Dopaminergic Neurotransmitter Systems Research Articles

Prepulse inhibition deficit as a transdiagnostic process in neuropsychiatric disorders: a systematic review

BackgroundPsychopathological research is moving from a specific approach towards transdiagnosis through the analysis of processes that appear transversally to multiple pathologies. A phenomenon disrupted in several disorders is prepulse inhibition (PPI) of the startle response, in which startle to an intense sensory stimulus, or pulse, is reduced if a weak stimulus, or prepulse, is previously presented.Objective and methodsThe present systematic review analyzed the role of PPI deficit as a possible transdiagnostic process for four main groups of neuropsychiatric disorders: (1) trauma-, stress-, and anxiety-related disorders (2) mood-related disorders, (3) neurocognitive disorders, and (4) other disorders such as obsessive-compulsive, tic-related, and substance use disorders. We used Web of Science, PubMed and PsycInfo databases to search for experimental case-control articles that were analyzed both qualitatively and based on their potential risk of bias. A total of 64 studies were included in this systematic review. Protocol was submitted prospectively to PROSPERO 04/30/2022 (CRD42022322031).Results and conclusionThe results showed a general PPI deficit in the diagnostic groups mentioned, with associated deficits in the dopaminergic neurotransmission system, several areas implied such as the medial prefrontal cortex or the amygdala, and related variables such as cognitive deficits and anxiety symptoms. It can be concluded that the PPI deficit appears across most of the neuropsychiatric disorders examined, and it could be considered as a relevant measure in translational research for the early detection of such disorders.

Neurotensin(8–13) analogs as dual NTS1 and NTS2 receptor ligands with enhanced effects on a mouse model of Parkinson's disease

The modulatory interactions between neurotensin (NT) and the dopaminergic neurotransmitter system in the brain suggest that NT may be associated with the progression of Parkinson's disease (PD). NT exerts its neurophysiological effects by interactions with the human NT receptors type 1 (hNTS1) and 2 (hNTS2). Therefore, both receptor subtypes are promising targets for the development of novel NT-based analogs for the treatment of PD. In this study, we used a virtually guided molecular modeling approach to predict the activity of NT(8–13) analogs by investigating the docking models of ligands designed for binding to the human NTS1 and NTS2 receptors. The importance of the residues at positions 8 and/or 9 for hNTS1 and hNTS2 receptor binding affinity was experimentally confirmed by radioligand binding assays. Further in vitro ADME profiling and in vivo studies revealed that, compared to the parent peptide NT(8–13), compound 10 exhibited improved stability and BBB permeability combined with a significant enhancement of the motor function and memory in a mouse model of PD. The herein reported NTS1/NTS2 dual-specific NT(8–13) analogs represent an attractive tool for the development of therapeutic strategies against PD and potentially other CNS disorders.

Acute administration of a dopamine D2/D3 receptor agonist alters behavioral and neural parameters in adult zebrafish

The dopaminergic neurotransmitter system is implicated in several brain functions and behavioral processes. Alterations in it are associated with the pathogenesis of several human neurological disorders. Pharmacological agents that interact with the dopaminergic system allow the investigation of dopamine-mediated cellular and molecular responses and may elucidate the biological bases of such disorders. Zebrafish, a translationally relevant biomedical research organism, has been successfully employed in prior psychopharmacology studies. Here, we evaluated the effects of quinpirole (dopamine D2/D3 receptor agonist) in adult zebrafish on behavioral parameters, brain-derived neurotrophic factor (BDNF) and neurotransmitter levels. Zebrafish received intraperitoneal injections of 0.5, 1.0, or 2.0 mg/kg quinpirole or saline (control group) twice with an inter-injection interval of 48 h. All tests were performed 24 h after the second injection. After this acute quinpirole administration, zebrafish exhibited decreased locomotor activity, increased anxiety-like behaviors and memory impairment. However, quinpirole did not affect social and aggressive behavior. Quinpirole-treated fish exhibited stereotypic swimming, characterized by repetitive behavior followed by immobile episodes. Moreover, quinpirole treatment also decreased the number of BDNF-immunoreactive cells in the zebrafish brain. Analysis of neurotransmitter levels demonstrated a significant increase in glutamate and a decrease in serotonin, while no alterations were observed in dopamine. These findings demonstrate that dopaminergic signaling altered by quinpirole administration results in significant behavioral and neuroplastic changes in the central nervous system of zebrafish. Thus, we conclude that the use of quinpirole administration in adult zebrafish may be an appropriate tool for the analysis of mechanisms underlying neurological disorders related to the dopaminergic system.

