The Effect of Maternal High-Fat or High-Carbohydrate Diet during Pregnancy and Lactation on Cytochrome P450 2D (CYP2D) in the Liver and Brain of Rat Offspring.

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 was to evaluate the effect of maternal modified types of diet: a high-fat diet (HFD) and high-carbohydrate diet (HCD) during pregnancy and lactation on CYP2D in the liver and brain of male offspring at 28 (adolescent) or 63 postnatal days (young adult). The CYP2D activity and protein level were measured in the liver microsomes and the levels of mRNAs of CYP2D1, 2D2 and 2D4 were investigated both in the liver and brain. In the liver, both HFD and HCD increased the mRNA levels of all the three investigated CYP2D genes in adolescents, but an opposite effect was observed in young adults. The CYP2D protein level increased in adolescents but not in young adults. In contrast, young adults showed significantly decreased CYP2D activity. Similar effect of HFD on the CYP2D mRNAs was observed in the prefrontal cortex, while the effect of HCD was largely different than in the liver (the CYP2D2 expression was not affected, the CYP2D4 expression was decreased in young adults). In conclusion, modified maternal diets influence the expression of individual CYP2D1, CYP2D2 and CYP2D4 genes in the liver and brain of male offspring, which may affect the metabolism of CYP2D endogenous substrates and drugs and alter susceptibility to brain diseases and pharmacotherapy outcome.

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/ß-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 ß-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 ß-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 high-sugar diet changes offspring vulnerability to reinstatement of cocaine-seeking behavior: Role of melanocortin-4 receptors.

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 offspring phenotype in the context of the rewarding and motivational effects of cocaine and changes within the central melanocortin (MC) system. Using an intravenous cocaine self-administration model, we showed that maternal HSD leads to increased relapse of cocaine-seeking behavior in male offspring. In addition, we demonstrated that cocaine induces changes in the level of MC-4 receptors in the offspring brain, and these changes depend on maternal diet. These studies also reveal that an MC-4 receptor antagonist reduces the reinstatement of cocaine-seeking behavior, and offspring exposed to maternal HSD are more sensitive to its effects than offspring exposed to the maternal control diet. Taken together, the results suggest that a maternal HSD and MC-4 receptors play an important role in cocaine relapse.

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.

Cocaine Administration and Its Abstinence Conditions Modulate Neuroglia.

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 necessary to further search for effective pharmacotherapy of this disease. The aim of this study was to investigate changes at the gene and protein levels associated with glial cell activity after cocaine exposure, as well as during early cocaine abstinence (3 days) with extinction training or in home cage isolation. Cocaine self-administration significantly decreased myelin regulatory factor (MYRF) and cyclic nucleotide phosphodiesterase (CNP) expression in the hippocampus as well as pleckstrin (PLEK) and T-lymphocyte activation antigen (CD86) in the rat striatum. Depending on cocaine abstinence conditions, microglial PLEK expression was increased through extinction training but did not change in the home cage isolation. In addition, downregulation of gene expression associated with oligodendrocytes (CNP, MYRF) and microglia regulator of G protein signaling 1 (RGS1) was observed in the hippocampus, regardless of the type of drug abstinence, while downregulation of myelin and lymphocyte protein (MAL) expression was found only in rats exposed to abstinence in the home cage. Taken together, the presented results strongly suggest that cocaine abstinence evokes significant changes in gene expression associated with the proper functioning of glial cells, suggesting their significant involvement in adaptive changes in the brain associated with cocaine exposure. Interestingly, drug abstinence conditions are important factors influencing observed changes at the transcript levels of selected genes, which may be of clinical interest.

Further proof on the role of accumbal nNOS in cocaine-seeking behavior in rats.

