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1.
Int J Mol Sci ; 25(9)2024 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-38731862

RESUMO

There are currently no disease-modifying therapies for Parkinson's disease (PD), a progressive neurodegenerative disorder associated with dopaminergic neuronal loss. There is increasing evidence that endogenous dopamine (DA) can be a pathological factor in neurodegeneration in PD. Tyrosine hydroxylase (TH) is the key rate-limiting enzyme for DA generation. Drugs that inhibit TH, such as alpha-methyltyrosine (α-MT), have recently been shown to protect against neurodegeneration in various PD models. DA receptor agonists can activate post-synaptic DA receptors to alleviate DA-deficiency-induced PD symptoms. However, DA receptor agonists have no therapeutic effects against neurodegeneration. Thus, a combination therapy with DA receptor agonists plus TH inhibitors may be an attractive therapeutic approach. TH inhibitors can protect and promote the survival of remaining dopaminergic neurons in PD patients' brains, whereas DA receptor agonists activate post-synaptic DA receptors to alleviate PD symptoms. Additionally, other PD drugs, such as N-acetylcysteine (NAC) and anticholinergic drugs, may be used as adjunctive medications to improve therapeutic effects. This multi-drug cocktail may represent a novel strategy to protect against progressive dopaminergic neurodegeneration and alleviate PD disease progression.


Assuntos
Agonistas de Dopamina , Doença de Parkinson , Tirosina 3-Mono-Oxigenase , Animais , Humanos , Dopamina/metabolismo , Agonistas de Dopamina/uso terapêutico , Agonistas de Dopamina/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Quimioterapia Combinada , Inibidores Enzimáticos/uso terapêutico , Inibidores Enzimáticos/farmacologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Tirosina 3-Mono-Oxigenase/antagonistas & inibidores , Tirosina 3-Mono-Oxigenase/metabolismo
2.
Behav Pharmacol ; 35(4): 193-200, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38567425

RESUMO

Prepulse inhibition (PPI) is a crucial indicator of sensorimotor gating that is often impaired in neuropsychiatric diseases. Although dopamine D1 receptor agonists have been found to disrupt PPI in mice, the underlying mechanisms are not fully understood. In this study, we aimed to identify the brain regions responsible for the PPI-disruptive effect of the D1 agonist in mice. Results demonstrated that intraperitoneal administration of the selective dopamine D1 receptor agonist SKF82958 dramatically inhibited PPI, while the dopamine D1 receptor antagonist SCH23390 enhanced PPI. Additionally, local infusion of SKF82958 into the nucleus accumbens and medial prefrontal cortex disrupted PPI, but not in the ventral hippocampus. Infusion of SCH23390 into these brain regions also failed to enhance PPI. Overall, the study suggests that the nucleus accumbens and medial prefrontal cortex are responsible for the PPI-disruptive effect of dopamine D1 receptor agonists. These findings provide essential insights into the cellular and neural circuit mechanisms underlying the disruptive effects of dopamine D1 receptor agonists on PPI and may contribute to the development of novel treatments for neuropsychiatric diseases.


Assuntos
Benzazepinas , Agonistas de Dopamina , Camundongos Endogâmicos C57BL , Núcleo Accumbens , Córtex Pré-Frontal , Inibição Pré-Pulso , Receptores de Dopamina D1 , Animais , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Agonistas de Dopamina/farmacologia , Camundongos , Benzazepinas/farmacologia , Masculino , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/metabolismo , Inibição Pré-Pulso/efeitos dos fármacos , Inibição Pré-Pulso/fisiologia , Reflexo de Sobressalto/efeitos dos fármacos , Filtro Sensorial/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia
3.
J Affect Disord ; 356: 586-596, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38657764

