PPI Response Research Articles

Baseline prepulse inhibition dependency of orexin A and REM sleep deprivation

RationalePrepulse inhibition (PPI) impairment reflects sensorimotor gating problems, i.e. in schizophrenia. This study aims to enlighten the role of orexinergic regulation on PPI in a psychosis-like model.ObjectivesIn order to understand the impact of orexinergic innervation on PPI and how it is modulated by age and baseline PPI (bPPI), chronic orexin A (OXA) injections was carried on non-sleep-deprived and sleep-deprived rats that are grouped by their bPPI.MethodsbPPI measurements were carried on male Wistar rats on P45 or P90 followed by grouping into low-PPI and high-PPI rats. The rats were injected with OXA twice per day for four consecutive days starting on P49 or P94, while the control groups received saline injections. 72 h REMSD was carried on via modified multiple platform technique on P94 and either OXA or saline was injected during REMSD. PPI tests were carried out 30 min. after the last injection.ResultsOur previous study with acute OXA injection after REMSD without bPPI grouping revealed that low OXA doses might improve REMSD-induced PPI impairment. Our current results present three important conclusions: (1) The effect of OXA on PPI is bPPI-dependent and age-dependent. (2) The effect of REMSD is bPPI-dependent. (3) The effect of OXA on PPI after REMSD also depends on bPPI.ConclusionOrexinergic regulation of PPI response with and without REMSD can be predicted by bPPI levels. Our findings provide potential insights into the regulation of sensorimotor gating by sleep/wakefulness systems and present potential therapeutic targets for the disorders, where PPI is disturbed.

Proximal esophageal impedance baseline increases the yield of impedance-pH and is associated with response to PPIs in chronic cough patients.

Chronic cough significantly impairs the quality of life. Although various studies focused on MNBI as assessed in the distal esophagus, scarce data are available on the clinical value of proximal measurements. To investigate the role of proximal MNBI in the workup of patients with chronic cough and its ability to predict PPI response. Demographic, clinical, endoscopy findings, impedance-pH and HRM tracings from consecutive cough patients were evaluated. MNBI was calculated at proximal and distal esophagus. One hundred and sixty four patients were included. In addition to traditional variables, when considering also the PSPW index or MNBI at 3 cm or 15 cm, the proportion of patients with pathological impedance-pH monitoring significantly increased. 70/164 patients were responders, while 94 (57.3%) were non-responder to double PPI dose (p < 0.05). Patients with pathologic MNBI at 3 cm and/or 15 cm as well as those with pathologic PSPW index were characterized by a significantly higher proportion of responders than that observed among patients with normal impedance-pH variables (p < 0.001). The proportion of responders with pathological MNBI at 15 cm was significantly higher than the proportion of responders with pathological MNBI at 3 cm (82.8% vs. 64.3%, p < 0.05). At multivariable model, pathological MNBI at both 3 cm and 15 cm as well as PSPW index were associated with PPI responsiveness. The strongest association with PPI response was observed for MNBI at 15 cm. The assessment of MNBI at proximal esophagus increases the diagnostic yield of impedance-pH monitoring and may represent a useful predictor of PPI responsiveness in the cumbersome clinical setting of suspected reflux-related cough.

Improved diagnosis of reflux hypersensitivity.

