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1.
J Integr Neurosci ; 22(1): 18, 2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36722243

RESUMO

BACKGROUND AND PURPOSE: REM sleep behavior disorder (RBD) in Parkinson's disease (PD) is associated with characteristic clinical subtypes and prognosis. In addition, nigrostriatal pathway, the most vulnerable anatomical area in PD, formed neuronal network interplaying with cortical and subcortical structures, and which may cause PD clinical phenotype. We evaluated the regional selectivity of presynaptic striatal dopaminergic denervation associated with RBD in PD. METHODS: We compared two groups (n = 16) of PD patients with and without RBD in terms of specific binding ratios (SBR) in subregions of the striatum, which were measured using positron emission tomography with 18F-FP-CIT. SBRs of the anterior and posterior caudate, ventral striatum, and posterior and ventral putamen regions were measured in more or less affected side, and right or left side, or bilateral sum of the striatum. RESULTS: Age, disease duration, and severity of parkinsonism were not significantly different between groups. Although group differences in all areas were not significant with multiple comparison corrections, SBR of the ventral striatum and anterior caudate in sum of both sides was significantly less in the RBD than in the non-RBD group without correction (p < 0.05). In the right anterior caudate and left ventral striatum, SBR was also lower in the RBD than in the non-RBD group without correction (p < 0.05). Attention function was impaired in the RBD group compared with the non-RBD group (p < 0.05). However, these statistical significances were not definite after correction of multiple comparisons (p > 0.05). CONCLUSIONS: There is a possibility that RBD in early PD may be associated with presynaptic dopaminergic denervation in the ventral striatum and anterior caudate, which may explain decreased attention in our RBD group. RBD in PD may imply a distinct pathological progression. However, further study using large numbers of participants or longitudinal observation is necessary for the statistical conclusion because of small sample size.


Assuntos
Doença de Parkinson , Transtorno do Comportamento do Sono REM , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , Transtorno do Comportamento do Sono REM/diagnóstico por imagem , Transtorno do Comportamento do Sono REM/etiologia , Corpo Estriado/diagnóstico por imagem , Dopamina
2.
Neurosurg Focus ; 54(2): E3, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36724520

RESUMO

OBJECTIVE: To the authors' knowledge, no data have been reported on dopamine fluctuations on subsecond timescales in humans with alcohol use disorder (AUD). In this study, dopamine release was monitored in 2 patients with and 2 without a history of AUD during a "sure bet or gamble" (SBORG) decision-making task to begin to characterize how subsecond dopamine responses to counterfactual information, related to psychological notions of regret and relief, in AUD may be altered. METHODS: Measurements of extracellular dopamine levels were made once every 100 msec using human voltammetric methods. Measurements were made in the caudate during deep brain stimulation electrode implantation surgeries (for treatment of movement disorders) in patients who did (AUD, n = 2) or did not (non-AUD, n = 2) have a history of AUD. Participants performed an SBORG decision-making task in which they made choices between sure bets and 50%-chance monetary gamble outcomes. RESULTS: Fast changes were found in dopamine levels that appear to be modulated by "what could have been" and by patients' AUD status. Positive counterfactual prediction errors (related to relief) differentiated patients with versus without a history of AUD. CONCLUSIONS: Dopaminergic encoding of counterfactual information appears to differ between patients with and without AUD. The current study has a major limitation of a limited sample size, but these data provide a rare insight into dopaminergic physiology during real-time decision-making in humans with an addiction disorder. The authors hope future work will expand the sample size and determine the generalizability of the current results.


Assuntos
Alcoolismo , Humanos , Alcoolismo/terapia , Dopamina , Emoções
3.
Sci Adv ; 9(2): eadd8417, 2023 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-36630507

RESUMO

Amphetamine (AMPH) is a psychostimulant that is commonly abused. The stimulant properties of AMPH are associated with its ability to increase dopamine (DA) neurotransmission. This increase is promoted by nonvesicular DA release mediated by reversal of DA transporter (DAT) function. Syntaxin 1 (Stx1) is a SNARE protein that is phosphorylated at Ser14 by casein kinase II. We show that Stx1 phosphorylation is critical for AMPH-induced nonvesicular DA release and, in Drosophila melanogaster, regulates the expression of AMPH-induced preference and sexual motivation. Our molecular dynamics simulations of the DAT/Stx1 complex demonstrate that phosphorylation of these proteins is pivotal for DAT to dwell in a DA releasing state. This state is characterized by the breakdown of two key salt bridges within the DAT intracellular gate, causing the opening and hydration of the DAT intracellular vestibule, allowing DA to bind from the cytosol, a mechanism that we hypothesize underlies nonvesicular DA release.


