Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 10.921
Filtrar
1.
Artigo em Inglês | MEDLINE | ID: mdl-36191805

RESUMO

Dopamine is a modulating factor in effort-based decision-making, and emerging evidence from pharmacological research suggests that the dopamine D1 receptor is the primary regulator. Given the limited selectivity of pharmacological tools, we further explored this hypothesis using dopamine D1 mutant (DAD1-/-) rats which have a specific genetic reduction in functional D1 receptors. Moreover, given the strong focus on males in neuroscience research in general and in the role of D1 receptors in effort-based learning, we compared both sexes in the present study. Adult male and female DAD1-/- mutant rats and wild type controls were trained to press a lever for a reinforcer. Once trained, subjects completed multiple fixed ratio, progressive ratio, and operant effort-choice (concurrent progressive ratio/chow feeding task [PROG/chow]) experiments. We predicted that DAD1-/- mutant rats would press the lever significantly less than controls across all experiments, have lower breakpoints, and consume more freely available food. As predicted, DAD1-/- mutant rats (regardless of sex) pressed the lever significantly less than controls and had lower breakpoints. Interestingly, there was a sex * genotype interaction for acquisition rates of lever pressing and change in breakpoints with free food available. Only 31% of DAD1-/- mutant males acquired lever pressing while 73% of DAD1-/- mutant females acquired lever pressing. Additionally, DAD1-/- mutant males had significantly larger decreases in breakpoints when free food was available. These findings extend the pharmacological research suggesting that the dopamine D1 receptor modulates decisions based on effort, which has implications for the development of treatment targeting amotivation in neuropsychiatric disorders. The sex * genotype interaction highlights the importance of including both sexes in future research, especially when there are sex differences in incidences and severity of neuropsychiatric disorders.


Assuntos
Antagonistas de Dopamina , Receptores de Dopamina D1 , Animais , Feminino , Masculino , Ratos , Condicionamento Operante , Tomada de Decisões , Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Ratos Sprague-Dawley , Receptores de Dopamina D1/genética , Caracteres Sexuais
2.
Behav Pharmacol ; 33(7): 435-441, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-36148834

RESUMO

INTRODUCTION: Anabolic-androgenic steroids (AAS) are performance-enhancing drugs used by both world-class and rank-and-file athletes. AAS abuse has been linked with risky decision-making, ranging from drunk driving to abusing multiple drugs. Our lab uses operant behavior in rats to test the effects of AAS (testosterone) on decision making. In our previous study, testosterone caused rats to work harder for food reward during an effort discounting (ED) task. ED is sensitive to dopamine in the nucleus accumbens, and AAS alter accumbens dopamine receptor expression. Accordingly, we determined if testosterone increases response to dopamine receptor antagonists during ED. METHODS: Rats were treated chronically with high-dose testosterone (7.5 mg/kg; n = 9) or vehicle (n = 9). We measured baseline preference for the large reward in an ED task, where rats choose between a small easy reward (one lever press for one sugar pellet) and a large difficult reward (2, 5, 10, or 15 presses for three pellets). Preference for the large reward was measured after administration of D1-like (SCH23390, 0.01 mg/kg) or D2-like (eticlopride, 0.06 mg/kg) receptor antagonists. RESULTS: At baseline, testosterone- and vehicle-treated rats showed similar preference for the large reward lever (FR5, testosterone: 68.6 ± 9.7% and vehicle: 85.7 ± 2.5%). SCH23390 reduced large reward preference significantly in both groups (FR5, testosterone: 41.3 ± 9.2%; vehicle: 49.1 ± 8.2%; F(1,16) = 17.7; P < 0.05). Eticlopride decreased large reward preference in both groups, but more strongly in testosterone-treated rats (FR5: testosterone: 37.0 ± 9.7%; vehicle: 56.3 ± 7.8%; F(1,16) = 35.3; P < 0.05). CONCLUSION: Testosterone increases response to dopamine D2-like receptor blockade, and this contributes to previously observed changes in decision-making behaviors.


