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1.
Braz J Med Biol Res ; 52(11): e8899, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31664307

RESUMO

Few behavioral tests allow measuring several characteristics and most require training, complex analyses, and/or are time-consuming. We present an apparatus based on rat exploratory behavior. Composed of three different environments, it allows the assessment of more than one behavioral characteristic in a short 3-min session. Factorial analyses have defined three behavioral dimensions, which we named Exploration, Impulsivity, and Self-protection. Behaviors composing the Exploration factor were increased by chlordiazepoxide and apomorphine and decreased by pentylenetetrazole. Behaviors composing the Impulsivity factor were increased by chlordiazepoxide, apomorphine, and both acute and chronic imipramine treatments. Behaviors composing the Self-protection factor were decreased by apomorphine. We submitted Wistar rats to the open-field test, the elevated-plus maze, and to the apparatus we are proposing. Measures related to exploratory behavior in all three tests were correlated. Measures composing the factors Impulsivity and Self-protection did not correlate with any measures from the two standard tests. Also, compared with existing impulsivity tests, the one we proposed did not require previous learning, training, or sophisticated analysis. Exploration measures from our test are as easy to obtain as the ones from other standard tests. Thus, we have proposed an apparatus that measured three different behavioral characteristics, was simple and fast, did not require subjects to be submitted to previous learning or training, was sensitive to drug treatments, and did not require sophisticated data analyses.


Assuntos
Ansiedade/psicologia , Comportamento Animal/fisiologia , Pesquisa Comportamental/instrumentação , Comportamento Exploratório/fisiologia , Medo/fisiologia , Comportamento Impulsivo/fisiologia , Animais , Ansiolíticos/farmacologia , Antidepressivos Tricíclicos/farmacologia , Apomorfina/farmacologia , Comportamento Animal/efeitos dos fármacos , Clordiazepóxido/farmacologia , Agonistas de Dopamina/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Medo/efeitos dos fármacos , Antagonistas GABAérgicos/farmacologia , Comportamento Impulsivo/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Modelos Animais , Pentilenotetrazol/farmacologia , Ratos Wistar , Fatores de Tempo
2.
Curr Top Med Chem ; 19(16): 1365-1380, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31553283

RESUMO

The dopamine D1 receptor (D1R) is essential for neurotransmission in various brain pathways where it modulates key functions including voluntary movement, memory, attention and reward. Not surprisingly, the D1R has been validated as a promising drug target for over 40 years and selective activation of this receptor may provide novel neurotherapeutics for neurodegenerative and neuropsychiatric disorders. Several pharmacokinetic challenges with previously identified small molecule D1R agonists have been recently overcome with the discovery and advancement of new ligands, including drug-like non-catechol D1R agonists and positive allosteric modulators. From this, several novel molecules and mechanisms have recently entered clinical studies. Here we review the major classes of D1R selective ligands including antagonists, orthosteric agonists, non-catechol biased agonists and positive allosteric modulators, highlighting their structure-activity relationships and medicinal chemistry. Recent chemistry breakthroughs and innovative approaches to selectively target and activate the D1R also hold promise for creating pharmacotherapy for several neurological diseases.


Assuntos
Agonistas de Dopamina/farmacologia , Transtornos Mentais/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Receptores de Dopamina D1/agonistas , Animais , Agonistas de Dopamina/síntese química , Agonistas de Dopamina/química , Humanos , Ligantes , Transtornos Mentais/metabolismo , Estrutura Molecular , Doenças Neurodegenerativas/metabolismo , Receptores de Dopamina D1/metabolismo
3.
Psychopharmacology (Berl) ; 236(8): 2337-2358, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31324936

