Significant advancements have been made in the treatment of psychotic disorders, yet current pharmacotherapy remains inadequate. Symptoms related to the misinterpretation of reality are crucial for diagnosis but pose challenges for preclinical research. In humans, a Mirror-Gazing test is used to examine abnormal self-experience and to predict the risk of schizophrenia.
View Article and Find Full Text PDFAddiction is a chronic and severe mental disorder with high gender- and sex-specificity. However, the pathogenesis of this disorder is not fully elucidated, and no targeted pharmacotherapy is available. A growing body of evidence points out the potential involvement of the ceramide system in the pathophysiology of addiction.
View Article and Find Full Text PDFSchizophrenia is a chronic and severe mental disorder. It is currently treated with antipsychotic drugs (APD). However, APD's work only in a limited number of patients and may have cognition impairing side effects.
View Article and Find Full Text PDFFor a proper representation of the causal structure of the world, it is adaptive to consider both evidence for and evidence against causality. To take punishment as an example, the causality of a stimulus is unlikely if there is a temporal gap before punishment is received, but causality is credible if the stimulus immediately precedes punishment. In contrast, causality can be ruled out if the punishment occurred first.
View Article and Find Full Text PDFAlcohol consumption is a widespread phenomenon throughout the world. However, how recreational alcohol use evolves into alcohol use disorder (AUD) remains poorly understood. The Smpd3 gene and its coded protein neutral sphingomyelinase (NSM) are associated with alcohol consumption in humans and alcohol-related behaviors in mice, suggesting a potential role in this transition.
View Article and Find Full Text PDFSerotonin (5-HT) is a vital modulatory neurotransmitter responsible for regulating most behaviors in the brain. An inefficient 5-HT synaptic function is often linked to various mental disorders. Primarily, membrane proteins controlling the expression and activity of 5-HT synthesis, storage, release, receptor activation, and inactivation are critical to 5-HT signaling in synaptic and extra-synaptic sites.
View Article and Find Full Text PDFPoint mutations in the α-synuclein coding gene may lead to the development of Parkinson's disease (PD). PD is often accompanied by other psychiatric conditions, such as anxiety, depression, and drug use disorders, which typically emerge in adulthood. Some of these point mutations, such as SNCA and A30T, have been linked to behavioral effects that are not commonly associated with PD, especially regarding alcohol consumption patterns.
View Article and Find Full Text PDFAlcohol consumption is a widespread behaviour that may eventually result in the development of alcohol use disorder (AUD). Alcohol, however, is rarely consumed in pure form but in fruit- or corn-derived preparations, like beer. These preparations add other compounds to the consumption, which may critically modify alcohol intake and AUD risk.
View Article and Find Full Text PDFPsychopharmacology (Berl)
April 2023
Rationale: The dopamine D4 receptors (DRD4) play a key role in numerous brain functions and are involved in the pathogenesis of various psychiatric disorders. DRD4 ligands have been shown to moderate anxiety, reward and depression-like behaviours, and cognitive impairments. Despite a series of promising but ambiguous findings, the therapeutic advantages of DRD4 stimulation remain elusive.
View Article and Find Full Text PDFDepression is a common mood disorder characterised by high comorbidity with other mental and somatic diseases. New studies reveal a shared genetic base for mental core symptoms and somatic comorbidities. Functional analyses showed multiple brain-body pathways involved.
View Article and Find Full Text PDFCognitive processes, particularly learning and memory, are crucial brain mechanisms mediating the successful adaptation of individuals to constantly changing environmental conditions. Impairments in memory performance during neurodegenerative disorders or dementias affect life quality of patients as well as their relatives and careers, and thus have a severe socio-economic impact. The last decades have viewed learning and memory as predominantly protein-mediated process at the synapses of brain neurons.
View Article and Find Full Text PDFMental 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 for NSM-2 (NSM) with alcohol consumption, but also with affective state, and bone mineralisation.