BACKGROUND: 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 ionotropic N-methyl-D-aspartate (NMDA) receptors or metabotropic receptors' type 5 (mGlu5) receptors in controlling the reinstatement of cocaine. Stimulation of the above molecules results in the activation of the downstream signaling targets such as neuronal nitric oxide synthase (nNOS) and the release of nitric oxide. METHODS: In this paper, we investigated the molecular changes in nNOS in the prefrontal cortex and nucleus accumbens following 3 and 10 days of cocaine abstinence as well as the effectiveness of nNOS blockade with the selective enzyme inhibitor N-ω-propyl-L-arginine hydrochloride (L-NPA) on cocaine seeking in male rats. The effect of L-NPA on locomotor activity in drug-naïve animals was investigated. RESULTS: Ten-day (but not 3-day) cocaine abstinence from cocaine self-administration increased nNOS gene and protein expression in the nucleus accumbens, but not in the prefrontal cortex. L-NPA (0.5-5 mg/kg) administered peripherally did not change locomotor activity but attenuated the reinstatement induced with cocaine priming or the drug-associated conditioned cue. CONCLUSIONS: Our findings support accumbal nNOS as an important molecular player for cocaine seeking while its inhibitors could be considered as anti-cocaine pharmacological tools in male rats.

A maternal high-fat diet during pregnancy and lactation disrupts short-term memory functions via altered hippocampal glutamatergic signaling in female rat offspring.

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 adolescent and young adult offspring were evaluated. We analyzed the expression of genes encoding the glutamatergic transporters in the hippocampus to verify the association between changes in glutamatergic transporters and behavioral changes in offspring. Next, we examined whether maternal diet-induced changes in the mRNA levels of genes encoding the NMDA receptor subunits and the AMPA receptor subunits, as well as BDNF in this structure in offspring. All significant changes were validated at the protein level. We found that a maternal HFD during pregnancy and lactation disrupts short-term memory in adolescent and young adult females. The latter change is likely related to the dysregulation of hippocampal levels of GluN2B subunit of NMDA receptors and of reduced levels of BDNF. In summary, we showed that a maternal HFD during pregnancy and lactation triggered several changes within the glutamatergic system in the hippocampus of rat offspring, which may be related to producing behavioral changes in offspring.

A maternal high-fat diet during pregnancy and lactation induced depression-like behavior in offspring and myelin-related changes in the rat prefrontal cortex.

In accordance with the developmental origins of health and disease, early-life environmental exposures, such as maternal diet, can enhance the probability and gravity of health concerns in their offspring in the future. Over the past few years, compelling evidence has emerged suggesting that prenatal exposure to a maternal high-fat diet (HFD) could trigger neuropsychiatric disorders in the offspring, such as depression. The majority of brain development takes place before birth and during lactation. Nevertheless, our understanding of the impact of HFD on myelination in the offspring's brain during both gestation and lactation remains limited. In the present study, we investigated the effects of maternal HFD (60% energy from fat) on depressive-like and myelin-related changes in adolescent and adult rat offspring. Maternal HFD increased immobility time during the forced swimming test in both adolescent and adult offspring. Correspondingly, the depressive-like phenotype in offspring correlated with dysregulation of several genes and proteins in the prefrontal cortex, especially of myelin-oligodendrocyte glycoprotein (MOG), myelin and lymphocyte protein (MAL), 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNPase), kallikrein 6, and transferrin in male offspring, as well as of MOG and kallikrein 6 in female offspring, which persist even into adulthood. Maternal HFD also induced long-lasting adaptations manifested by the reduction of immature and mature oligodendrocytes in the prefrontal cortex in adult offspring. In summary, maternal HFD-induced changes in myelin-related genes are correlated with depressive-like behavior in adolescent offspring, which persists even to adulthood.

The effects of cocaine exposure in adolescence: Behavioural effects and neuroplastic mechanisms in experimental models.