Chronic Dietary α-Linolenic Acid Deficiency Alters Dopaminergic and Serotoninergic Neurotransmission in Rats , ,

This study examined the effects of dietary alpha-linolenic acid [18:3(n-3)] deficiency on dopaminergic serotoninergic neurotransmission systems in 60-d-old male rats. Rats were fed semipurified diets containing either peanut oil [the (n-3)-deficient group] or peanut plus rapeseed oil (control group). We measured the densities of the serotonin-2 (5-HT2) receptors and the dopamine-2 (D2) receptors by autoradiography and membrane-binding assays in relation to the fatty acid composition and levels of endogenous monoamines in three cerebral regions: the frontal cortex, the striatum and the cerebellum. Long-term feeding of the (n-3)-deficient diet induced a significantly higher 5-HT2 receptor density in the frontal cortex compared with the control rats without any difference in the endogenous serotonin concentrations. The results also showed some modification of dopaminergic neurotransmission specifically in the frontal cortex in the rats deficient in alpha-linolenic acid, with a significantly lower density of D2 receptors and a significantly lower concentration of endogenous dopamine than in control animals. Moreover, there were lower levels of (n-3) fatty acids in all the regions studied in the deficient rats, balanced by greater levels of (n-6) fatty acids. These results suggest that chronic consumption of an alpha-linolenic acid-deficient diet could induce modifications of the neurotransmission pathways; this might induce the behavioral disturbances previously described in this fatty acid-deficient animal model.

From Natural Behavior to Drug Screening: Invertebrates as Models to Study Mechanisms Associated with Alcohol Use Disorders.

Humans consume ethanol-containing beverages, which may cause an uncontrollable or difficult-to-control intake of ethanol-containing liquids and may result in alcohol use disorders. How the transition at the molecular level from "normal" ethanol-associated behaviors to addictive behaviors occurs is still unknown. One problem is that the components contributing to normal ethanol intake and their underlying molecular adaptations, especially in neurons that regulate behavior, are not clear. The fruit fly Drosophila melanogaster and the earthworm Caenorhabditis elegans show behavioral similarities to humans such as signs of intoxication, tolerance, and withdrawal. Underlying the phenotypic similarities, invertebrates and vertebrates share mechanistic similarities. For example in Drosophila melanogaster, the dopaminergic neurotransmitter system regulates the positive reinforcing properties of ethanol and in Caenorhabditis elegans, serotonergic neurons regulate feeding behavior. Since these mechanisms are fundamental molecular mechanisms and are highly conserved, invertebrates are good models for uncovering the basic principles of neuronal adaptation underlying the behavioral response to ethanol. This review will focus on the following aspects that might shed light on the mechanisms underlying normal ethanol-associated behaviors. First, the current status of what is required at the behavioral and cellular level to respond to naturally occurring levels of ethanol is summarized. Low levels of ethanol delay the development and activate compensatory mechanisms that in turn might be beneficial for some aspects of the animal's physiology. Repeated exposure to ethanol however might change brain structures involved in mediating learning and memory processes. The smell of ethanol is already a key component in the environment that is able to elicit behavioral changes and molecular programs. Minimal networks have been identified that regulate normal ethanol consumption. Other environmental factors that influence ethanol-induced behaviors include the diet, dietary supplements, and the microbiome. Second, the molecular mechanisms underlying neuronal adaptation to the cellular stressor ethanol are discussed. Components of the heat shock and oxidative stress pathways regulate adaptive responses to low levels of ethanol and in turn change behavior. The adaptive potential of the brain cells is challenged when the organism encounters additional cellular stressors caused by aging, endosymbionts or environmental toxins or excessive ethanol intake. Finally, to underline the conserved nature of these mechanisms between invertebrates and higher organisms, recent approaches to identify drug targets for ethanol-induced behaviors are provided. Already approved drugs regulate ethanol-induced behaviors and they do so in part by interfering with cellular stress pathways. In addition, invertebrates have been used to identify new compounds targeting molecules involved in the regulation in ethanol withdrawal-like symptoms. This review primarily highlights the advances of the last 5years concerning Drosophila melanogaster, but also provides intriguing examples of Caenorhabditis elegans and Apis mellifera in support.

