Małgorzata Filip

Polish Academy of Sciences | PAN · Department of Pharmacology

The N-methyl-D-aspartate (NMDA) glutamate receptor is a major target of ethanol, and it is implicated in learning and memory formation, and other cognitive functions. Glycine acts as a co-agonist for this receptor. We examined whether Org24598, a selective inhibitor of glycine transporter1 (GlyT1), affects ethanol withdrawal-induced deficits in rec...

Background Maternal high-fat diet (HFD) during pregnancy and lactation induces depression- like phenotype and provokes myelin-related changes in rat offspring in the prefrontal cortex (PFCTX), which persist even to adulthood. Objective Due to the plasticity of the developing brain, it was decided to analyze whether depressionlike phenotype and mye...

Υ-aminobutyric acid (GABA) type-B (GABAB) receptors and their positive allosteric modulators (PAMs) are indicated as potential pharmacological tools for use in the treatment of a series of brain disorders, including substance use disorder (SUD). This chapter describes the current state of preclinical findings on (i) the interaction of drugs of abus...

Cytochrome P450 2D (CYP2D) is important in psychopharmacology as it is engaged in the metabolism of drugs, neurosteroids and neurotransmitters. An unbalanced maternal diet during pregnancy and lactation can cause neurodevelopmental abnormalities and increases the offspring’s predisposition to neuropsychiatric diseases. The aim of the present study...

Cannabidiol (CBD), a phytocannabinoid, appeared to satisfy several criteria for a safe approach to preventing drug-taking behavior, including opioids. However, most successful preclinical and clinical results come from studies in adult males. We examined whether systemic injections of CBD (10 mg/kg, i.p.) during extinction of oxycodone (OXY, 3 mg/k...

Cocaine use disorder (CUD) remains a severe health problem with no effective pharmacological therapy. One of the potential pharmacological strategies for CUD pharmacotherapy includes manipulations of the brain glutamatergic (Glu) system which is particularly involved in drug withdrawal and relapse. Previous research indicated a pivotal role of iono...

Children with fetal alcohol spectrum disorders (FASDs) demonstrate deficits in social functioning that contribute to early withdrawal from school and delinquency, as well as the development of anxiety and depression. Dopamine is involved in reward, motivation, and social behavior. Thus, we evaluated whether neonatal ethanol exposure (in an animal m...

Background: Cocaine use disorder (CUD) is a relapsing brain disease caused by a chronic drug intake that involves neural mechanisms and psychological processes, including depression. Preclinical and clinical studies have demonstrated the promise of pharmacological drugs in controlling the reinstatement of cocaine by targeting the N-methyl-D-aspart...

Previous studies have indicated that acute treatment with the monoamine stabilizer OSU-6162 (5 mg/kg), which has a high affinity for Sigma1R, significantly increased the density of accumbal shell D2R-Sigma1R and A2AR-D2R heteroreceptor complexes following cocaine self-administration. Ex vivo studies using the A2AR agonist CGS21680 also suggested th...

The lack of selective pharmacological tools has limited the full unraveling of G protein-coupled receptor 18 (GPR18) functions. The present study was aimed at discovering the activities of three novel preferential or selective GPR18 ligands, one agonist (PSB-KK-1415) and two antagonists (PSB-CB-5 and PSB-CB-27). We investigated these ligands in sev...

Anxiety and depression are the most common mental disorders affecting people worldwide. Recent studies have highlighted that a maternal high-sugar diet (HSD) could be a risk factor for neurobehavioural dysregulations, including mood disorders. Increased consumption of added sugar in food such as refined fructose/glucose can increase the risk of met...

Obesity is a substantial health and economic issue, and serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter system involved in the regulation of body weight. The 5-HT2C receptors (5-HT2CRs), one of 16 of the 5-HT receptor (5-HTRs) subtypes, play a significant role in food intake and body weight control. In this review, we focused...

A maternal high-fat diet (HFD) provokes changes in the offspring's brain's structure, function, and development. These changes may cause neuropsychiatric disorders in the early life of offspring the basis of which may be memory impairment. In this study, the effects of maternal HFD during pregnancy and lactation on the short-term memory in adolesce...

One of the most important yet still underappreciated mechanisms of depression is distorted cognition, with aberrant sensitivity to negative feedback being one of the best-described examples. As serotonin has been identified as an important modulator of sensitivity to feedback and because the hippocampus has been implicated in the mediation of learn...

Extending the click chemistry concept, the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reac- tion was used to synthesize a series of 1,4-disubstituted and 1,4,5-trisubstituted 1,2,3-triazoles using 1- (2-hydroxycyclohexyl)-4-dimethylaminomethyl 1,2,3-triazole (AMTC) as the Cu-binding ligand. The 1,4,5- trisubstituted 1,2,3-triazoles were ob...

