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Frontiers in Psychiatry 2024Abuse or misuse of tobacco, e-cigarettes, or antidepressants may have serious clinical consequences during adolescence, a sensitive period during brain development when...
INTRODUCTION
Abuse or misuse of tobacco, e-cigarettes, or antidepressants may have serious clinical consequences during adolescence, a sensitive period during brain development when the distinct neurobiology of adolescent serotonin (5-HT) and dopamine (DA) systems create unique behavioral vulnerabilities to drugs of abuse.
METHODS
Using a pharmacological approach, we modeled the behavioral and neurochemical effects of subchronic (4-day) nicotine (60µg/kg, i.v.) or fluoxetine (1mg/kg, i.v.) exposure in adolescent and adult male rats.
RESULTS
Nicotine and fluoxetine significantly enhance quinpirole-induced locomotor activity and initial cocaine self-administration in adolescents, but not adults. These effects were blocked by serotonin 5-HT receptor antagonists, WAY-100,635 (100 µg/kg, i.v.) or S-15535 (300 µg/kg, i.v.). Neurochemical and anatomical autoradiographic analysis of 8-OH-DPAT-stimulated [S]GTPγS reveal that prior exposure to nicotine and fluoxetine results in both overlapping and distinct effects on regional 5-HT1A receptor activity. Both fluoxetine and nicotine enhance adolescent 5-HT1A receptor activity in the primary motor cortex (M1), whereas fluoxetine alone targets prefrontal cortical neurocircuitry and nicotine alone targets the amygdala.
DISCUSSION
Given their different pharmacological profiles, comparison between WAY-100,635 and S-15535 indicates that postsynaptic 5-HT receptors mediate the behavioral effects of prior nicotine and fluoxetine exposure. In addition, within the adolescent M1, maladaptive changes in 5-HT signaling and 5-HT activity after nicotine or fluoxetine exposure may potentiate hyper-responsiveness to dopaminergic drugs and prime adolescent vulnerability for future substance abuse.
PubMed: 38919632
DOI: 10.3389/fpsyt.2024.1380123 -
BioRxiv : the Preprint Server For... Jun 2024Striatonigral neurons, known to promote locomotion, reside in both the patch and matrix compartments of the dorsal striatum. However, their compartment-specific...
Striatonigral neurons, known to promote locomotion, reside in both the patch and matrix compartments of the dorsal striatum. However, their compartment-specific contributions to locomotion remain largely unexplored. Using molecular identifier and , we showed in mouse models that patch and matrix striatonigral neurons exert opposite influences on locomotion. Matrix striatonigral neurons reduced their activity before the cessation of self-paced locomotion, while patch striatonigral neuronal activity increased, suggesting an inhibitory function. Indeed, optogenetic activation of patch striatonigral neurons suppressed ongoing locomotion with reduced striatal dopamine release, contrasting with the locomotion-promoting effect of matrix striatonigral neurons, which showed an initial increase in dopamine release. Furthermore, genetic deletion of the GABA-B receptor in Aldehyde dehydrogenase 1A1-positive (ALDH1A1 ) nigrostriatal dopaminergic neurons completely abolished the locomotion-suppressing effect of patch striatonigral neurons. Our findings unravel a compartment-specific mechanism governing locomotion in the dorsal striatum, where patch striatonigral neurons suppress locomotion by inhibiting ALDH1A1 nigrostriatal dopaminergic neurons.
PubMed: 38915717
DOI: 10.1101/2024.06.12.598675 -
BioRxiv : the Preprint Server For... Jun 2024The classic output pathways of the basal ganglia are known as the direct-D1 and indirect-D2, or "Go/No-Go", pathways. Balance of the activity in these canonical...