RESUMO

BACKGROUND: Diabetes mellitus (DM) is frequently associated with the occurrence and development of depression, and the co-occurrence of diabetes mellitus with depression (DD) may further reduce patients' quality of life. Recent research indicates that dopamine receptors (DRs) play a crucial role in immune and metabolic regulation. Pramipexole (PPX), a D2/3R agonist, has demonstrated promising neuroprotective and immunomodulatory effects. Nevertheless, the therapeutic effects and mechanisms of action of PPX on DM-induced depression are not clear at present. METHODS: Depression, DM, and DD were induced in a rat model through a combination of a high-fat diet (HFD) supplemented with streptozotocin (STZ) and chronic unpredictable mild stress (CUMS) combined with solitary cage rearing. The pathogenesis of DD and the neuroprotective effects of DRs agonists were investigated using behavioral assays, enzyme-linked immunosorbent assay (ELISA), hematoxylin-eosin (HE) staining, Nissl staining, Western blotting (WB) and immunofluorescence (IF). RESULTS: DD rats exhibited more severe dopaminergic, neuroinflammatory, and neuroplastic impairments and more pronounced depressive behaviors than rats with depression alone or DM. Our findings suggest that DRs agonists have significant therapeutic effects on DD rats and that PPX improved neuroplasticity and decreased neuroinflammation in the hippocampus of DD rats while also promoting DG cell growth and differentiation, ultimately mitigating depression-like behaviors. LIMITATION: Our study is based on a rat model. Further evidence is needed to determine whether the therapeutic effects of PPX apply to patients suffering from DD. CONCLUSIONS: Neuroinflammation mediated by damage to the dopaminergic system is one of the key pathogenic mechanisms of DD. We provide evidence that PPX has a neuroprotective effect on the hippocampus in DD rats and the mechanism may involve the inhibition of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation by DRs to attenuate the neuroinflammatory response and neuroplasticity damage.


Assuntos
Depressão , Diabetes Mellitus Experimental , Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Plasticidade Neuronal , Pramipexol , Animais , Pramipexol/farmacologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos , Plasticidade Neuronal/efeitos dos fármacos , Masculino , Inflamassomos/efeitos dos fármacos , Depressão/tratamento farmacológico , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/complicações , Ratos Sprague-Dawley , Doenças Neuroinflamatórias/tratamento farmacológico , Agonistas de Dopamina/farmacologia , Hipocampo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças
4.
Artigo em Russo | MEDLINE | ID: mdl-38676674

RESUMO

The article is of a review nature and is devoted to tremor, one of the maladaptive and difficult-to-treat symptoms of Parkinson's disease (PD). Along with the classic rest tremor, patients with PD may experience tremor of other modalities: postural tremor, kinetic tremor, which reflects a multimodal mechanism of tremor formation involving multiple neurotransmitter systems. The unpredictable response to therapeutic options, the ambiguous response to levodopa, also reflects the role of multiple underlying pathophysiological processes. Among the drug methods of tremor correction, preference is given to dopamine receptor agonists - due to the spectrum of their pharmaceutical action, high efficiency in relation to all leading motor and a number of non-motor manifestations. The evidence for advanced neurosurgical, non-invasive modalities is mixed, and there are insufficient comparative studies to assess their efficacy in patients with tremor-dominant forms of PD.


Assuntos
Levodopa , Doença de Parkinson , Tremor , Humanos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/fisiopatologia , Tremor/tratamento farmacológico , Tremor/etiologia , Tremor/fisiopatologia , Levodopa/uso terapêutico , Agonistas de Dopamina/uso terapêutico , Antiparkinsonianos/uso terapêutico
5.
Pharmacol Res Perspect ; 12(2): e1190, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38597598

RESUMO

Analysis was conducted to compare levodopa/carbidopa pharmacokinetics and drug-related material in plasma of healthy participants after receiving a continuous infusion of Levodopa/Carbidopa Intestinal Gel (LCIG) to a continuous subcutaneous infusion of foslevodopa/foscarbidopa. Study samples were from a randomized, open-label, 2-period crossover study in 20 healthy participants. Participants received either 24-h foslevodopa/foscarbidopa SC infusion to the abdomen or LCIG delivered for 24 h to the jejunum through a nasogastric tube with jejunal extension. Serial blood samples were collected for PK. Comparability of the LD PK parameters between the two treatment regimens was determined. Selected plasma samples were pooled per treatment group and per time point for metabolite profiling. LC-MSn was performed using high-resolution mass spectrometry to identify drug-related material across the dosing regimens and time points. The LD PK parameter central values and 90% confidence intervals following the foslevodopa/foscarbidopa subcutaneous infusion were between 0.8 and 1.25 relative to the LCIG infusion. With LCIG administration, LD, CD, 3-OMD, DHPA, DOPAC, and vanillacetic acid were identified in plasma at early and late time points (0.75 and 24 h); the metabolic profile after administration of foslevodopa/foscarbidopa demonstrated the same drug-related compounds with the exception of the administered foslevodopa. 3-OMD and vanillacetic acid levels increased over time in both treatment regimens. Relative quantification of LC-MS peak areas showed no major differences in the metabolite profiles. These results indicate that neither the addition of monophosphate prodrug moieties nor SC administration affects the circulating metabolite profile of foslevodopa/foscarbidopa compared to LCIG.