Reflux hypersensitivity (RH) is characterized by normal esophageal exposure to acid and positive correlation of symptoms to reflux episodes. Positivity of Symptomatic Index (SI) and/or Symptom Association Probability (SAP) is used diagnostically, though experts support that concordance of both is needed. We evaluated differences among patients with RH and concordance of SI/SAP or not. Patients with typical reflux symptoms without previous GERD diagnosis, submitted simultaneously to Ph-Impedance off PPI and high resolution manometry were included. Self-response to PPI was evaluated. Patients showing SI and/or SAP positivity were considered having RH and further classified to definite RH if both SI/SAP were positive or indefinite if only one positive. Totally 2659 patients (M/F: 35.6%/64.7%, mean age: 45 ± 14) were included. Final diagnosis was; FH: 21.8%, RH: 29.3% (definite: 14.3%/indefinite: 15%), GERD: 36% and inconclusive GERD: 12.9%. Patients with definite RH showed increased total reflux time, total number of reflux episodes and length of hiatus hernia, and also numerically but not statistically significant increased rates of PPI responsiveness versus indefinite RH and decreased mean nocturnal baseline impedance. Moreover, they showed significantly increased rate of PPI response versus patients with functional heartburn (FH). Some PPI responsiveness is frequent among patients with RH as also with FH, and cannot discriminate those entities clinically when diagnosing RH using SI and/or SAP positive criterion. Patients with RH and SI/SAP concordance differ from patients without. Implementation of a strict RH definition (both SI and SAP positive) can better distinguish RH from FH and should be used in the future.

Prospective validation of reflux monitoring by impedance-pH in predicting PPI response in typical GERD.

The Lyon Consensus proposed a hierarchical approach to GERD diagnosis based on conventional and new impedance-pH metrics, namely acid exposure time (AET), number of reflux episodes, post-reflux swallow-induced peristaltic wave (PSPW) index, and mean nocturnal baseline impedance (MNBI). To define the value of conventional and new impedance-pH parameters as predictors of response to label-dose PPI in typical GERD. Consecutive adult patients with typical esophageal symptoms were prospectively studied with impedance-pH monitoring and treated with 8-week label-dose PPI. At the end of the PPI course, symptoms response was assessed. Among 255 patients who entered the study, 168 (65.9%) reported symptom remission. At ROC analysis, both MNBI and PSPW index were significantly associated to PPI responsiveness with AUC of 0.783 and 0.801, respectively. Cut-off values of 1747Ω for MNBI and 50% for PSPW index were identified as discriminators between response and non-response to label-dose PPI. At multivariate analysis, MNBI, PSPW index, and AET >6% were efficient predictors of PPI responses (OR 3, 5.4 and 2.3, respectively). Number of reflux episodes did not predict PPI response. The novel MII-pH variables together with pathological are highly predictive of response of the typical GERD syndrome to label-dose PPI.

Proximal esophageal impedance baseline increases the yield of impedance-pH monitoring for GERD diagnosis and is associated with heartburn response to PPI.

Impairment of esophageal mucosal integrity as assessed by low mean nocturnal baseline impedance (MNBI) measured in the distal esophagus increases the diagnostic yield of impedance-pH in patients with inconclusive GERD diagnosis as defined by Lyon criteria. To assess the diagnostic yield of MNBI measurement in the proximal esophagus, and its relationship with PPI response. Expert review of off-therapy impedance-pH tracings from consecutive patients with heartburn, 80 responders and 80 non-responders to label-dose PPI. Data were compared to those from 36 healthy controls using ROC analysis. Multivariate analysis was performed to measure the strength of association of MNBI with PPI response. A threshold value of 2665 Ω was defined for proximal MNBI by ROC analysis, affording 91.7% sensitivity and 86.5% specificity. Proximal and distal MNBI were significantly lower in non-responder cases as compared to responders. Adding proximal MNBI positivity to pathologic (>6%) acid exposure time (AET) and positive symptom-reflux association, the proportion of patients with abnormal impedance-pH findings increased from 74/160 (46%) to 106/160 (66.3%) (p = 0.0016). Among the 12 patients with pathologic proximal MNBI as the only positive impedance-pH finding, 9 cases (75%) were PPI responders. According to multivariate analysis, AET and pathological distal and proximal MNBI were significantly associated with PPI response, the strongest association observed for proximal MNBI. Impedance baseline assessment in the proximal esophagus may increase the diagnostic yield of impedance-pH monitoring. Heartburn response to PPI is directly related to ultrastructural mucosal damage in the distal and in the proximal esophagus as well.

Continuing Medical Education Questions: November 2021.

