Łukasz Kurach

The rewarding effects of psychostimulants are strongly influenced by social context, yet the underlying neurochemical and neuropeptidergic mechanisms remain unclear. This study examined the role of oxytocin (OT) and vasopressin (AVP) in context‐dependent reward induced by subchronic mephedrone treatment in rats. Using classic‐ and social‐conditioned place preference (CPP) we assessed reward and later—monoamine levels in the prefrontal cortex (PFC) and hippocampus, plasma OT and AVP levels, and mRNA expression of oxytocin (OTRs) and vasopressin V1A (AVPV _1A Rs) receptors in the nucleus accumbens (NAc) and hippocampus. Pharmacological manipulations of OTRs and AVPV _1A Rs were used to evaluate their role in social‐CPP. We confirmed that mephedrone (5 mg/kg) induced social‐ but not classic‐CPP. In classic‐CPP, mephedrone elevated PFC dopamine, an effect abolished under social conditioning, which instead reduced hippocampal serotonin and noradrenaline. Social context alone lowered baseline monoamines, suggesting dampened neurochemical signaling. Social conditioning increased plasma OT and AVP, whereas mephedrone selectively reversed the OT rise. At the receptor level, mephedrone up‐regulated AVPV _1A R mRNA in the hippocampus and OTR mRNA in the NAc, indicating central adaptations distinct from peripheral peptide changes. Behaviorally, social‐CPP was abolished by OTR agonism (carbetocin) or AVPV _1A R antagonism (SR49059), while OTR antagonism (L‐368,899) or peripheral AVP had no effect. These findings show that mephedrone‐induced social reward is shaped by OT and AVP systems. Social context modulates peripheral neuropeptides and engages central receptor adaptations in the hippocampus and NAc, influencing behavioral outcomes. This study provides insights into the neurobiological mechanisms through which the social environment alters drug reward.

Background and Purpose: Recognition and procedural memory are modulated by the noradrenergic system, whose terminals release noradrenaline along with neuropeptide Y, acting via Y1 and Y2 receptors. This study aims to investigate the role of Y1 and Y2 receptor antagonists (BMS‐193885 and SF‐11) on recognition and procedural memory, including their co‐administration with clenbuterol, a β ₂ ‐adrenoceptor agonist, with additional focus on the molecular mechanisms underlying memory‐related behavioural changes. Experimental Approach: Recognition memory was assessed in mice using the novel object recognition task. Motor learning and procedural memory were evaluated in the accelerating rotarod test. Memory‐related behavioural outcomes were complemented by analyses of NPY levels, the phosphorylation status of CaMKII and ERK1/2, along with the concentrations of 5‐HT, dopamine, noradrenaline and its metabolite in selected brain regions, including the prefrontal cortex, hippocampus and cerebellum. Key Results: SF‐11 at 5 mg·kg ⁻¹ impaired recognition memory, prolonged procedural memory retention and inhibited CaMKII, but at 20 mg·kg ⁻¹ , SF‐11 disrupted both recognition and procedural memory increasing NPY. BMS‐193885, at 5 mg·kg ⁻¹ , prolonged procedural memory retention, but at 20 mg·kg ⁻¹ , it impaired long‐term recognition memory, prolonged procedural memory retention, increased NPY and decreased phospho‐CaMKII. Clenbuterol enhanced procedural memory retention, but this pro‐cognitive effect was diminished by co‐administration with either Y receptor antagonist, which correlated with decreased noradrenaline levels. Conclusions and Implications: NPY receptor antagonists modulate memory processes in a dose‐ and memory‐type‐dependent manner, and these effects appear to be linked to hippocampal function. NPY receptors may serve as therapeutic targets to treat cognitive impairments.

Nano- (NPs) and microplastics (MPs) are ubiquitous and raising concerns about their toxicity. A popular model for studying acute toxicity is Danio rerio. This study investigated the acute toxicity in FET test of polystyrene nanoparticles (500 nm, nanoPS) at different concentrations (0.01, 0.1, and 0.2 mg/mL), with different surface groups (non-modified, amine, carboxyl) and discuss the toxicological contribution of commercially added compounds. Different behavioural tests were used to investigate the neurotoxicity of nanoPS and sodium azide: coiling assay test, light–dark preference test, and colour preference test. Sodium azide and other preservatives are often present in commercially available NP and MP solutions frequently used in microplastic toxicity tests, but their effects on the results remain largely unknown. In the FET test, nanoPS did not increase mortality or affect the heart rate or body length. A higher hatching rate was observed at 48 hpf. Although nanoPS showed no acute toxicity, behavioural tests revealed subtle neurotoxic effects (changes in colour preference), suggesting a potential impact on neurological function. Additionally, sodium azide exhibited toxicity, indicating that additives may confound toxicity assessments. This highlights the need for careful consideration of preservatives in nanoparticle research to avoid misleading conclusions.