Assuntos
Carbidopa , Doença de Parkinson , Humanos , Carbidopa/farmacocinética , Levodopa/farmacocinética , Antiparkinsonianos/farmacocinética , Estudos Cross-Over , Voluntários Saudáveis , Doença de Parkinson/tratamento farmacológico , Géis/uso terapêutico , Agonistas de Dopamina
6.
Sci Rep ; 14(1): 8424, 2024 04 10.
Artigo em Inglês | MEDLINE | ID: mdl-38600209

RESUMO

Using deep learning has demonstrated significant potential in making informed decisions based on clinical evidence. In this study, we deal with optimizing medication and quantitatively present the role of deep learning in predicting the medication dosage for patients with Parkinson's disease (PD). The proposed method is based on recurrent neural networks (RNNs) and tries to predict the dosage of five critical medication types for PD, including levodopa, dopamine agonists, monoamine oxidase-B inhibitors, catechol-O-methyltransferase inhibitors, and amantadine. Recurrent neural networks have memory blocks that retain crucial information from previous patient visits. This feature is helpful for patients with PD, as the neurologist can refer to the patient's previous state and the prescribed medication to make informed decisions. We employed data from the Parkinson's Progression Markers Initiative. The dataset included information on the Unified Parkinson's Disease Rating Scale, Activities of Daily Living, Hoehn and Yahr scale, demographic details, and medication use logs for each patient. We evaluated several models, such as multi-layer perceptron (MLP), Simple-RNN, long short-term memory (LSTM), and gated recurrent units (GRU). Our analysis found that recurrent neural networks (LSTM and GRU) performed the best. More specifically, when using LSTM, we were able to predict levodopa and dopamine agonist dosage with a mean squared error of 0.009 and 0.003, mean absolute error of 0.062 and 0.030, root mean square error of 0.099 and 0.053, and R-squared of 0.514 and 0.711, respectively.


Assuntos
Doença de Parkinson , Humanos , Doença de Parkinson/tratamento farmacológico , Levodopa/uso terapêutico , Catecol O-Metiltransferase , Atividades Cotidianas , Agonistas de Dopamina/uso terapêutico , Redes Neurais de Computação
7.
Arch Endocrinol Metab ; 68: e230504, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38578473

RESUMO

Dopamine agonists are the first line of treatment for patients with symptomatic hyperprolactinemia due to prolactinomas and in those with idiopathic hyperprolactinemia. Treatment with these agents is effective in 80%-90% of the cases. Infertility treatment of patients with hyperprolactinemia is also carried out with dopamine agonists, aiming for the normalization of prolactin levels. The risk of symptomatic growth of prolactinomas during pregnancy is dependent on the tumor's size, duration of previous treatments, and prolactin levels. Notably, the corresponding risk is relatively low in cases of microprolactinomas (<5%). Remission of hyperprolactinemia occurs in about 30% of the patients after drug treatment and may also occur after pregnancy and menopause. The use of some drugs, such as antidepressants and antipsychotics, is a frequent cause of hyperprolactinemia, and managing this occurrence involves unique considerations. This position statement by the Brazilian Federation of Gynecology and Obstetrics Associations (Febrasgo) and Brazilian Society of Endocrinology and Metabolism (SBEM) addresses the recommendations for measurement of serum prolactin levels and the investigations of symptomatic and asymptomatic hyperprolactinemia and drug-induced hyperprolactinemia in women.


Assuntos
Hiperprolactinemia , Neoplasias Hipofisárias , Prolactinoma , Gravidez , Humanos , Feminino , Hiperprolactinemia/tratamento farmacológico , Prolactinoma/terapia , Agonistas de Dopamina/efeitos adversos , Prolactina , Neoplasias Hipofisárias/terapia , Brasil
8.
Mol Pharm ; 21(5): 2512-2533, 2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38602861