Treatment of Post-Traumatic Stress Disorder (PTSD) is complicated by the presence of drug use disorder comorbidity. Here, we examine whether conditioned fear (PTSD model) modifies the rewarding effect of mephedrone and if repeated mephedrone injections have impact on trauma-related behaviors (fear sensitization, extinction, and recall of the fear r...

Background Epidemiological data indicate a high rate of comorbidity of depression and cocaine use disorder (CUD). The role of serotonin 2C (5-HT 2C ) receptors in the mechanisms responsible for the coexistence of depression and CUD was not investigated. Methods We combined bilateral olfactory bulbectomy (OBX), an animal model of depression, with i...

Recent years have provided more and more evidence confirming the important role of Wnt/β-catenin signaling in the pathophysiology of mental illnesses, including cocaine use disorder. High relapse rates, which is a hallmark of drug addiction, prompt the study of changes in Wnt signaling elements (Wnt5a, Wnt7b, and Ctnnb1) in the motivational aspects...

Prenatal stress is a critical life event often resulting in mental illnesses in the offspring. The critical developmental processes, which might trigger a cascade of molecular events resulting in mental disorders in adulthood, are still to be elucidated. Here we proposed that sex hormones, particularly testosterone, might determine the “development...

Maternal separation (MS) is a key contributor to neurodevelopmental disorders, including learning disabilities. To test the hypothesis that dopamine signaling is a major factor in this, an atypical new dopamine transporter (DAT) inhibitor, CE-123, was assessed for its potential to counteract the MS-induced spatial learning and memory deficit in mal...

Carbohydrates are important macronutrients in human and rodent diet patterns that play a key role in crucial metabolic pathways and provide the necessary energy for proper body functioning. Sugar homeostasis and intake require complex hormonal and nervous control to proper body energy balance. Added sugar in processed food results in metabolic, car...

Adverse early life experiences are associated with an enhanced risk for mental and physical health problems, including substance abuse. Despite clinical evidence, the mechanisms underlying these relationships are not fully understood. Maternal separation (MS) is a commonly used animal model of early neglect. The aim of the current study is to deter...

Epidemiological data indicate a high rate of comorbidity of depression and cocaine use disorder (CUD). The role of 5-HT2C receptors in the mechanisms responsible for the coexistence of CUD and depression has not been investigated. Here, we combined bilateral olfactory bulbectomy (OBX), an animal model of depression, with intravenous cocaine self-ad...

Epidemiological data indicate a high rate of comorbidity of depression and cocaine use disorder (CUD). The role of 5-HT2C receptors in the mechanisms responsible for the coexistence of CUD and depression has not been investigated. Here, we combined bilateral olfactory bulbectomy (OBX), an animal model of depression, with intravenous cocaine self-ad...

Alcohol use, abuse, and addiction, and resulting health hazards are highly sex-dependent with unknown mechanisms. Previously, strong links between the SMPD3 gene and its coded protein neutral sphingomyelinase 2 (NSM) and alcohol abuse, emotional behavior, and bone defects were discovered and multiple mechanisms were identified for females. Here we...

Neurochemical studies were previously performed on the effects of a 10 day extinction learning from cocaine self-administration on D2R and A2AR recognition and D2R Gi/o coupling in the ventral striatum. In the present study biochemical receptor binding and proximity ligation assay were used to study possible changes in the allosteric receptor-recep...

Mephedrone, a synthetic cathinone, is widely abused by adolescents and young adults. The aim of this study was to determine: i) whether prior mephedrone exposure would alter ethanol reward and ii) whether age and matrix metalloproteinase-9 (MMP-9) are important in this regard. In our research, male Wistar rats at postnatal day 30 (PND30) received m...

Substance use disorder (SUD) is a chronic and serious brain disorder. Several drugs can lead to addictive behavior including psychostimulants, opioids, cannabinoids (CB), nicotine, and alcohol. Their behavioral outcomes are realized through distinct effector mechanisms, such as neurotransmitter transporters, ion channels, and receptor proteins. The...

Mental disorders are highly comorbid and occur together with physical diseases, which are often considered to arise from separate pathogenic pathways. We observed in alcohol-dependent patients increased serum activity of neutral sphingomyelinase. A genetic association analysis in 456,693 volunteers found associations of haplotypes of SMPD3 coding f...

Background Cocaine use disorder is associated with compulsive drug-seeking and drug-taking, whereas relapse may be induced by several factors, including stress, drug-related places, people, and cues. Recent observations strongly support the involvement of the N-methyl-D-aspartate (NMDA) receptors in cocaine use disorders and abstinence, whereas wit...

