Mechanisms Of Addiction Research Articles

Oncogenic mechanism-based pharmaceutical validation of therapeutics targeting MET receptor tyrosine kinase.

Aberrant expression and/or activation of the MET receptor tyrosine kinase is characterized by genomic recombination, gene amplification, activating mutation, alternative exon-splicing, increased transcription, and their different combinations. These dysregulations serve as oncogenic determinants contributing to cancerous initiation, progression, malignancy, and stemness. Moreover, integration of the MET pathway into the cellular signaling network as an addiction mechanism for survival has made this receptor an attractive pharmaceutical target for oncological intervention. For the last 20 years, MET-targeting small-molecule kinase inhibitors (SMKIs), conventional therapeutic monoclonal antibodies (TMABs), and antibody-based biotherapeutics such as bispecific antibodies, antibody–drug conjugates (ADC), and dual-targeting ADCs have been under intensive investigation. Outcomes from preclinical studies and clinical trials are mixed with certain successes but also various setbacks. Due to the complex nature of MET dysregulation with multiple facets and underlying mechanisms, mechanism-based validation of MET-targeting therapeutics is crucial for the selection and validation of lead candidates for clinical trials. In this review, we discuss the importance of various types of mechanism-based pharmaceutical models in evaluation of different types of MET-targeting therapeutics. The advantages and disadvantages of these mechanism-based strategies for SMKIs, conventional TMABs, and antibody-based biotherapeutics are analyzed. The demand for establishing new strategies suitable for validating novel biotherapeutics is also discussed. The information summarized should provide a pharmaceutical guideline for selection and validation of MET-targeting therapeutics for clinical application in the future.

Parental favoritism and mobile phone addiction in Chinese adolescents: The role of sibling relationship and gender difference

• Firstly, based on family system theory, investigating both paternal favoritism, maternal favoritism, and their joint effect. • Secondly, the mediating role of sibling relationship is investigated, to reveal the underlying connection in multiple-child families. • Thirdly, multiple-child families are the dominant type of family across the world, and are in need of more research. Mobile phone addiction has raised increasing public concern in recent years, and researchers constantly demonstrated one of its factors as family risk. Parental favoritism, a common phenomenon in multiple-child family, is tightly linked to negative developmental outcomes, such as addiction and substance use, however, few studies have related it with mobile phone addiction. To investigate the underlying mechanism of parental favoritism and mobile phone addiction in Chinese adolescents, this study used the favoritism subscale of EMBU, Sibling Relationship Inventory, and Mobile Phone Addiction Index Scale, on 304 elementary school children and 303 junior school students (M age = 12.56, SD = 1.17, 45.9% boys) from two-child families. Results suggest that parental favoritism can positively predict adolescents’ mobile phone addiction, which is further mediated by sibling hostility. Moreover, the mediating model is only significant in girls, but not in boys. That is, for girls, combination of both high paternal favoritism and maternal favoritism is associated with highest sibling hostility. To conclude, this study demonstrated the mechanism underlying the relationship between parental favoritism and adolescents’ mobile phone addiction and gender differences, contributing to the understanding of the complex mechanism between family dynamics and children’s developmental outcomes.

Identification and Characterization of Biomarkers and Their Role in Opioid Addiction by Integrated Bioinformatics Analysis.