CURRENT UNDERSTANDING OF THE ROLE OF THE MONOAMINERGIC NEUROTRANSMITTER SYSTEM IN ANXIOGENESIS

Anxiety disorders are widespread in the world and Ukraine, and their frequency is constantly growing. In the brain, the prefrontal cortex, thalamus, hypothalamus, amygdala, and associated areas of these structures are responsible for the development of anxiety pathology. It has been shown that a wide variety of serotonergic structures of the brain are involved in the formation and progression of anxiety pathology. At the same time, selective serotonin reuptake inhibitors (SSRIs) are the main drugs in the treatment of these conditions, although they have not been confirmed to enhance or weaken serotonergic transmission. Disorders of the noradrenergic system constitute another leading link in the pathogenesis of neuroses, which is confirmed by the effectiveness of drugs that reduce the activity of the corresponding structures in the central nervous system. In neuroses, the sensitivity of central adrenergic receptors changes, and the relationship with the serotonergic neurotransmitter system is discussed. The dopaminergic system of the brain makes a certain contribution to the pathogenesis of neurotic disorders. Such disorders of this system, changes in the content of the dopamine mediator, and the sensitivity of D-receptors can provoke generalized anxiety states and other diseases. The possibility of adverse reactions, in particular social phobias, after the administration of D-receptor blockers is also discussed. It has been shown that metabolism of monoaminergic mediators is disrupted during anxiety. Therefore, the leading role in the development and progression of anxiety pathology belongs to the imbalance of the serotonergic, adrenergic, and dopaminergic neurotransmitter systems of the central nervous system.

Effects of dopamine D2/3 and opioid receptor antagonism on the trade-off between model-based and model-free behaviour in healthy volunteers.

Human behaviour requires flexible arbitration between actions we do out of habit and actions that are directed towards a specific goal. Drugs that target opioid and dopamine receptors are notorious for inducing maladaptive habitual drug consumption; yet, how the opioidergic and dopaminergic neurotransmitter systems contribute to the arbitration between habitual and goal-directed behaviour is poorly understood. By combining pharmacological challenges with a well-established decision-making task and a novel computational model, we show that the administration of the dopamine D2/3 receptor antagonist amisulpride led to an increase in goal-directed or 'model-based' relative to habitual or 'model-free' behaviour, whereas the non-selective opioid receptor antagonist naltrexone had no appreciable effect. The effect of amisulpride on model-based/model-free behaviour did not scale with drug serum levels in the blood. Furthermore, participants with higher amisulpride serum levels showed higher explorative behaviour. These findings highlight the distinct functional contributions of dopamine and opioid receptors to goal-directed and habitual behaviour and support the notion that even small doses of amisulpride promote flexible application of cognitive control.

Acute Administration of Ethanol and of a D1-Receptor Antagonist Affects the Behavior and Neurochemistry of Adult Zebrafish.

Alcohol abuse represents major societal problems, an unmet medical need resulting from our incomplete understanding of the mechanisms underlying alcohol's actions in the brain. To uncover these mechanisms, animal models have been proposed. Here, we explore the effects of acute alcohol administration in zebrafish, a promising animal model in alcohol research. One mechanism via which alcohol may influence behavior is the dopaminergic neurotransmitter system. As a proof-of-concept analysis, we study how D1 dopamine-receptor antagonism may alter the effects of acute alcohol on the behavior of adult zebrafish and on whole brain levels of neurochemicals. We conduct these analyses using a quasi-inbred strain, AB, and a genetically heterogeneous population SFWT. Our results uncover significant alcohol x D1-R antagonist interaction and main effects of these factors in shoaling, but only additive effects of these factors in measures of exploratory behavior. We also find interacting and main effects of alcohol and the D1-R antagonist on dopamine and DOPAC levels, but only alcohol effects on serotonin. We also uncover several strain dependent effects. These results demonstrate that acute alcohol may act through dopaminergic mechanisms for some but not all behavioral phenotypes, a novel discovery, and also suggest that strain differences may, in the future, help us identify molecular mechanisms underlying acute alcohol effects.