Assuntos
Dopamina , Drosophila melanogaster , Animais , Dopamina/metabolismo , Sintaxina 1/metabolismo , Fosforilação , Drosophila melanogaster/metabolismo , Anfetamina/farmacologia
5.
Biomed Pharmacother ; 158: 114179, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36592493

RESUMO

The abnormal fear memory will lead to the onset of stress disorders, such as post-traumatic stress disorder (PTSD) and so on. Therefore, the intervention in the formation of abnormal fear memory will provide a new strategy for the prevention and treatment of PTSD. In our previous studies, we found that blockade of dopamine D3 receptor (DRD3) with highly selective antagonist YQA14 or knockout of DRD3 was able to attenuate the expression or retrieval of fear memory in PTSD animal models. However, the neurobiological mechanism of regulation of DRD3 in fear is unclear. In the present research, we clarified that DRD3 was expressed in the dopaminergic (DAergic) neurons in the ventral tegmental area (VTA). Then, we identified that microinjection of YQA14 (1 µg/0.2 µl/side) in VTA before the aversive stimuli in the training session or during days subsequent to the shock significantly meliorated the freezing behaviors in the inescapable electric foot-shock model. At last, using fiber photometry system, we found that microinjection of YQA14 in VTA promoted the dopamine neurotransmitter release in the basolateral amygdala (BLA), and pre-training YQA14 infusion in VTA lowered the increase of dopamine (DA) in BLA induced by shock during the training session or by context during the retrieval session. All above the results demonstrated that YQA14 attenuated the fear learning through the blockade of DRD3 in VTA decreasing the excitability of the projection to BLA. This study may provide new mechanisms and potential intervention targets for stress disorders with abnormal fear memory.


Assuntos
Receptores de Dopamina D3 , Área Tegmentar Ventral , Animais , Área Tegmentar Ventral/metabolismo , Receptores de Dopamina D3/metabolismo , Dopamina/metabolismo , Tonsila do Cerebelo , Medo
6.
eNeuro ; 10(1)2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36599671

RESUMO

Midbrain dopaminergic (DAergic) neurons of the ventral tegmental area (VTA) are engaged by rewarding stimuli and encode reward prediction error to update goal-directed learning. However, recent data indicate that VTA DAergic neurons are functionally heterogeneous with emerging roles in aversive signaling, salience, and novelty, based in part on anatomic location and projection, highlighting a need to functionally characterize the repertoire of VTA DAergic efferents in motivated behavior. Previous work identifying a mesointerpeduncular circuit consisting of VTA DAergic neurons projecting to the interpeduncular nucleus (IPN), a midbrain area implicated in aversion, anxiety-like behavior, and familiarity, has recently come into question. To verify the existence of this circuit, we combined presynaptic targeted and retrograde viral tracing in the dopamine transporter-Cre mouse line. Consistent with previous reports, synaptic tracing revealed that axon terminals from the VTA innervate the caudal IPN; whereas, retrograde tracing revealed DAergic VTA neurons, predominantly in the paranigral region, project to the nucleus accumbens shell, as well as the IPN. To test whether functional DAergic neurotransmission exists in the IPN, we expressed the genetically encoded DA sensor, dLight 1.2, in the IPN of C57BL/6J mice and measured IPN DA signals in vivo during social and anxiety-like behavior using fiber photometry. We observed an increase in IPN DA signal during social investigation of a novel but not familiar conspecific and during exploration of the anxiogenic open arms of the elevated plus maze. Together, these data confirm VTA DAergic neuron projections to the IPN and implicate this circuit in encoding motivated exploration.