Although numerous studies have confirmed that the mechanisms of opiate addiction include genetic and epigenetic aspects, the results of such studies are inconsistent. Here, we downloaded gene expression profiling information, GSE87823, from the Gene Expression Omnibus database. Samples from males between ages 19 and 35 were selected for analysis of differentially expressed genes (DEGs). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) enrichment analyses were used to analyze the pathways associated with the DEGs. We further constructed protein-protein interaction (PPI) networks using the STRING database and used 10 different calculation methods to validate the hub genes. Finally, we utilized the Basic Local Alignment Search Tool (BLAST) to identify the DEG with the highest sequence similarity in mouse and detected the change in expression of the hub genes in this animal model using RT-qPCR. We identified three key genes, ADCY9, PECAM1, and IL4. ADCY9 expression decreased in the nucleus accumbens of opioid-addicted mice compared with control mice, which was consistent with the change seen in humans. The importance and originality of this study are provided by two aspects. Firstly, we used a variety of calculation methods to obtain hub genes; secondly, we exploited homology analysis to solve the difficult challenge that addiction-related experiments cannot be carried out in patients or healthy individuals. In short, this study not only explores potential biomarkers and therapeutic targets of opioid addiction but also provides new ideas for subsequent research on opioid addiction.

Aversion-resistant fentanyl self-administration in mice.

Animal models of compulsive drug use that continues despite negative consequences can be used to investigate the neural mechanisms of addiction. However, models of punished or aversion-resistant opioid self-administration are notably lacking. We sought to develop an aversion-resistant, oral fentanyl self-administration paradigm. In Experiment 1, C57BL/6J male and female, adult mice consumed fentanyl (10μg/mL) in a two-bottle drinking in the dark task and escalating concentrations of quinine were added to the bottles. In Experiment 2, mice were trained to administer oral fentanyl (10μg/mL) in an operant response task. Quinine was next added to the fentanyl solution in escalating concentrations. In Experiment 3, mice were trained to respond for oral fentanyl or fentanyl adulterated with 500μM quinine on every session. In Experiment 4, mice were trained to respond for a 1% sucrose solution before introduction of quinine. Quinine reduced two-bottle choice consumption in males but not in females. Both sexes demonstrated the ability to detect the selected concentrations of quinine in fentanyl. In the operant chamber, mice responded robustly for oral fentanyl but introduction of quinine at any stage of training was insufficient to reduce responding. In contrast, quinine reduced responding for sucrose at concentrations above 250μM. Mice will respond for and consume oral fentanyl in both a two-bottle choice and an operant response task. Quinine is detectable in fentanyl but mice will continue to respond for and consume fentanyl with quinine in both paradigms. These data support the use of these models in behavioral studies of compulsive-like opioid use.

Targeting neuroinflammation: The therapeutic potential of ω-3 PUFAs in substance abuse.

Substance abuse is a chronic relapsing disorder that results in serious health and socioeconomic issues worldwide. Addictive drugs induce long-lasting morphologic and functional changes in brain circuits and account for the formation of compulsive drug-seeking and drug-taking behaviors. Yet, there remains a lack of reliable therapy. In recent years, accumulating evidence indicated that neuroinflammation was implicated in the development of drug addiction. Findings from both our and other laboratories suggest that ω-3 polyunsaturated fatty acids (PUFAs) are effective in treating neuroinflammation-related mental diseases, and indicate that they could exert positive effects in treating drug addiction. Thus, in the present review, we summarized and evaluated recently published articles reporting the neuroinflammation mechanism in drug addiction and the immune regulatory ability of ω-3 PUFAs. We also sought to identify some of the challenges ahead in the translation of ω-3 PUFAs into addiction treatment.

ERG-Mediated Coregulator Complex Formation Maintains Androgen Receptor Signaling in Prostate Cancer.