Effects of Environmentally Relevant Concentrations of Antipsychotic Drugs (Sulpiride and Clozapine) on Serotonergic and Dopaminergic Neurotransmitter Systems in Octopus Brain Tissue

Pharmaceuticals and personal care products (PPCPs) from specific activities often enter surface and groundwater, adversely affecting the physiological functions of non-target organisms and posing a serious threat to a wide range of aquatic organisms. Therefore, the aim of this study was to investigate the effects of environmentally relevant concentrations of the antipsychotic drugs sulpiride and clozapine on dopaminergic (DAergic) and serotonergic (5-hydroxytryptaminergic, i.e., 5-HTergic) neurotransmitter systems in the brain of a short-arm octopus (Octopus ochellatus). Octopus ochellatus adults were exposed to environmentally relevant concentrations of sulpiride, clozapine, or a mixture of sulpiride and clozapine. The effects of the drug on the transcription and expression levels of major functional molecules in the DAergic and 5-HTergic systems of the brain were analyzed. By antagonizing the dopamine receptor D2 (DRD2) or 5-hydroxytryptamine receptor 2A (5-HTR2A), the two drugs induced abnormal transcription and expression levels of important functional molecules in the brain’s DA and 5-HT signaling pathways. In addition, dose-dependent adverse reactions were observed with these antipsychotics. Our results suggest that sulpiride and clozapine interfere with DAergic and 5-HTergic neurotransmitter systems in the brain of Amphioctopus fangsiao (O. ochellatus), possibly affecting brain functions, such as reproduction, predation, camouflage, learning, and memory. As a result, they pose a serious threat to the health of Amphioctopus fangsiao.

Childhood ADHD, Going Beyond the Brain: A Meta-Analysis on Peripheral Physiological Markers of the Heart and the Gut.

Attention-Deficit/Hyperactivity Disorder (ADHD) is the most common neurodevelopmental disorder diagnosed in children. Questions regarding its increased diagnostic rates and pharmacological treatments in developing children have led to a more holistic review of the multi-system pathophysiology observed in ADHD. The dopaminergic neurotransmitter system, known for its influence on reward-motivated behaviors and motor control, and the frontostriatal systems, that mediate motor, cognition, and behavior, are associated with ADHD’s development. However, studies have shown that these neural systems do not wholly account for ADHD’s multilayered and heterogeneous symptom presentation. For instance, the literature suggests that emotional dysregulation, the inability to regulate one’s emotional responses to provoking stimuli, is associated with increased risk for social impairment in ADHD. A broader examination of physiological systems in children with ADHD has found potential markers in the heart-brain and gut-brain axes that correspond with certain behaviors associated with emotional dysregulation in recent studies. Hence, the purpose of this meta-analysis is to aggregate ten applicable published case studies and analyze task-related heart rate reactivity (HRR; n = 5 studies) and gut microbiota (n = 5 studies) data in children with and without ADHD. Data from a total of 531 youth with ADHD and 603 youth without ADHD revealed significant small and medium effect sizes for higher Chao1 levels and Actinobacteria levels in the ADHD group, respectively, but no evidence of altered task-related HRR. Thus, further research into multi-system psychophysiological measures of emotional dysregulation and ADHD is warranted. The clinical, empirical, and educational implications of these findings are discussed.Systematic Review Registration https://www.crd.york.ac.uk/prospero/, identifier PROSPERO (CRD42021236819).