Assuntos
Androgênios , Substâncias para Melhoria do Desempenho , Androgênios/metabolismo , Androgênios/farmacologia , Animais , Condicionamento Operante , Tomada de Decisões , Dopamina/metabolismo , Antagonistas de Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Humanos , Núcleo Accumbens/metabolismo , Substâncias para Melhoria do Desempenho/metabolismo , Substâncias para Melhoria do Desempenho/farmacologia , Ratos , Ratos Long-Evans , Receptores de Dopamina D1/metabolismo , Recompensa , Salicilamidas , Açúcares/metabolismo , Açúcares/farmacologia , Testosterona/farmacologia
3.
Behav Pharmacol ; 33(7): 492-504, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-36148837

RESUMO

The intrinsic pain inhibitory mechanisms can be activated by fear, anxiety, and stress. Stressful experiences produce analgesia, referred to as stress-induced analgesia (SIA). Major components of the limbic system, including the ventral tegmental area, nucleus accumbens, amygdala, and hippocampus, are involved in the SIA. In this study, we tried to understand the role of dopamine receptors in the cornu ammonis area 1 (CA1) of the hippocampus in the forced swim stress (FSS)-induced analgesia. Stereotaxic surgery was unilaterally performed on 129 adult male Wistar rats weighing 220-280 g. SCH23390 (0.25, 1, and 4 µg/0.5 µl saline) or sulpiride (0.25, 1, and 4 µg/0.5 µl DMSO), as D1- and D2-like dopamine receptor antagonists, respectively, were microinjected into the CA1 area, 5 min before exposure to FSS for a 6-min period. The vehicle groups received saline or DMSO instead of SCH23390 or sulpiride, respectively. The formalin test was done using formalin injection (50 µl; 2.5%) into the plantar surface of the rat's hind paw immediately after exposure to FSS. The results demonstrated that FSS produces analgesia during the early and late phases of the formalin test. However, intra-CA1 microinjection of SCH23390 or sulpiride attenuated the FSS-induced analgesia in both phases of the formalin test. This study provides new insight into the role of D1- and D2-like dopamine receptors in the CA1 area in the FSS-induced analgesia during persistent inflammatory pain.


Assuntos
Analgesia , Sulpirida , Animais , Benzazepinas/farmacologia , Dimetil Sulfóxido , Modelos Animais de Doenças , Antagonistas de Dopamina/farmacologia , Formaldeído , Hipocampo/metabolismo , Masculino , Dor/tratamento farmacológico , Ratos , Ratos Wistar , Receptores Dopaminérgicos , Receptores de Dopamina D1/metabolismo , Sulpirida/farmacologia
4.
Int J Mol Sci ; 23(17)2022 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-36077488

RESUMO

Perturbations in striatal dopamine (DA) homeostasis might underlie the behavioral and pathobiological consequences of METH use disorder in humans. To identify potential consequences of long-term METH exposure, we modeled the adverse consequence DSM criterion of substance use disorders by giving footshocks to rats that had escalated their intake of METH during a drug self-administration procedure. Next, DA D1 receptor antagonist, SCH23390 was injected. Thereafter, rats were euthanized to measure several indices of the striatal dopaminergic system. Footshocks split the METH rats into two phenotypes: (i) shock-sensitive that decreased their METH-intake and (ii) shock-resistant that continued their METH intake. SCH23390 caused substantial dose-dependent reduction of METH taking in both groups. Stopping SCH23390 caused re-emergence of compulsive METH taking in shock-resistant rats. Compulsive METH takers also exhibited greater incubation of METH seeking than non-compulsive rats during withdrawal from METH SA. Analyses of DA metabolism revealed non-significant decreases (about 35%) in DA levels in resistant and sensitive rats. However, striatal contents of the deaminated metabolites, DOPAL and DOPAC, were significantly increased in sensitive rats. VMAT2 and DAT protein levels were decreased in both phenotypes. Moreover, protein expression levels of the D1-like DA receptor, D5R, and D2-like DA receptors, D3R and D4R, were significantly decreased in the compulsive METH takers. Our results parallel findings in post-mortem striatal tissues of human METH users who develop Parkinsonism after long-term METH intake and support the use of this model to investigate potential therapeutic interventions for METH use disorder.


Assuntos
Metanfetamina , Animais , Corpo Estriado/metabolismo , Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Humanos , Ratos , Ratos Sprague-Dawley , Autoadministração
5.
J Med Chem ; 65(18): 12124-12139, 2022 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-36098685

RESUMO

To better understand the role of dopamine D4 receptor (D4R) in glioblastoma (GBM), in the present paper, new ligands endowed with high affinity and selectivity for D4R were discovered starting from the brain penetrant and D4R selective lead compound 1-(3-(4-phenylpiperazin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one (6). In particular, the D4R antagonist 24, showing the highest affinity and selectivity over D2R and D3R within the series (D2/D4 = 8318, D3/D4 = 3715), and the biased ligand 29, partially activating D4R Gi-/Go-protein and blocking ß-arrestin recruitment, emerged as the most interesting compounds. These compounds, evaluated for their GBM antitumor activity, induced a decreased viability of GBM cell lines and primary GBM stem cells (GSC#83), with the maximal efficacy being reached at a concentration of 10 µM. Interestingly, the treatment with both compounds 24 and 29 induced an increased effect in reducing the cell viability with respect to temozolomide, which is the first-choice chemotherapeutic drug in GBM.