Autism spectrum disorder (ASD) is a disruptive neurodevelopmental disorder manifested by abnormal social interactions, communication, emotional circuits, and repetitive behaviors and is more often diagnosed in boys than in girls. It is postulated that ASD is caused by a complex interaction between genetic and environmental factors. Epigenetics prov...

Epidemiological and preclinical studies suggest that maternal obesity increases the risk of autism spectrum disorder (ASD) in offspring. Here, we assessed the effects of exposure to modified maternal diets limited to pregnancy and lactation on brain development and behavior in rat offspring of both sexes. Among the studied diets, a maternal high-fa...

The role of adenosine A2A receptor (A2AR) and striatal-enriched protein tyrosine phosphatase (STEP) interactions in the striatal-pallidal GABA neurons was recently discussed in relation to A2AR overexpression and cocaine-induced increases of brain adenosine levels. As to phosphorylation, combined activation of A2AR and metabotropic glutamate recept...

Cocaine use disorder is a serious, chronic and relapsing disease of the nervous system, for which effective treatments do not yet exist. Recently, the role of the N-methyl-d-aspartate (NMDA) receptor subunit GluN2B has been highlighted in cocaine abstinence followed by extinction training. Since the GluN2B subunit is stabilized at synaptic level by...

The activation of the endocannabinoid system controls the release of many neurotransmitters involved in the brain reward pathways, including glutamate. Both endocannabinoid and glutamate systems are crucial for alcohol relapse. In the present study, we hypothesize that N-methyl-D-aspartate (NMDA) glutamate receptors regulate the ability of a primin...

Background Opioid use disorders are serious contributors to the harms associated with the drug use. Unfortunately, therapeutic interventions for opioid addicts after detoxification have been limited and not sufficiently effective. Recently, several studies have led to promising results with disulfiram (DSF), a dopamine β-hydroxylase (DBH) inhibitor...

Membrane receptor, for example, G-protein-coupled receptors (GPCRs), operates via coordinated changes between the receptor expression, their modifications, and interactions between each other. Perturbation in specific heteroreceptor complexes and/or their balance/equilibrium with other heteroreceptor complexes and corresponding homoreceptor complex...

Background Recent studies have shown a relationship between the composition of the maternal diet and acquiring a risk of mental illnesses through changes in the offspring’s brain. This study assessed the role of a modified maternal diet on the levels of serotonin (5-HT) 2C and 5-HT 2A receptors in the offspring brain. Methods Wistar rat dams durin...

Substance use disorder (SUD) is a chronic brain condition, with compulsive and uncontrollable drug-seeking that leads to long-lasting and harmful consequences. The factors contributing to the development of SUD, as well as its treatment settings, are not fully understood. Alterations in brain glutamate homeostasis in humans and animals implicate a...

Different neuronal alterations within glutamatergic system seem to be crucial for developing of cocaine-seeking behavior. Cocaine exposure provokes a modulation of the NMDA receptor subunit expression in rodents, which probably contributes to cocaine-induced behavioral alterations. The aim of this study was to examine the composition of the NMDA re...

N‐acetylcysteine (NAC) is a well‐known and safe mucolytic agent, also used in patients with paracetamol overdose. In addition to these effects, recent preclinical and clinical studies have shown that NAC exerts beneficial effects on different psychiatric disorders. Many potential mechanisms have been proposed to underlie the therapeutic effects of...

Glutamate transmission is an important mediator of the development of substance use disorders, particularly with regard to relapse. The present review summarizes the changes in glutamate levels in the reward system (the prefrontal cortex, nucleus accumbens, dorsal striatum, hippocampus, and ventral tegmental area) observed in preclinical studies at...

The widespread distribution of heteroreceptor complexes with allosteric receptor-receptor interactions in the CNS represents a novel integrative molecular mechanism in the plasma membrane of neurons and glial cells. It was proposed that they form the molecular basis for learning and short-and long-term memories. This is also true for drug memories...

Keywords: Depressive-like behavior Fetal programming High-fat diet Maternal diet Offspring frontal cortex RNA-seq A B S T R A C T Environmental factors such as maternal diet, determine the pathologies that appear early in life and can persist in adulthood. Maternally modified diets provided through pregnancy and lactation increase the predispositio...

Environmental factors such as maternal diet, determine the pathologies that appear early in life and can persist in adulthood. Maternally modified diets provided through pregnancy and lactation increase the predisposition of offspring to the development of many diseases, including obesity, diabetes, and neurodevelopmental and mental disorders such...

Cocaine use disorder develops in part due to the strong associations formed between drugs and the stimuli associated with drug use. Recently, treatment strategies including manipulations of drug-associated memories have been investigated, and the possibility of interfering with N-methyl-d-aspartate (NMDA)-mediated neurotransmission may represent an...