Structural alterations in psychotic disorders co-localize with serotonergic and dopaminergic neurotransmitter systems

Structural alterations in psychotic disorders co-localize with serotonergic and dopaminergic neurotransmitter systems

Functional MRI Derived Resting-State Alterations in Huntington’s Disease are Associated With the Distribution of Serotonergic and Dopaminergic Neurotransmitter Systems

Huntington’s disease (HD) is characterized by progressive striatal atrophy and widespread degeneration during the course of disease. Functionally, altered resting-state activity and connectivity in networks involving cortical, subcortical and cerebellar regions can be observed. The relationship of brain alterations in HD with specific neurotransmitter systems remains largely unknown.

Repeated toluene exposure leads to neuroadaptation in dopamine release mechanisms within the nucleus accumbens core

BackgroundIntentionally inhaling volatile organic solvent like toluene for its intoxicating effects continues to be a public health concern. While repeated abuse of toluene has deleterious behavioral and health effects, little is known about the actions of toluene on the dopaminergic neurotransmitter system within the central nervous system. MethodThe present study employed complementary neurochemical techniques of slice fast-scan cyclic voltammetry (FSCV) and in vivo microdialysis, to assess dopamine (DA) dynamics immediately after repeated exposure to 2000- or 4000-ppm toluene. DA D3 autoreceptor functionality, measured by FSCV with pharmacological manipulations and brain tissue content analysis with high performance liquid chromatography, were also used to account for the changes in the DA dynamics. ResultsToluene-exposed mice had decreased stimulated DA release only in the nucleus accumbens core immediately after seven days of repeated exposure. DA uptake was decreased in the core only after 2000-ppm exposure. The differences in stimulated DA release were not attributed to alterations in intraneuronal DA levels as measured by tissue content analysis. Basal extracellular DA levels were not significantly different between the air- and toluene-treated mice. However, following an additional toluene exposure, mice had elevated extracellular DA levels in the nucleus accumbens during recovery. This potentiation in extracellular accumbal DA levels was further heightened following potassium stimulation. The accumbal DA D3 autoreceptor function did not appear to play a role as a potential mediator for these differences. ConclusionOur FSCV and microdialysis results suggest a neuroadaptation in DA release mechanics within the nucleus accumbens, but the exact neuronal mechanism of toluene's impact remains elusive.

Therapeutic effects of anodal transcranial direct current stimulation in a rat model of ADHD.

Most therapeutic candidates for treating attention-deficit hyperactivity disorder (ADHD) have focused on modulating the dopaminergic neurotransmission system with neurotrophic factors. Regulation of this system by transcranial direct current stimulation (tDCS) could contribute to the recovery of cognitive symptoms observed in patients with ADHD. Here, male spontaneously hypertensive rats (SHR) were subjected to consecutive high-definition tDCS (HD-tDCS) (20 min, 50 μA, current density 63.7 A/m2, charge density 76.4 kC/m2) over the prefrontal cortex. This treatment alleviated cognitive deficits, with an increase in tyrosine hydroxylase and vesicular monoamine transporter two and significantly decreased plasma membrane reuptake transporter (DAT). HD-tDCS application increased the expression of several neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF), and activated hippocampal neurogenesis. Our results suggest that anodal HD-tDCS over the prefrontal cortex may ameliorate cognitive dysfunction via regulation of DAT and BDNF in the mesocorticolimbic dopaminergic pathways, and therefore represents a potential adjuvant therapy for ADHD.

Impact of Tetrahydropyrido[2,1-b][1,3,5]thiadiazines on L-DOPA Effects in the Tail Suspension Test