RESUMO

RATIONALE: Disorders of compulsivity such as stimulant use disorder (SUD) and obsessive-compulsive disorder (OCD) are characterised by deficits in behavioural flexibility, some of which have been captured using probabilistic reversal learning (PRL) paradigms. OBJECTIVES: This study used computational modelling to characterise the reinforcement learning processes underlying patterns of PRL behaviour observed in SUD and OCD and to show how the dopamine D2/3 receptor agonist pramipexole and the D2/3 antagonist amisulpride affected these responses. METHODS: We applied a hierarchical Bayesian method to PRL data across three groups: individuals with SUD, OCD, and healthy controls. Participants completed three sessions where they received placebo, pramipexole, and amisulpride, in a double-blind placebo-controlled, randomised design. We compared seven models using a bridge sampling estimate of the marginal likelihood. RESULTS: Stimulus-bound perseveration, a measure of the degree to which participants responded to the same stimulus as before irrespective of outcome, was significantly increased in SUD, but decreased in OCD, compared to controls (on placebo). Individuals with SUD also exhibited reduced reward-driven learning, whilst both the SUD and OCD groups showed increased learning from punishment (nonreward). Pramipexole and amisulpride had similar effects on the control and OCD groups; both increased punishment-driven learning. These D2/3-modulating drugs affected the SUD group differently, remediating reward-driven learning and reducing aspects of perseverative behaviour, amongst other effects. CONCLUSIONS: We provide a parsimonious computational account of how perseverative tendencies and reward- and punishment-driven learning differentially contribute to PRL in SUD and OCD. D2/3 agents modulated these processes and remediated deficits in SUD in particular, which may inform therapeutic effects.


Assuntos
Transtorno Obsessivo-Compulsivo/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Reversão de Aprendizagem/fisiologia , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Adulto , Estimulantes do Sistema Nervoso Central/uso terapêutico , Cognição/efeitos dos fármacos , Cognição/fisiologia , Agonistas de Dopamina/farmacologia , Agonistas de Dopamina/uso terapêutico , Antagonistas de Dopamina/farmacologia , Antagonistas de Dopamina/uso terapêutico , Antagonistas dos Receptores de Dopamina D2/farmacologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Neurológicos , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Transtorno Obsessivo-Compulsivo/psicologia , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D3/agonistas , Receptores de Dopamina D3/antagonistas & inibidores , Reversão de Aprendizagem/efeitos dos fármacos , Recompensa , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Transtornos Relacionados ao Uso de Substâncias/psicologia , Adulto Jovem
4.
Folia Med (Plovdiv) ; 61(2): 258-265, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31301661

RESUMO

BACKGROUND: Parkinson's disease (PD) is the second most common neurode-generative disease, usually detected by its motor symptoms. The non-motor symptoms, including cognitive deficits, have been of great interest to researchers in the last few decades. AIM: To assess the effect of pramipexole on learning and memory in naïve and haloperidol-challenged rats. MATERIALS AND METHODS: Male Wistar rats divided into 9 groups (n=8): naïve - saline, pramipexole 0.5; 1 and 3 mg/kg bw; Haloperidol groups - saline, haloperidol, haloperidol + pramipexole 0.5; 1 and 3 mg/kg bw. Two-way active avoidance test (TWAA) and activity cage were performed. The studied parameters were: number of conditioned and unconditioned responses, vertical and horizontal movements. Statistical analysis was done using SPSS 19. RESULTS: The naïve experimental groups significantly increased the number of conditioned responses during the tests for short- and long-term memory, compared with the saline groups (p<0.05). During the short-memory test only the animals with the lowest dose of PMX significantly increased the number of unconditioned responses whereas during the long-term memory test all experimental groups increased the number of escapes in comparison with the saline groups (p<0.05). Challenge dose of haloperidol attenuates learning and memory in pramipexol treated rats. Only the highest dose of pramipexol showed significant increase in conditioned and unconditioned responses compared with the haloperidol group (p<0.05). CONCLUSION: Pramipexole improves learning and memory in naïve rats by enhancing dopaminergic neurotransmission. This is probably not the only mechanism involved. This is confirmed by the decrease in learning and memory ability in rats with haloperidol-challenge.


Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Memória/efeitos dos fármacos , Pramipexol/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Haloperidol/farmacologia , Aprendizagem/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar
5.
Neurology ; 93(7): e675-e687, 2019 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-31311842