Assuntos
Núcleo Interpeduncular , Área Tegmentar Ventral , Camundongos , Animais , Área Tegmentar Ventral/fisiologia , Dopamina , Camundongos Endogâmicos C57BL , Núcleo Accumbens , Neurônios Dopaminérgicos/fisiologia
7.
Toxicology ; 485: 153424, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36610655

RESUMO

Hydrogen sulfide (H2S) is a toxin affecting the cardiovascular, respiratory, and central nervous systems. Acute H2S exposure is associated with a high rate of mortality and morbidity. The precise pathophysiology of H2S-induced death is a controversial topic; however, inhibition of the respiratory center in the brainstem is commonly cited as a cause of death. There is a knowledge gap on toxicity and toxic mechanisms of acute H2S poisoning on the brainstem, a brain region responsible for regulating many reflective and vital functions. Serotonin (5-HT), dopamine (DA), and γ-aminobutyric acid (GABA) play a role in maintaining a normal stable respiratory rhythmicity. We hypothesized that the inhibitory respiratory effects of H2S poisoning are mediated by 5-HT in the respiratory center of the brainstem. Male C57BL/6 mice were exposed once to an LCt50 concentration of H2S (1000 ppm). Batches of surviving mice were euthanized at 5 min, 2 h, 12 h, 24 h, 72 h, and on day 7 post-exposure. Pulmonary function, vigilance state, and mortality were monitored during exposure. The brainstem was analyzed for DA, 3,4-dehydroxyphenyl acetic acid (DOPAC), 5-HT, 5-hydroxyindoleatic acid (5-HIAA), norepinephrine (NE), GABA, glutamate, and glycine using HPLC. Enzymatic activities of monoamine oxidases (MAO) were also measured in the brainstem using commercial kits. Neurodegeneration was assessed using immunohistochemistry and magnetic resonance imaging. Results showed that DA and DOPAC were significantly increased at 5 min post H2S exposure. However, by 2 h DA returned to normal. Activities of MAO were significantly increased at 5 min and 2 h post-exposure. In contrast, NE was significantly decreased at 5 min and 2 h post-exposure. Glutamate was overly sensitive to H2S-induced toxicity manifesting a time-dependent concentration reduction throughout the 7 day duration of the study. Remarkably, there were no changes in 5-HT, 5-HIAA, glycine, or GABA concentrations. Cytochrome c oxidase activity was inhibited but recovered by 24 h. Neurodegeneration was observed starting at 72 h post H2S exposure in select brainstem regions. We conclude that acute H2S exposure causes differential effects on brainstem neurotransmitters. H2S also induces neurodegeneration and biochemical changes in the brainstem. Additional work is needed to fully understand the implications of both the short- and long-term effects of acute H2S poisoning on vital functions regulated by the brainstem.


Assuntos
Sulfeto de Hidrogênio , Camundongos , Masculino , Animais , Sulfeto de Hidrogênio/toxicidade , Serotonina , Ácido Hidroxi-Indolacético , Ácido 3,4-Di-Hidroxifenilacético , Camundongos Endogâmicos C57BL , Tronco Encefálico , Dopamina , Monoaminoxidase , Ácido gama-Aminobutírico
8.
Clin Sci (Lond) ; 137(2): 149-161, 2023 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-36598165

RESUMO

The placenta represents a non-neuronal organ capable of transporting and metabolizing monoamines. Since these bioactive molecules participate in numerous processes essential for placental and fetal physiology, any imbalance in their levels during pregnancy may affect brain development, projecting a higher risk of behavioral disorders in childhood or adulthood. Notably, the monoamine system in the placenta is a target of various psychoactive drugs and can be disrupted in several pregnancy pathologies. As research in pregnant women poses significant ethical restrictions, animal models are widely employed to study monoamine homeostasis as a mechanism involved in fetal programming. However, detailed knowledge of monoamine transport in the rat placenta is still lacking. Moreover, relatability to the human placental monoamine system is not examined. The present study provides insights into the transplacental monoamine dynamics between maternal and fetal circulation. We show that norepinephrine maternal-to-fetal transport is <4% due to high metabolism within the trophoblast. In contrast, dopamine maternal-to-fetal transport exceeds 25%, likely through passive transport across the membrane. In addition, we show high clearance of norepinephrine and dopamine from the fetal circulation mediated by the organic cation transporter 3 (OCT3). Altogether, we present transcriptional and functional evidence that the in situ rat placenta perfusion represents a suitable model for (patho)physiological investigation of dopamine and norepinephrine homeostasis in the fetoplacental unit. With the rapid advancements in drug discovery and environmental toxicity, the use of rat placenta as a preclinical model could facilitate screening of possible xenobiotic effects on monoamine homeostasis in the placenta.


