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14 pages, 307 KiB

Open AccessArticle

Association between Psychopathological Symptoms and Aggression and Selected Biochemical Parameters in Adolescents with Behavioural and Emotional Disturbances

by Małgorzata Śmiarowska, Małgorzata Pawlicka, Agnieszka Boroń, Anna Grzywacz, Krzysztof Safranow, Dariusz Chlubek and Violetta Dziedziejko

Int. J. Mol. Sci. 2023, 24(8), 7097; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24087097 - 12 Apr 2023

Cited by 1 | Viewed by 1048

Abstract

Behavioural and emotional disturbances (F92.8) are the most recognized disorders in a developmental psychiatry. As the problem is still alarmingly increasing, the searches for their etiopathogenesis and more effective preventing and therapy methods are required. The aim of the study was to assess [...] Read more.

Behavioural and emotional disturbances (F92.8) are the most recognized disorders in a developmental psychiatry. As the problem is still alarmingly increasing, the searches for their etiopathogenesis and more effective preventing and therapy methods are required. The aim of the study was to assess the association between the quality of life, some psychopathological features, concentrations of selected immunoprotective (brain-derived neurotrophin, BDNF), and endocrine (cortisol, F) factors while adolescent disturbances. The study was performed in 123 inpatients of a psychiatric ward with F92.8 diagnosis, aged 13–18 years. The complete patients’ interview, physical examination, and routine laboratory tests, including serum F and BDNF tests, were performed. All patients completed standardized questionnaires to estimate: the severity of psychopathological symptoms (SCL-90), the level of aggression (Buss–Perry). The changes in the plasma BDNF and F concentrations were shown in patients raised in foster homes and institutions. The significantly lower BDNF was observed in youth from foster and suicide-experienced families. The more severe psychopathological symptoms, especially aggression and hostility, were found in these ones, who abused alcohol, attempted suicide, had lower self-esteem and cognitive processes, and were lacking safety in dysfunctional families. Full article

(This article belongs to the Special Issue Role of Dopamine in Health and Disease—Biological Aspect)

11 pages, 844 KiB

Open AccessArticle

DNA Methylation of the Dopamine Transporter DAT1 Gene—Bliss Seekers in the Light of Epigenetics

by Krzysztof Chmielowiec, Jolanta Chmielowiec, Jolanta Masiak, Aleksandra Strońska-Pluta, Milena Lachowicz, Agnieszka Boroń, Dariusz Larysz, Magdalena Dzitkowska-Zabielska, Paweł Cięszczyk and Anna Grzywacz

Int. J. Mol. Sci. 2023, 24(6), 5265; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24065265 - 09 Mar 2023

Cited by 1 | Viewed by 1366

Abstract

DNA methylation (leading to gene silencing) is one of the best-studied epigenetic mechanisms. It is also essential in regulating the dynamics of dopamine release in the synaptic cleft. This regulation relates to the expression of the dopamine transporter gene (DAT1). We [...] Read more.

DNA methylation (leading to gene silencing) is one of the best-studied epigenetic mechanisms. It is also essential in regulating the dynamics of dopamine release in the synaptic cleft. This regulation relates to the expression of the dopamine transporter gene (DAT1). We examined 137 people addicted to nicotine, 274 addicted subjects, 105 sports subjects and 290 people from the control group. After applying the Bonferroni correction, our results show that as many as 24 out of 33 examined CpG islands had statistically significantly higher methylation in the nicotine-dependent subjects and athletes groups compared to the control group. Analysis of total DAT1 methylation revealed a statistically significant increase in the number of total methylated CpG islands in addicted subjects (40.94%), nicotine-dependent subjects (62.84%) and sports subjects (65.71%) compared to controls (42.36%). The analysis of the methylation status of individual CpG sites revealed a new direction of research on the biological aspects of regulating dopamine release in people addicted to nicotine, people practicing sports and people addicted to psychoactive substances. Full article

(This article belongs to the Special Issue Role of Dopamine in Health and Disease—Biological Aspect)

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22 pages, 4207 KiB

Open AccessArticle

Heterozygote Dopamine Transporter Knockout Rats Display Enhanced Cocaine Locomotion in Adolescent Females

by Marta Pardo, Michele Martin, Raul R. Gainetdinov, Deborah C Mash and Sari Izenwasser

Int. J. Mol. Sci. 2022, 23(23), 15414; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232315414 - 06 Dec 2022

Cited by 5 | Viewed by 1599

Abstract

Cocaine is a powerful psychostimulant that is one of the most widely used illicit addictive. The dopamine transporter (DAT) plays a major role in mediating cocaine’s reward effect. Decreases in DAT expression increase rates of drug abuse and vulnerability to comorbid psychiatric disorders. [...] Read more.