View Article and Find Full Text PDFBackground: The therapeutic effects of antipsychotic drugs (APDs) are mainly attributed to their postsynaptic inhibitory functions on the dopamine D2 receptor, which, however, cannot explain the delayed onset of full therapeutic efficacy. It was previously shown that APDs accumulate in presynaptic vesicles during chronic treatment and are released like neurotransmitters in an activity-dependent manner triggering an auto-inhibitory feedback mechanism. Although closely mirroring therapeutic action onset, the functional consequence of the APD accumulation process remained unclear.
View Article and Find Full Text PDFSphingolipids 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 mechanisms of two different types of memory, such as appetitively and aversively motivated memory, which are considered to be mediated by different neural mechanisms.
View Article and Find Full Text PDFObjective: Parkinson disease (PD) has useful symptomatic treatments that do not slow the neurodegenerative process, and no significant disease-modifying treatments are approved. A key therapeutic target in PD is α-synuclein (αS), which is both genetically implicated and accumulates in Lewy bodies rich in vesicles and other lipid membranes. Reestablishing αS homeostasis is a central goal in PD.
View Article and Find Full Text PDFBackground: Ceramides are lipid molecules determining cell integrity and intercellular signaling, and thus, involved in the pathogenesis of several psychiatric and neurodegenerative disorders. However, little is known about the role of particular enzymes of the ceramide metabolism in the mechanisms of normal behavioral plasticity. Here, we studied the contribution of neutral ceramidase (NC), one of the main enzymes mediating ceramide degradation, in the mechanisms of learning and memory in rats and non-human primates.
View Article and Find Full Text PDFCocaine 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 composition and dynamics in the brain.
View Article and Find Full Text PDFGerminal matrix hemorrhage (GMH) is a detrimental form of neonatal CNS injury. Following GMH-mediated eNOS inhibition, inflammation arises, contributing to GMH-induced brain injury. We investigated the beneficial effects of Serelaxin, a clinical tested recombinant Relaxin-2 protein, on brain injury after GMH in rats.
View Article and Find Full Text PDFPsychostimulants are widely abused drugs that may cause addiction in vulnerable individuals. While the reward circuitry of the brain is involved in addiction establishment, various pathways in the brain may provide protection at the molecular level that limits the acute and chronic effects of drugs. These targets may be used for strategies designed to prevent and treat addiction.
View Article and Find Full Text PDFDepression and alcohol dependence are associated with increased plasma ceramide concentrations in humans. Pharmacological increase in C16 ceramide concentrations in the dorsal hippocampus (DH) induced a depressive-like phenotype in naïve mice. However, the effects of C16 ceramide on alcohol consumption and anxiety-like behavior as well as the behavioral effects of other ceramide species are yet unknown.
View Article and Find Full Text PDFFront Neuroendocrinol
October 2019
Emotional stress leads to the development of peripheral disorders and is recognized as a modifiable risk factor for psychiatric disorders, particularly depression and anxiety. However, not all individuals develop the negative consequences of emotional stress due to different stress coping strategies and resilience to stressful stimuli. In this review, we discuss individual differences in coping styles and the potential mechanisms that contribute to individual vulnerability to stress, such as parameters of the immune system and oxidative state.
View Article and Find Full Text PDFMajor depression and alcohol use disorder are severe psychiatric diseases affecting the world's population with high comorbidity level. However, the pathogenesis of this comorbidity remains unclear, and no selective treatment for this condition is available. A pathogenic pathway and a possible therapeutic target for the treatment of depression-alcoholism comorbidity based on the hyperfunction of acid sphingomyelinase (Asm) were recently suggested.
View Article and Find Full Text PDFThere is still no widely effective pharmacotherapy for alcohol addiction available in the clinic. FK506-binding protein 51 (FKBP51) is a negative regulator of the glucocorticoid receptor signaling pathway that regulates the stress-induced glucocorticoid feedback circuit. Here we asked whether selective inhibitors of FKBP51, exemplified by SAFit2, may serve as a new pharmacological strategy to reduce alcohol consumption and conditioned alcohol effects in a mouse model.
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