Assuntos
Antagonistas de Dopamina , Glioblastoma , Receptores de Dopamina D4 , Antagonistas de Dopamina/farmacologia , Antagonistas de Dopamina/uso terapêutico , Glioblastoma/tratamento farmacológico , Humanos , Ligantes , Temozolomida , beta-Arrestinas/metabolismo
6.
Cell Host Microbe ; 30(10): 1401-1416.e8, 2022 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-36057258

RESUMO

The gastrointestinal tract facilitates food digestion, with the gut microbiota playing pivotal roles in nutrient breakdown and absorption. However, the microbial molecules and downstream signaling pathways that activate food digestion remain unexplored. Here, by establishing a food digestion system in C. elegans, we discover that food breakdown is regulated by the interaction between bacterial outer membrane proteins (OMPs) and a neural-immune pathway. E. coli OmpF/A activate digestion by increasing the neuropeptide NLP-12 that acts on the receptor CCKR. NLP-12 is homologous to mammalian cholecystokinin, known to stimulate dopamine, and we found that loss of dopamine receptors or addition of a dopamine antagonist inhibited OMP-mediated digestion. Dopamine and NLP-12-CKR-1 converge to inhibit PMK-1/p38 innate immune signaling. Moreover, directly inhibiting PMK-1/p38 boosts food digestion. This study uncovers a role of bacterial OMPs in regulating animal nutrient uptake and supports a key role for innate immunity in digestion.


Assuntos
Proteínas de Caenorhabditis elegans , Proteínas de Escherichia coli , Animais , Proteínas da Membrana Bacteriana Externa/metabolismo , Caenorhabditis elegans/microbiologia , Proteínas de Caenorhabditis elegans/metabolismo , Colecistocinina/metabolismo , Dopamina/metabolismo , Antagonistas de Dopamina/metabolismo , Escherichia coli/metabolismo , Proteínas de Escherichia coli/metabolismo , Imunidade Inata , Mamíferos , Receptores Dopaminérgicos/metabolismo
7.
Exp Brain Res ; 240(10): 2581-2594, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35976391

RESUMO

Research characterizing the neuronal substrate of anxiety has implicated different brain areas, including the medial septal nucleus (m-SEPT). Previous reports indicated a role of dopamine and nitric oxide (NO) in anxiety-related behaviors. In this study, the extracellular single-unit recording was performed from the m-SEPT in adult male albino Wistar rats. Baseline activity was recorded for 5 min, and the post-injection recording was performed for another 5 min after the microinjection of each drug. The results showed that (1) both D1- and D2-like receptor agonists (SKF-38393 and quinpirole) enhanced the firing rate of m-SEPT neurons; (2) both D1- and D2-like antagonists (SCH-23390 and sulpiride) attenuated the firing rate of m-SEPT neurons; (3) L-arginine (NO precursor) increased the firing rate of m-SEPT neurons, but a non-specific NOS inhibitor, L-NAME, elicited no significant alterations; (4) the non-specific NOS inhibitor reversed the enhanced firing rate produced by SKF-38393 and quinpirole; (5) neither of the dopaminergic antagonists changed the enhanced activity resulted from the application of the NO precursor. These results contribute to our understanding of the complex neurotransmitter interactions in the m-SEPT and showed that both dopaminergic and NO neurotransmission are involved in the modulation of the firing rate of neurons in the m-SEPT.