Cocaine is a powerful psychostimulant that is one of the most widely used illicit addictive. The dopamine transporter (DAT) plays a major role in mediating cocaine’s reward effect. Decreases in DAT expression increase rates of drug abuse and vulnerability to comorbid psychiatric disorders. We used the novel DAT transgenic rat model to study the effects of cocaine on locomotor behaviors in adolescent rats, with an emphasis on sex. Female rats showed higher response rates to cocaine at lower acute and chronic doses, highlighting a higher vulnerability and perceived gender effects. In contrast, locomotor responses to an acute high dose of cocaine were more marked and sustained in male DAT heterozygous (HET) adolescents. The results demonstrate the augmented effects of chronic cocaine in HET DAT adolescent female rats. Knockout (KO) DAT led to a level of hyperdopaminergia which caused a marked basal hyperactivity that was unchanged, consistent with a possible ceiling effect. We suggest a role of alpha synuclein (α-syn) and PICK 1 protein expressions to the increased vulnerability in female rats. These proteins showed a lower expression in female HET and KO rats. This study highlights gender differences associated with mutations which affect DAT expression and can increase susceptibility to cocaine abuse in adolescence. Full article

(This article belongs to the Special Issue Role of Dopamine in Health and Disease—Biological Aspect)

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14 pages, 1871 KiB

Open AccessArticle

Haloperidol-Induced Immediate Early Genes in Striatopallidal Neurons Requires the Converging Action of cAMP/PKA/DARPP-32 and mTOR Pathways

by Oriane Onimus, Emmanuel Valjent, Gilberto Fisone and Giuseppe Gangarossa

Int. J. Mol. Sci. 2022, 23(19), 11637; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911637 - 01 Oct 2022

Cited by 1 | Viewed by 1615

Abstract

Antipsychotics share the common pharmacological feature of antagonizing the dopamine 2 receptor (D2R), which is abundant in the striatum and involved in both the therapeutic and side effects of this drug’s class. The pharmacological blockade of striatal D2R, by disinhibiting the D2R-containing medium-sized [...] Read more.

Antipsychotics share the common pharmacological feature of antagonizing the dopamine 2 receptor (D2R), which is abundant in the striatum and involved in both the therapeutic and side effects of this drug’s class. The pharmacological blockade of striatal D2R, by disinhibiting the D2R-containing medium-sized spiny neurons (MSNs), leads to a plethora of molecular, cellular and behavioral adaptations, which are central in the action of antipsychotics. Here, we focused on the cell type-specific (D2R-MSNs) regulation of some striatal immediate early genes (IEGs), such as cFos, Arc and Zif268. Taking advantage of transgenic mouse models, pharmacological approaches and immunofluorescence analyses, we found that haloperidol-induced IEGs in the striatum required the synergistic activation of A2a (adenosine) and NMDA (glutamate) receptors. At the intracellular signaling level, we found that the PKA/DARPP-32 and mTOR pathways synergistically cooperate to control the induction of IEGs by haloperidol. By confirming and further expanding previous observations, our results provide novel insights into the regulatory mechanisms underlying the molecular/cellular action of antipsychotics in the striatum. Full article

(This article belongs to the Special Issue Role of Dopamine in Health and Disease—Biological Aspect)

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16 pages, 1060 KiB

Open AccessArticle

Novel Dopamine Transporter Inhibitor, CE-123, Ameliorates Spatial Memory Deficits Induced by Maternal Separation in Adolescent Rats: Impact of Sex

by Pawel Grochecki, Irena Smaga, Paulina Surowka, Marta Marszalek-Grabska, Predrag Kalaba, Vladimir Dragacevic, Patrycja Kotlinska, Malgorzata Filip, Gert Lubec and Jolanta H. Kotlinska

Int. J. Mol. Sci. 2022, 23(18), 10718; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810718 - 14 Sep 2022

Cited by 6 | Viewed by 1728

Abstract

Maternal separation (MS) is a key contributor to neurodevelopmental disorders, including learning disabilities. To test the hypothesis that dopamine signaling is a major factor in this, an atypical new dopamine transporter (DAT) inhibitor, CE-123, was assessed for its potential to counteract the MS-induced [...] Read more.