The classic output pathways of the basal ganglia are known as the direct-D1 and indirect-D2, or "Go/No-Go", pathways. Balance of the activity in these canonical direct-indirect pathways is considered a core requirement for normal movement control, and their imbalance is a major etiologic factor in movement disorders including Parkinson's disease. We present evidence for a conceptually equivalent parallel system of direct-D1 and indirect-D2 pathways that arise from striatal projection neurons (SPNs) of the striosome compartment rather than from the matrix. These striosomal direct (S-D1) and indirect (S-D2) pathways, as a pair, target dopamine-containing neurons of the substantia nigra (SNpc) instead of the motor output nuclei of the basal ganglia. The novel anatomically and functionally distinct indirect-D2 striosomal pathway targets dopaminergic SNpc cells indirectly via a core region of the external pallidum (GPe). We demonstrate that these S-D1 and S-D2 pathways oppositely modulate striatal dopamine release in freely behaving mice under open-field conditions and oppositely modulate locomotor and other movements. These S-D1 and S-D2 pathways further exhibit different, time-dependent responses during performance of a probabilistic decision-making maze task and respond differently to rewarding and aversive stimuli. These contrasts depend on mediolateral and anteroposterior striatal locations of the SPNs as are the classic direct and indirect pathways. The effects of S-D1 and S-D2 stimulation on striatal dopamine release and voluntary locomotion are nearly opposite. The parallelism of the direct-indirect circuit design motifs of the striosomal S-D and S-D2 circuits and canonical matrix M-D1 and M-D2, and their contrasting behavioral effects, call for a major reformulation of the classic direct-indirect pathway model of basal ganglia function. Given that some striosomes receive limbic and association cortical inputs, the S-D1 and S-D2 circuits likely influence motivation for action and behavioral learning, complementing and possibly reorienting the motoric activities of the canonical matrix pathways. At a fundamental level, these findings suggest a unifying framework for aligning two sets of circuits that share the organizational motif of opponent D1 and D2 regulation, but that have different outputs and can even have opposite polarities in their targets and effects, albeit conditioned by striatal topography. Our findings further delineate a potentially therapeutically important set of pathways influencing dopamine, including a D2 receptor-linked S-D2 pathway likely unknowingly targeted by administration of many therapeutic drugs including those for Parkinson's disease. The novel parallel pathway model that we propose here could help to account for the normally integrated modulatory influence of the basal ganglia on motivation for actions as well as the actions themselves.
PubMed: 38915684
DOI: 10.1101/2024.06.01.596922 -
BioRxiv : the Preprint Server For... Jun 2024The catecholamine neurotransmitter dopamine is classically known for regulation of central nervous system (CNS) functions such as reward, movement, and cognition....
The catecholamine neurotransmitter dopamine is classically known for regulation of central nervous system (CNS) functions such as reward, movement, and cognition. Increasing evidence also indicates that dopamine regulates critical functions in peripheral organs and is an important immunoregulatory factor. We have previously shown that dopamine increases NF-κB activity, inflammasome activation, and the production of inflammatory cytokines such as IL-1β in human macrophages. As myeloid lineage cells are central to the initiation and resolution of acute inflammatory responses, dopamine-mediated dysregulation of these functions could both impair the innate immune response and exacerbate chronic inflammation. However, the exact pathways by which dopamine drives myeloid inflammation are not well defined, and studies in both rodent and human systems indicate that dopamine can impact the production of inflammatory mediators through both D1-like dopamine receptors (DRD1, DRD5) and D2-like dopamine receptors (DRD2, DRD3, and DRD4). Therefore, we hypothesized that dopamine-mediated production of IL-1β in myeloid cells is regulated by the ratio of different dopamine receptors that are activated. Our data in primary human monocyte-derived macrophages (hMDM) indicate that DRD1 expression is necessary for dopamine-mediated increases in IL-1β, and that changes in the expression of DRD2 and other dopamine receptors can alter the magnitude of the dopamine-mediated increase in IL-1β. Mature hMDM have a high D1-like to D2-like receptor ratio, which is different relative to monocytes and peripheral blood mononuclear cells (PBMCs). We further confirm in human microglia cell lines that a high ratio of D1-like to D2-like receptors promotes dopamine-induced increases in IL-1β gene and protein expression using pharmacological inhibition or overexpression of dopamine receptors. RNA-sequencing of dopamine-treated microglia shows that genes encoding functions in IL-1β signaling pathways, microglia activation, and neurotransmission increased with dopamine treatment. Finally, using HIV as an example of a chronic inflammatory disease that is substantively worsened by comorbid substance use disorders (SUDs) that impact dopaminergic signaling, we show increased effects of dopamine on inflammasome activation and IL-1β in the presence of HIV in both human macrophages and microglia. These data suggest that use of addictive substances and dopamine-modulating therapeutics could dysregulate the innate inflammatory response and exacerbate chronic neuroimmunological conditions like HIV. Thus, a detailed understanding of dopamine-mediated changes in inflammation, in particular pathways regulating IL-1β, will be critical to effectively tailor medication regimens.