Assuntos
Dopamina , Núcleos Septais , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Animais , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Neurônios/metabolismo , Óxido Nítrico , Quimpirol/farmacologia , Ratos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Núcleos Septais/metabolismo , Sulpirida
8.
Eur J Pharmacol ; 932: 175230, 2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-36027983

RESUMO

Cancer is one of the most common and dreaded diseases affecting the vastness of society. Unfortunately, still some people die especially when cancer is not diagnosed and thus caught early enough. On the other hand, using available chemo- or radiotherapy may result in serious side effects. Therefore, cancer-specific medications seem to be the most desired and safe therapy. Knowing that some cancers are characterized by overexpression of specific receptors on the cell surface, target-mediated drugs could serve as a unique and effective form of therapy. In line with this, recently dopaminergic receptors were presented important in cancer therapy as several dopaminergic ligands revealed their efficacy in tumor growth reduction as well as in apoptosis mediation. Unfortunately, the indication of whether DA receptor agonists or antagonists are the best choices in cancer treatment is quite difficult, since both of them may exert either pro- or anticancer effects. In this review, we analyze the therapeutic efficacy of compounds, both of exogenous and endogenous origin, targeting dopaminergic receptor-expressing cancers.


Assuntos
Antagonistas de Dopamina , Neoplasias , Dopamina , Agonistas de Dopamina , Humanos , Ligantes , Neoplasias/tratamento farmacológico , Receptores Dopaminérgicos , Receptores de Dopamina D1/agonistas
9.
Life Sci ; 308: 120918, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36041503

RESUMO

Dopamine receptors have been extensively studied in the mammalian brain and spinal cord, as dopamine is a vital determinant of bodily movement, cognition, and overall behavior. Thus, dopamine receptor antagonist antipsychotic drugs are commonly used to treat multiple psychiatric disorders. Although less discussed, these receptors are also expressed in other peripheral organ systems, such as the kidneys, eyes, gastrointestinal tract, and cardiac tissue. Consequently, therapies for certain psychiatric disorders which target dopamine receptors could have unidentified consequences on certain functions of these peripheral tissues. The existence of an intrinsic dopaminergic system in the human heart remains controversial and debated within the literature. Therefore, this review focuses on literature related to dopamine receptors within cardiac tissue, specifically dopamine receptor 3 (D3R), and summarizes the current state of knowledge while highlighting areas of research which may be lacking. Additionally, recent findings regarding crosstalk between D3R and dopamine receptor 1 (D1R) are examined. This review discusses the novel concept of understanding the role of the loss of function of D3R may play in collagen accumulation and cardiac fibrosis, eventually leading to heart failure.


Assuntos
Antipsicóticos , Receptores de Dopamina D3 , Animais , Dopamina , Agonistas de Dopamina , Antagonistas de Dopamina , Fibrose , Humanos , Mamíferos , Receptores de Dopamina D1
10.
J Clin Psychopharmacol ; 42(5): 454-460, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36018237

RESUMO

PURPOSE/BACKGROUND: Tardive dyskinesia (TD) is a hyperkinetic movement disorder caused by exposure to dopamine-receptor blockers. Data on TD burden in Israel are scarce. This analysis assesses the clinical and economic burden of TD in Israeli patients. METHODS/PROCEDURES: This retrospective analysis used a national health plan database (Maccabi Healthcare Services), representing 25% of the Israeli population. The study included adults alive at index date with an International Classification of Diseases, Ninth Revision, Clinical Modification TD diagnosis before 2018 and more than or equal to 1-year enrollment before diagnosis. Tardive dyskinesia patients were matched to non-TD patients (1:3) by underlying psychiatric condition, birth year, and sex. Treatment patterns and 2018 annual health care resource utilization and costs were assessed. FINDINGS/RESULTS: Of 454 TD patients alive between 2013 and 2018, 333 alive on January 1, 2018, were matched to 999 non-TD patients. At baseline, TD patients had lower socioeconomic status and higher proportion of chronic kidney disease and antipsychotic medication use; all analyses were adjusted accordingly. Tardive dyskinesia patients had significantly more visits to general physicians, neurologists, psychiatrists, physiotherapists, and emergency departments versus non-TD patients (all P < 0.05). Tardive dyskinesia patients also had significantly longer hospital stays than non-TD patients ( P = 0.003). Total healthcare and medication costs per patient were significantly higher in the TD versus non-TD population (US $11,079 vs US $7145, P = 0.018). IMPLICATIONS/CONCLUSIONS: Israeli TD patients have higher clinical and economic burden than non-TD patients. Understanding real-world health care resource utilization and costs allows clinicians and decision makers to quantify TD burden and prioritize resources for TD patients' treatment.


