Changes in the brain endocannabinoid system in rat models of depression

A growing body of evidence implicates the endocannabinoid (eCB) system in the pathophysiology of depression. The aim of this study was to investigate the influence of changes in the eCB system, such as levels of neuromodulators, eCB synthesizing and degrading enzymes, and cannabinoid (CB) receptors, in different brain structures in animal models of depression using behavioral and biochemical analyses. Both models used, i.e., bulbectomized (OBX) and Wistar Kyoto (WKY) rats, were characterized at the behavioral level by increased immobility time. In the OBX rats, anandamide (AEA) levels were decreased in the prefrontal cortex, hippocampus, and striatum and increased in the nucleus accumbens, while 2-arachidonoylglycerol (2-AG) levels were increased in the prefrontal cortex and decreased in the nucleus accumbens with parallel changes in the expression of eCB metabolizing enzymes in several structures. It was also observed that CB(1) receptor expression decreased in the hippocampus, dorsal striatum, and nucleus accumbens, and CB(2) receptor expression decreased in the prefrontal cortex and hippocampus. In WKY rats, the levels of eCBs were reduced in the prefrontal cortex (2-AG) and dorsal striatum (AEA) and increased in the prefrontal cortex (AEA) with different changes in the expression of eCB metabolizing enzymes, while the CB(1) receptor density was increased in several brain regions. These findings suggest that dysregulation in the eCB system is implicated in the pathogenesis of depression, although neurochemical changes were linked to the particular brain structure and the factor inducing depression (surgical removal of the olfactory bulbs vs. genetic modulation)

The effects of acute or repeated administration of tianeptine on the level of the endocannabinoids and N-acylethanolamines in selected rat brain structures

W ostatnich latach coraz częściej podkreślany jest potencjalny udział układu endokanabinoidowego w patogenezie depresji oraz w mechanizmie działania leków przeciwdepresyjnych. Przedmiotem owych badań było zbadanie wpływu skutecznego klinicznie, atypowego leku przeciwdepresyjnego - tianeptyny (TIA, 10 mg/kg) na poziom endokanabinoidów: anandamidu (AEA), 2-arachidonyloglicerolu (2-AG) oraz N-acyloetanoloamin (NAEs): palmityloetanoloamidu (PEA) i oleiloetanoloamidu (OEA) w wybranych strukturach mózgowych szczurów, w tym korze przedczołowej i czołowej, hipokampie, prążkowiu grzbietowym, jądrze półleżącym przegrody i móżdżku. Poziomy badanych endokanabinoidów i NAEs oznaczano za pomocą metody LC-MS/MS. Ostre podanie TIA spowodowało zmniejszenie poziomu tkankowego PEA w hipokampie. Chroniczne (14 dni) podanie TIA wywołało wzrost stężenia AEA w hipokampie oraz poziomu 2-AG w korze czołowej i prążkowiu grzbietowym. Dodatkowo odnotowano zmniejszony poziom tkankowy PEA i OEA w hipokampie i korze przedczołowej. 10-dniowy okres odstawienia TIA skutkował wzrostem stężenia OEA i PEA w jądrze półleżącym oraz redukcją korowego poziomu 2-AG. Uzyskane dane wskazują na zaangażowanie układu endokanabinoidowego w mechanizm działania TIA, lecz bardziej szczegółowe wyjaśnienie i potwierdzenie tego mechanizmu wymaga przeprowadzenia dalszych badań.The potential participation of the endocannabinoid system in the pathogenesis of depression and in the mechanism of action of antidepressants has been highlighted in recent years. The aim of this study was to investigate the effect of the clinically effective atypical antidepressant - tianeptine (TIA, 10 mg/kg), on the level of endocannabinoids: anandamide (AEA) and 2-arachidonoylglycerol (2-AG) and of N-acylethanolamines (NAEs): palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) in different rat brain structures including the prefrontal and frontal cortex, hippocampus, dorsal striatum, nucleus accumbens and cerebellum. The levels of examined endocannabinoids and NAEs were evaluated with LC-MS/MS system. Administered acutely TIA resulted in the decreased levels of PEA in the hippocampus. The chronic (14 days) TIA administration increased the AEA levels in the hippocampus and dorsal striatum and the 2-AG levels in the frontal cortex and dorsal striatum. Furthermore, the decrease of PEA and OEA in the hippocampus and prefrontal cortex was reported. TIA-free period (10-day washout period) evoked enhancement in the accumbal OEA and PEA concentration and reduction in the cortical 2-AG level. These data suggest the engagement of the endocannabinoid system in the effects of TIA, but the more detailed explanation of this mechanism requires further investigations

