Endogén ligandok interakciója gerincvelői szinten = Interaction of endogenous ligands at the spinal level

Az OTKA pályázat keretében több irányban végeztünk kutatásokat a fájdalom mechanizmusok tisztázása érdekében. Meghatároztuk számos, a cannabinoid receptoron ható endogén ligand fájdalomcsillapító hatását és interakciójukat gerincvelői szinten. Az endomorphin-1, agmatin, adenozin, kinurénsav hármas és négyes kombinációban adva kedvező interakciót mutattak, így kombinációban tovább csökkenthető az alkalmazott dózis, s ezzel a mellékhatások veszélye tovább mérsékelhető. Kísérleteket végezünk a viszketésben szerepet játszó spinális mechanizmusok feltárására is. Az intratekálisan adott naltrexon csökkentette a viszketési magatartást, az NMDA antagonista ketamin nem befolyásolta azt jelentős mértékben, ugyanakkor az endogén kinurénsav már hatékony volt. Kifejlesztettünk egy szubkrónikus izületi gyulladásos modellt, és meghatároztuk számos, az izületbe injektált endogén ligandok hatását az izületi gyulladás okozta mechanikus allodyniára. Laboratóriumunkban kifejlesztettünk egy komplex, krónikus szkizofrénia modellt, melyben az állatok hőfájdalom szenzitivitása megváltozott. A modell további jellemzésére egy Minimitter készüléket szereztünk be, mely lehetővé teszi a hőszabályozás és a motoros aktivitás folyamatos regisztrálását telemetriás módszerrel. Legújabb vizsgálatainkban a fiatalkori capsaicin deszenzitizáció fájdalomküszöböt befolyásoló hatását jellemeztük igazolva, hogy a deszenzitizáció elsősorban a gyulladásos fájdalomérzékenységet csökkenti. | Thanks to the OTKA grant we performed several experiments to characterize the pain mechanisms in different aspects. We determined the antinociceptive effects and the interactions of several endogenous cannabinoid ligands at spinal level. We found that the triple and quadruple combinations of endomorphin-1, agmatine, adenosin and kynurenic acid induced effective antinociception without any side effects. We investigated the spinal mechanisms responsible for pruritus. The intrathecally administered naltrexone and kynurenic acid significantly decreased the pruritic behavior, while ketamine did not influence it. A subchronic inflammatory model was developed and characterized. We showed the antinociceptive potency and interactions of several endogenous ligands at peripheral level. It is well-known that the schizophrenic patients show decreased pain sensitivity. We developed and characterized a new, complex, chronic schizophrenia model. We proved that these animals show increased pain threshold. We invested a telemetric instrument (Minimitter) to further characterize this model (thermoregulation, motor activity). We also investigated the pain threshold changes in different pain models after juvenile capsaicin desensitization. We have shown that the inflammatory pain sensitivity decreased and the morphine has higher potency in these animals

Well-being profiles in adolescence:psychometric properties and latent profile analysis of the mental health continuum model – a methodological study

Abstract Background: The Adolescent Mental Health Continuum Short Form (MHC-SF) is a psychometrically valid tool to evaluate the domains of subjective well-being, but there is a lack of investigations which could distinguish subgroups with distinct subjective well-being profiles based on this measurement. Therefore, after testing the competing measurement models of the MHC-SF, our main aim was to identify subjective well-being profiles in a large adolescent sample. Methods: On a representative Hungarian adolescent sample (N=1572; 51% girl; mean age was 15.39, SD=2.26) confirmatory factor analyses (CFA) and exploratory structural equation modeling (ESEM) were used to test the factor stucture of the Adolescents MHC-SF. In addition, gender invariance of the best fitting model was also tested. Latent Profile Analyses (LPA) were conducted to reveal distinct subgroups and these profiles were then compared. Results: Results support the bifactor model of MHC-SF: the general and specific well-being factors which were invariant across gender. LPA yielded four subgroups, three of them have been theoretically hypothesized in previous works (i.e. flourishing, moderate mental health, languishing), but an emotionally vulnerable subgroup also emerged. Compared to the languishing group, this new subgroup demonstrated higher scores on prosocial behaviour, but had comparable level of loneliness and internalizing symptoms. Conclusions: Our results suggest that the MHC-SF is a reliable and valid instrument for assessing overall well-being and its components. In addition, the identification of young people to be at risk for low mental health may help us to tailor mental health promotion programs to their special needs. Keywords: Well-being, Positive Mental Health, Mental Health Continuum Model, Adolescents, Confirmatory Factor Analysis, Exploratory Structural Equation Modeling, Gender Invariance, Latent Profile Analyse