Assuntos
Dopamina , Placenta , Animais , Feminino , Gravidez , Ratos , Transporte Biológico , Dopamina/metabolismo , Dopamina/farmacologia , Troca Materno-Fetal , Norepinefrina/metabolismo , Placenta/metabolismo , Trofoblastos/metabolismo
9.
Sci Rep ; 13(1): 897, 2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36650256

RESUMO

The amygdala is modulated by dopaminergic and cholinergic neurotransmission, and this modulation is altered in mood disorders. Therefore, this study was designed to evaluate the presence/absence of quantitative alterations in the expression of main dopaminergic and cholinergic markers in the amygdala of mice with oestrogen receptor ß (ERß) knock-out which exhibit increased anxiety, using immunohistochemistry and quantitative methods. Such alterations could either contribute to increased anxiety or be a compensatory mechanism for reducing anxiety. The results show that among dopaminergic markers, the expression of tyrosine hydroxylase (TH), dopamine transporter (DAT) and dopamine D2-like receptor (DA2) is significantly elevated in the amygdala of mice with ERß deprivation when compared to matched controls, whereas the content of dopamine D1-like receptor (DA1) is not altered by ERß knock-out. In the case of cholinergic markers, muscarinic acetylcholine type 1 receptor (AChRM1) and alpha-7 nicotinic acetylcholine receptor (AChRα7) display overexpression while the content of acetylcholinesterase (AChE) and vesicular acetylcholine transporter (VAChT) remains unchanged. In conclusion, in the amygdala of ERß knock-out female the dopaminergic and cholinergic signalling is altered, however, to determine the exact role of ERß in the anxiety-related behaviour further studies are required.


Assuntos
Dopamina , Receptor beta de Estrogênio , Camundongos , Feminino , Animais , Dopamina/metabolismo , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Acetilcolinesterase/metabolismo , Tonsila do Cerebelo/metabolismo , Receptores Muscarínicos/genética , Receptores Muscarínicos/metabolismo , Colinérgicos/metabolismo
10.
Int J Mol Sci ; 24(2)2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36675321

RESUMO

Eugenol, cinnamaldehyde and D-limonene, the main components of natural essential oils, are endowed with antioxidant and anti-inflammatory properties which allow them to induce beneficial effects on intestinal, cardiac and neuronal levels. In order to characterize their pharmacokinetic profiles and aptitude to permeate in the central nervous system after intravenous and oral administration to rats, new analytical procedures, easily achievable with HPLC-UV techniques, were developed. The terminal half-lives of these compounds range from 12.4 ± 0.9 (D-limonene) and 23.1 ± 1.6 min (cinnamaldehyde); their oral bioavailability appears relatively poor, ranging from 4.25 ± 0.11% (eugenol) to 7.33 ± 0.37% (cinnamaldehyde). Eugenol evidences a marked aptitude to permeate in the cerebrospinal fluid (CSF) of rats following both intravenous and oral administrations, whereas cinnamaldehyde appears able to reach the CSF only after intravenous administration; limonene is totally unable to permeate in the CSF. Eugenol was therefore recruited for in vitro studies of viability and time-/dose-dependent dopamine release in neuronal differentiated PC12 cells (a recognized cellular model mimicking dopaminergic neurons), evidencing its ability to increase cell viability and to induce dopamine release according to a U-shaped time-course curve. Moreover, concentration-response data suggest that eugenol may induce beneficial effects against Parkinson's disease after oral administration.