PubMed: 38915663
DOI: 10.1101/2024.06.09.598137 -
Biomolecules & Therapeutics Jun 2024Colorectal cancer (CRC) continues to demonstrate high incidence and mortality rates, emphasizing that implementing strategic measures for prevention and treatment is...
Colorectal cancer (CRC) continues to demonstrate high incidence and mortality rates, emphasizing that implementing strategic measures for prevention and treatment is crucial. Recently, the dopamine receptor D2 (DRD2), a G protein-coupled receptor, has been reported to play multiple roles in growth of tumor cells. This study investigated the anticancer potential of domperidone, a dopamine receptor D2 antagonist, in HCT116 human CRC cells. Domperidone demonstrated concentration- and time-dependent reductions in cell viability, thereby inducing apoptosis. The molecular mechanism revealed that domperidone modulated the mitochondrial pathway, decreasing mitochondrial Bcl-2 levels, elevating cytosolic cytochrome C expression, and triggering caspase- 3, -7, and -9 cleavage. Domperidone decreased in formation of β-arrestin2/MEK complex, which contributing to inhibition of ERK activation. Additionally, treatment with domperidone diminished JAK2 and STAT3 activation. Treatment of U0126, the MEK inhibitor, resulted in reduced phosphorylation of MEK, ERK, and STAT3 without alteration of JAK2 activation, indicating that domperidone targeted both MEK-ERK-STAT3 and JAK2-STAT3 signaling pathways, respectively. Immunoblot analysis revealed that domperidone also downregulated DRD2 expression. Domperidone-induced reactive oxygen species (ROS) generation and -acetylcysteine treatment mitigated ROS levels and restored cell viability. An xenograft study verified the significant antitumor effects of domperidone. These results emphasize the multifaceted anticancer effects of domperidone, highlighting its potential as a promising therapeutic agent for human CRC.
PubMed: 38914471
DOI: 10.4062/biomolther.2024.048 -
Frontiers in Neuroscience 2024Dopamine (DA) plays a pivotal role in reward processing, cognitive functions, and emotional regulation. The prefrontal cortex (PFC) is a critical brain region for these...
Dopamine (DA) plays a pivotal role in reward processing, cognitive functions, and emotional regulation. The prefrontal cortex (PFC) is a critical brain region for these processes. Parvalbumin-positive (PV+) neurons are one of the major classes of inhibitory GABAergic neurons in the cortex, they modulate the activity of neighboring neurons, influencing various brain functions. While DA receptor expression exhibits age-related changes, the age-related changes of these receptors in PV+ neurons, especially in the PFC, remain unclear. To address this, we investigated the expression of DA D1 (D1R) and D2 (D2R) receptors in PV+ neurons within the orbitofrontal (OFC) and prelimbic (PrL) cortices at different postnatal ages (P28, P42, P56, and P365). We found that the expression of D1R and D2R in PV+ neurons showed both age- and region-related changes. PV+ neurons in the OFC expressed a higher abundance of D1 than those in the PrL, and those neurons in the OFC also showed higher co-expression of D1R and D2R than those in the PrL. In the OFC and PrL, D1R in PV+ neurons increased from P28 and reached a plateau at P42, then receded to express at P365. Meanwhile, D2R did not show significant age-related changes between the two regions except at P56. These results showed dopamine receptors in the prefrontal cortex exhibit age- and region-specific changes, which may contribute to the difference of these brain regions in reward-related brain functions.
PubMed: 38903598
DOI: 10.3389/fnins.2024.1364067 -
Psychiatry Research Jun 2024The risk of fatal choking for people with schizophrenia and associations with antipsychotic medication are largely unknown. Therefore, we calculated the choking-related...