Article Title: Results From Up-Front Esophageal Testing Predicts PPI Response in Patients With Chronic Cough.

INZ-701 Prevents Ectopic Tissue Calcification and Restores Bone Architecture and Growth in ENPP1-Deficient Mice.

Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is the major enzyme that cleaves extracellular adenosine triphosphate (ATP) to generate pyrophosphate (PPi), an inorganic metabolite with potent anticalcification activity. Loss-of-function mutations cause hypopyrophosphatemia and lead to a state of ENPP1 deficiency, which has an acute infantile phase known as generalized arterial calcification of infancy (GACI) and a pediatric to adult phase known as autosomal-recessive hypophosphatemic rickets type 2 (ARHR2). ENPP1 deficiency manifests as ectopic calcification of multiple tissues, neointimal proliferation, premature mortality, impaired growth, and bone deformities. INZ-701, a human ENPP1-Fc protein, is in clinical development as an enzyme replacement therapy for the treatment of ENPP1 deficiency. The pharmacokinetic and pharmacodynamic profile and therapeutic effect of INZ-701 were investigated in Enpp1asj/asj mice, a murine model of ENPP1 deficiency. Enpp1asj/asj mice have undetectable plasma PPi, lower plasma phosphate, and higher FGF23 levels compared with wild-type (WT) mice. Enpp1asj/asj mice on the acceleration diet, containing high phosphate and low magnesium, quickly develop clinical signs, including dehydration, rough hair coat, pinned ears, stiffed legs, and hunched back. Enpp1asj/asj mice treated with vehicle had aforementioned clinical signs plus severe ectopic calcification in multiple tissues and bone defects, characteristics of the clinical phenotype observed in GACI and ARHR2 patients. Our results showed a durable PPi response for more than 3 days after a single dose of INZ-701. Treatment of ENPP1-deficient mice every other day with INZ-701 for 8 weeks restored circulating levels of PPi, prevented pathological calcification in all the tested organs, restored growth parameters, corrected bone defects, improved clinical signs, and decreased mortality in Enpp1asj/asj mice, demonstrating the potential of INZ-701 to treat ENPP1 deficiency. © 2021 American Society for Bone and Mineral Research (ASBMR).

Dysregulation of behavioral and autonomic responses to emotional and social stimuli following bidirectional pharmacological manipulation of the basolateral amygdala in macaques

The amygdala is a key component of the neural circuits mediating the processing and response to emotionally salient stimuli. Amygdala lesions dysregulate social interactions, responses to fearful stimuli, and autonomic functions. In rodents, the basolateral and central nuclei of the amygdala have divergent roles in behavioral control. However, few studies have selectively examined these nuclei in the primate brain. Moreover, the majority of non-human primate studies have employed lesions, which only allow for unidirectional manipulation of amygdala activity. Thus, the effects of amygdala disinhibition on behavior in the primate are unknown. To address this gap, we pharmacologically inhibited by muscimol or disinhibited by bicuculline methiodide the basolateral complex of the amygdala (BLA; lateral, basal, and accessory basal) in nine awake, behaving male rhesus macaques (Macaca mulatta). We examined the effects of amygdala manipulation on: (1) behavioral responses to taxidermy snakes and social stimuli, (2) food competition and social interaction in dyads, (3) autonomic arousal as measured by cardiovascular response, and (4) prepulse inhibition of the acoustic startle (PPI) response. All modalities were impacted by pharmacological inhibition and/or disinhibition. Amygdala inhibition decreased fear responses to snake stimuli, increased examination of social stimuli, reduced competitive reward-seeking in dominant animals, decreased heart rate, and increased PPI response. Amygdala disinhibition restored fearful response after habituation to snakes, reduced competitive reward-seeking behavior in dominant animals, and lowered heart rate. Thus, both hypoactivity and hyperactivity of the basolateral amygdala can lead to dysregulated behavior, suggesting that a narrow range of activity is necessary for normal functions.