Maternal separation (MS) is a key contributor to neurodevelopmental disorders, including learning disabilities. To test the hypothesis that dopamine signaling is a major factor in this, an atypical new dopamine transporter (DAT) inhibitor, CE-123, was assessed for its potential to counteract the MS-induced spatial learning and memory deficit in male and female rats. Hence, neonatal rats (postnatal day (PND)1 to 21) were exposed to MS (180 min/day). Next, the acquisition of spatial learning and memory (Barnes maze task) and the expression of dopamine D1 receptor, dopamine transporter (DAT), and the neuronal GTPase, RIT2, which binds DAT in the vehicle-treated rats were evaluated in the prefrontal cortex and hippocampus in the adolescent animals. The results show that MS impairs the acquisition of spatial learning and memory in rats, with a more severe effect in females. Moreover, the MS induced upregulation of DAT and dopamine D1 receptors expression in the prefrontal cortex and hippocampus in adolescent rats. Regarding RIT2, the expression was decreased in the hippocampus for both the males and females, however, in the prefrontal cortex, reduction was found only in the females, suggesting that there are region-specific differences in DAT endocytic trafficking. CE-123 ameliorated the behavioral deficits associated with MS. Furthermore, it decreased the MS-induced upregulation of D1 receptor expression level in the hippocampus. These effects were more noted in females. Overall, CE-123, an atypical DAT inhibitor, is able to restore cognitive impairment and dopamine signaling in adolescent rats exposed to MS—with more evident effect in females than males. Full article

(This article belongs to the Special Issue Role of Dopamine in Health and Disease—Biological Aspect)

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16 pages, 2796 KiB

Open AccessArticle

Sex-Specific Alterations in Dopamine Metabolism in the Brain after Methamphetamine Self-Administration

by Atul P. Daiwile, Patricia Sullivan, Subramaniam Jayanthi, David S. Goldstein and Jean Lud Cadet

Int. J. Mol. Sci. 2022, 23(8), 4353; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23084353 - 14 Apr 2022

Cited by 6 | Viewed by 2356

Abstract

Methamphetamine (METH) use disorder affects both sexes, with sex differences occurring in behavioral, structural, and biochemical consequences. The molecular mechanisms underlying these differences are unclear. Herein, we used a rat model to identify potential sex differences in the effects of METH on brain [...] Read more.

Methamphetamine (METH) use disorder affects both sexes, with sex differences occurring in behavioral, structural, and biochemical consequences. The molecular mechanisms underlying these differences are unclear. Herein, we used a rat model to identify potential sex differences in the effects of METH on brain dopaminergic systems. Rats were trained to self-administer METH for 20 days, and a cue-induced drug-seeking test was performed on withdrawal days 3 and 30. Dopamine and its metabolites were measured in the prefrontal cortex (PFC), nucleus accumbens (NAc), dorsal striatum (dSTR), and hippocampus (HIP). Irrespective of conditions, in comparison to females, male rats showed increased 3,4-dihydroxyphenylalanine (DOPA) in the PFC, dSTR, and HIP; increased cys-dopamine in NAc; and increased 3,4-dihydroxyphenylethanol (DOPET) and 3,4-dihydroxyphenylacetic acid (DOPAC) in dSTR. Males also showed METH-associated decreases in DA levels in the HIP but increases in the NAc. Female rats showed METH-associated decreases in DA, DOPAL, and DOPAC levels in the PFC but increases in DOPET and DOPAC levels in the HIP. Both sexes showed METH-associated decreases in NAc DA metabolites. Together, these data document sex differences in METH SA-induced changes in DA metabolism. These observations provide further support for using sex as an essential variable when discussing therapeutic approaches against METH use disorder in humans. Full article