Assuntos
Antipsicóticos , Discinesia Tardia , Adulto , Antipsicóticos/efeitos adversos , Análise de Dados , Antagonistas de Dopamina , Estresse Financeiro , Humanos , Israel/epidemiologia , Estudos Retrospectivos , Discinesia Tardia/induzido quimicamente , Discinesia Tardia/tratamento farmacológico , Discinesia Tardia/epidemiologia
11.
Sci Rep ; 12(1): 14131, 2022 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-35986048

RESUMO

Dopamine has been implicated in the reinforcing effects of smoking. However, there remains a need for a better understanding of the effects of dopamine D1-like receptor agonists on nicotine intake and the role of sex differences in the effects of dopaminergic drugs on behavior. This work studied the effects of D1-like receptor stimulation and blockade on operant responding for nicotine and food and locomotor activity in male and female rats. The effects of the D1-like receptor antagonist SCH 23390 (0.003, 0.01, 0.03 mg/kg) and the D1-like receptor agonist A77636 (0.1, 0.3, 1 mg/kg) on responding for nicotine and food, and locomotor activity were investigated. The effects of SCH 23390 were investigated 15 min and 24 h after treatment, and the effects of the long-acting drug A77636 were investigated 15 min, 24 h, and 48 h after treatment. Operant responding for nicotine and food and locomotor activity were decreased immediately after treatment with SCH 23390. Treatment with SCH 23390 did not have any long-term effects. Operant responding for nicotine was still decreased 48 h after treatment with A77636, and food responding was decreased up to 24 h after treatment. Treatment with A77636 only decreased locomotor activity at the 48 h time point. There were no sex differences in the effects of SCH 23390 or A77636. In conclusion, the D1-like receptor antagonist SCH 23390 reduces nicotine intake and causes sedation in rats. Stimulation of D1-like receptors with A77636 decreases nicotine intake at time points that the drug does not cause sedation.


Assuntos
Dopamina , Nicotina , Animais , Benzazepinas , Condicionamento Operante , Dopamina/farmacologia , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Feminino , Masculino , Nicotina/farmacologia , Ratos , Receptores de Dopamina D1/agonistas , Fumar
12.
Artigo em Inglês | MEDLINE | ID: mdl-35793735

RESUMO

Chelonoidis carbonaria aortic rings present endothelium-derived release of dopamine, noradrenaline, adrenaline and 6-nitrodopamine (6-ND). Here it was investigated whether 6-ND release is coupled to nitric oxide (NO) synthesis and its action on the vascular smooth muscle reactivity. Basal release of 6-ND from aortic rings in the absence and presence of the NO synthesis inhibitor L-NAME was quantified by LC-MS-MS. Aortic rings were suspended vertically between two metal hooks in 10-mL organ baths containing Krebs-Henseleit's solution and attached to isometric transducers. The tissues were allowed to equilibrate for 1 h before starting the experiments. The release of 6-ND was significantly reduced by previous incubation with L-NAME. 6-ND (up to 300 µM) had no contractile activity in the aortic rings. 6-ND (1, 3 and 10 µM) produced significant rightward shifts of the concentration-response curves to dopamine in endothelium-intact (pA2 6.09) and L-NAME pre-treated endothelium-intact (pA2 7.06) aortic rings. Contractions induced by noradrenaline and adrenaline were not affected by pre-incubation with 6-ND. The EFS (16 Hz)-induced aortic contractions were significantly inhibited by incubation with 6-ND (10 µM). In the thromboxane A2 mimetic U-46619 (30 nM) pre-contracted endothelium intact aortic rings, 6-ND (1 nM-1 µM) and the dopamine D2-receptor antagonist haloperidol (1 nM-1 µM) induced concentration-dependent relaxations. The relaxations were not present in endothelium-removed aortic rings but they were not affected by incubation with L-NAME in endothelium-intact aortic rings. The results indicate that the synthesis of this novel catecholamine in Chelonoidis carbonaria aortic rings is coupled to NO release and that 6-ND acts as a highly selective dopamine D2-like receptor antagonist.