Many toxic effects of cocaine are attributed to reactive oxygen species (ROS) generated during its metabolism. Recently, it has been suggested that the biological action of ROS is often confused with endogenously generated reactive sulfur species (RSS). The aim of this study was to evaluate the impact of cocaine on thiols and RSS in the rat liver a...

A synthetic cathinone, mephedrone is widely abused by adolescents and young adults. Despite its widespread use, little is known regarding its long-term effects on cognitive function. Therefore, we assessed, for the first time, whether (A) repeated mephedrone (30 mg/kg, i.p., 10 days, once a day) exposure during adolescence (PND 40) induces deleteri...

Struggle with addiction to at least two substances, particularly alcohol and opioids, is a common phenomenon these days. Indeed, narcotic drug abuse people also suffer from extensive alcohol consumption, as this depressant strongly augments opioids intake. As it is thought that to stop drinking is easier than to stop taking drugs, the first step to...

Cocaine induces neuronal changes as well as non-neuronal (astrocytes, microglia, oligodendroglia) mechanisms, but these changes can also be modulated by various types of drug abstinence. Due to the very complex and still incompletely understood nature of cocaine use disorder, understanding of the mechanisms involved in addictive behavior is necessa...

Glutamate is a key excitatory neurotransmitter in the central nervous system. The balance of glutamatergic transporter proteins allows long-term maintenance of glutamate homeostasis in the brain, which is impaired during cocaine use disorder. The aim of this study was to investigate changes in the gene expression of SLC1A2 (encoding GLT-1), and SLC...

Sphingolipids and enzymes of the sphingolipid rheostat determine synaptic appearance and signaling in the brain, but sphingolipid contribution to normal behavioral plasticity is little understood. Here we asked how the sphingolipid rheostat contributes to learning and memory of various dimensions. We investigated the role of these lipids in the mec...

Cocaine addiction is a severe psychiatric condition for which currently no effective pharmacotherapy is available. Brain mechanisms for the establishment of addiction‐related behaviors are still not fully understood, and specific biomarkers for cocaine use are not available. Sphingolipids are major membrane lipids, which shape neuronal membrane com...

The abundance of research indicates that enriched environment acts as a beneficial factor reducing the risks of relapse in substance use disorder. There is also strong evidence showing the engagement of brain dopaminergic and glutamatergic signaling through the dopamine D2-like and metabotropic glutamate type 5 (mGlu5) receptors, respectively, that...

Cocaine-induced plasticity in the glutamatergic transmission and its N-methyl-d-aspartate (NMDA) receptors are critically involved in the development of substance use disorder. The presynaptic active zone proteins control structural synaptic plasticity; however, we are still far from understanding the molecular determinants important for cocaine se...

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Several psychoactive drugs can evoke substance use disorders (SUD) in humans and animals, and these include psychostimulants, opioids, cannabinoids (CB), nicotine, and alcohol. The etiology, mechanistic processes, and the therapeutic options to deal with SUD are not well understood. The common feature of all abused drugs is that they increase dopam...

A balanced maternal diet is essential for proper fetal development, and the consumption of a nutritionally inadequate diet during intrauterine development and early childhood is associated with a significantly increased risk of metabolic and brain disorders in offspring. The current literature indicates that maternal exposure to a high-fat diet exe...

Recent studies have emphasized the role of the maternal diet in the development of mental disorders in offspring. Substance use disorder is a major global health and economic burden. Therefore, the search for predisposing factors for the development of this disease can contribute to reducing the health and social damage associated with addiction. I...

Maternal diet significantly influences the proper development of offspring in utero. Modifications of diet composition may lead to metabolic and mental disorders that may predispose offspring to a substance use disorder. We assessed the impact of a maternal high‐sugar diet (HSD, rich in sucrose) consumed during pregnancy and lactation on the offspr...

Ceftriaxone is a beta-lactam antibiotic that increases the expression of the major glutamate transporter, GLT-1. As such, ceftriaxone ameliorates symptoms across multiple rodent models of neurological diseases and substance use disorders. However, the mechanism behind GLT-1 upregulation is unknown. The present review synthesizes this literature in...

Background Antagonistic adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) receptor–receptor interactions have previously been demonstrated in A2AR–D2R heteroreceptor complexes in the rat dorsal striatum. They mainly involve a reduction of affinity in the high-affinity component of the D2R agonist binding site upon activation in vivo of the A...

Cocaine was previously shown to act at the Sigma1R which is a target for counteracting cocaine actions. It therefore becomes of interest to test if the monoamine stabilizer (–) OSU-6162 (OSU-6162) with a nanomolar affinity for the Sigma1R can acutely modulate in low doses the effects of cocaine self-administration. In behavioral studies, OSU-6162 (...