Chills, Bets, and Dopamine

During the past decade, research in cognitive neuroscience has tried to understand how the organized acoustic information we call music is decoded in the brain as pleasant and rewarding stimulus. In this chapter, the authors retrace part of this intriguing journey: from the first positron emission tomography study revealing the association between the mesolimbic system and musical pleasure to the recent pharmacological interventions showing that dopamine causally mediates the subjectively rewarding experience elicited by music. The dopamine-dependent hedonic and motivational responses to music may depend on the modulations of several neural mechanisms related not only to emotion, but also to attention and memory. Musical reward arises therefore as a complex set of processes which constitute a special access key to the study of human cognition.

THE RESULTS OF THE SEARCH FOR LABORATORY SIGNS OF AUTOIMMUNE REACTIONS TO CEREBRAL AND EXTRACEREBRAL AUTOANTIGENS IN CHILDREN WITH AUTISM SPECTRUM DISORDERS ASSOCIATED WITH GENETIC DEFICIENCY OF THE FOLATE CYCLE

Relevance. The results of five meta-analyzes of randomized controlled clinical trials indicate an association between genetic deficiency of the folate cycle (GDFC) and autism spectrum disorders (ASD) in children. Autoimmune mechanisms play a special role in the pathogenesis of encephalopathy in children with ASD associated with GDFC. Objective: to study the structure of autoimmune reactions in children with ASD associated with GDFC, according to the accumulated evidence base and to identify associations of laboratory signs of autoimmunity and microorganisms to improve understanding of encephalopathy pathogenesis and diagnostic, monitoring and treatment algorithms. Materials and methods. The medical data of 225 children aged 2 to 9 years with GDFC, who had clinical manifestations of ASD (183 boys and 42 girls) were retrospectively analyzed. The diagnosis of ASD was made by child psychiatrists according to the criteria DSM-IV-TR (Diagnostic and Statistical Manual of mental disorders) and ICD-10 (The International Statistical Classification of Diseases and Related Health Problems) (study group; SG). The control group (CG) included 51 clinically healthy children (37 boys and 14 girls) of similar age and gender distribution who did not suffer from GDFC and ASD. Pathogenic polymorphic variants of folate cycle genes were determined by PCR with restriction (Sinevo, Ukraine). Autoantibodies to autoantigens of CNS subcortical ganglion neurons in blood serum were determined using a Cunningham panel (Moleculera Labs, Inc, USA). Serum autoantibodies to neurons of the mesolimbic system of the brain were identified by ELISA (MDI Limbach Berlin GmbH, Germany). Autoimmunization to myelin was assessed by serum autoantibody titer to basic myelin protein (ELISA) and signs of neutrophil and CD8+ T-lymphocyte sensitization to hemispheric white matter autoantigens (cell-based assay; department of neuroimmunology at the Neurosurgery Institute; Ukraine). Serum autoantibodies to nuclei of connective tissue cells and striated muscle proteins were determined by western blot analysis (Sinevo, Ukraine). To determine the significance of the differences between the indicators in the observation groups, we used the Student's parametric T-test with the confidence probability p and the nonparametric criterion – the number of signs Z according to Urbach Yu.V. The odds ratio (OR) and the 95% confidence interval (95% CI) were used to study the associations between the studied indicators. The study was performed as a fragment of research work commissioned by the Ministry of Health of Ukraine (№ state registration 0121U107940). Research. Positive results of the Cunningham panel occurred in 32%, laboratory signs of autoimmunization to neurons of the mesolimbic system – 36%, myelin of white matter of the hemispheres – 43%, nuclei autoantigens of connective tissue cells – 53%, proteins of striated muscles – 48% of cases among children SG (in general – 68% of cases; p < 0.05; Z < Z0.05). Serological signs of autoimmunization to autoantigens of the subcortical ganglia of the cerebral hemispheres were associated with Streptococcus pyogenes and Borrelia, to neurons of the mesolimbic system – EBV, HHV-6, HHV-7, Toxoplasma and TTV, to CNS myelin – EBV, HHV-6, HHV-7, Borrelia and TTV, to the nuclei of connective tissue cells and striated muscles – EBV, HHV-6, HHV-7, Borrelia and TTV. Conclusions. In children with ASD associated with GDFC laboratory sings of microbial-induced autoimmunity to a number of cerebral and extracerebral autoantigens has been evaluated, which affects the mental and physical health of patients and is a potential target for effective therapeutic interventions.