Assuntos
Dopamina , Tartarugas , Animais , Aorta , Aorta Torácica , Dopamina/análogos & derivados , Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Epinefrina/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico , Norepinefrina/farmacologia
13.
Neuropsychopharmacology ; 47(13): 2309-2318, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35879349

RESUMO

The non-medical use of opioids has become a national crisis in the USA. Developing non-opioid pharmacotherapies for controlling this opioid epidemic is urgent. Dopamine D3 receptor (D3R) antagonists and low efficacy partial agonists have shown promising profiles in animal models of opioid use disorders (OUD). However, to date, advancement to human studies has been limited. Here we report the effects of (S)- and (R)-enantiomers of (±)-ABS01-113, structural analogs of the D3R partial agonist, (±)-VK4-40, in which the 3-OH in the linking chain is replaced by 3-F group. (S)- and (R)-ABS01-113 are identical in chemical structure but with opposite chirality. In vitro receptor binding and functional assays indicate that (S)-ABS01-113 is an efficacious (55%) and potent (EC50 = 7.6 ± 3.9 nM) D3R partial agonist, while the (R)-enantiomer is a potent D3R antagonist (IC50 = 11.4 nM). Both (S)- and (R)-ABS01-113 bind with high affinity to D3R (Ki = 0.84 ± 0.16 and 0.37 ± 0.06 nM, respectively); however, the (S)-enantiomer is more D3/D2-selective (>1000-fold). Pharmacokinetic analyses indicate that both enantiomers display excellent oral bioavailability and high brain penetration. Systemic administration of (S)- or (R)-ABS01-113 alone failed to alter open-field locomotion in male rats and mice. Interestingly, pretreatment with (S)- or (R)-ABS01-113 attenuated heroin-enhanced hyperactivity, heroin self-administration, and (heroin + cue)-induced reinstatement of drug-seeking behavior. Together, these findings reveal that both enantiomers, particularly the highly selective and efficacious D3R partial agonist (S)-ABS01-113, demonstrate promising translational potential for the treatment of OUD.


Assuntos
Transtornos Relacionados ao Uso de Opioides , Receptores de Dopamina D3 , Animais , Ratos , Masculino , Camundongos , Humanos , Receptores de Dopamina D3/metabolismo , Heroína , Antagonistas de Dopamina/farmacologia , Comportamento de Procura de Droga , Analgésicos Opioides/farmacologia , Agonistas de Dopamina/farmacologia
14.
Int Clin Psychopharmacol ; 37(6): 263-275, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-35815937

RESUMO

Antipsychotic polypharmacy in psychotic disorders is widespread despite international guidelines favoring monotherapy. Previous evidence indicates the utility of low-dose partial dopamine agonist (PDAs) add-ons to mitigate antipsychotic-induced metabolic adverse effects or hyperprolactinemia. However, clinicians are often concerned about using PDAs combined with high-potency, full dopaminergic antagonists (FDAs) due to the risk of psychosis relapse. We, therefore, conducted a literature review to find studies investigating the effects of combined treatment with PDAs (i.e. aripiprazole, cariprazine and brexpiprazole) and FDAs having a strong D 2 receptor binding affinity. Twenty studies examining the combination aripiprazole - high-potency FDAs were included, while no study was available on combinations with cariprazine or brexpiprazole. Studies reporting clinical improvement suggested that this may require a relatively long time (~11 weeks), while studies that found symptom worsening observed this happening in a shorter timeframe (~3 weeks). Patients with longer illness duration who received add-on aripiprazole on ongoing FDA monotherapy may be at greater risk for symptomatologic worsening. Especially in these cases, close clinical monitoring is therefore recommended during the first few weeks of combined treatment. These indications may be beneficial to psychiatrists who consider using this treatment strategy. Well-powered randomized clinical trials are needed to derive more solid clinical recommendations.


Assuntos
Antipsicóticos , Transtornos Psicóticos , Antipsicóticos/efeitos adversos , Aripiprazol/efeitos adversos , Dopamina , Agonistas de Dopamina/uso terapêutico , Antagonistas de Dopamina/uso terapêutico , Humanos , Polimedicação , Transtornos Psicóticos/tratamento farmacológico , Quinolonas , Tiofenos
15.
Anim Reprod Sci ; 244: 107036, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35908300

RESUMO

This paper describes a study in which different types of the reproduction of wild vimba bream (Vimba vimba) under controlled conditions were compared. Reproduction was performed by using three methods: spontaneous (natural spawning- NS groups): without hormones but with nests, semi-artificial (S groups) with hormones and nests, and artificial (A groups) with hormones and manual stripping of gametes. In groups S and A, different types of hormonal stimulation were tested: common carp pituitary homogenate (CPH), human chorionic gonadotropin (hCG), and commercial pellets containing mammalian GnRHa and dopamine antagonist-metoclopramide (Ovopel). The number of spawning fish, i.e., spermiating males and ovulating females, were compared depending on the type of breeding and the stimulant used. The lowest number of finally matured fish: spermiating males (67 %) and ovulating females (0 %) were noted in the spontaneously reproduced group. The best method of reproducing wild vimba bream under controlled conditions was the semi-artificial approach with hormonal stimulation and spawning nests, where ovulation rates in hormonally treated groups were between 43 % and 71 %, vs 26-57 % in artificial spawning groups. No ovulation observe in control groups in S and A types of reproduction. The highest embryo survival to the eyed-egg-stage was noted in group A-hCG (average 88.2). A higher value of spawning effectiveness (Se) with the use of the same hormones was obtained for groups S (0.374-0.574) than for groups A (0.252-0.493). In both cases, the highest Se was recorded for Ovopel stimulated fish and the lowest in hCG stimulated groups.