The TMPRSS2-ERG fusion is the most common genomic rearrangement in human prostate cancer. However, in established adenocarcinoma, it is unknown how the ERG oncogene promotes a cancerous phenotype and maintains downstream androgen receptor (AR) signaling pathways. In this study, we utilized a murine prostate organoid system to explore the effects of ERG on tumorigenesis and determined the mechanism underlying prostate cancer dependence on ERG. Prostate organoids lacking PTEN and overexpressing ERG (Pten-/- R26-ERG) faithfully recapitulated distinct stages of prostate cancer disease progression. In this model, deletion of ERG significantly dampened AR-dependent gene expression. While ERG was able to reprogram the AR cistrome in the process of prostate carcinogenesis, ERG knockout in established prostate cancer organoids did not drastically alter AR binding, H3K27ac enhancer, or open chromatin profiles at these reprogrammed sites. Proteomic analysis of DNA-bound AR complexes demonstrated that ERG deletion causes a loss of recruitment of critical AR coregulators and basal transcriptional machinery, including NCOA3 and RNA polymerase II, but does not alter AR binding itself. Together, these data reveal a novel mechanism of ERG oncogene addiction in prostate cancer, whereby ERG facilitates AR signaling by maintaining coregulator complexes at AR bound sites across the genome. SIGNIFICANCE: These findings exploit murine organoid models to uncover the mechanism of ERG-mediated tumorigenesis and subsequent oncogenic dependencies in prostate cancer.

Changes in the Expression of DNA Methylation Related Genes in Leukocytes of Persons with Alcohol and Drug Dependence

Abstract Background and objectives. Though numerous studies have shown that the dysregulation of the epigenetic control is involved in disease manifestation, limited data is available on the transcriptional activity of DNA methylation related genes in alcohol and drug addiction. With regard to this, in this study we analyzed the expression levels of genes involved in DNA methylation, including DNMT1, DNMT3a, MeCP2, MBD1, MBD2, MBD3 and MBD4, in blood samples of alcohol and drug dependent persons in comparison to healthy abstainers. Methods. The study included 51 participants: 16 persons with alcohol dependence, 17 persons with drug dependence and 18 clinically healthy controls. To detect the relative mRNA expression levels of the studied genes, Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis was applied. Results. Of the seven studied genes, four showed altered expression. MeCP2 and MBD1 were downregulated in the alcohol dependent group (FC = 0.805, p = 0.015 and FC = 0.846, p = 0.034, respectively), while DNMT1 and MBD4 were upregulated in the group with drug dependence (FC = 1.262, p = 0.001 and FC = 1.249, p = 0.005, respectively). No statistically significant changes in the relative mRNA expression were found for DNMT3a, MBD2 and MBD3 genes. Conclusions. Our results are indicative for a role of DNA methylation related genes in alcohol and drug addiction mediated through changes in their transcriptional activity. Studies in this direction will enable better understanding of the underlying mechanisms of addictions supporting the development of more effective therapeutic strategies.

Maladaptive Rumination Mediates the Relationship between Self-Esteem, Perfectionism, and Work Addiction: A Largescale Survey Study.

Background: Empirical evidence suggests that low self-esteem and high perfectionism are significant personality correlates of work addiction, but the mechanisms underlying these relationships are still unclear. Consequently, exploring cognitive mechanisms will help to better understand work addiction. For instance, rumination is one of the under-researched topics in work addiction, although it may explain specific thinking processes of work-addicted individuals. The purpose of the study was to test the mediating role of maladaptive rumination (i.e., brooding) in the relationship between personality and addiction. Methods: In a largescale cross-sectional, unrepresentative, online study, 4340 adults with a current job participated. The following psychometric instruments were used: Work Addiction Risk Test Revised, Rosenberg Self-Esteem Scale, Multidimensional Perfectionism Scale, and Ruminative Response Scale. Results: It was found that self-oriented perfectionism, socially prescribed perfectionism, and self-esteem had both direct and indirect relationships with work addiction via the mediating effect of maladaptive rumination. The two paths involving brooding explained 44% of the direct relationship. Conclusions: The study demonstrated that brooding type of rumination as a putatively maladaptive strategy explains why individuals characterized by low self-esteem and high perfectionism may have a higher risk of work addiction. The results suggest that cognitive-affective mechanisms in work addiction are similar to those found in other addictive disorders.

