‐HT) and BDNF; however, little is known of the specific relationship between BDNF and the 5‐HT_2C receptor. Therefore, in this study we investigated BDNF expression in 5‐HT_2C receptor knockout mice (5‐HT_2CKO). We also assessed functional consequences of any changes in BDNF using a behavioral test battery. Western blot analysis demonstrated a significant 2.2‐fold increase in the expression of the mature form of BDNF in 5‐HT_2CKO mice when compared with wild‐type controls (WT) in the hippocampus (P = 0.008), but not frontal cortex or striatum. No differences in the expression of the pro‐BDNF isoform were found, and the ratio of mature/pro BDNF was significantly increased in 5‐HT_2CKO (P = 0.003). BDNF mRNA expression in the hippocampus was not different between the genotypes. Hence, increased mature BDNF levels in 5‐HT_2CKO hippocampus are most likely due to increased extracellular cleavage rates of pro‐BDNF to its mature form. Protein expression of the BDNF receptor, tropomycin‐related receptor B (TrkB), was also unchanged in the hippocampus, frontal cortex and striatum. With repeated training in a 10‐day win‐shift radial arm maze task, 5‐HT_2CKO and WT showed similar decreases of the number of working memory and reference memory errors. In addition, no genotype specific differences were observed for passive or active avoidance learning. 5‐HT_2CKO showed modest locomotor hyperactivity but no differences in tests for anxiety, sensorimotor gating, or depressive‐like behaviors; however, in the tail suspension test 5‐HT_2CKO showed significantly reduced climbing (P < 0.05). In conclusion, loss of 5‐HT_2C receptor expression leads to a marked and selective increase in levels of the mature form of BDNF in the hippocampus. Despite this marked increase, 5‐HT_2CKO show only subtle behavioral changes. © 2010 Wiley‐Liss, Inc.     

Luminal 5‐HT4 receptors—A successful target for prokinetic actions

The prokinetic effects of 5‐HT₄ receptor (5‐HT₄R) agonists have been utilized clinically for almost three decades to relieve symptoms of constipation. Surprisingly, the mechanism(s) of action of these compounds is still being debated. Recent studies highlight luminal 5‐HT₄Rs as an alternative and effective target for these prokinetic agents. These include the study by Shokrollahi et al (2019, Neurogastroenterol Motil, e13598) published in the current issue of Neurogastroenterology and Motility, who found that activation of mucosal 5‐HT₄Rs by intraluminal prucalopride, significantly enhanced propulsive motor patterns in rabbit colon. The authors highlight the idea that development of agonists targeting luminal 5‐HT₄Rs in the colonic mucosa might be more effective and safer in achieving prokinetic effects on intestinal motility. The purpose of this mini‐review is to discuss the evidence for luminal 5‐HT₄Rs as an emerging target for prokinetic agents in facilitating propulsive motor patterns in the colon.     

Aggression is related to frontal serotonin‐1A receptor distribution as revealed by PET in healthy subjects

Objectives: Various studies indicate that serotonin regulates impulsivity and the inhibitory control of aggression. Aggression is also known to be modified by sex hormones, which exert influence on serotonergic neurotransmission. The present study aimed to elucidate potential interactions between human aggression, the inhibitory serotonergic 5‐HT_1A receptor, and sex hormones. Experimental Design: Thirty‐three healthy volunteers (16 women, aged 26.24 ± 5.5 yr) completed a validated questionnaire incorporating five dimensions of aggression. Subsequently, all subjects underwent positron emission tomography with the radioligand [carbonyl‐¹¹C]WAY‐100635 to quantify 5‐HT_1A binding potentials (BP_NDs) in the prefrontal cortex, limbic areas, and midbrain. Also, plasma levels of testosterone, 17ß‐estradiol and sex hormone‐binding globulin (SHBG) were measured. Relations between aggression scores, regional 5‐HT_1A BP_NDs, and hormone levels were analyzed using correlations, multivariate analyses of variance, and linear regressions. Principal Observations: Statistical analyses revealed higher 5‐HT_1A receptor BP_NDs in subjects exhibiting higher aggression scores in prefrontal (all P < 0.041) and anterior cingulate cortices (P = 0.016). More aggressive subjects were also characterized by lower SHBG levels (P = 0.015). Moreover, higher SHBG levels were associated with lower 5‐HT_1A BP_NDs in frontal (P = 0.048) and cingulate cortices (all P < 0.013) and in the amygdala (P = 0.03). Conclusions: The present study provides first‐time evidence for a specific interrelation between the 5‐HT_1A receptor distribution, sex hormones, and aggression in humans. Our findings point to a reduced down‐stream control due to higher amounts or activities of frontal 5‐HT_1A receptors in more aggressive subjects, which is presumably modulated by sex hormones. Hum Brain Mapp 30:2558–2570, 2009. © 2008 Wiley‐Liss, Inc.     

Trait Openness and serotonin 2A receptors in healthy volunteers: A positron emission tomography study

Recent research found lasting increases in personality trait Openness in healthy individuals and patients after administration of the serotonin 2A receptor (5‐HT_2AR) agonist psilocybin. However, no studies have investigated whether 5‐HT_2AR availability as imaged using positron emission tomography (PET) is associated with this trait. In 159 healthy individuals (53 females), the association between 5‐HT_2AR binding in neocortex imaged with [¹⁸F]altanserin or [¹¹C]Cimbi‐36 PET and personality trait Openness was investigated using linear regression models. In these models the influence of sex on the association was also investigated. Trait Openness was assessed with the NEO Personality Inventory‐Revised. No significant associations between neocortical 5‐HT_2AR binding and trait Openness were found for [¹⁸F]altanserin (p = 0.5) or [¹¹C]Cimbi‐36 (p = 0.8). Pooling the data in a combined model did not substantially change our results (p = 0.4). No significant interactions with sex were found (p > 0.35). Our results indicate that differences in 5‐HT_2AR availability are not related to variations in trait Openness in healthy individuals. Although stimulation of the 5‐HT_2AR with compounds such as psilocybin may contribute to long‐term changes in trait Openness, there is no evidence in favor of an association between 5‐HT_2AR and trait Openness.