Metabotropic Glutamate Receptor 2 and Dopamine Receptor 2 Gene Expression Predict Sensorimotor Gating Response in the Genetically Heterogeneous NIH-HS Rat Strain.

Disruption of sensorimotor gating causes "flooding" of irrelevant sensory input and is considered a congenital trait in several neurodevelopmental disorders. Prepulse inhibition of acoustic startle response (PPI) is the operational measurement and has a high translational validity. Pharmacological studies in rodents have linked alterations in serotonin, dopamine and glutamate signalling to PPI disruption. How PPI response is associated with gene expression levels of these receptors is unknown. PPI response was assessed in 39 genetically heterogeneous National Institutes of Health-Heterogeneous Stock (NIH-HS) rats. Animals were classified as high, medium or low PPI. Expression levels of glutamate metabotropic receptor 2 (Grm2), dopamine receptor D2 (Drd2), dopamine receptor D1 (Drd1), serotonin receptor 1A (Htr1a), serotonin receptor 2A (Htr2a) and homer scaffolding protein 1 (Homer1) were investigated in prefrontal cortex (PFC) and striatum (STR). When comparing the two extreme phenotypes, only Drd2 in STR showed increased expression in the low PPI group. A multinomial model fitting all genes and all groups indicated that Grm2 in PFC, and Grm2 and Drd2 in the STR predicted PPI group. This was corroborated by a linear relationship of Grm2 with PPI in PFC, and Drd2 with PPI in STR. An interaction between levels of H3K27 trimethylation, associated with transcriptional repression, and PPI phenotype was observed for Drd2 in STR. Gene set enrichment analysis on a microarray dataset on Lewis rats confirmed enrichment of Drd2 in PFC in relation to PPI. These findings contribute to the understanding of the genetic substrate behind alterations in sensorimotor gating, relevant for its linkage to neurodevelopmental disorders.

Behavioural effects of high fat diet in adult Nrg1 type III transgenic mice

Some diets appear to have detrimental effects on schizophrenia symptoms. Neuregulin 1 (NRG1) is a risk gene for schizophrenia and a recently developed transgenic mouse model for Nrg1 type III demonstrates a schizophrenia-relevant phenotype. The current study evaluated the behavioural response of Nrg1 type III transgenic mice to a high fat diet (HFD) to determine the potential interactive impact of diets and genetic risk factors on disease symptoms.Male and female Nrg1 III and control littermates (N = 13–24) were exposed during adulthood to either HFD or standard chow diet (CHOW) for eight weeks before being tested in behavioural domains relevant to schizophrenia. Locomotion and exploration, anxiety, social behaviours (including social preference), sensorimotor gating (i.e. prepulse inhibition, PPI), associative learning, and anhedonia were assessed.HFD increased the body weight gain of mice, suppressed locomotion, exploration, and anxiety-related behaviours in a sex-dependent manner. HFD augmented the PPI response in male mice and decreased anhedonia in a sucrose preference test. Finally, HFD had a sex-dependent impact on fear-associated memory with HFD-induced cognitive impairments being most prominent in Nrg1 transgenic females.In conclusion, HFD and mutant Nrg1 III interactively impair particular cognitive domains in a sex-specific manner. Thus, our preclinical data suggest that genetic predisposition to the schizophrenia risk gene NRG1 may modulate detrimental behavioural effects of diets. This indicates the importance to research further the role of particular diets in the context of populations at risk to develop schizophrenia.