The risk of fatal choking for people with schizophrenia and associations with antipsychotic medication are largely unknown. Therefore, we calculated the choking-related standardized mortality ratio for schizophrenia relative to the general population (SMR). We also computed adjusted hazard ratios (aHR) of choking-related mortality for antipsychotics in a nationwide cohort of patients with schizophrenia (N = 59,916). SMR was 20.5 (95 % confidence interval (CI)=17.1-23.9). The aHR was 1.74 (95 %CI=1.19-2.55) for strong dopamine 2-antagonists. For other antipsychotics, CIs included 1. Importantly, aHRs were particularly high for high dose categories of strong dopamine D2 receptor (D2R) antagonists. In conclusion, a schizophrenia diagnosis is associated with a 20-fold risk of death due to choking. This risk is elevated during use of strong D2R antagonist antipsychotics, particularly when prescribed in high dosages.
PubMed: 38901365
DOI: 10.1016/j.psychres.2024.116012 -
MSystems Jun 2024Platinum-based chemotherapy failure represents a significant challenge in the management of ovarian cancer (OC) and contributes to disease recurrence and poor prognosis....
Platinum-based chemotherapy failure represents a significant challenge in the management of ovarian cancer (OC) and contributes to disease recurrence and poor prognosis. Recent studies have shed light on the involvement of the gut microbiota in modulating anticancer treatments. However, the precise underlying mechanisms, by which gut microbiota regulates the response to platinum-based therapy, remain unclear. Here, we investigated the role of gut microbiota on the anticancer response of cisplatin and its underlying mechanisms. Our results demonstrate a substantial improvement in the anticancer efficacy of cisplatin following antibiotic-induced perturbation of the gut microbiota in OC-bearing mice. 16S rRNA sequencing showed a pronounced alteration in the composition of the gut microbiome in the cecum contents following exposure to cisplatin. Through metabolomic analysis, we identified distinct metabolic profiles in the antibiotic-treated group, with a notable enrichment of the gut-derived metabolite 3-methylxanthine in antibiotic-treated mice. Next, we employed a strategy combining transcriptome analysis and chemical-protein interaction network databases. We identified metabolites that shared structural similarity with 3-methylxanthine, which interacted with genes enriched in cancer-related pathways. It is identified that 3-methylxanthinesignificantly enhances the effectiveness of cisplatin by promoting apoptosis both and . Importantly, through integrative multiomics analyses, we elucidated the mechanistic basis of this enhanced apoptosis, revealing a dopamine receptor D1-dependent pathway mediated by 3-methylxanthine. This study elucidated the mechanism by which gut-derived metabolite 3-methylxanthine mediated cisplatin-induced apoptosis. Our findings highlight the potential translational significance of 3-methylxanthine as a promising adjuvant in conjunction with cisplatin, aiming to improve treatment outcomes for OC patients.IMPORTANCEThe precise correlation between the gut microbiota and the anticancer effect of cisplatin in OC remains inadequately understood. Our investigation has revealed that manipulation of the gut microbiota via the administration of antibiotics amplifies the efficacy of cisplatin through the facilitation of apoptosis in OC-bearing mice. Metabolomic analysis has demonstrated that the cecum content from antibiotic-treated mice exhibits an increase in the levels of 3-methylxanthine, which has been shown to potentially enhance the therapeutic effectiveness of cisplatin by an integrated multiomic analysis. This enhancement appears to be attributable to the promotion of cisplatin-induced apoptosis, with 3-methylxanthine potentially exerting its influence via the dopamine receptor D1-dependent pathway. These findings significantly contribute to our comprehension of the impact of the gut microbiota on the anticancer therapy in OC. Notably, the involvement of 3-methylxanthine suggests its prospective utility as a supplementary component for augmenting treatment outcomes in patients afflicted with ovarian cancer.
PubMed: 38899930
DOI: 10.1128/msystems.01301-23 -
Addiction Biology Jun 2024The association of impaired dopaminergic neurotransmission with the development and maintenance of alcohol use disorder is well known. More specifically, reduced...