RESUMO

Parkinson's disease (PD) is a debilitating neurodegenerative disease primarily impacting neurons responsible for dopamine production within the brain. Pramipexole (PRA) is a dopamine agonist that is currently available in tablet form. However, individuals with PD commonly encounter difficulties with swallowing and gastrointestinal motility, making oral formulations less preferable. Microneedle (MN) patches represent innovative transdermal drug delivery devices capable of enhancing skin permeability through the creation of microconduits on the surface of the skin. MNs effectively reduce the barrier function of skin and facilitate the permeation of drugs. The work described here focuses on the development of polymeric MN systems designed to enhance the transdermal delivery of PRA. PRA was formulated into both dissolving MNs (DMNs) and directly compressed tablets (DCTs) to be used in conjunction with hydrogel-forming MNs (HFMNs). In vivo investigations using a Sprague-Dawley rat model examined, for the first time, if it was beneficial to prolong the application of DMNs and HFMNs beyond 24 h. Half of the patches in the MN cohorts were left in place for 24 h, whereas the other half remained in place for 5 days. Throughout the entire 5 day study, PRA plasma levels were monitored for all cohorts. This study confirmed the successful delivery of PRA from DMNs (Cmax = 511.00 ± 277.24 ng/mL, Tmax = 4 h) and HFMNs (Cmax = 328.30 ± 98.04 ng/mL, Tmax = 24 h). Notably, both types of MNs achieved sustained PRA plasma levels over a 5 day period. In contrast, following oral administration, PRA remained detectable in plasma for only 48 h, achieving a Cmax of 159.32 ± 113.43 ng/mL at 2 h. The HFMN that remained in place for 5 days demonstrated the most promising performance among all investigated formulations. Although in the early stages of development, the findings reported here offer a hopeful alternative to orally administered PRA. The sustained plasma profile observed here has the potential to reduce the frequency of PRA administration, potentially enhancing patient compliance and ultimately improving their quality of life. This work provides substantial evidence advocating the development of polymeric MN-mediated drug delivery systems to include sustained plasma levels of hydrophilic pharmaceuticals.


Assuntos
Administração Cutânea , Sistemas de Liberação de Medicamentos , Agulhas , Doença de Parkinson , Pramipexol , Ratos Sprague-Dawley , Pramipexol/administração & dosagem , Pramipexol/farmacocinética , Animais , Ratos , Doença de Parkinson/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Masculino , Absorção Cutânea/efeitos dos fármacos , Pele/metabolismo , Pele/efeitos dos fármacos , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/farmacocinética , Agonistas de Dopamina/administração & dosagem , Agonistas de Dopamina/farmacocinética , Hidrogéis/química
9.
Behav Neurosci ; 138(2): 85-93, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38661668

RESUMO

Rodent behavioral studies have largely focused on male animals, which has limited the generalizability and conclusions of neuroscience research. Working with humans and rodents, we studied sex effects during interval timing that requires participants to estimate an interval of several seconds by making motor responses. Interval timing requires attention to the passage of time and working memory for temporal rules. We found no differences between human females and males in interval timing response times (timing accuracy) or the coefficient of variance of response times (timing precision). Consistent with prior work, we also found no differences between female and male rodents in timing accuracy or precision. In female rodents, there was no difference in interval timing between estrus and diestrus cycle stages. Because dopamine powerfully affects interval timing, we also examined sex differences with drugs targeting dopaminergic receptors. In both female and male rodents, interval timing was delayed after administration of sulpiride (D2-receptor antagonist), quinpirole (D2-receptor agonist), and SCH-23390 (D1-receptor antagonist). By contrast, after administration of SKF-81297 (D1-receptor agonist), interval timing shifted earlier only in male rodents. These data illuminate sex similarities and differences in interval timing. Our results have relevance for rodent models of both cognitive function and brain disease by increasing representation in behavioral neuroscience. (PsycInfo Database Record (c) 2024 APA, all rights reserved).


Assuntos
Percepção do Tempo , Feminino , Masculino , Animais , Percepção do Tempo/fisiologia , Percepção do Tempo/efeitos dos fármacos , Humanos , Caracteres Sexuais , Dopamina/metabolismo , Ratos , Receptores de Dopamina D2/metabolismo , Sulpirida/farmacologia , Quimpirol/farmacologia , Agonistas de Dopamina/farmacologia , Agonistas de Dopamina/administração & dosagem , Antagonistas de Dopamina/farmacologia , Antagonistas de Dopamina/administração & dosagem , Adulto , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Benzazepinas/farmacologia , Adulto Jovem , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D1/antagonistas & inibidores , Memória de Curto Prazo/fisiologia , Memória de Curto Prazo/efeitos dos fármacos
10.
Pharmacol Biochem Behav ; 239: 173754, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38537873