Investigating the influence of perinatal nicotine and alcohol exposure on the genetic profiles of dopaminergic neurons in the VTA using miRNA\u2013mRNA analysis

Nicotine and alcohol are two of the most commonly used and abused recreational drugs, are often used simultaneously, and have been linked to significant health hazards. Furthermore, patients diagnosed with dependence on one drug are highly likely to be dependent on the other. Several studies have shown the effects of each drug independently on gene expression within many brain regions, including the ventral tegmental area (VTA). Dopaminergic (DA) neurons of the dopamine reward pathway originate from the VTA, which is believed to be central to the mechanism of addiction and drug reinforcement. Using a well-established rat model for both nicotine and alcohol perinatal exposure, we investigated miRNA and mRNA expression of dopaminergic (DA) neurons of the VTA in rat pups following perinatal alcohol and joint nicotine–alcohol exposure. Microarray analysis was then used to profile the differential expression of both miRNAs and mRNAs from DA neurons of each treatment group to further explore the altered genes and related biological pathways modulated. Predicted and validated miRNA-gene target pairs were analyzed to further understand the roles of miRNAs within these networks following each treatment, along with their post transcription regulation points affecting gene expression throughout development. This study suggested that glutamatergic synapse and axon guidance pathways were specifically enriched and many miRNAs and genes were significantly altered following alcohol or nicotine–alcohol perinatal exposure when compared to saline control. These results provide more detailed insight into the cell proliferation, neuronal migration, neuronal axon guidance during the infancy in rats in response to perinatal alcohol/ or nicotine–alcohol exposure.

Looking for Sunshine: Genetic Predisposition to Sun Seeking in 265,000 Individuals of European Ancestry

Despite growing public awareness of the adverse consequences of excessive sun exposure, modifying sun-seeking behavior is challenging because it appears to be driven by addictive mechanisms. This can have effects on health because sun exposure, although beneficial, when prolonged and repeated shows a causal relationship with skin cancer risk. Using data from 2,500 United Kingdom twins, we observed sun seeking to be significantly heritable (h2 ≥ 58%). In a GWAS meta-analysis of sun-seeking behavior in 261,915 subjects of European ancestry, we identified five GWAS-significant loci previously associated with addiction, behavioral and personality traits, cognitive function, and educational attainment and enriched for CNS gene expression: MIR2113 (P= 2.08× 10-11), FAM76B/MTMR2/CEP57 (P= 3.70× 10-9), CADM2 (P= 9.36× 10-9), TMEM182 (P=1.64× 10-8), and PLCL1/LINC01923/SATB2 (P= 3.93× 10-8). These findings imply that the behavior concerning UV exposure is complicated by a genetic predisposition shared with neuropsychological traits. This should be taken into consideration when designing awareness campaigns and may help improve people's attitudes toward sun exposure.

BDNF and nicotine dependence: associations and potential mechanisms.

Smoking is the leading preventable cause of death worldwide and tobacco addiction has become a serious public health problem. Nicotine is the main addictive component of tobacco, and the majority of people that smoke regularly develop nicotine dependence. Nicotine addiction is deemed to be a chronic mental disorder. Although it is well known that nicotine binds to the nicotinic acetylcholine receptors (nAChRs) and activates the mesolimbic dopaminergic system (MDS) to generate the pleasant and rewarding effects, the molecular mechanisms of nicotine addiction are not fully understood. Brain-derived neurotrophic factor (BDNF) is the most prevalent growth factor in the brain, which regulates neuron survival, differentiation, and synaptic plasticity, mainly through binding to the high affinity receptor tyrosine kinase receptor B (TrkB). BDNF gene polymorphisms are associated with nicotine dependence and blood BDNF levels are altered in smokers. In this review, we discussed the effects of nicotine on BDNF expression in the brain and summarized the underlying signaling pathways, which further indicated BDNF as a key regulator in nicotine dependence. Further studies that aim to understand theneurobiological mechanism of BDNF in nicotine addcition would provide a valuable reference for quitting smoking and developing the treatment of other addictive substances.

Common and gender-specific associations with cocaine use on gray matter volume: Data from the ENIGMA addiction working group.