Aim.Evaluation of the impact of tetrahydropyrido[2,1-b][1,3,5]thiadiazine derivatives on L-DOPA effects in the tail suspension test.Materials and methods.Some tetrahydropyrido[2,1-b][1,3,5]thiadiazines exhibit a pronounced antidepressant and adaptogenic activity. We selected compounds that demonstrated the most potent antidepressant effect in the Porsolt’s forced swim test. We chose to combine two approaches in the study: estimation of the antidepressant drug impact on levodopa effects and the tail suspension test. Caffeine sodium benzoate, amitriptyline and fluoxetine were chosen as the reference compounds. Studies of the 1,3,5-thiadiazine effects on levodopa activity were undertaken to ground detailed downstream analyses of associated responses in the dopaminergic neurotransmitter system. We measured the rectal temperature in laboratory rats prior to and after tail suspension and the total active time during 5 min in the test.Results.Administration of levodopa at a dose of 150 mg/kg led to a reduction in rectal temperature and the total time of physical activity in rats in the tail suspension test. The dosage of 500 mg/kg led to a temperature increase of 0.7°C prior to and after the stress and a longer maintenance of physical activity. Rats exhibited exophthalmos and polyuria.Levodopa at a 150 mg/kg dosage in combination with caffeine sodium benzoate did not cause a significant increase in the body temperature and prolonged physical activity by 69% in the test vs. the control group. Amitriptyline in combination with levodopa at a dose of 150 mg/kg triggered a temperature increase of 1.3°C prior to and 1.85°C after tail suspension, thus leading to a prolonged physical activity. Levodopa at a dose of 150 mg/kg in combination with fluoxetine led to elevation of the body temperature by 0.6°C prior to and 0.55°C after the stress. The total active time exhibited a declining trend.The substance TD-0348 reveals an antidepressant activity. Physical active time increased by 32% in the test vs. the control group. Temperature elevation by 1.15°C prior to and 1.25°C after the stress suggests activation of the autonomic nervous system. TD-0470 in combination with levodopa (150 mg/kg) led to a rectal temperature elevation by 0.4°C prior to and 0.7°C after tail suspension. Physical activity was prolonged compared to the levodopa-treated group (150 mg/ kg). TD-0479 led to a temperature elevation by 0.85°C prior to and 0.95°C after the stress and caused polyuria. Treatment with TD-0164 did not provide sufficient data to suggest an impact on dopamine metabolism.Conclusions.The compounds TD-0348, TD-0470 and TD-0479 affect physiological processes in experimental rats in response to treatment with L-DOPA at a dose of 150 mg/kg, which suggests the autonomic nervous system (ANS) activation. TD-0470 exhibits antidepressant properties. Treatment with TD-0164 does not provide sufficient data to evaluate its dopamine-related effects.

O5.2. CBD MODULATION OF HIPPOCAMPAL GLUTAMATE IN PSYCHOSIS

BackgroundEmerging evidence supports the antipsychotic effect of cannabidiol (CBD), a non-intoxicating component of cannabis, in people with psychosis. However, how CBD might exert its antipsychotic effect remains unclear. While current antipsychotic medications typically target the dopaminergic neurotransmitter system, preclinical findings suggest that CBD may directly or indirectly affect multiple distinct modes of neural signalling, including both glutamate and dopamine. However, no study has as yet investigated the effect of CBD on brain glutamate levels in patients with psychosis as a potential mechanism underlying its antipsychotic effects.MethodsWe investigated the effects of a single oral dose of CBD (600mg), compared to a matched placebo, in patients within 5 years of onset of psychosis, using a double-blind, randomized, placebo-controlled, repeated-measures, within-subject cross-over design, with at least a one-week interval between scans to allow washout of CBD. After drug administration, 13 patients (mean age 27.73, 66.7% male) were scanned using proton magnetic resonance spectroscopy to measure left hippocampal glutamate levels. Symptom severity was assessed using the Positive and Negative syndrome scale (PANSS) 60mins before drug administration (T1, pre scan), and 270mins after drug administration (T2, post scan). Effects of CBD on left hippocampal glutamate levels, symptoms, and correlations between hippocampal glutamate and symptoms were investigated.ResultsCompared to placebo, there was a significant increase in left hippocampal glutamate in the psychosis patients under CBD treatment (z= -1.80; p=0.035). Under placebo treatment, change in positive psychotic symptoms (as indexed using the T1 minus T2 PANSS positive symptoms subscale scores) was directly correlated with left hippocampal glutamate levels (rho= 0.69, p=0.004), such that symptoms increased as hippocampal glutamate levels decreased. This significant relationship was not observed under the CBD treatment (rho= 0.102, p=0.72).DiscussionThis suggests that positive psychotic symptoms may be driven by abnormal hippocampal glutamate concentration, which is sensitive to modulation by CBD. These findings are in keeping with the purported antipsychotic effects of CBD in psychosis, and provide novel insight into the neurochemical interactions underlying these effects.