Su1067 - Clinical and Impedance-Ph Factors Associated to PPI Response in Patientswith with Extraesophageal Symptoms Suggestive of Gerd

Su1067 - Clinical and Impedance-Ph Factors Associated to PPI Response in Patientswith with Extraesophageal Symptoms Suggestive of Gerd

Ankylosaurus back sign: novel endoscopic finding in esophageal eosinophilia patients indicating proton pump inhibitor response

Background and study aims Characteristic endoscopic findings, such as linear furrows, rings, and whitish exudates, indicate the presence of esophageal eosinophilia (EE), though no specific findings are known to distinguish eosinophilic esophagitis (EoE) from proton pump inhibitor-responsive esophageal eosinophilia (PPI-REE). Here, we present a novel endoscopic finding in some EE patients possessing a linear longitudinal arrangement of whitish nodules with the appearance of the back of an Ankylosaurus dinosaur, termed Ankylosaurus back sign (ABS), and evaluations of its significance in affected patients. Patients and methods Fifty-five patients diagnosed with EE (≥ 15 eosinophils/high power field) who were treated at our hospital and shown to evaluate a PPI response were enrolled. Endoscopic findings at baseline and clinical parameters were retrospectively reviewed. Furthermore, the clinicopathological features of patients with ABS, as well as the relationship between its presence and PPI response were evaluated. Results Fifty-five patients (47 males, 8 females) with EE (17 with EoE, 38 with PPI-REE) were evaluated, of whom 50 (90.9 %) had linear furrows, the most frequently found feature, while ABS was found in 9 (16.4 %). Inter-observer agreement was substantial for ABS (κ 0.77). Interestingly, all patients with ABS had PPI-REE. Our findings revealed that the presence of ABS was closely associated with reflux esophagitis (RE) in patients with PPI-REE. Conclusions Although ABS was less frequent than typical endoscopic findings such as linear furrows in EE, this novel finding was closely associated with PPI-REE accompanied with RE. The clinical implications of ABS in patients with EE should be investigated further.

Dose-dependent and opposite effects of orexin A on prepulse inhibition response in sleep-deprived and non-sleep-deprived rats

Orexin is a novel neurotransmitter released from lateral hypothalamus, that is a crucial modulator in sleep/wakefulness system. Recent studies also suggest its possible role in the neurodevelopmental disorders, such as schizophrenia. Our study consists of two experiments, where we investigate the effect of orexin A (OXA), one of two isoforms of orexin that can pass blood brain barrier, on the prepulse inhibition of acoustic startle reflex. The first experiment tested the effect of OXA on PPI response of non-sleep-deprived rats via intraperitoneal injection 30min before testing. Our results show that 40μg/kg OXA attenuates PPI% at 78dB and 86dB prepulse intensities. The second experiment utilized 72-h REM sleep deprivation, as a model for sleep-deprivation-induced impairment of PPI response. Here, we tested the effect of OXA on PPI% of sleep-deprived rats via intraperitoneal injection at the last 30min of sleep deprivation, testing for PPI immediately afterwards. Our results showed that (1) sleep deprivation attenuates the PPI% at 74dB, 78dB and 86dB prepulse intensities and (2) 10μg/kg OXA completely restores the impaired PPI% at 78dB only, where the highest PPI% impairment was observed. These results suggest that orexin A modulates PPI response in rats in a dose-dependent manner, oppositely for non-sleep-deprived and sleep-deprived rats, and a more detailed investigation for the etiology of this effect should follow.

Mice lacking interleukin-18 gene display behavioral changes in animal models of psychiatric disorders: Possible involvement of immunological mechanisms