Assuntos
Dopamina , Eugenol , Ratos , Animais , Eugenol/farmacologia , Limoneno , Células PC12 , Acroleína/farmacologia , Encéfalo
11.
J Agric Food Chem ; 71(3): 1748-1757, 2023 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-36647270

RESUMO

Spirodela polyrhiza (Araceae family) is a duckweed species that serves as a potential resource for feed, food, bioremediation, and pharmaceutical applications. In this study, we assessed the effects of different concentrations of melatonin (0, 0.1, 1, and 10 µM) on the growth of S. polyrhiza during in vitro culture and the metabolic profiles and productivities of useful metabolites using gas chromatography-mass spectrometry coupled with multivariable statistical analysis. We found that exogenous melatonin significantly improved the total dry weight and altered the metabolic profiles of S. polyrhiza cultures. Melatonin significantly enhanced the cellular production of useful metabolites, such as γ-aminobutyric acid, dopamine, threonine, valine, and phytosterols. The volumetric productivities (mg/L) of γ-aminobutyric acid, dopamine, campesterol, ß-sitosterol, and stigmasterol were the highest in the presence of 10 µM melatonin on day 12. Moreover, the productivities of ascorbic acid and serotonin were the highest in the presence of 1 µM melatonin on day 12. Therefore, melatonin could be used to enhance the production of biomass and useful metabolites during large-scale S. polyrhiza cultivation in cosmetic, food/feed, and pharmaceutical industries.


Assuntos
Araceae , Melatonina , Melatonina/farmacologia , Melatonina/metabolismo , Dopamina/metabolismo , Araceae/metabolismo , Biodegradação Ambiental , Ácido gama-Aminobutírico/metabolismo
12.
Sci Rep ; 13(1): 1025, 2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36658269

RESUMO

Substantia nigra pars compacta (SNc) dopamine neurons are required for voluntary movement and reward learning, and advanced age is associated with motor and cognitive decline. In the midbrain, D2-type dopamine receptors located at dendrodendritic synapses between dopamine neurons control cell firing through G protein-activated potassium (GIRK) channels. We previously showed that aging disrupts dopamine neuron pacemaker firing in mice, but only in males. Here we show that the amplitude of D2-receptor inhibitory postsynaptic currents (D2-IPSCs) are moderately reduced in aged male mice. Local application of dopamine revealed a reduction in the amplitude of the D2-receptor currents in old males compared to young, pointing to a postsynaptic mechanism. Further experiments indicated that reduced D2 receptor signaling was not due to a general reduction in GIRK channel currents or degeneration of the dendritic arbor. Kinetic analysis showed no differences in D2-IPSC shape in old versus young mice or between sexes. Potentiation of D2-IPSCs by corticotropin releasing factor (CRF) was also not affected by age, indicating preservation of one mechanism of plasticity. These findings have implications for understanding dopamine transmission in aging, and reduced D2 receptor inhibition could contribute to increased susceptibility of males to SNc dopamine neuron degeneration in Parkinson's disease.


Assuntos
Dopamina , Neurônios Dopaminérgicos , Camundongos , Masculino , Animais , Neurônios Dopaminérgicos/metabolismo , Cinética , Substância Negra/metabolismo , Parte Compacta da Substância Negra/metabolismo , Receptores de Dopamina D2/metabolismo
13.
Pharmaceut Med ; 37(1): 37-52, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36611111