Gray matter volume (GMV) in frontal cortical and limbic regions is susceptible to cocaine‐associated reductions in cocaine‐dependent individuals (CD) and is negatively associated with duration of cocaine use. Gender differences in CD individuals have been reported clinically and in the context of neural responses to cue‐induced craving and stress reactivity. The variability of GMV in select brain areas between men and women (e.g., limbic regions) underscores the importance of exploring interaction effects between gender and cocaine dependence on brain structure. Therefore, voxel‐based morphometry data derived from the ENIGMA Addiction Consortium were used to investigate potential gender differences in GMV in CD individuals compared to matched controls (CTL). T1‐weighted MRI scans and clinical data were pooled from seven sites yielding 420 gender‐ and age‐matched participants: CD men (CDM, n = 140); CD women (CDW, n = 70); control men (CTLM, n = 140); and control women (CTLW, n = 70). Differences in GMV were assessed using a 2 × 2 ANCOVA, and voxelwise whole‐brain linear regressions were conducted to explore relationships between GMV and duration of cocaine use. All analyses were corrected for age, total intracranial volume, and site. Diagnostic differences were predominantly found in frontal regions (CD < CTL). Interestingly, gender × diagnosis interactions in the left anterior insula and left lingual gyrus were also documented, driven by differences in women (CDW < CTLW). Further, lower right hippocampal GMV was associated with greater cocaine duration in CDM. Given the importance of the anterior insula to interoception and the hippocampus to learning contextual associations, results may point to gender‐specific mechanisms in cocaine addiction.

The role of the metabotropic glutamate receptor 5 in nicotine addiction.

This review summarizes the evidence for the potential involvement of metabotropic glutamate receptor 5 (mGluR5) in the development of nicotine addiction. Nicotine is consumed worldwide and is highly addictive. Previous research has extensively investigated the role of dopamine in association with reward learning and addiction, which has provided strong evidence for the involvement of dopaminergic neuronal circuitry in nicotine addiction. More recently, researchers focused on glutamatergic transmission after nicotine abuse, and its involvement in the reinforcing and rewarding effects of nicotine addiction. A number of robust preclinical and clinical studies have shown mGluR5 signaling as a facilitating mechanism of nicotine addiction and nicotine withdrawal. Specifically, clinical studies have illustrated lower cortical mGluR5 density in smokers compared to nonsmokers in the human brain. In addition, mGluR5 might selectively regulate craving and withdrawal. This suggests that mGluR5 could be a key receptor in the development of nicotine addiction and therefore clinical trials to examine the therapeutic potential of mGluR5 agents could help to contribute to reduce nicotine addiction in society.

A multivariate pattern analysis of resting-state functional MRI data in Naïve and chronic betel quid chewers.

Betel quid (BQ) is the fourth most commonly consumed psychoactive substance in the world. However, comprehensive functional magnetic resonance imaging (fMRI) studies exploring the neurophysiological mechanism of BQ addiction are lacking. Betel-quid-dependent (BQD) individuals (n = 24) and age-matched healthy controls (HC) (n = 26) underwent fMRI before and after chewing BQ. Multivariate pattern analysis (MVPA) was used to explore the acute effects of BQ-chewing in both groups. A cross-sectional comparison was conducted to explore the chronic effects of BQ-chewing. Regression analysis was used to investigate the relationship between altered circuits of BQD individuals and the severity of BQ addiction. MVPA achieved classification accuracies of up to 90% in both groups for acute BQ-chewing. Suppression of the default-mode network was the most prominent feature. BQD showed more extensive and intensive within- and between-network dysconnectivity of the default, frontal-parietal, and occipital regions associated with high-order brain functions such as self-awareness, inhibitory control, and decision-making. In contrast, the chronic effects of BQ on the brain function were mild, but impaired circuits were predominately located in the default and frontal-parietal networks which might be associated with compulsive drug use. Simultaneously quantifying the effects of both chronic and acute BQ exposure provides a possible neuroimaging-based BQ addiction foci. Results from this study may help us understand the neural mechanisms involved in BQ-chewing and BQ dependence.