RESUMO

BACKGROUND: Pituitary lactotrophs are under tonic dopaminergic inhibitory control and bromocriptine treatment blocks prolactin secretion. METHODS: Sleep and local field potential were addressed for 72 h after bromocriptine treatments applied during the different stages of the estrus cycle and for 24 h in the early- and middle postpartum period characterized by spontaneously different dynamics of prolactin release in female rats. RESULTS: Sleep changes showed strong dependency on the estrus cycle phase of the drug application. Strongest increase of wakefulness and reduction of slow wave sleep- and rapid eye movements sleep appeared during diestrus-proestrus and middle postpartum treatments. Stronger sleep-wake effects appeared in the dark phase in case of the estrus cycle treatments, but in the light phase in postpartum treatments. Slow wave sleep and REM sleep loss in case of estrus cycle treatments was not compensated at all and sleep loss seen in the first day post-injection was gained further later. In opposition, slow wave sleep loss in the light phase after bromocriptine injections showed compensation in the postpartum period treatments. Bromocriptine treatments resulted in a depression of local field potential delta power during slow wave sleep while an enhancement in beta and gamma power during wakefulness regardless of the treatment timing. CONCLUSIONS: These results can be explained by the interplay of dopamine D2 receptor agonism, lack of prolactin release and the spontaneous homeostatic sleep drive being altered in the different stages of the estrus cycle and the postpartum period.


Assuntos
Bromocriptina , Agonistas de Dopamina , Ciclo Estral , Período Pós-Parto , Ratos Wistar , Receptores de Dopamina D2 , Sono , Animais , Bromocriptina/farmacologia , Feminino , Período Pós-Parto/efeitos dos fármacos , Ratos , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Agonistas de Dopamina/farmacologia , Ciclo Estral/efeitos dos fármacos , Sono/efeitos dos fármacos , Vigília/efeitos dos fármacos , Prolactina
11.
Expert Opin Drug Metab Toxicol ; 20(3): 133-142, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38482850

RESUMO

INTRODUCTION: Restless legs syndrome/Willis-Ekbom disease (RLS/WED) is a sleep-related sensory-motor disorder associated with poor sleep quality and impaired daily functioning. In patients affected by chronic RLS/WED, a pharmacological therapy is recommended. International guidelines suggest to start the treatment with a α2δ calcium channel ligand in most cases, unless contraindicated. AREAS COVERED: The present review is based on an extensive Internet and PubMed search from 1986 to 2024. Our purpose is to describe the absorption, distribution, metabolism, and toxicology (ADMET) of the α2δ ligands, with common consideration for the therapeutic class, specificities of different compounds, efficacy, and safety in relation to other treatment options. EXPERT OPINION: α2δ ligands are quite similar in their ADMET profiles, sharing most of the pharmacokinetics and potential adverse effects. However, we highlight the linear kinetic of gabapentin enacarbil and pregabalin, differently from gabapentin. α2δ ligands are safe and effective for the treatment of RLS/WED. Additional benefits can be obtained in comorbid insomnia, chronic pain syndromes, history of impulse control disorder, and comorbid anxiety. The use of α2δ ligands is associated with poor risk of augmentation. We still need new long-term safe and effective treatments, which could be developed along with our knowledge of RLS/WED pathophysiology.


Assuntos
Agonistas de Dopamina , Síndrome das Pernas Inquietas , Humanos , Agonistas de Dopamina/uso terapêutico , Canais de Cálcio/metabolismo , Canais de Cálcio/uso terapêutico , Síndrome das Pernas Inquietas/tratamento farmacológico , Ligantes , Gabapentina/efeitos adversos
15.
Horm Behav ; 160: 105492, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38306878

RESUMO

Research in women showed that testosterone is associated with decreased selective attention towards infant stimuli, which can be compensated for by oxytocin administration. In theory, caregiving behavior is thought to be mediated by oxytocin. Oxytocin binds to dopaminergic neurons and thus supposedly motivates aspects of caregiving through its influence on dopaminergic transmission. Most previous studies on caregiving behaviors were thereby performed in women under hormonal contraception to avoid hormonal fluctuations. However, recent studies repeatedly demonstrated decisive influences of the hormonal changes across the female menstrual cycle on dopamine-mediated behaviors, suggesting that estradiol acts as dopamine agonist in the follicular phase and progesterone as dopamine antagonist in the luteal phase. In the present study, we investigated selective attention towards infants as one central aspect of caregiving behavior over the natural menstrual cycle and in relation to interindividual differences of estradiol and progesterone. As expected, we found that women with higher estradiol in the follicular phase also showed higher selective attention towards infant faces among adult distractors, whereas the correlation disappeared in the luteal phase. In contrast, progesterone did not correlate with selective attention towards infants. The present findings collectively support the assumption that estradiol may act as dopamine agonist in the follicular phase, thereby supposedly promoting an important aspect of caretaking behavior.