RESUMO

Problematic gambling has been suggested to be a possible consequence of dopaminergic medications used mainly in neurological conditions, i.e. pramipexole and ropinirole, and possibly by one antipsychotic compound, aripiprazole. Patients with Parkinson's disease, restless legs syndrome and other conditions potentially treated with dopamine agonists, as well as patients treated for psychotic disorders, are vulnerable patient groups with theoretically increased risk of developing gambling disorder (GD), for example due to higher rates of mental ill-health in these groups. The aim of the present paper is to review the epidemiological, clinical, and neurobiological evidence of the association between dopaminergic medications and GD, and to describe risk groups and treatment options. The neurobiology of GD involves the reward and reinforcement system, based mainly on mesocorticolimbic dopamine projections, with the nucleus accumbens being a crucial area for developing addictions to substances and behaviors. The addictive properties of gambling can perhaps be explained by the reward uncertainty that activates dopamine signaling in a pathological manner. Since reward-related learning is mediated by dopamine, it can be altered by dopaminergic medications, possibly leading to increased gambling behavior and a decreased impulse control. A causal relationship between the medications and GD seems likely, but the molecular mechanisms behind this association have not been fully described yet. More research is needed in order to fully outline the clinical picture of GD developing in patient groups with dopaminergic medications, and data are needed on the differentiation of risk in different compounds. In addition, very few interventional studies are available on the management of GD induced by dopaminergic medications. While GD overall can be treated, there is need for treatment studies testing the effectiveness of tapering of the medication or other gambling-specific treatment modalities in these patient groups.


Assuntos
Jogo de Azar , Doença de Parkinson , Síndrome das Pernas Inquietas , Humanos , Jogo de Azar/induzido quimicamente , Jogo de Azar/epidemiologia , Jogo de Azar/terapia , Dopamina/efeitos adversos , Agonistas de Dopamina/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Síndrome das Pernas Inquietas/induzido quimicamente , Síndrome das Pernas Inquietas/tratamento farmacológico
14.
BMC Neurol ; 23(1): 38, 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36694119

RESUMO

BACKGROUND: Parkinsonism after ventriculoperitoneal shunt in patients with hydrocephalus is a rare and profound complication that is often misdiagnosed, causing treatment to be delayed. To date, the characteristics of this disease have not been well described and summarized. Here, we report a rare case of parkinsonism after ventriculoperitoneal shunt; symptoms were aggravated by antipsychotic drugs but showed a good response to Madopar. Such cases have rarely been reported previously. CASE PRESENTATION: A 44-year-old man presented with parkinsonism, bilateral pyramidal tract signs, and oculomotor impairment four years after a successful ventriculoperitoneal shunt for idiopathic aqueduct stenosis resulting in obstructive hydrocephalus. Brain magnetic resonance imaging and computed tomography showed fluctuations in the lateral ventricle and the third ventricle without any intervention. The patient's condition was aggravated by antipsychotic drugs but showed a good response to Madopar. CONCLUSION: This observation suggests that parkinsonism in this patient was caused by reversible dysfunction of the presynaptic nigrostriatal dopaminergic pathway due to fluctuations in the lateral ventricle, representing the first hit to the dopaminergic signalling pathway, and antipsychotic drugs had an antagonistic effect on dopamine D2 receptors, representing the second hit. In addition, we summarize the pathophysiological mechanisms, clinical manifestations, treatments, and prognoses of this complication in 38 patients who met the inclusion criteria in 24 previous studies to increase neurologists' understanding of the disease.


Assuntos
Antipsicóticos , Hidrocefalia , Transtornos Parkinsonianos , Masculino , Humanos , Adulto , Derivação Ventriculoperitoneal/efeitos adversos , Transtornos Parkinsonianos/etiologia , Transtornos Parkinsonianos/complicações , Hidrocefalia/cirurgia , Hidrocefalia/etiologia , Dopamina
15.
Nature ; 614(7946): 108-117, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36653449

RESUMO

Spontaneous animal behaviour is built from action modules that are concatenated by the brain into sequences1,2. However, the neural mechanisms that guide the composition of naturalistic, self-motivated behaviour remain unknown. Here we show that dopamine systematically fluctuates in the dorsolateral striatum (DLS) as mice spontaneously express sub-second behavioural modules, despite the absence of task structure, sensory cues or exogenous reward. Photometric recordings and calibrated closed-loop optogenetic manipulations during open field behaviour demonstrate that DLS dopamine fluctuations increase sequence variation over seconds, reinforce the use of associated behavioural modules over minutes, and modulate the vigour with which modules are expressed, without directly influencing movement initiation or moment-to-moment kinematics. Although the reinforcing effects of optogenetic DLS dopamine manipulations vary across behavioural modules and individual mice, these differences are well predicted by observed variation in the relationships between endogenous dopamine and module use. Consistent with the possibility that DLS dopamine fluctuations act as a teaching signal, mice build sequences during exploration as if to maximize dopamine. Together, these findings suggest a model in which the same circuits and computations that govern action choices in structured tasks have a key role in sculpting the content of unconstrained, high-dimensional, spontaneous behaviour.