Drug addiction is a devastating disorder with a huge economic and social burden for modern society. Although an individual may slip into drug abuse throughout his/her life, adolescents are at higher risk, but, so far, only a few studies have attempted to elucidate the underlying cellular and molecular bases of such vulnerability. Indeed, preclinical evidence indicates that psychostimulants and adolescence interact and contribute to promoting a dysfunctional brain. In this review, we have focused our attention primarily on changes in neuroplasticity brought about by cocaine, taking into account that there is much less evidence from exposure to cocaine in adolescence, compared with that from adults. This review clearly shows that exposure to cocaine during adolescence, acute or chronic, as well as contingent or non-contingent, confers a vulnerable endophenotype, primarily, by causing changes in neuroplasticity. Given the close relationship between drug abuse and psychiatric disorders, we also discuss the translational implications providing an interpretative framework for clinical studies involving addictive as well as affective or psychotic behaviours. LINKED ARTICLES: This article is part of a themed issue on New discoveries and perspectives in mental and pain disorders. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.17/issuetoc.

Maternal feeding patterns affect the offspring's brain: focus on serotonin 5-HT2C and 5-HT2A receptors.

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-HT2A receptors in the offspring brain. METHODS: Wistar rat dams during gestation and lactation were maintained either on a standard (SD) or special diets: high-fat (HFD), high-carbohydrate (rich in sucrose, HCD) or mixed (MD). Offspring were weaned to SD after lactation, and at postnatal days (PNDs) 28 and 63 changes in the 5-HT2C and 5-HT2A receptor levels were evaluated in their prefrontal cortex (PFCx), nucleus accumbens (NAc), dorsal striatum (DSTR) and hippocampus (HIP). RESULTS: Maternal HFD reduced the expression of 5-HT2C receptors in male rats at PND 28 in the PFCx, NAc, and DSTR but increased it at PND 63 in male animals in the NAc and DSTR. HCD induced a decrease in the expression of 5-HT2C receptors in male offspring at PND 28 but increased it in female rats at PND 63 in the PFCx. MD reduced 5-HT2C receptor expression in males at PND 28 in the PFCx and increased it in male and female offspring at PND 28 in the HIP. Moreover, maternal HFD reduced 5-HT2A receptor levels within the PFCx in adolescent male offspring. CONCLUSION: Our findings indicate that a modified maternal diet induces age- and sex-specific adaptive changes mainly in 5-HT2C receptors, which may contribute to disturbances in the offspring brain.

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.

Relationship of maternal high-fat diet during pregnancy and lactation to offspring health.

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 exerts an irreversible influence on the general health of the offspring. This review of preclinical research examines the relationship between a maternal high-fat diet during pregnancy or lactation and metabolic changes, molecular alterations in the brain, and behavioral disorders in offspring. Animal models indicate that offspring exposed to a maternal high-fat diet during pregnancy and lactation manifest increased depressive-like and aggressive behaviors, reduced cognitive development, and symptoms of metabolic syndrome. Recently, epigenetic and molecular studies have shown that maternal nutrition during pregnancy and the suckling period modifies the development of neurotransmitter circuits and many other factors important to central nervous system development. This finding confirms the importance of a balanced maternal diet for the health of offspring.

Prenatal MAM treatment altered fear conditioning following social isolation: Relevance to schizophrenia.

Adolescent social isolation (SI) might change the trajectory of brain development. In the present study, we investigated the effect of short-term adolescent SI on fear memory, anxiety and protein levels in the adult medial prefrontal cortex of rats prenatally treated with methylazoxymethanol, MAM-E17 model of schizophrenia. The animals were maintained in standard housing (SH) or social isolation (P30-P40, SI) conditions. Behavioural tests (trace or delay fear conditioning, light/dark box) were performed in late adolescence and early adulthood. The results showed that MAM treatment did not alter fear memory, which was investigated with the use of either trace or delay fear conditioning, at any age, and SI decreased the fear response in adult control animals only under trace conditioning. Neither MAM nor SI influenced anxiety-related behaviour measured in the light/dark box. A proteomics study showed that both MAM and SI changed the protein levels related to synapse maturation and cytoskeletal organization, energy transfer and metabolic processes. Prenatal or adolescent environmental factors are able to change the expression of proteins that are correlated with behavioural impairments. Moreover, SI reversed some alterations in proteins induced by MAM. Thus, normally developing brains showed different responses to adolescent SI than those with altering courses of MAM administration.