Maternal High-Fat Diet Modulates Cnr1 Gene Expression in Male Rat Offspring

In recent years, strong evidence has emerged that exposure to a maternal high-fat diet (HFD) provokes changes in the structure, function, and development of the offspring’s brain and may induce several neurodevelopmental and psychiatric illnesses. The aims of this study were to evaluate the effects of a maternal HFD during pregnancy and lactation on depressive-like behavior and Cnr1 gene expression (encoding the CB1 receptor) in brain structures of rat offspring and to investigate the epigenetic mechanism involved in this gene expression. We found that a maternal HFD during pregnancy and lactation induced a depressive-like phenotype at postnatal days (PNDs) 28 and 63. We found that a maternal HFD decreased the Cnr1 mRNA levels in the prefrontal cortex with the increased levels of miR-212-5p and methylation of CpG islands at the Cnr1 promoter and reduced the level of Cnr1 gene expression in the dorsal striatum with an increased level of miR-154-3p in adolescent male offspring. A contrasting effect of a maternal HFD was observed in the hippocampus, where upregulation of Cnr1 gene expression was accompanied by a decrease of miR-154-3p (at PNDs 28 and 63) and miR-212-5p (at PND 63) expression and methylation of CpG islands at the Cnr1 promoter in male offspring. In summary, we showed that a maternal HFD during pregnancy and lactation triggered several epigenetic mechanisms in the brains of rat offspring, which may be related to long-lasting alterations in the next generation and produce behavioral changes in offspring, including a depressive-like phenotype

Antidepressants and changes in concentration of endocannabinoids and N-Acylethanolamines in rat brain structures

The endocannabinoid (eCB) system has recently been implicated in both the pathogenesis of depression and the action of antidepressants. Here, we investigated the effect of acutely or chronically administering antidepressants [imipramine (IMI) (15 mg/kg), escitalopram (ESC) (10 mg/kg), and tianeptine (10 mg/kg)] on the levels of both eCBs [anandamide (AEA) and 2-arachidonoylglycerol (2-AG)] and N-acylethanolamines (NAEs) [palmitoylethanolamide (PEA) and oleoylethanolamide (OEA)] in various rat brain regions. We also examined the ability of the acute and chronic administration of N-acetylcysteine (NAC) (a mucolytic drug; 100 mg/kg) or URB597 (a fatty acid amide hydrolase inhibitor; 0.3 mg/kg), which have both elicited antidepressant activity in preclinical studies, to affect eCB and NAE levels. Next, we determined whether the observed effects are stable 10 days after the chronic administration of these drugs was halted. We report that the chronic administration of all investigated drugs increased AEA levels in the hippocampus and also increased both AEA and 2-AG levels in the dorsal striatum. NAE levels in limbic regions also increased after treatment with IMI (PEA/OEA), ESC (PEA), and NAC (PEA/OEA). Removing chronic ESC treatment for 10 days affected eCB and NAE levels in the frontal cortex, hippocampus, dorsal striatum, and cerebellum, while a similar tianeptine-free period enhanced accumbal NAE levels. All other drugs maintained their effects after the 10-day washout period. Therefore, the eCB system appears to play a significant role in the mechanism of action of clinically effective and potential antidepressants and may serve as a target for drug design and discovery

Cocaine and Its Abstinence Condition Modulate Striatal and Hippocampal Wnt Signaling in a Male Rat Model of Drug Self-Administration