Correlation of striatal dopamine D2/3 receptor availability with GABA level in the anterior cingulate cortex in healthy controls but not in alcohol-dependent subjects and individuals at high risk: A multimodal magnetic resonance spectroscopy and positron emission tomography study.
BACKGROUND
The association of impaired dopaminergic neurotransmission with the development and maintenance of alcohol use disorder is well known. More specifically, reduced dopamine D2/3 receptors in the striatum of subjects with alcohol dependence (AD) compared to healthy controls have been found in previous studies. Furthermore, alterations of gamma-aminobutyric acid (GABA) and glutamate (Glu) levels in the anterior cingulate cortex (ACC) of AD subjects have been documented in several studies. However, the interaction between cortical Glu levels and striatal dopamine D2/3 receptors has not been investigated in AD thus far.
METHODS
This study investigated dopamine D2/3 receptor availability via 18F-fallypride positron emission tomography (PET) and GABA as well as Glu levels via magnetic resonance spectroscopy (MRS) in 19 detoxified AD subjects, 18 healthy controls (low risk, LR) controls and 19 individuals at high risk (HR) for developing AD, carefully matched for sex, age and smoking status.
RESULTS
We found a significant negative correlation between GABA levels in the ACC and dopamine D2/3 receptor availability in the associative striatum of LR but not in AD or HR individuals. Contrary to our expectations, we did not observe a correlation between Glu concentrations in the ACC and striatal D2/3 receptor availability.
CONCLUSIONS
The results may reflect potential regulatory cortical mechanisms on mesolimbic dopamine receptors and their disruption in AD and individuals at high risk, mirroring complex neurotransmitter interactions associated with the pathogenesis of addiction. This is the first study combining 18F-fallypride PET and MRS in AD subjects and individuals at high risk.
Topics: Humans; Positron-Emission Tomography; Gyrus Cinguli; Male; Alcoholism; Receptors, Dopamine D2; Adult; Female; Receptors, Dopamine D3; gamma-Aminobutyric Acid; Magnetic Resonance Spectroscopy; Middle Aged; Corpus Striatum; Case-Control Studies; Glutamic Acid; Benzamides
PubMed: 38899357
DOI: 10.1111/adb.13424 -
Addiction Biology Jun 2024Alcohol consumption occurring in a social or solitary setting often yields different behavioural responses in human subjects. For example, social drinking is associated...
Alcohol consumption occurring in a social or solitary setting often yields different behavioural responses in human subjects. For example, social drinking is associated with positive effects while solitary drinking is linked to negative effects. However, the neurobiological mechanism by which the social environment during alcohol intake impacts on behavioural responses remains poorly understood. We investigated whether distinct social environments affect behavioural responses to ethanol and the role of the dopamine system in this phenomenon in the fruit fly Drosophila melanogaster. The wild-type Canton-S (CS) flies showed higher locomotor response when exposed to ethanol in a group setting than a solitary setting, and there was no difference in females and males. Dopamine signalling is crucial for the locomotor stimulating effect of ethanol. When subjected to ethanol exposure alone, the dopamine transport mutant flies fumin (fmn) with hyper dopamine displayed the locomotor response similar to CS. When subjected to ethanol in a group setting, however, the fmn's response to the locomotor stimulating effect was substantially augmented compared with CS, indicating synergistic interaction of dopamine signalling and social setting. To identify the dopamine signalling pathway important for the social effect, we examined the flies defective in individual dopamine receptors and found that the D1 receptor dDA1/Dop1R1 is the major receptor mediating the social effect. Taken together, this study underscores the influence of social context on the neural and behavioural responses to ethanol.
Topics: Animals; Ethanol; Dopamine; Drosophila melanogaster; Male; Female; Drosophila Proteins; Receptors, Dopamine D1; Social Environment; Signal Transduction; Locomotion; Receptors, Dopamine; Behavior, Animal; Central Nervous System Depressants; Social Behavior; Dopamine Plasma Membrane Transport Proteins; Motor Activity
PubMed: 38898729
DOI: 10.1111/adb.13420