Pharmacological challenges examining the underlying mechanism of altered response inhibition and attention due to circadian disruption in adult Long-Evans rats

Endogenous circadian rhythms govern behavior and physiology, while circadian disruption is an environmental factor that impacts cognition by altering the circadian clock at a molecular level. We modeled the effects of 2 sources of circadian disruption – activity occurring during typical rest periods and untimely light exposure – to evaluate the effects of circadian disruption on behavior and underlying neurochemistry. Firstly, adult Long-Evans rats of both sexes were maintained on a 12 h:12 h light:dark cycle and tested using a 5-choice serial reaction time task (5-CSRTT) under 3 conditions: 4 h into the dark phase with no exposure to ambient light during testing (control), 4 h into the dark phase with exposure to ambient light during testing, and 4 h into the light phase. Both models resulted in impulsive behavior and reduced attention compared to control. We established that changes in the diurnal expression pattern occur in the clock gene Period 2 (Per2) in the light phase-tested model. Choline acetyltransferase (Chat) and Dopamine receptor 1 (Drd1) showed rhythmic expression with peak expression during the dark phase regardless of light-testing condition. Next, we performed drug challenges in a new rat cohort to examine the interaction between the cholinergic and dopaminergic neurotransmitter systems in regulating the behavioral changes caused by circadian disruption. We administered the cholinergic agonist nicotine and either the dopamine-1 receptor (DR1) antagonist SCH23390 or the DR2 antagonist eticlopride under the 3 circadian conditions to identify differential drug responses between treatment groups. Rats in both models demonstrated increased sensitivity to nicotine as compared to control, while SCH23390 and eticlopride ameliorated the effect of nicotine on 5-CSRTT performance in both models. Our study is the first to identify detrimental effects of both models of circadian disruption on impulsive behavior, and that the effects of circadian disruption are mediated by an interaction between cholinergic and dopaminergic systems.

Genetic features of the dopaminergic neurotransmitter system in patients with alcohol dependence and depression comorbidity

Aim. Test the hypothesis about the effect of polymorphisms of the DA system on the risk of developing depression in patients with alcohol dependence. Material and methods. 104 patients: 64 patients with a combination of diagnoses of “alcohol dependence” and “depression” (F10.2 and F32, F33 according to ICD-10, average age 41.23 ± 9.903 years) and 40 patients with a diagnosis of alcohol dependence (F10 .2 according to ICD-10, average age 45.57 ± 10.853 years) and 113 control (average age 43.65 ± 4.318 years). Results. In patients with a combination of AD and depression, the frequency of occurrence of the C allele C polymorphism rs1611115 of the DBH gene is higher than in the control group (p = 0.087, trend). In patients with a combination of AD and depression, the frequency of occurrence of the A allele of the rs1108580 polymorphism of the DBH gene is higher than in patients with AD (p = 0.059, trend). In patients with AD allele A, the DBH gene rs1108580 polymorphism increases the risk of depression by 174.0% (p = 0.009), the DBH gene rs1108580 AA polymorphism increases the risk of depression by 684.1% (p = 0.010), the rs1108580 gene AG polymorphism rs1108580 in the gene DBH increases the risk of depression by 261.1% (p = 0.010). Conclusion. It has been shown for the first time that polymorphic variants of the rs1108580 locus of the DBH gene act as important risk factors for depression in patients with AD. Polymorphism rs1611115 of the DBH gene can also play an important role in the development of depression in patients with AD, which requires further study.

Weekly ethanol exposure alters dopaminergic parameters in zebrafish brain

Binge drinking is defined as the infrequent consumption of excessive doses of alcohol in a short period of time. Zebrafish is a reliable model to investigate ethanol consumption impact on the CNS, including reward signaling like dopaminergic neurotransmission system. The aim of this study was to evaluate zebrafish brain dopaminergic parameters after intermittent weekly ethanol exposure (WEE), which mimics binge drinking. Thus, adult zebrafish were exposed to ethanol (1.4% v/v) for 30 min, once a week for three consecutive weeks. The groups were divided according to different time points after the third exposure and name as follow: immediately (WEEI), two days (WEE-2), and nine days (WEE-9) after last exposure to ethanol. Brain dopaminergic function was assessed by the activity of the dopamine transporters (DAT); monoamine oxidase (MAO) activity; dopamine and noradrenaline levels by chromatography. The WEE-I and WEE-2 groups presented a significant increase in DAT activity. The MAO activity was decreased for WEE-2 and WEE-9 groups. The WEE-2 and WEE-9 groups presented an increase in brain dopamine levels, while noradrenaline levels were not affected. Therefore, dopaminergic parameters are still altered two and nine days after the last ethanol exposure in this binge experimental model, resulting in a modulatory event in this neurotransmission pathway.