Assuntos
Ocitocina , Progesterona , Adulto , Feminino , Humanos , Progesterona/metabolismo , Agonistas de Dopamina , Ciclo Menstrual/fisiologia , Fase Luteal/fisiologia , Fase Folicular/fisiologia , Estradiol/metabolismo , Atenção
16.
Neuropharmacology ; 248: 109851, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38325772

RESUMO

Heightened risk-based decision-making is observed across several neuropsychiatric disorders including schizophrenia, bipolar disorder, and Parkinson's disease, yet no treatments exist that effectively normalize this aberrant behavior. Preclinical risk-based decision-making paradigms have identified the important modulatory roles of dopamine and sex in the performance of such tasks, though specific task parameters may alter such effects (e.g., punishment and reward values). Previous work has highlighted the role of dopamine 2-like receptors (D2R) during performance of the Risk Preference Task (RPT) in male rats, however sex was not considered as a factor in this study, nor were treatments identified that reduced risk preference. Here, we utilized the RPT to determine sex-dependent differences in baseline performance and impact of the D2R receptor agonist pramipexole (PPX), and antagonist sulpiride (SUL) on behavioral performance. Female rats exhibited heightened risk-preference during baseline testing. Consistent with human studies, PPX increased risk-preference across sex, though the effects of PPX were more pronounced in female animals. Importantly, SUL reduced risk-preference in these rats across sexes. Thus, under the task specifications of the RPT that does not include punishment, female rats were more risk-preferring and required higher PPX doses to promote risky choices compared to males. Furthermore, blockade of D2R receptors may reduce risk-preference of rats, though further studies are required.


Assuntos
Dopamina , Caracteres Sexuais , Humanos , Ratos , Feminino , Masculino , Animais , Dopamina/farmacologia , Agonistas de Dopamina/farmacologia , Pramipexol/farmacologia , Receptores Dopaminérgicos , Tomada de Decisões , Recompensa
17.
Transl Psychiatry ; 14(1): 86, 2024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38336862

RESUMO

Impulse control disorders (ICDs), a wide spectrum of maladaptive behaviors which includes pathological gambling, hypersexuality and compulsive buying, have been recently suggested to be triggered or aggravated by treatments with dopamine D2/3 receptor agonists, such as pramipexole (PPX). Despite evidence showing that impulsivity is associated with functional alterations in corticostriatal networks, the neural basis of the exacerbation of impulsivity by PPX has not been elucidated. Here we used a hotspot analysis to assess the functional recruitment of several corticostriatal structures by PPX in male rats identified as highly (HI), moderately impulsive (MI) or with low levels of impulsivity (LI) in the 5-choice serial reaction time task (5-CSRTT). PPX dramatically reduced impulsivity in HI rats. Assessment of the expression pattern of the two immediate early genes C-fos and Zif268 by in situ hybridization subsequently revealed that PPX resulted in a decrease in Zif268 mRNA levels in different striatal regions of both LI and HI rats accompanied by a high impulsivity specific reduction of Zif268 mRNA levels in prelimbic and cingulate cortices. PPX also decreased C-fos mRNA levels in all striatal regions of LI rats, but only in the dorsolateral striatum and nucleus accumbens core (NAc Core) of HI rats. Structural equation modeling further suggested that the anti-impulsive effect of PPX was mainly attributable to the specific downregulation of Zif268 mRNA in the NAc Core. Altogether, our results show that PPX restores impulse control in highly impulsive rats by modulation of limbic frontostriatal circuits.


