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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., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Translational schizophrenia research depends on the relevance of animal models supported by reliable tests. Human data suggest that the intensive cognitive training in schizophrenia improves the memory impairments and decreases the chance of acute psychiatric remission. Here we examined the effects of a 10-day long training session in the behavioral architecture of a new schizophrenia-like rat substrain (Wisket) in a narrow square corridor with food rewards (AMBITUS). The instrument was designed to model the natural environment of rats and enable the simultaneous recording of multiple behavioral parameters. For the compact visualization of differences between the Wisket and control animals in several parameters (behavioromics), color-coded grid plots were applied. The Wisket animals exhibited an altered pattern and/or amount of locomotion, exploratory and food collecting activity at the first few days, revealing impaired motivation, attention, anxiety and learning ability (face validity). Most of the parameters normalized with training, except for the decreased exploratory activity. This resembles the effects of cognitive behavioral therapy in human schizophrenics providing a significant support for the predictive validity of this substrain as an animal model of schizophrenia. This study also highlights the importance of behavior tests that investigate the egocentric learning ability during reward-based tasks., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The Ranvier nodes of thick myelinated nerve fibers contain almost exclusively voltage-gated sodium channels (Navs), while the unmyelinated fibers have several receptors (e.g., cannabinoid, transient receptor potential vanilloid receptor 1), too. Therefore, a nerve which contains only motor fibers can be an appropriate in vivo model for selective influence of Navs. The goals were to evaluate the potency of local anesthetic drugs on such a nerve in vivo; furthermore, to investigate the effects of ligands with different structures (arachidonic acid, anandamide, capsaicin and nisoxetine) that were proved to inhibit Navs in vitro with antinociceptive properties. The marginal mandibular branch of the facial nerve was explored in anesthetized Wistar rats; after its stimulation, the electrical activity of the vibrissae muscles was registered following the perineural injection of different drugs. Lidocaine, bupivacaine and ropivacaine evoked dose-dependent decrease in electromyographic activity, i.e., lidocaine had lower potency than bupivacaine or ropivacaine. QX-314 did not cause any effect by itself, but its co-application with lidocaine produced a prolonged inhibition. Nisoxetine had a very low potency. While anandamide and capsaicin in high doses caused about 50% decrease in the amplitude of action potential, arachidonic acid did not influence the responses. We proved that the classical local anesthetics have high potency on motor nerves, suggesting that this method might be a reliable model for selective targeting of Navs in vivo circumstances. It is proposed that the effects of these endogenous lipids and capsaicin on sensory fibers are not primarily mediated by Navs., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Kynurenic acid (KYNA) is a neuroactive metabolite that interacts with NMDA, AMPA/kainate and alpha 7 nicotinic receptors. The goal of this study was to clarify the roles of these receptors in the action of KYNA at a spinal level by using highly specific receptor antagonists alone or in triple combinations. Chronic osteoarthritis-like joint pain was induced with monosodium-iodoacetate in male Wistar rats. Mechanical allodynia and motor function were quantified. In the first series we determined the dose-response and time course effects of intrathecally administered KYNA (10-100 μg), D-(-)-2-amino-5-phosphonopentanoic acid (AP5; an NMDA receptor antagonist; 10-200 μg), methyllycaconitine (MLA; an alpha 7 nicotinic receptor antagonist; 100-200 μg) and 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzoquinoxaline-7-sulfonamide (NBQX; an AMPA/kainate receptor antagonist; 1-20 μg). In the second series, four different triple combinations of MLA, AP5 and NBQX were investigated. Intrathecal administration of KYNA caused a dose-dependent motor impairment and antinociception. The highly specific NMDA receptor antagonist AP5 caused a motor impairment and antinociception with lower potency. High doses of NBQX resulted in significant antinociception with a slight motor impairment, while only the highest dose of MLA gave rise to significant antinociception with a slight motor impairment. After the coadministration of these ligands as combinations, no potentiation was observed. It may be supposed that the effects of KYNA are primarily due to the inhibition of NMDA receptors at both glycine and phencyclidine (PCP) binding sites, and not to the interactions at the different ionotropic receptors, but the mechanisms behind its high bio-efficiency are still unknown., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Capsaicin desensitization leads to behavioral changes, some of which are related to schizophrenia, but investigations into these effects have been scarce. The goal of this study was to characterize the consequences of juvenile capsaicin desensitization on different functions: acute and inflammation-induced thermal and mechanical sensitivity, urinary bladder capacity and thermoregulation, and also on the potentially schizophrenia-related impairments in sensory-motor gating, motor activity and cognitive functioning. Male Wistar rats desensitized with increasing doses of subcutaneous capsaicin after weaning were investigated. Heat and mechanical pain sensitivity did not change significantly; however, morphine produced a prolonged decrease in the nociceptive response to inflammation in desensitized animals. Ultrasound examination of the bladder revealed enhanced bladder volume in treated animals. Capsaicin-treated animals had higher body temperature at 22 °C in both dark and light periods, and they also showed prolonged hyperthermia in new environmental circumstances. Warm environment induced a profound impairment of thermoregulation in desensitized animals. The treated animals also showed higher levels of activity during the active phase and at both cool and warm temperatures. The amplitude of the responses to auditory stimuli and prepulse inhibition did not differ between the two groups, but the desensitized animals showed learning impairments in the novel object recognition test. These results suggest that juvenile capsaicin desensitization leads to sustained changes in several functions that may be related to schizophrenia. We propose that capsaicin desensitization, together with other interventions, may lead to an improved chronic animal model of schizophrenia., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Kynurenic acid as an endogenous ligand antagonizes all types of ionotropic glutamate receptors, with preferential affinity for the glycine-binding site of the N-methyl-D-aspartate (NMDA) receptor. The purpose of the present study was to investigate the antinociceptive potency of continuously administered kynurenic acid on carrageenan-induced thermal hyperalgesia by means of a paw withdrawal test in awake rats. The possible interaction between kynurenic acid and the endogenous mu-opioid receptor agonist peptide, endomorphin-1, was examined in the same set-up. Kynurenic acid at the higher doses (1-4 microg/min) significantly decreased the thermal hyperalgesia and increased the paw withdrawal latencies on the non-inflamed side. These doses were also associated with motor impairment on both sides. Low doses of kynurenic acid (0.01-0.1 microg/min) potentiated, but did not prolong, the antinociceptive effect of endomorphin-1 (0.1-1 microg/min) on the inflamed side. There was no sign of motor impairment during the combined treatment. These findings demonstrate that the combination of low doses of these two endogenous ligands provides effective and well-controlled antinociception without side effects.