ИЗМЕНЕНИЯ ЦЕРЕБРО-КАРДИАЛЬНЫХ ВЗАИМОДЕЙСТВИЙ ПРИ ВЕГЕТАТИВНОМ СОСТОЯНИИ В ОТВЕТ НА НЕЙРОТРОПНУЮ ТЕРАПИЮ

Целью исследования было изучение особенностей цереброкардиальных взаимодействий у пациентов с острой церебральной недостаточностью различного генеза с исходом в вегетативное состояние, исследование эффективности холина альфосцерата у данной категории пациентов. Материалы и методы. В статье использованы данные открытого проспективного исследования по типу «случай-контроль» в 2011-2018 годах на базе Донецкого клинического территориального медицинского объединения. Группу исследования составили 11 пациентов с острой церебральной недостаточностью в результате тяжелой черепно-мозговой травмы (5 пациентов), мозгового инсульта (3 больных), после «постасистолического синдрома» (3 пациента). Диагноз вегетативного состояния у пациентов ГИ был выставлен на основании принятых международных критериев (Vegetative State and Minimally Conscious State, 2010). Проводили анализ уровня сознания по шкалам ком Глазго, Глазго-Питсбургской шкалы ком, Скандинавской шкалы инсультов и исходов Глазго, количественной ЭЭГ (система Nihon Kohden Corporation EEG-1200K), вариабельности сердечного ритма (Ютас ЮМ 200). Церебро-кардиальные взаимодействия исследовали на фоне фармакологических проб с препаратом холина альфосцерата. Длительность наблюдения пациентов от 2 до 8 месяцев. Статистическая обработка данных включала исследование плотности корреляционной связи (программа MedStat). Результаты и обсуждения. В результате лечения была зафиксирована трансформация вегетативного состояния в «состояние малого сознания» у 5 больных. Состояние без изменений – у 3 пациентов. Трое больных умерло.В ответ на введение препарата холина альфосцерата были выявлены статистически значимые (р≤0,05) увеличения параметров относительной спектральной мощности в ЭЭГ-диапазоне бета1-, бета2- ритма (максимально в правой гемисфере), в диапазоне альфа- активности (максимально в области центральных и окципитальных отведений билатерально), в «узких» диапазонах 14-16 Гц и 11-12 Гц, что отражало значимую активацию ГАМК-ергических и дофаминергических нейромедиаторных систем ЦНС. Не было выявлено статистически значимых изменений (р>0,05) относительной спектральной мощности в ЭЭГ-диапазоне тета- ритма, в диапазоне 6-7,5 Гц, связанном с активацией холинергический нейромедиаторных структур. В ответ на введение холина альфосцерата было зафиксировано значительное увеличение плотности с изменением характера корреляционных связей между параметрами вариабельности сердечного ритма и количественной ЭЭГ. Выводы. Особенности церебро-кардиальных взаимодействий у пациентов, у которых кома трансформировалась в вегетативное состояние, свидетельствовали о формировании нескольких патологических систем в ЦНС, связано с межполушарным разобщением и отсутствием взаимодействий между ретикулярной формацией верхнестволового и диэнцефального уровня. Изучение церебро-кардиальных взаимодействий позволяет выявить нейромедиаторные (холин-, ГАМК-, дофамин- и серотонинергические) предикторы в формировании вегетативного состояния. Применение центрального холиномиметика холина альфосцерата уже на первом этапе исследования позволяло выявить нетипичные изменения в т.н. «холинергический» нейромедиаторных структурах, связанные с формированием патологических систем.