Assuntos
Agonistas de Dopamina , Comportamento Impulsivo , Ratos , Masculino , Animais , Pramipexol/farmacologia , Comportamento Impulsivo/fisiologia , Agonistas de Dopamina/farmacologia , Dopamina/metabolismo , RNA Mensageiro
18.
Addict Biol ; 29(2): e13369, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38380709

RESUMO

Here, we present recent studies suggesting that specific DRD3 single nucleotide polymorphisms (SNPs, e.g. rs324029 and rs2654754) might serve as prognostic biomarkers for opioid use disorder (OUD). Additionally, preclinical studies with novel dopamine 3 receptor (D3R) partial agonists and antagonists have been evaluated as candidate OUD therapeutics and have shown a reduced risk of cardiovascular toxicity compared with the original D3R antagonist. From these findings, we argue that DRD3 SNPs could serve as a diagnostic tool for assessing OUD risk and that more research is warranted examining the D3R as a safe and effective therapeutic target for treating OUD.


Assuntos
Transtornos Relacionados ao Uso de Opioides , Receptores Dopaminérgicos , Humanos , Dopamina , Receptores de Dopamina D3/genética , Transtornos Relacionados ao Uso de Opioides/genética , Antagonistas de Dopamina , Agonistas de Dopamina , Analgésicos Opioides
19.
Pituitary ; 27(2): 197-203, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38345719

RESUMO

BACKGROUND: Impulse control disorders (ICDs) have been described as underrecognized side effects of dopamine agonists (DAs) in neurological disorders but are not sufficiently understood in endocrine conditions. OBJECTIVE: To identify the prevalence of DAs induced ICDs and determine potential risk factors related to these disorders in patients with prolactinoma and non-function pituitary adenomas (NFPAs). METHODS: This is a cross-sectional multicenter study involving 200 patients with prolactinoma and NFPAs, who received follow-ups in tertiary referral centers. DA-induced ICDs were assessed using ICD questionnaires modified from prior studies. RESULT: At least one ICD was reported by 52% of participants, among whom 28.5% mentioned compulsive shopping, 24.5% punding, and 24.5% hypersexuality. Furthermore, 33% of the patients reported the presence of one type of ICD behavior, while 12% specified two and 7% had three types of such behavior. The multivariable logistic regression showed that the significant risk factors of ICD were younger age (adjusted odds ratio [AOR]: 0.92, 95% confidence interval [CI]: 0.88-0.97, p 0.001), being single (AOR: 0.15, 95%CI: 0.03-0.84, p 0.03), and a positive history of psychiatric illness (AOR: 7.67, 95% CI: 1.37-42.97, p 0.021). CONCLUSION: ICDs with a broad range of psychiatric symptoms are common in individuals with DA-treated prolactinoma and NFPAs. Endocrinologists should be aware of this potential side effect, particularly in patients with a personal history of psychiatric disorder.


Assuntos
Transtornos Disruptivos, de Controle do Impulso e da Conduta , Neoplasias Hipofisárias , Prolactinoma , Humanos , Neoplasias Hipofisárias/tratamento farmacológico , Prolactinoma/tratamento farmacológico , Agonistas de Dopamina/efeitos adversos , Estudos Transversais , Transtornos Disruptivos, de Controle do Impulso e da Conduta/induzido quimicamente , Transtornos Disruptivos, de Controle do Impulso e da Conduta/epidemiologia , Transtornos Disruptivos, de Controle do Impulso e da Conduta/tratamento farmacológico
20.
Clin Neurol Neurosurg ; 237: 108145, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38340430

RESUMO

Abulia is a common problem that manifests following various brain conditions, including brain surgeries. Abulia is felt to be related to dysfunction with the brain's dopamine-dependent circuitry. The role of default mode network (DMN) in its pathogenesis is crucial. In this case report, we detail the presentation of abulia in an elderly woman following surgical resection of a right frontal glioblastoma involving the DMN. Connectomic imaging was used pre-operatively and post-operatively, demonstrating disruption of regions integral to the DMN and the central executive network. We observed a significant cognitive improvement following the administration of levodopa and carbidopa. Preoperative assessment of both anatomical and functional networks can help ensure surgical safety and predict postoperative deficits. This evaluation not only enhances preparedness and facilitates early case diagnosis but also expedites the initiation of prompt and potentially targeted treatments. This case highlights the potential efficacy of levodopa and carbidopa in addressing DMN dysfunction and broadly suggests the potential for connectomics-guided post-operative therapies.


Assuntos
Conectoma , Feminino , Humanos , Idoso , Encéfalo/patologia , Agonistas de Dopamina/uso terapêutico , Levodopa/uso terapêutico , Carbidopa/uso terapêutico , Imageamento por Ressonância Magnética , Cognição , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/cirurgia
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