Wisket rat model of schizophrenia : Impaired motivation and, altered brain structure, but no anhedonia

It is well-known that the poor cognition in schizophrenia is strongly linked to negative symptoms, including motivational deficit, which due to, at least partially, anhedonia. The goal of this study was to explore whether the schizophrenia-like Wisket animals with impaired motivation (obtained in the reward-based hole-board test), also show decreased hedonic behavior (investigated with the sucrose preference test). While neurochemical alterations of different neurotransmitter systems have been detected in the Wisket rats, no research has been performed on structural changes. Therefore, our additional aim was to reveal potential neuroanatomical and structural alterations in different brain regions in these rats. The rats showed decreased general motor activity (locomotion, rearing and exploration) and impaired task performance in the hole-board test compared to the controls, whereas no significant difference was observed in the sucrose preference test between the groups. The Wisket rats exhibited a significant decrease in the frontal cortical thickness and the hippocampal area, and moderate increases in the lateral ventricles and cell disarray in the CA3 subfield of hippocampus. To our knowledge, this is the first study to investigate the hedonic behavior and neuroanatomical alterations in a multi-hit animal model of schizophrenia. The results obtained in the sucrose preference test suggest that anhedonic behavior might not be involved in the impaired motivation obtained in the hole-board test. The neuropathological changes agree with findings obtained in patients with schizophrenia, which refine the high face validity of the Wisket model

Nonproductive thoughts, somatic symptoms and well-being in adolescence: testing the moderator role of age and gender in a representative study

BACKGROUND: Previous findings suggest a female preponderance in nonproductive thoughts -rumination and worry-, but studies on gender differences in the strength of the relationship between nonproductive thoughts, somatic symptoms and subjective well-being are scarce. Our aim was to test whether gender and age would moderate these associations. METHODS: 1572 adolescents were involved in this representative cross-sectional study (770 boys; mean age = 15.39; SD = 2.26 years). Nonproductive thoughts were measured by Nonproductive Thoughts Questionnaire for Children (NPTQ-C), somatic symptoms were assessed by Somatic Complaint List (SCL), while Mental Health Continuum-Short Form (MHC-SF) was used to measure subjective well-being. To assess the moderation effects of age and gender on the relationship between nonproductive thoughts, somatic symptoms and well-being, four multiple indicator multiple causes (MIMIC) models were defined. RESULTS: Our results suggested that higher rates of nonproductive thoughts predicted a higher level of somatic symptoms and a lower level of subjective well-being. The analyses revealed that although nonproductive thoughts were strongly and equally associated with somatic symptoms among boys and girls, age was a significant moderator. Gender also moderated the relationship between nonproductive thoughts and subjective well-being. CONCLUSIONS: Our results support the importance of nonproductive thoughts in somatic symptoms and highlight that the strength of the relationship is similar across both genders but could be dependent upon age. The findings also shed light on the decreased well-being of girls, especially with elevated level of nonproductive thoughts

Automating, Analyzing and Improving Pupillometry with Machine Learning Algorithms

The investigation of the pupillary light reflex (PLR) is a well-known method to provide information about the functionality of the autonomic nervous system. Pupillometry, a non-invasive technique, was applied to study the PLR alterations in a new, schizophrenia-like rat substrain, named WISKET. The pupil responses to light impulses were recorded with an infrared camera; the videos were automatically processed and features were extracted from the pupillograms. Besides the classical statistical analysis (ANOVA), feature selection and classification were applied to reveal the significant differences in the PLR parameters between the control and WISKET animals. Based on these results, the disadvantages of this method were analyzed and the measurement setup was redesigned and improved. The pupil segmentation method has also been adapted to the new videos. 2564 images were annotated manually and used to train a fully-convolutional neural network to produce pupil mask images. The method was evaluated on 329 test images and achieved 4% median relative error. With the new setup, the pupil detection became reliable and the new data acquisition offers robustness to the experiments

The mediating effect of anger rumination, coping and conformity motives on the association between hostility and problematic cannabis use