A Maternal High-Fat Diet during Early Development Provokes Molecular Changes Related to Autism Spectrum Disorder in the Rat Offspring Brain.

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 provides a mechanistic link between exposure to an unbalanced maternal diet and persistent modifications in gene expression levels that can lead to phenotype changes in the offspring. To better understand the impact of the early development environment on the risk of ASD in offspring, we assessed the effect of maternal high-fat (HFD), high-carbohydrate, and mixed diets on molecular changes in adolescent and young adult offspring frontal cortex and hippocampus. Our results showed that maternal HFD significantly altered the expression of 48 ASD-related genes in the frontal cortex of male offspring. Moreover, exposure to maternal HFD led to sex- and age-dependent changes in the protein levels of ANKRD11, EIF4E, NF1, SETD1B, SHANK1 and TAOK2, as well as differences in DNA methylation levels in the frontal cortex and hippocampus of the offspring. Taken together, it was concluded that a maternal HFD during pregnancy and lactation periods can lead to abnormal brain development within the transcription and translation of ASD-related genes mainly in male offspring.

Maternal dietary patterns are associated with susceptibility to a depressive-like phenotype in rat offspring.

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 as depression. Fetal and early postnatal development are sensitive periods in the offspring's life in which maternal nutrition influences epigenetic modifications, which results in changes in gene expression and affects molecular phenotype. This study aimed to evaluate the impact of maternal modified types of diet, including a high-fat diet (HFD), high-carbohydrate diet (HCD) and mixed diet (MD) during pregnancy and lactation on phenotypic changes in rat offspring with respect to anhedonia, depressive- and anxiety-like behavior, memory impairment, and gene expression profile in the frontal cortex. Behavioral results indicate that maternal HFD provokes depressive-like behavior and molecular findings showed that HFD leads to persistent transcriptomics alterations. Moreover, a HFD significantly influences the expression of neuronal markers specific to excitatory and inhibitory cortical neurons. Collectively, these experiments highlight the complexity of the impact of maternal modified diet during fetal programming. Undoubtedly, maternal HFD affects brain development and our findings suggest that nutrition exerts significant changes in brain function that may be associated with depression.

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.

Extinction Training after Cocaine Self-Administration Influences the Epigenetic and Genetic Machinery Responsible for Glutamatergic Transporter Gene Expression in Male Rat Brain.

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 SLC7A11 (encoding xCT), in rat brain structures after short-term (3 days) and long-term (10 days) extinction training using microarray analysis and quantitative real-time PCR. Furthermore, we analyzed the expression of genes encoding transcription factors, i.e., NFKB1 and NFKB2 (encoding NF-κB), PAX6, (encoding Pax6), and NFE2L2 (encoding Nrf2), to verify the correlation between changes in glutamatergic transporters and changes in their transcriptional factors and microRNAs (miRNAs; miR-124a, miR-543-3p and miR-342-3p) and confirm the epigenetic mechanism. We found reduced GLT-1 transcript and mRNA level in the prefrontal cortex (PFCTX) and dorsal striatum (DSTR) in rats that had previously self-administered cocaine after 3 days of extinction training, which was associated with downregulation of PAX6 (transcript and mRNA) and NFKB2 (mRNA) level in the PFCTX and with upregulation of miR-543-3p and miR-342-3p in the DSTR. The xCT mRNA level was reduced in the PFCTX and DSTR, and NFE2L2 transcript level in the PFCTX was decreased on the 3rd day of extinction training. In conclusion, 3-day drug-free period modulates GLT-1 and xCT gene expression through genetic and epigenetic mechanisms, and such changes in expression seem to be potential molecular targets for developing a treatment for cocaine-seeking behavior.

The impact of GABAB receptors and their pharmacological stimulation on cocaine reinforcement and drug-seeking behaviors in a rat model of depression.