RESUMO

OBJECTIVE: To describe the prevalence, natural history, and risk factors for impulse control behaviors (ICBs) among people with Parkinson disease (PD), those with REM sleep behavior disorder (RBD), and controls. METHODS: Participants with early PD (within 3.5 years of diagnosis), those with RBD, and controls were clinically phenotyped and screened for ICBs longitudinally (with the Questionnaire for Impulsivity in Parkinson's Disease). ICB-positive individuals were invited for a semistructured interview, repeated 1 year later. The severity of the ICB was assessed with the Parkinson's Impulse Control Scale. Multiple imputation and regression models were used to estimate ICB prevalence and associations. RESULTS: Data from 921 cases of PD at baseline, 768 cases at 18 months, and 531 cases at 36 months were included, with 21% to 25% screening positive for ICBs at each visit. Interviews of ICB screen-positive individuals revealed that 10% met formal criteria for impulse control disorders (ICD), while 33% had subsyndromal ICD (ICB symptoms without reaching the formal diagnostic criteria for ICD). When these data were combined through the use of multiple imputation, the prevalence of PD-ICB was estimated at 19.1% (95% confidence interval 10.1-28.2). On follow-up, 24% of cases of subsyndromal ICD had developed full symptoms of an ICD. PD-ICD was associated with dopamine agonist use, motor complications, and apathy but not PD-RBD. ICD prevalence in the RBD group (1%) was similar to that in controls (0.7%). CONCLUSIONS: ICBs occur in 19.1% of patients with early PD, many persisting or worsening over time. RBD is not associated with increased ICD risk. Psychosocial drivers, including mood and support networks, affect severity.


Assuntos
Transtornos Disruptivos, de Controle do Impulso e da Conduta/complicações , Comportamento Impulsivo/efeitos dos fármacos , Doença de Parkinson/complicações , Transtorno do Comportamento do Sono REM/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Transtornos Disruptivos, de Controle do Impulso e da Conduta/tratamento farmacológico , Agonistas de Dopamina/farmacologia , Feminino , Humanos , Comportamento Impulsivo/fisiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Transtorno do Comportamento do Sono REM/complicações , Transtorno do Comportamento do Sono REM/tratamento farmacológico , Fatores de Risco
6.
Pharmacol Biochem Behav ; 184: 172737, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31228508

RESUMO

Methylphenidate (MPD) is a widely prescribed psychostimulant for the treatment of attention deficit hyperactivity disorder, and is growing in use as a recreational drug and academic enhancer. MPD acts on the reward/motive and motor circuits of the CNS to produce its effects on behavior. The caudate nucleus (CN) is known to be a part of these circuits, so a lesion study was designed to elucidate the role of the CN in response to acute and chronic MPD exposure. Five groups of n = 8 rats were used: control, sham CN lesions, non-specific electrolytic CN lesions, dopaminergic-specific (6-OHDA toxin) CN lesion, and glutaminergic-specific (ibotenic acid toxin) CN lesions. On experimental day (ED) 1, all groups received saline injections. On ED 2, surgeries took place, followed by a 5-day recovery period (ED 3-7). Groups then received six daily MPD 2.5 mg/kg injections (ED 9-14), then three days of washout with no injection (ED 15-17), followed by a re-challenge with the previous 2.5 mg/kg MPD dose (ED 18). Locomotive activity was recorded for 60 min after each injection by a computerized animal activity monitor. The electrolytic CN lesion group responded to the MPD acute and chronic exposures similarly to the control and sham groups, showing an increase in locomotive activity, i.e. sensitization. The dopaminergic-specific CN lesion group failed to respond to MPD exposure both acute and chronically. The glutaminergic-specific CN lesion group responded to MPD exposure acutely but failed to manifest chronic effects. This confirms the CN's dopaminergic system is necessary for MPD to manifest its acute and chronic effects on behavior, and demonstrates that the CN's glutaminergic system is necessary for the chronic effects of MPD such as sensitization. Thus, the dopaminergic and glutaminergic components of the CN play a significant role in differentially modulating the acute and chronic effects of MPD respectively.


Assuntos
Comportamento Animal/efeitos dos fármacos , Núcleo Caudado/metabolismo , Estimulantes do Sistema Nervoso Central/farmacologia , Agonistas de Dopamina/farmacologia , Ácido Glutâmico/metabolismo , Metilfenidato/farmacologia , Animais , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Núcleo Caudado/anatomia & histologia , Núcleo Caudado/cirurgia , Estimulantes do Sistema Nervoso Central/administração & dosagem , Dopamina/metabolismo , Agonistas de Dopamina/administração & dosagem , Agonistas de Dopamina/uso terapêutico , Relação Dose-Resposta a Droga , Locomoção/efeitos dos fármacos , Masculino , Metilfenidato/administração & dosagem , Metilfenidato/uso terapêutico , Motivação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Recompensa
7.
Adv Pharmacol ; 84: 79-100, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31229178