Assuntos
Gonadotropina Coriônica , Peixes , Reprodução , Animais , Gonadotropina Coriônica/farmacologia , Antagonistas de Dopamina , Feminino , Peixes/fisiologia , Humanos , Masculino , Hipófise , Reprodução/fisiologia
16.
Psychopharmacology (Berl) ; 239(9): 2985-2996, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35796814

RESUMO

RATIONALE: Learning the association between rewards and predictive cues is critical for appetitive behavioral responding. The mesolimbic dopamine system is thought to play an integral role in establishing these cue-reward associations. The dopamine response to cues can signal differences in reward value, though this emerges only after significant training. This suggests that the dopamine system may differentially regulate behavioral responding depending on the phase of training. OBJECTIVES: The purpose of this study was to determine whether antagonizing dopamine receptors elicited different effects on behavior depending on the phase of training or the type of Pavlovian task. METHODS: Separate groups of male rats were trained on Pavlovian tasks in which distinct audio cues signaled either differences in reward size or differences in reward rate. The dopamine receptor antagonist flupenthixol was systemically administered prior to either the first ten sessions of training (acquisition phase) or the second ten sessions of training (expression phase), and we monitored the effect of these manipulations for an additional ten training sessions. RESULTS: We identified acute effects of dopamine receptor antagonism on conditioned responding, the latency to respond, and post-reward head entries in both Pavlovian tasks. Interestingly, dopamine receptor antagonism during the expression phase produced persistent deficits in behavioral responding only in rats trained on the reward size Pavlovian task. CONCLUSIONS: Together, our results illustrate that dopamine's control over behavior in Pavlovian tasks depends upon one's prior training experience and the information signaled by the cues.


Assuntos
Condicionamento Operante , Dopamina , Animais , Condicionamento Clássico , Sinais (Psicologia) , Dopamina/metabolismo , Antagonistas de Dopamina/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Receptores Dopaminérgicos , Recompensa
17.
Neuroscience ; 499: 64-103, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35853563

RESUMO

Dopamine facilitates approach to reward via its actions on dopamine receptors in the nucleus accumbens. For example, blocking either D1 or D2 dopamine receptors in the accumbens reduces the proportion of reward-predictive cues to which rats respond with cued approach. Recent evidence indicates that accumbens dopamine also promotes wakefulness and arousal, but the relationship between dopamine's roles in arousal and reward seeking remains unexplored. Here, we show that the ability of systemic or intra-accumbens injections of the D1 antagonist SCH23390 to reduce cued approach to reward depends on the animal's state of arousal. Handling the animal, a manipulation known to increase arousal, was sufficient to reverse the behavioral effects of the antagonist. In addition, SCH23390 reduced spontaneous locomotion and increased time spent in sleep postures, both consistent with reduced arousal, but also increased time spent immobile in postures inconsistent with sleep. In contrast, the ability of the D2 antagonist haloperidol to reduce cued approach was not reversible by handling. Haloperidol reduced spontaneous locomotion but did not increase sleep postures, instead increasing immobility in non-sleep postures. We place these results in the context of the extensive literature on dopamine's contributions to behavior, and propose the arousal-motor hypothesis. This novel synthesis, which proposes that two main functions of dopamine are to promote arousal and facilitate motor behavior, accounts both for our findings and many previous behavioral observations that have led to disparate and conflicting conclusions.