Is It Possible to Shift from Down to Top Rank? A Focus on the Mesolimbic Dopaminergic System and Cocaine Abuse

Impaired social behavior is a common feature of many psychiatric disorders, in particular with substance abuse disorders. Switching the preference of the substance-dependent individual toward social interaction activities remains one of the major challenges in drug dependence therapy. However, social interactions yield to the emergence of social ranking. In this review, we provide an overview of the studies that examined how social status can influence the dopaminergic mesolimbic system and how drug-seeking behavior is affected. Generally, social dominance is associated with an increase in dopamine D2/3 receptor binding in the striatum and a reduced behavioral response to drugs of abuse. However, it is not clear whether higher D2 receptor availability is a result of increased D2 receptor density and/or reduced dopamine release in the striatum. Here, we discuss the possibility of a potential shift from down to top rank via manipulation of the mesolimbic system. Identifying the neurobiology underlying a potential rank switch to a resilient phenotype is of particular interest in order to promote a positive coping behavior toward long-term abstinence from drugs of abuse and a protection against relapse to drugs. Such a shift may contribute to a more successful therapeutic approach to cocaine addiction.

Selected Landmark Studies in the Role of the Mesolimbic System

The mesolimbic system has been demonstrated to have a major role in the perception of pain, but the mechanisms by which this occurs are poorly understood. In this paper, we review selected landmark studies that have contributed to our present understanding of the role of the mesolimbic system. The included studies outline the molecular mechanisms of the mesolimbic system's role in analgesia, pain relief, and feelings of decreased motivation and depression as a result of chronic pain. Because chronic pain is among the most highly-cited reasons for decreased quality of life, advancing our understanding of the function and mechanism of the mesolimbic system may be critical to improving the quality of life for millions of people around the globe.

Selected Landmark Studies in the Role of the Mesolimbic System

The mesolimbic system has been demonstrated to have a major role in the perception of pain, but the mechanisms by which this occurs are poorly understood. In this paper, we review selected landmark studies that have contributed to our present understanding of the role of the mesolimbic system. The included studies outline the molecular mechanisms of the mesolimbic system's role in analgesia, pain relief, and feelings of decreased motivation and depression as a result of chronic pain. Because chronic pain is among the most highly-cited reasons for decreased quality of life, advancing our understanding of the function and mechanism of the mesolimbic system may be critical to improving the quality of life for millions of people around the globe

Association between Chronic Pain and Alterations in the Mesolimbic Dopaminergic System

Chronic pain (pain lasting for >3 months) decreases patient quality of life and even occupational abilities. It can be controlled by treatment, but often persists even after management. To properly control pain, its underlying mechanisms must be determined. This review outlines the role of the mesolimbic dopaminergic system in chronic pain. The mesolimbic system, a neural circuit, delivers dopamine from the ventral tegmental area to neural structures such as the nucleus accumbens, prefrontal cortex, anterior cingulate cortex, and amygdala. It controls executive, affective, and motivational functions. Chronic pain patients suffer from low dopamine production and delivery in this system. The volumes of structures constituting the mesolimbic system are known to be decreased in such patients. Studies on administration of dopaminergic drugs to control chronic pain, with a focus on increasing low dopamine levels in the mesolimbic system, show that it is effective in patients with Parkinson’s disease, restless legs syndrome, fibromyalgia, dry mouth syndrome, lumbar radicular pain, and chronic back pain. However, very few studies have confirmed these effects, and dopaminergic drugs are not commonly used to treat the various diseases causing chronic pain. Thus, further studies are required to determine the effectiveness of such treatment for chronic pain.

GABAergic and glutamatergic effects on nigrostriatal and mesolimbic dopamine release in the rat

In this review, a series of experiments is presented, in which γ-amino butyric acid (GABA)ergic and glutamatergic effects on dopamine function in the rat nigrostriatal and mesolimbic system was systematically assessed after pharmacological challenge with GABAA receptor (R) and and N-methyl d-aspartate (NMDA)R agonists and antagonists. In these studies, [123I]iodobenzamide binding to the D2/3R was mesured in nucleus accumbens (NAC), caudateputamen (CP), substantia nigra/ventral tegmental area (SN/VTA), frontal (FC), motor (MC) and parietal cortex (PC) as well as anterior (aHIPP) and posterior hippocampus (pHIPP) with small animal SPECT in baseline and after injection of either the GABAAR agonist muscimol (1 mg/kg), the GABAAR antagonist bicuculline (1 mg/kg), the NMDAR agonist d-cycloserine (20 mg/kg) or the NMDAR antagonist amantadine (40 mg/kg). Muscimol reduced D2/3R binding in NAC, CP, SN/VTA, THAL and pHIPP, while, after amantadine, decreases were confined to NAC, CP and THAL. In contrast, d-cycloserine elevated D2/3R binding in NAC, SN/VTA, THAL, frontal cortex, motor cortex, PC, aHIPP and pHIPP, while, after bicuculline, increases were confined to CP and THAL. Taken together, similar actions on regional dopamine levels were exterted by the GABAAR agonist and the NMDAR antagonist on the one side and by the GABAAR antagonist and the NMDAR agonist on the other, with agonistic action, however, affecting more brain regions. Thereby, network analysis suggests different roles of GABAARs and NMDARs in the mediation of nigrostriatal, nigrothalamocortical and mesolimbocortical dopamine function.