BACKGROUND: Anger rumination is consistently associated with maladaptive psychopathological outcomes. However, there is a lack of research on the association between problematic cannabis use, cannabis use motives and anger rumination. Coping motives showed positive relationships with negative affectivity and emotion dysregulation, thus it might be possible that coping motives can mediate the effects of hostility and anger rumination on problematic cannabis use. AIMS: The goal of the present study was to examine the mediating role of anger rumination and cannabis use motives on the relationship between hostility and problematic cannabis use. METHODS: The cross-sectional study used a convenience sample of 764 past year cannabis users with a risk for problematic cannabis use (Males: 70.42% [N = 538], Age: M = 29.24 [SD = 7.55]). Standardized and online questionnaires measured problematic use and motives of cannabis use, anger rumination and hostility. RESULTS: Structural equation modelling was used to test the proposed mediation model. Four significant indirect effects were identified in the mediation model. The positive effect of hostility on cannabis use problems was mediated (i) via coping motives, (ii) via anger rumination, (iii) via anger rumination and coping motives, and (iv) via anger rumination and conformity motives. CONCLUSIONS: The present study was the first that examined the construct of anger rumination in the context of cannabis use. Possible risk mechanisms via anger rumination and cannabis use motives with negative reinforcement were suggested in the context of problematic cannabis use. Self-medication tendencies and emotion dysregulation processes might explain these pathways

The synergistic antinociceptive interactions of endomorphin-1 with dexmedetomidine and/or S(+)-ketamine in rats

Spinal administration of the endogenous mu-opioid agonist peptide, endomorphin-1, results in antinociception in rodents, but there are few data about its interaction with other antinociceptive drugs. We investigated the antinociceptive interactions at the spinal level of endomorphin-1 with the N-methyl-D-aspartate antagonist S(+)-ketamine, the alpha2-adrenoceptor agonist dexmedetomidine, or both in awake rats. Nociception was assessed by the tail-flick test. Dose-response curves were determined for endomorphin-1 (0.6-50 microg), for dexmedetomidine (0.1-10 microg), for mixtures of S(+)-ketamine (30 or 100 microg) with endomorphin-1 (2-18 microg) or of endomorphin-1 with dexmedetomidine in a fixed ratio (4:1), and for the triple combination of the three drugs after intrathecal administration. Endomorphin-1 and dexmedetomidine both produced dose-dependent antinociception. The coadministration of 100 microg S(+)-ketamine significantly enhanced the antinociceptive effect of 6 microg endomorphin-1. Isobolographic analysis of the combinations of endomorphin-1 and dexmedetomidine revealed a synergistic interaction between these drugs. The 80% effective dose for the triple combination was significantly less than that for either binary combination. These data indicate that S(+)-ketamine and dexmedetomidine, acting via different receptors, produce synergistic antinociceptive interaction with endomorphin-1 at the spinal level. Furthermore, the triple combination of an opioid agonist, an alpha2-adrenoceptor agonist, and an N-methyl-D-aspartate receptor antagonist shows potent antinociceptive activity. IMPLICATIONS: The coadministration of the N-methyl-D-aspartate antagonist receptor antagonist, S(+)-ketamine, or the specific alpha2-adrenoceptor agonist, dexmedetomidine, significantly enhances the antinociceptive effect of the endogenous mu-opioid agonist, endomorphin-1, at the spinal level. The triple combination of the three drugs causes a further improved antinociception

Neurobehavioral impairments in ciprofloxacin-treated osteoarthritic adult rats

Background and purpose – Ciprofloxacin (CIP) is a broad-spectrum antibiotic widely used in clinical practice to treat musculoskeletal infections. Fluoroquinoloneinduced neurotoxic adverse events have been reported in a few case reports, all the preclinical studies on its neuropsychiatric side effects involved only healthy animals. This study firstly investigated the behavioral effects of CIP in an osteoarthritis rat model with joint destruction and pain, which can simulate inflammation-associated musculoskeletal pain. Furthermore, effects of CIP on regional brain-derived neurotrophic factor (BDNF) expression were examined given its major contributions to the neuromodulation and plasticity underlying behavior and cognition. Methods – Fourteen days after induction of chronic osteoarthritis, animals were administered vehicle, 33 mg/kg or 100 mg/kg CIP for five days intraperitoneally. Motor activity, behavioral motivation, and psychomotor learning were examined in a reward-based behavioral test (Ambitus) on Day 4 and sensorimotor gating by the prepulse inhibition test on Day 5. Thereafter, the prolonged BDNF mRNA and protein expression levels were measured in the hippocampus and the prefrontal cortex. Results – CIP dose-dependently reduced both locomotion and reward-motivated exploratory activity, accompanied with impaired learning ability. In contrast, there were no significant differences in startle reflex and sensory gating among treatment groups; however, CIP treatment reduced motor activity of the animals in this test, too. These alterations were associated with reduced BDNF mRNA and protein expression levels in the hippocampus but not the prefrontal cortex. Conclusion – This study revealed the detrimental effects of CIP treatment on locomotor activity and motivation/learning ability during osteoarthritic condition, which might be due to, at least partially, deficient hippocampal BDNF expression and ensuing impairments in neural and synaptic plasticity