Methamphetamine-Induced Neuronal Damage: Neurotoxicity and Neuroinflammation.

Methamphetamine (METH) is a highly addictive psychostimulant and one of the most widely abused drugs worldwide. The continuous use of METH eventually leads to drug addiction and causes serious health complications, including attention deficit, memory loss and cognitive decline. These neurological complications are strongly associated with METH-induced neurotoxicity and neuroinflammation, which leads to neuronal cell death. The current review investigates the molecular mechanisms underlying METH-mediated neuronal damages. Our analysis demonstrates that the process of neuronal impairment by METH is closely related to oxidative stress, transcription factor activation, DNA damage, excitatory toxicity and various apoptosis pathways. Thus, we reach the conclusion here that METH-induced neuronal damages are attributed to the neurotoxic and neuroinflammatory effect of the drug. This review provides an insight into the mechanisms of METH addiction and contributes to the discovery of therapeutic targets on neurological impairment by METH abuse.

Drug addiction-the neurochemical perspective of brain in drug-seeking behavior

A critical challenge of the investigation in the neurobiological mechanism of drug addiction is how acute actions become transformed into chronic effects that underlie the compulsive drug-seeking and craving in addiction. Repeated administrations of psychostimulants can enhance the behavioral response upon reinstatement of the drug, a prominent phenomenon known as behavioral sensitization. It has been implicated that the neuronal changes brought about by sensitization in the mesocorticolimbic pathways have close relationship with compulsive drug seeking in addicts. Dopamine and glutamate are the two major neurotransmitters involved in the sensitization of abused drugs. The authors reviewed literature pertinent to amphetamine and cocaine addiction in order to address the recent important concepts and findings in dopaminergic and glutamatergic neurochemical systems of mesolimbic and mesocortical circuits associated with drug-related behavior. The present review also discusses the role of associative learning as manifested in the relationship between environmental cues of drug administration and intractable drug-seeking behavior.

Discovery of a Role for Rab3b in Habituation and Cocaine Induced Locomotor Activation in Mice Using Heterogeneous Functional Genomic Analysis.

Substance use disorders are prevalent and present a tremendous societal cost but the mechanisms underlying addiction behavior are poorly understood and few biological treatments exist. One strategy to identify novel molecular mechanisms of addiction is through functional genomic experimentation. However, results from individual experiments are often noisy. To address this problem, the convergent analysis of multiple genomic experiments can discern signal from these studies. In the present study, we examine genetic loci that modulate the locomotor response to cocaine identified in the recombinant inbred (BXD RI) genetic reference population. We then applied the GeneWeaver software system for heterogeneous functional genomic analysis to integrate and aggregate multiple studies of addiction genomics, resulting in the identification of Rab3b as a functional correlate of the locomotor response to cocaine in rodents. This gene encodes a member of the RAB family of Ras-like GTPases known to be involved in trafficking of secretory and endocytic vesicles in eukaryotic cells. The convergent evidence for a role of Rab3b includes co-occurrence in previously published genetic mapping studies of cocaine related behaviors; methamphetamine response and cocaine- and amphetamine-regulated transcript prepropeptide (Cartpt) transcript abundance; evidence related to other addictive substances; density of polymorphisms; and its expression pattern in reward pathways. To evaluate this finding, we examined the effect of RAB3 complex perturbation in cocaine response. B6;129-Rab3btm1Sud Rab3ctm1sud Rab3dtm1sud triple null mice (Rab3bcd–/–) exhibited significant deficits in habituation, and increased acute and repeated cocaine responses. This previously unidentified mechanism of the behavioral predisposition and response to cocaine is an example of many that can be identified and validated using aggregate genomic studies.