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 of cocaine use and early drug-free period (3 days after the last exposure to cocaine). For this purpose, an animal model of intravenous cocaine self-administration and two types of drug-free period (extinction training and abstinence in the home cage) were used. The studies showed that chronic cocaine self-administration mainly disturbs the expression of Wnt5a and Ctnnb1 (the gene encoding β-catenin) in the examined brain structures (striatum and hippocampus), and the examined types of early abstinence are characterized by a different pattern of changes in the expression of these genes. At the same time, in cocaine self-administrated animals, there were no changes in the level of Wnt5a and β-catenin proteins at the tested time points. Moreover, exposure to cocaine induces a significant reduction in the striatal and hippocampal expression of miR-374 and miR-544, which can regulate Wnt5a levels post-transcriptionally. In summary, previous observations from experimenter-administered cocaine have not been fully validated in the cocaine self-administration model. Yoked cocaine administration appears to disrupt Wnt signaling more than cocaine self-administration. The condition of the cocaine-free period, the routes of drug administration, and the motivational aspect of drug administration play an important role in the type of drug-induced molecular changes observed. Furthermore, in-depth research involving additional brain regions is needed to determine the exact role of Wnt signaling in short-term and long-lasting plasticity as well as in the motivational aspects of cocaine use, and thus to assess its potential as a target for new drug therapy for cocaine use disorder

Maternal Diet Influences the Reinstatement of Cocaine-Seeking Behavior and the Expression of Melanocortin-4 Receptors in Female Offspring of Rats

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. In this study, we focused on the impact of the maternal diet on changes in melanocortin-4 (MC-4) receptors as well as on behavioral changes related to cocaine addiction. Rat dams consumed a high-fat diet (HFD), high-sugar diet (HSD, rich in sucrose), or mixed diet (MD) during pregnancy and lactation. Using an intravenous cocaine self-administration model, the susceptibility of female offspring to cocaine reward and cocaine-seeking propensities was evaluated. In addition, the level of MC-4 receptors in the rat brain structures related to cocaine reward and relapse was assessed. Modified maternal diets did not affect cocaine self-administration in offspring. However, the maternal HSD enhanced cocaine-seeking behavior in female offspring. In addition, we observed that the maternal HSD and MD led to increased expression of MC-4 receptors in the nucleus accumbens, while increased MC-4 receptor levels in the dorsal striatum were observed after exposure to the maternal HSD and HFD. Taken together, it can be concluded that a maternal HSD is an important factor that triggers cocaine-seeking behavior in female offspring and the expression of MC-4 receptors

The endocannabinoid/endovanilloid system and depression

Depression is one of the most frequent causes of disability in the 21st century. Despite the many preclinical and clinical studies that have addressed this brain disorder, the pathophysiology of depression is not well understood and the available antidepressant drugs are therapeutically inadequate in many patients. In recent years, the potential role of lipid-derived molecules, particularly endocannabinoids (eCBs) and endovanilloids, has been highlighted in the pathogenesis of depression and in the action of antidepressants. There are many indications that the eCB/endovanilloid system is involved in the pathogenesis of depression, including the localization of receptors, modulation of monoaminergic transmission, inhibition of the stress axis and promotion of neuroplasticity in the brain. Preclinical pharmacological and genetic studies of eCBs in depression also suggest that facilitating the eCB system exerts antidepressant-like behavioral responses in rodents. In this article, we review the current knowledge of the role of the eCB/endovanilloid system in depression, as well as the effects of its ligands, models of depression and antidepressant drugs in preclinical and clinical settings

Alteration of the Early Development Environment by Maternal Diet and the Occurrence of Autistic-like Phenotypes in Rat Offspring

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-fat diet (HFD) disturbed the expression of ASD-related genes (Cacna1d, Nlgn3, and Shank1) and proteins (SHANK1 and TAOK2) in the prefrontal cortex of male offspring during adolescence. In addition, a maternal high-fat diet induced epigenetic changes by increasing cortical global DNA methylation and the expression of miR-423 and miR-494. As well as the molecular changes, behavioral studies have shown male-specific disturbances in social interaction and an increase in repetitive behavior during adolescence. Most of the observed changes disappeared in adulthood. In conclusion, we demonstrated the contribution of a maternal HFD to the predisposition to an ASD-like phenotype in male adolescent offspring, while a protective effect occurred in females