Mephedrone is a psychoactive drug that increases dopamine, serotonin and noradrenaline levels in the central nervous system via interaction with transporters or monoamines. The aim of the presented study was to assess the role of the GABA-ergic system in the expression of mephedrone-induced reward. For this purpose, we conducted (a) a behavioral evaluation of the impact of baclofen (a GABA_B receptors agonist) and GS39783 (a positive allosteric modulator of GABA_B receptors) on the expression of mephedrone-induced conditioned place preference (CPP) in rats, (b) an ex vivo chromatographic determination of the GABA level in the hippocampi of rats subchronically treated with mephedrone and (c) an in vivo evaluation of GABA hippocampal concentration in rats subchronically administered with mephedrone using magnetic resonance spectroscopy (MRS). The results show that GS39783 (but not baclofen) blocked the expression of CPP induced by (20 mg/kg of) mephedrone. The behavioral effect was consistent with chromatographic analysis, which showed that mephedrone (5 and 20 mg/kg) led to a decrease in GABA hippocampal concentration. Altogether, the presented study provides a new insight into the involvement of the GABA-ergic system in the rewarding effects of mephedrone, implying that those effects are at least partially mediated through GABA_B receptors, which suggests their potential role as new targets for the pharmacological management of mephedrone use disorder.

Aim: Bendiocarb is used against a wide range of insects but has already been withdrawn from the market in some countries. It poses a high risk to birds as they can accidentally ingest it while searching for food, followed by toxic effects. This paper presents the results of toxicological and histopathological studies of 48 cases of intentional birds of prey poisoning with bendiocarb in Eastern Europe, specifically Poland. Materials and methods: A novel ultra-high-performance liquid chromatography-triple quadrupole-tandem mass spectrometry (UHPLC-ESI-MS/MS) method for bendiocarb determination in animal liver samples was developed and fully validated. The sample preparation technique was based on one-step precipitation of proteins with cold acetonitrile. The internal standard used was carbaryl-d7. Full time of analysis was less than 10 minutes. The application of the UHPLC-ESI-MS/MS method allowed us to achieve the lowest LOQ (1 ng/g) of bendiocarb in biological samples to date. Results: Necropsies and histopathological examinations of common ravens (Corvus corax), western marsh harriers (Circus aeruginosus), red kites (Milvus milvus), and a white-tailed eagle (Haliaeetus albicilla) revealed multi-organ toxicity manifested as congestion, oedema, or stagnation of blood. An analytical investigation confirmed the presence of bendiocarb in liver in the 1808–7721 ng/g range. Furthermore, the presence of this compound was qualitatively confirmed in the stomach and beak contents and also in the bait located near the deceased animals. Conclusions: A comprehensive forensic examination is crucial to monitor wildlife fatalities, especially applying a combined analytical and histopathological approach to identify and eliminate highly toxic substances which pose a threat to the ecosystem.

Electric cell–substrate impedance sensing is an advanced in vitro impedance measuring system which uses alternating current to determine behavior of cells in physiological conditions. In this study, we used the abovementioned method for checking the anticancer activities of betulin and betulinic acid, which are some of the most commonly found triterpenes in nature. In our experiment, the threshold concentrations of betulin required to elicit antiproliferative effects, verified by MTT and LDH release methods, were 7.8 µM for breast cancer (T47D), 9.5 µM for lung carcinoma (A549), and 21.3 µM for normal epithelial cells (Vero). The ECIS results revealed the great potential of betulin and betulinic acid’s antitumor properties and their maintenance of cytotoxic substances to the breast cancer T47D line. Moreover, both substances showed a negligible toxic effect on healthy epithelial cells (Vero). Our investigation showed that the ECIS method is a proper alternative to the currently used assay for testing in vitro anticancer activity of compounds, and that it should thus be introduced in cellular routine research. It is also a valuable tool for live-monitoring changes in the morphology and physiology of cells, which translates into the accurate development of anticancer therapies.

Synthetic opioids are gaining more and more popularity among recreational users as well as regular abusers. One of such novel psychoactive substance, is etazene, which is the most popular opioid drug in the darknet market nowadays. Due to limited information available concerning its activity, we aimed to characterize its developmental toxicity, including cardiotoxicity with the use of in vivo Danio rerio and in silico tools. Moreover, we aimed, for the first time, to characterize the metabolite of etazene, which could become a potential marker of its use for future forensic analysis. The results of our study proved severe dose-dependent developmental toxicity of etazene (applied concentrations 10–300 µM), including an increase in mortality, developmental malformations, and serious cardiotoxic effects, as compared with well-known and used opioid—morphine (applied concentrations 1–50 mM). In silico findings indicate the high toxic potential of etazene which may lead to drug-drug interactions and accumulation of substances. Furthermore, phase I metabolite of etazene resulting from N-dealkylation reaction was identified, and therefore it should be considered as a target for toxicological screening. Nonetheless, the exact mechanism of observed effects in response to etazene should be further examined.