SsGSEA score-based Ras dependency indexes derived from gene expression data reveal potential Ras addiction mechanisms with possible clinical implications

For nearly a decade, the difficulties associated with both the determination and reproducibility of Ras-dependency indexes (RDIs) have limited their application and further delineation of the biology underlying Ras dependency. In this report, we describe the application of a computational single sample gene set enrichment analysis (ssGSEA) method to derive RDIs with gene expression data. The computationally derived RDIs across the Cancer Cell Line Encyclopedia (CCLE) cell lines show excellent agreement with the experimentally derived values and high correlation with a previous in-house siRNA effector node (siREN) study and external studies. Using EMT signature-derived RDIs and data from cell lines representing the extremes in RAS dependency, we identified enriched pathways distinguishing these classes, including the Fas signaling pathway and a putative Ras-independent pathway first identified in NK cells. Importantly, extension of the method to patient samples from The Cancer Genome Atlas (TCGA) showed the same consensus differential expression patterns for these two pathways across multiple tissue types. Last, the computational RDIs displayed a significant association with TCGA cancer patients’ survival outcomes. Together, these lines of evidence confirm that our computationally derived RDIs faithfully represent a measure of Ras dependency in both cancer cell lines and patient samples. The application of such computational RDIs can provide insights into Ras biology and potential clinical applications.

Simple Aesthetic Sense and Addiction Emerge in Neural Relations of Cost-Benefit Decision in Foraging

A rudimentary aesthetic sense is found in the stimulus valuations and cost-benefit decisions made by primitive generalist foragers. These are based on factors governing personal economic decisions: incentive, appetite, and learning. We find that the addictive process is an extreme expression of aesthetic dynamics. An interactive, agent-based model, ASIMOV, reproduces a simple aesthetic sense from known neural relations of cost-benefit decision in foraging. In the presence of very high reward, an addiction-like process emerges. A drug-like prey provides extreme reward with no nutritive value, initiating high selectivity and prolonged cravings for drug through reward learning. Varying reward experience, caused by homeostatic changes in the neural circuitry of reward, further establishes the course of addiction, consisting of desensitization, withdrawal, resensitization, and associated changes in nutritional choice and pain sensitivity. These observations are consistent with the early evolution of addiction mechanisms in simple generalist foragers as an aesthetic sense for evaluating prey. ASIMOV is accessible to inspection, modification, and experiment, is adaptable as an educational tool, and provides insight on the possible coevolutionary origins of aesthetics and the addiction process.

Neurochemical mechanisms and pharmacology of ghrelins

The purpose of the review was to analyze the neurochemical and neurophysiological mechanisms of the ghrelin system and the role of ghrelin in body functions and behavior. The focus is on the participation of ghrelin in the mechanisms of reinforcement and the formation of addictive behavior. At the beginning of the review a history of the first works on the field of ghrelin and its receptor was described. Then, genetic control, molecular precursor of ghrelin, molecular forms of ghrelin and ghrelin receptor were represented. In particular, the distribution of the ghrelin receptor, ghrelin-producing cells in the brain and its participation in various physiological functions of the body were shown. The hypothalamic functions of ghrelin were discussed: energy balance, regulation of glucose metabolism, stimulation of eating behavior, regulation of hypophys-pituitary axis (HPA) system. The connection of ghrelin with the brain CRH system was demonstrated. In particular, activation of HPA was described as a possible mechanism through which ghrelin regulates a number of physiological processes. Extrahypothalamic action of ghrelin was shown on the basis of the mechanisms of reinforcement and addiction. On the basis of their own data and literary, it was concluded that action of alcohol and psychoactive drugs are reduced after the ghrelin receptors blockade. In particular, it has been demonstrated that alcoholization of mothers affects the activity of the ghrelin system during the prenatal and early postnatal periods of development in the offspring of rats. It was shown the participation of ghrelin in memory and learning. The further perspective of the study and practical application of ghrelin-based pharmacological agents was analyzed.