Depression and cocaine use disorder represent frequent co-current diagnoses and the GABAB receptors are involved in both conditions. This research involved the application of the animal model of depression (bulbectomy, OBX) and cocaine use disorder (self-administration) to assess the efficiency of GABAB receptor agonists, baclofen and SKF-97541, on cocaine rewarding property and reinforcement of seeking-behaviors in rats with depressive phenotype. Additionally, we applied immunoreactive techniques to determine changes in the expression of GABAB receptor subunit 1 and 2 in rats with depression and cocaine addiction. The results obtained the study illustrate that the GABAB receptor agonists reduced the rewarding property of cocaine in both OBX and control (SHAM) rats. Both agonists significantly reduced cue- and cocaine-induced reinstatement in both groups. This is the first report demonstrating a different impact of cocaine abuse on GABAB receptor levels in depressed animals. It was documented that the expression of GABAB1 subunit in the infralimbic cortex increased during self-administration and extinction training in OBX animals. The lower level of expression for this subunit in addictive SHAM rats during self-administration, and increased in extinguished addictive OBX rats was found in the ventrolateral striatum. The expression of GABAB2 subunit changed only in the case of cocaine self-administration paradigm, as a decline of the subunit level in the nucleus accumbens and ventral hippocampus was observed only in OBX rats. The relevance of GABAB receptors in depression and addiction comorbidity is clearly implicated and can open a new era of drug discovery for individuals with dual diagnosis.

Adenosine A2AReceptors in Substance Use Disorders: A Focus on Cocaine.

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 dopamine (DA) neurotransmission within the mesocorticolimbic circuitry of the brain followed by the activation of DA receptors. D2 receptors were proposed as important molecular targets for SUD. The findings showed that D2 receptors formed heteromeric complexes with other GPCRs, which forced the addiction research area in new directions. In this review, we updated the view on the brain D2 receptor complexes with adenosine (A)2A receptors (A2AR) and discussed the role of A2AR in different aspects of addiction phenotypes in laboratory animal procedures that permit the highly complex syndrome of human drug addiction. We presented the current knowledge on the neurochemical in vivo and ex vivo mechanisms related to cocaine use disorder (CUD) and discussed future research directions for A2AR heteromeric complexes in SUD.

Adaptive mechanisms following antidepressant drugs: Focus on serotonin 5-HT2A receptors.

BACKGROUND: There is a strong support for the role of serotonin (5-HT) neurotransmission in depression and in the mechanism of action of antidepressants. Among 5-HT receptors, 5-HT2A receptor subtype seems to be an important target implicated in the above disorder. METHODS: The aim of the study was to investigate the effects of antidepressants, such as imipramine (15 mg/kg), escitalopram (10 mg/kg) and tianeptine (10 mg/kg) as well as drugs with antidepressant activity, including N-acetylcysteine (100 mg/kg) and URB597 (a fatty acid amide hydrolase inhibitor, 0.3 mg/kg) on the 5-HT2A receptor labeling pattern in selected rat brain regions. Following acute or chronic (14 days) drug administration, rat brains were analyzed by using autoradiography with the 5-HT2A receptor antagonist [3H]ketanserin. RESULTS: Single dose or chronic administration of imipramine decreased the radioligand binding in the claustrum and cortical subregions. The [3H]ketanserin binding either increased or decreased in cortical areas after acute N-acetylcysteine and URB597 administration, respectively. A similar shift towards reduction of the [3H]ketanserin binding was detected in the nucleus accumbens shell following either acute treatment with imipramine, escitalopram, N-acetylcysteine and URB597 or repeated administration of imipramine, tianeptine and URB597. CONCLUSIONS: In conclusion, the present result indicate different sensitivity of brain 5-HT2A receptors to antidepressant drugs depending on schedule of drug administration and rat brain regions. The decrease of accumbal shell 5-HT2A receptor labeling by antidepressant drugs exhibiting different primary mechanism of action seems to be a common targeting mechanism associated with the outcome of depression treatment.