Preclinical and clinical evidence suggests pro-inflammatory cytokines might play an important role in the neurobiology of schizophrenia and stress-related psychiatric disorders. Interleukin-18 (IL-18) is a member of the IL-1 family of cytokines and it is widely expressed in brain regions involved in emotional regulation. Since IL-18 involvement in the neurobiology of mental illnesses, including schizophrenia, remains unknown, this work aimed at investigating the behavior of IL-18 null mice (KO) in different preclinical models: 1. the prepulse inhibition test (PPI), which provides an operational measure of sensorimotor gating and schizophrenic-like phenotypes; 2. amphetamine-induced hyperlocomotion, a model predictive of antipsychotic activity; 3. resident-intruder test, a model predictive of aggressive behavior. Furthermore, the animals were submitted to models used to assess depressive- and anxiety-like behavior. IL-18KO mice showed impaired baseline PPI response, which was attenuated by d-amphetamine at a dose that did not modify PPI response in wild-type (WT) mice, suggesting a hypodopaminergic prefrontal cortex function in those mice. d-Amphetamine, however, induced hyperlocomotion in IL-18KO mice compared to their WT counterparts, suggesting hyperdopaminergic activity in the midbrain. Moreover, IL-18KO mice presented increased basal levels of IL-1β levels in the hippocampus and TNF-α in the prefrontal cortex, suggesting an overcompensation of IL-18 absence by increased levels of other proinflammatory cytokines. Although no alteration was observed in the forced swimming or in the elevated plus maze tests in naïve IL-18KO mice, these mice presented anxiogenic-like behavior after exposure to repeated forced swimming stress. In conclusion, deletion of the IL-18 gene resembled features similar to symptoms observed in schizophrenia (positive and cognitive symptoms, aggressive behavior), in addition to increased susceptibility to stress. The IL-18KO model, therefore, could provide new insights into how changes in brain immunological homeostasis induce behavioral changes related to psychiatric disorders, such as schizophrenia.

Challenges and Pitfalls of Entrainment Mapping of Ventricular Tachycardia: Ten Illustrative Concepts.

The use and interpretation of entrainment mapping, or continuous resetting, of a reentrant tachycardia has been regarded as the gold standard for delineation of the components of a reentrant circuit.1,2 The response during and after overdrive pacing, whereby 2 wavefronts enter the circuit antidromically (with fusion) and orthodromically, is used to confirm reentry as the arrhythmia mechanism and determine the relationship of the pacing site to the circuit. The fulfillment of classical criteria outlined by Waldo and colleagues3,4 were synthesized into an anatomic concept for scar-related ventricular tachycardia (VT) by Stevenson et al5 to portray the structural and architectural basis of circuit conduction meandering between regions of fibrosis. In this construct, a central corridor, or protected isthmus, is bordered between 2 regions of dense scar with a single entrance that is distinct from a single exit, which yields the QRS morphology.6 This reentrant model has been central to our current mechanistic understanding of scar-mediated VT and is critically important for differentiating critical sites from bystander sites and regions that are unlikely to interrupt or eliminate reentry.7 However, the nature of reentrant VT in man is more complex than our idealized working construct for many reasons. In clinical practice, the majority of VT is hemodynamically unstable, which precludes the ability to perform entrainment mapping and activation mapping of the entire circuit.8 Differences in the circuit between patients with untolerated and tolerated VT are not well understood. VT circuits are 3 dimensionally complex with transmural conduction and circuit conduction is unlikely to be planar, as depicted by electroanatomic mapping of the myocardial surface. Exits may be multiple9,10 and patterns other than loop reentry around scar are likely. Channels of preserved myocardium are frequently not “normal” in voltage (>1.5 mV) …

Tu1877 Different Contractile and Relaxant Effects of Trypsin in Phasic Smooth Muscles of the Esophageal Body and the Tonic Lower Esophageal Sphincter

G A A b st ra ct s significant difference was observed for age (mean age 52 years in both groups, p=0.922), gender (50% men vs 34%, p=0.097) and body mass index (median 25 kg/m2 vs 24.7 kg/ m2, p=0.569). Patients with typical symptoms were non-responders in 86%, those with atypical symptoms alone in 74% and those with atypical symptoms dominant in 92%. The results of pH-impedance tests were not significantly different between PPI-responders and non-responders. The prevalence of PDS was significantly higher in PPI-non responders, while the prevalence of EPS and IBS almost reach statistical significance (Table). Conclusion This study confirms that pH-impedance monitoring does not help to predict clinical response or non-response to PPI treatment. Functional digestive disorders (EBS, PDS or IBS) appear more frequent in PPI-non responders. Visceral hypersensitivity may be a predictive factor of PPI-non-response in patients with typical or atypical GERD symptoms.