Assuntos
Dopamina , Reforço Psicológico , Camundongos , Animais , Recompensa , Corpo Estriado , Encéfalo
16.
In Vivo ; 37(1): 304-309, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36593045

RESUMO

BACKGROUND/AIM: The dorsal striatum is a brain area integrating information for movement output. The local field potentials (LFPs) reflect the neuronal activity that can be used for monitoring brain activities and controlling movement. MATERIALS AND METHODS: Rhythmic low gamma power activity (30.1-45 Hz) in the dorsal striatum was monitored according to voluntary motor movement in rotarod and bar tests in 0.5 mg/kg haloperidol-induced mice. RESULTS: Haloperidol can effectively induce movement impairment indicated by decreased low gamma LFP with the lessened rotarod test's latency fall, and the enhanced bar test's descending latency. L-DOPA was used for the induction of a dopamine-dependent signal. The results showed that 25 mg/kg of L-DOPA could reverse the effect of haloperidol by enhancing low gamma oscillation concomitantly with the improvement in behavioral movement as fast as 60 min after administration, suggesting that dopamine signaling increases low gamma frequency of LFP in correlation with the improved mice movement. This work supports quantitative LFP assessment as a monitoring tool to track drug action on the nervous system. CONCLUSION: In animal models of motor impairment, oral dopaminergic treatment can be effective in restoring motor dysfunction by stimulating low gamma power activity in the dorsal striatum.


Assuntos
Dopamina , Transtornos Motores , Camundongos , Animais , Levodopa , Haloperidol/efeitos adversos , Transtornos Motores/induzido quimicamente , Transtornos Motores/tratamento farmacológico , Encéfalo
17.
Int Clin Psychopharmacol ; 38(2): 117-120, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36719339

RESUMO

Zolpidem is a non-benzodiazepine agent used for short-term treatment of insomnia. Several cases of dependence and withdrawal from zolpidem are reported in the literature. Furthermore, involuntary movements after prolonged zolpidem misuse have been described. In this case report, a 69-year-old Italian woman with no history of diagnosed psychiatric or neurologic diseases developed uncontrolled movements and a depressive-anxious syndrome after twelve-year zolpidem misuse. The underlying mechanisms of involuntary movements occurring after long-term zolpidem intake are unknown; yet, we suggest that zolpidem might induce an increase in dopamine release through inhibition of gamma-aminobutyric acid neurons tonically suppressing dopamine cells. Future studies on the occurrence of persistent disorders after long-term benzodiazepine or Z-drug abuse are needed and clinicians should pay attention to the risk of tardive syndromes related to zolpidem misuse, especially in the case of long-term intake of over-therapeutic dosages.


Assuntos
Discinesias , Piridinas , Feminino , Humanos , Idoso , Zolpidem/efeitos adversos , Piridinas/efeitos adversos , Dopamina , Hipnóticos e Sedativos/efeitos adversos , Benzodiazepinas , Discinesias/tratamento farmacológico
18.
Int Clin Psychopharmacol ; 38(2): 102-109, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36719338

RESUMO

Both the underutilization of clozapine and treatment resistance of patients to clozapine are serious problems worldwide. Identifying clinical markers predicting response to clozapine would help clinicians more effectively utilize clozapine treatment. The present study retrospectively assessed dopamine supersensitivity psychosis (DSP) in addition to other measures such as age at disease onset and delay of clozapine introduction for a total of 47 treatment-resistant schizophrenia (TRS) patients. The response to clozapine was judged with CGI-C at 1 and 2 years from clozapine introduction. Results revealed that the DSP group tended to have a longer delay between designation of TRS and introduction of clozapine and continued to have slightly more severe psychopathology after treatment with clozapine, showing only slight improvement. The logistic regression analysis showed that the age at disease onset was the only significant indicator, predicting responsiveness to clozapine: patients with an onset age <20 years had a significantly better response to clozapine than patients with an onset age ≥20 years. The present study suggests that DSP might be related to a longer delay in clozapine introduction and the persistence of refractory symptoms despite clozapine treatment, whereas early age of disease onset might be related to a better response to clozapine.