(This article belongs to the Special Issue Role of Dopamine in Health and Disease—Biological Aspect)

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16 pages, 2234 KiB

Open AccessArticle

Deficiency in RCAT-1 Function Causes Dopamine Metabolism Related Behavioral Disorders in Caenorhabditis elegans

by Haelim Jeong, Jun Young Park, Ji-Hyun Lee, Ja-Hyun Baik, Chae-Yeon Kim, Jin-Young Cho, Monica Driscoll and Young-Ki Paik

Int. J. Mol. Sci. 2022, 23(4), 2393; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23042393 - 21 Feb 2022

Cited by 3 | Viewed by 2547

Abstract

When animals are faced with food depletion, food search-associated locomotion is crucial for their survival. Although food search-associated locomotion is known to be regulated by dopamine, it has yet to investigate the potential molecular mechanisms governing the regulation of genes involved in dopamine [...] Read more.

When animals are faced with food depletion, food search-associated locomotion is crucial for their survival. Although food search-associated locomotion is known to be regulated by dopamine, it has yet to investigate the potential molecular mechanisms governing the regulation of genes involved in dopamine metabolism (e.g., cat-1, cat-2) and related behavioral disorders. During the studies of the pheromone ascaroside, a signal of starvation stress in C. elegans, we identified R02D3.7, renamed rcat-1 (regulator of cat genes-1), which had previously been shown to bind to regulatory sequences of both cat-1 and cat-2 genes. It was found that RCAT-1 (R02D3.7) is expressed in dopaminergic neurons and functions as a novel negative transcriptional regulator for cat-1 and cat-2 genes. When a food source becomes depleted, the null mutant, rcat-1(ok1745), exhibited an increased frequency of high-angled turns and intensified area restricted search behavior compared to the wild-type animals. Moreover, rcat-1(ok1745) also showed defects in state-dependent olfactory adaptation and basal slowing response, suggesting that the mutants are deficient in either sensing food or locomotion toward food. However, rcat-1(ok1745) has normal cuticular structures and locomotion genes. The discovery of rcat-1 not only identifies a new subtype of dopamine-related behaviors but also provides a potential therapeutic target in Parkinson’s disease. Full article

(This article belongs to the Special Issue Role of Dopamine in Health and Disease—Biological Aspect)

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15 pages, 1006 KiB

Open AccessReview

Phosphorylation Signals Downstream of Dopamine Receptors in Emotional Behaviors: Association with Preference and Avoidance

by Xinjian Zhang, Daisuke Tsuboi, Yasuhiro Funahashi, Yukie Yamahashi, Kozo Kaibuchi and Taku Nagai

Int. J. Mol. Sci. 2022, 23(19), 11643; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911643 - 01 Oct 2022

Cited by 3 | Viewed by 2374

Abstract

Dopamine regulates emotional behaviors, including rewarding and aversive behaviors, through the mesolimbic dopaminergic pathway, which projects dopamine neurons from the ventral tegmental area to the nucleus accumbens (NAc). Protein phosphorylation is critical for intracellular signaling pathways and physiological functions, which are regulated by [...] Read more.

Dopamine regulates emotional behaviors, including rewarding and aversive behaviors, through the mesolimbic dopaminergic pathway, which projects dopamine neurons from the ventral tegmental area to the nucleus accumbens (NAc). Protein phosphorylation is critical for intracellular signaling pathways and physiological functions, which are regulated by neurotransmitters in the brain. Previous studies have demonstrated that dopamine stimulated the phosphorylation of intracellular substrates, such as receptors, ion channels, and transcription factors, to regulate neuronal excitability and synaptic plasticity through dopamine receptors. We also established a novel database called KANPHOS that provides information on phosphorylation signals downstream of monoamines identified by our kinase substrate screening methods, including dopamine, in addition to those reported in the literature. Recent advances in proteomics techniques have enabled us to clarify the mechanisms through which dopamine controls rewarding and aversive behaviors through signal pathways in the NAc. In this review, we discuss the intracellular phosphorylation signals regulated by dopamine in these two emotional behaviors. Full article

(This article belongs to the Special Issue Role of Dopamine in Health and Disease—Biological Aspect)

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