Tu1850 Reflux Patterns and Role of Impedance-pH Variables in Predicting PPI Response in Patients With Suspected GERD-Related Chronic Cough

Tu1850 Reflux Patterns and Role of Impedance-pH Variables in Predicting PPI Response in Patients With Suspected GERD-Related Chronic Cough

Tu1767 Impedance-pH Findings Cannot Predict the PPI Response in Patients With Suspected GERD-Related Extra-Esophageal Symptoms

Tu1767 Impedance-pH Findings Cannot Predict the PPI Response in Patients With Suspected GERD-Related Extra-Esophageal Symptoms

Chronic blockade of CB1 receptors reverses startle gating deficits and associated neurochemical alterations in rats reared in isolation

BACKGROUND AND PURPOSE Pharmacological interventions aimed at restoring the endocannabinoid system functionality have been proposed as potential tools in the treatment of schizophrenia. Based on our previous results suggesting a potential antipsychotic‐like profile of the CB1 receptor inverse agonist/antagonist, AM251, here we further investigated the effect of chronic AM251 administration on the alteration of the sensorimotor gating functions and endocannabinoid levels induced by isolation rearing in rats.EXPERIMENTAL APPROACH Using the post‐weaning social isolation rearing model, we studied its influence on sensorimotor gating functions through the PPI paradigm. The presence of alterations in the endocannabinoid levels as well as in dopamine and glutamate receptor densities was explored in specific brain regions following isolation rearing. The effect of chronic AM251 administration on PPI response and the associated biochemical alterations was assessed.KEY RESULTS The disrupted PPI response in isolation‐reared rats was paralleled by significant alterations in 2‐AG content and dopamine and glutamate receptor densities in specific brain regions. Chronic AM251 completely restored normal PPI response in isolated rats. This behavioural recovery was paralleled by the normalization of 2‐AG levels in all the brain areas analysed. Furthermore, AM251 partially antagonized isolation‐induced changes in dopamine and glutamate receptors.CONCLUSIONS AND IMPLICATIONS These results demonstrate the efficacy of chronic AM251 treatment in the recovery of isolation‐induced disruption of PPI. Moreover, AM251 counteracted the imbalances in the endocannabinoid content, specifically 2‐AG levels, and partially reversed the alterations in dopamine and glutamate systems associated with the disrupted behaviour. Together, these findings support the potential antipsychotic‐like activity of CB1 receptor blockade.LINKED ARTICLES This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.167.issue‐8

Impedance baseline and reflux perception in responder and non-responder non-erosive reflux disease patients

Background.It was recently shown that GERD patients have lower impedance baseline (IB) values than healthy controls and, that the esophageal acid exposure time (AET) correlates with IB levels. Goals.To explore the sensitivity of IB measurements in NERD patients, responders and non-responders to PPIs, when compared with pH-impedance (MII-pH) variables, and to evaluate whether this variable could represent a marker of GERD symptoms. Reproducibility and inter-observer agreement of IB measurement were also assessed. Study.MII-pH tracings from 44 NERD responders and 22 non-responders were analysed. Ten healthy volunteers underwent the same protocol. IB values were measured at the distal and proximal esophagus. IB was also analysed in a subgroup of patients and in controls with two methods and by two blinded operators. Results. Mean IB values at the distal esophagus were significantly lower in NERD patients than in controls. IB values did not differ between responders and non-responders. Of the 8 responders with negative AET and symptom association probability (SAP), 3 (37.5%) showed IB values lower than controls. IB values in responders with positive and negative SAP were similar (1832 (1596–2068) Ω vs 1667 (1361–1973) Ω, p: n.s.). No differences were found between the IB values measured with the two methods and the inter-observer agreement was good. Conclusions.IB is a promising and easy to calculate MII-pH variable and appears to increase the sensitivity of MII-pH monitoring. IB values cannot predict PPI response and are not associated with reflux perception in NERD patients.