Assuntos
Antagonistas de Dopamina , Dopamina , Animais , Nível de Alerta , Dopamina/fisiologia , Antagonistas de Dopamina/farmacologia , Haloperidol/farmacologia , Núcleo Accumbens , Ratos , Receptores de Dopamina D1 , Recompensa
18.
J Gen Virol ; 103(6)2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35731650

RESUMO

Oncolytic adenoviruses (OAds) have attracted much attention as novel anticancer agents. Numerous studies have examined the antitumour effects of combinational use of an OAd and anticancer agents; however, few chemical compounds enhancing OAd infection have been reported. In this study, we screened a food and drug administration (FDA)-approved drug library containing 1134 small chemical compounds to identify chemical compounds that enhance OAd replication in human tumour cells. We found that domperidone, a dopamine D2 receptor antagonist, significantly enhanced the replication of an OAd in human tumour cells, including human pancreatic tumour cells, by two-fivefold, resulting in improvement of OAd-mediated tumour cell killing activities. The E1A mRNA levels were significantly increased in domperidone-pre-treated cells following OAd infection, which contributed to the promotion of OAd replication. However, mRNA levels of the dopamine D2 receptor (DRD2), which is known to be a target molecule of domperidone, were undetectable in most of the tumour cells by real-time reverse transcription (RT)-PCR analysis, indicating that domperidone promoted OAd replication by acting on a molecule other than DRD2. This study provides important clues for the improvement of OAd-mediated cancer therapy.


Assuntos
Infecções por Adenoviridae , Antineoplásicos , Terapia Viral Oncolítica , Vírus Oncolíticos , Adenoviridae/genética , Linhagem Celular Tumoral , Domperidona/farmacologia , Antagonistas de Dopamina/farmacologia , Humanos , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/genética , RNA Mensageiro/genética
19.
eNeuro ; 9(4)2022.
Artigo em Inglês | MEDLINE | ID: mdl-35768212

RESUMO

The orbitofrontal cortex (OFC) and piriform cortex (Pir) play a role in fentanyl relapse after food choice-induced voluntary abstinence, a procedure mimicking abstinence because of availability of alternative nondrug rewards. We used in situ hybridization and pharmacology to determine the role of OFC and Pir cannabinoid and dopamine receptors in fentanyl relapse. We trained male and female rats to self-administer food pellets for 6 d (6 h/d) and intravenous fentanyl (2.5 µg/kg/infusion) for 12 d (6 h/d). We assessed fentanyl relapse after 12 discrete choice sessions between fentanyl and food (20 trials/d), in which rats voluntarily reduced fentanyl self-administration. We used RNAscope to determine whether fentanyl relapse is associated with activity (indicated by Fos) in OFC and Pir cells expressing Cnr1 [which encodes cannabinoid 1 (CB1) receptors] or Drd1 and Drd2 (which encode dopamine D1 and D2 receptors). We injected a CB1 receptor antagonist or agonist (0.3 or 1.0 µg AM251 or WIN55,212-2/hemisphere) into OFC or a dopamine D1 receptor antagonist (1.0 or 3.0 µg SCH39166/hemisphere) into Pir to determine the effect on fentanyl relapse. Fentanyl relapse was associated with OFC cells co-expressing Fos and Cnr1 and Pir cells co-expressing Fos and Drd1 However, injections of the CB1 receptor antagonist AM251 or agonist WIN55,212-2 into OFC or the dopamine D1 receptor antagonist SCH39166 into Pir had no effect on fentanyl relapse. Fentanyl relapse is associated with activation of Cnr1-expressing OFC cells and Drd1-expressing Pir cells, but pharmacological manipulations do not support causal roles of OFC CB1 receptors or Pir dopamine D1 receptors in fentanyl relapse.


Assuntos
Canabinoides , Córtex Piriforme , Animais , Canabinoides/farmacologia , Dopamina , Antagonistas de Dopamina/farmacologia , Feminino , Fentanila/farmacologia , Masculino , Ratos , Receptor CB1 de Canabinoide , Receptores de Dopamina D1/metabolismo , Recidiva
20.
Learn Mem ; 29(6): 142-145, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35577394

RESUMO

Dopamine participates in encoding memories and could either encode rewarding/aversive value of unconditioned stimuli or act as a novelty signal triggering contextual learning. Here we show that intraperitoneal injection of the dopamine D1/5R antagonist SCH23390 impairs contextual fear conditioning and tone-shock association, while intrahippocampal injection only impairs contextual fear conditioning. By using the context pre-exposure facilitation effect test, we show that SCH23390 is able to block the encoding of the context during the pre-exposure phase. Thus, we provide additional evidence that dopamine is involved in encoding conjunctive representations of new contexts.


Assuntos
Dopamina , Receptores de Dopamina D1 , Condicionamento Clássico , Antagonistas de Dopamina/farmacologia , Medo , Aprendizagem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...