Assuntos
Antipsicóticos , Clozapina , Transtornos Psicóticos , Esquizofrenia , Humanos , Adulto Jovem , Adulto , Clozapina/efeitos adversos , Esquizofrenia/tratamento farmacológico , Esquizofrenia/diagnóstico , Dopamina , Antipsicóticos/efeitos adversos , Esquizofrenia Resistente ao Tratamento , Estudos Retrospectivos , Transtornos Psicóticos/tratamento farmacológico
19.
Transl Psychiatry ; 13(1): 28, 2023 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-36720847

RESUMO

Age-related dopamine reductions have been suggested to contribute to maladaptive working memory (WM) function in older ages. One promising intervention approach is to increase physical activity, as this has been associated with plasticity of the striatal dopamine system and WM improvements, however with individual differences in efficacy. The present work focused on the impact of individual differences in white-matter lesion burden upon dopamine D2-like receptor (DRD2) availability and WM changes in response to a 6 months physical activity intervention. While the intervention altered striatal DRD2 availability and WM performance in individuals with no or only mild lesions (p < 0.05), no such effects were found in individuals with moderate-to-severe lesion severity (p > 0.05). Follow-up analyses revealed a similar pattern for processing speed, but not for episodic memory performance. Linear analyses further revealed that lesion volume (ml) at baseline was associated with reduced DRD2 availability (r = -0.41, p < 0.05), and level of DRD2 change (r = 0.40, p < 0.05). Taken together, this study underlines the necessity to consider cerebrovascular health in interventions with neurocognitive targets. Future work should assess whether these findings extend beyond measures of DRD2 availability and WM.


Assuntos
Envelhecimento , Exercício Físico , Memória de Curto Prazo , Plasticidade Neuronal , Substância Branca , Humanos , Cognição , Dopamina , Substância Branca/diagnóstico por imagem
20.
J Mater Chem B ; 11(4): 837-851, 2023 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-36594635

RESUMO

The delayed healing of diabetic wounds is directly affected by the disturbance of wound microenvironment, resulting from persistent inflammation, insufficient angiogenesis, and impaired cell functions. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) showed considerable therapeutic potential in diabetic wound healing. However, the low retention rate of MSC-EVs at wound sites hampers their efficacy. For skin wounds exposed to the outer environment, using a hydrogel with tissue adhesiveness under a moist wound condition is a promising strategy for wound healing. In this study, we modified methacryloyl-modified gelatin (GelMA) hydrogel with catechol motifs of dopamine to fabricate a GelMA-dopamine hydrogel. EVs isolated from MSCs were applied in the synthesized GelMA-dopamine hydrogel to prepare a GelMA-dopamine-EV hydrogel. The results demonstrated that the newly formed GelMA-dopamine hydrogel possessed improved properties of softness, adhesiveness, and absorptive capacity, as well as high biocompatibility in the working concentration (15% w/v). In addition, MSC-EVs were verified to promote cell migration and angiogenesis in vitro. In the skin wound model of diabetic rats, the GelMA-dopamine-EV hydrogel exerted prominent wound healing efficacy estimated by collagen deposition, skin appendage regeneration, and the expression of IL-6, CD31, and TGF-ß. In conclusion, this combination of MSC-EVs and the modified hydrogel not only accelerates wound closure but also promotes skin structure normalization by rescuing the homeostasis of the healing microenvironment of diabetic wounds, which provides a potential approach for the treatment of diabetic wounds.


Assuntos
Diabetes Mellitus Experimental , Vesículas Extracelulares , Células-Tronco Mesenquimais , Ratos , Animais , Hidrogéis/química , Diabetes Mellitus Experimental/tratamento farmacológico , Adesivos/farmacologia , Adesivos/uso terapêutico , Dopamina/uso terapêutico , Cicatrização/fisiologia , Gelatina/química
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