RESUMO

Dopaminergic treatments targeting the D3 receptor subtype to reduce the symptoms of RLS show substantial initial clinical benefits but fail to maintain their efficacy over time. Sensorimotor circuits in the spinal cord are the gateway for the sensory processing of the symptoms and critical for the associated leg movements that relieve the symptoms and the periodic limb movements that often develop during sleep. There is a high preponderance of the inhibitory D3 receptor in the sensory-processing areas of the spinal cord (dorsal horn), whereas the motor areas in the ventral horn more strongly express the excitatory D1 receptor subtype. D3 and D1 receptors can form functional heteromeric ensembles that influence each other. In the spinal cord, long-term treatment with D3 receptor agonists is associated with the upregulation of the D1 receptor subtype and block of D1 receptor function at this stage can restore the D3 receptor effect. Alternate scenarios for a role of dopamine involve a role for the D5 receptor in regulating motor excitability and for the D4 receptor subtype in controlling D3-like effects. A model emerges that proposes that the behavioral changes in RLS, while responsive to D3 receptor agonists, may be ultimately be the result of unmasked increased D1-like receptor activities.


Assuntos
Agonistas de Dopamina/uso terapêutico , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D3/metabolismo , Síndrome das Pernas Inquietas/tratamento farmacológico , Yin-Yang , Animais , Dopamina/metabolismo , Agonistas de Dopamina/farmacologia , Humanos , Modelos Biológicos
8.
Psychopharmacology (Berl) ; 236(8): 2307-2323, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31218428

RESUMO

RATIONALE: Dopamine D2-like receptors (D2R) are important drug targets in schizophrenia and Parkinson's disease, but D2R ligands also cause cognitive inflexibility such as poor reversal learning. The specific role of D2R in reversal learning remains unclear. OBJECTIVES: We tested the hypotheses that D2R agonism impairs reversal learning by blocking negative feedback and that antagonism of D1-like receptors (D1R) impairs learning from positive feedback. METHODS: Male Lister Hooded rats were trained on a novel visual reversal learning task. Performance on "probe trials", during which the correct or incorrect stimulus was presented with a third, probabilistically rewarded (50% of trials) and therefore intermediate stimulus, revealed individual learning curves for the processes of positive and negative feedback. The effects of D2R and D1R agonists and antagonists were evaluated. A separate cohort was tested on a spatial probabilistic reversal learning (PRL) task after D2R agonism. Computational reinforcement learning modelling was applied to choice data from the PRL task to evaluate the contribution of latent factors. RESULTS: D2R agonism with quinpirole dose-dependently impaired both visual reversal and PRL. Analysis of the probe trials on the visual task revealed a complete blockade of learning from negative feedback at the 0.25 mg/kg dose, while learning from positive feedback was intact. Estimated parameters from the model that best described the PRL choice data revealed a steep and selective decrease in learning rate from losses. D1R antagonism had a transient effect on the positive probe trials. CONCLUSIONS: D2R stimulation impairs reversal learning by blocking the impact of negative feedback.


Assuntos
Retroalimentação Fisiológica/fisiologia , Estimulação Luminosa/métodos , Receptores de Dopamina D2/metabolismo , Reversão de Aprendizagem/fisiologia , Percepção Espacial/fisiologia , Animais , Dopamina/farmacologia , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Retroalimentação Fisiológica/efeitos dos fármacos , Masculino , Ratos , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/agonistas , Reversão de Aprendizagem/efeitos dos fármacos , Percepção Espacial/efeitos dos fármacos , Percepção Visual/efeitos dos fármacos , Percepção Visual/fisiologia
9.
Eur J Pharmacol ; 859: 172499, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31242439

RESUMO

The leading causes of death in breast cancer patients are disease recurrence and metastasis. Growing evidence has suggested that metastasis possibly originates from cancer stem-like cells (CSCs). Previous studies indicated dopamine decreased CSC frequency through activating dopamine D1 receptor pathway. Hence, this study explored the efficacy of two dopamine D1 receptor agonists in lung metastasis of breast cancer and the preliminary mechanism. The two dopamine D1 receptor agonists, fenoldopam (FEN) and l-stepholidine (l-SPD), performed well in decreasing lung metastasis in 4T1 breast cancer model. And the cGMP in the primary tumor was significantly elevated while cAMP mildly elevated in FEN and l-SPD dosing groups. CSC markers (CD44+/CD24- and ALDH+) and MMP2 in 4T1 primary tumor were repressed after dopamine D1 receptor agonist administration while E-cadherin up-regulated. FEN and l-SPD also inhibited cancer stemness and cell motility in vitro, and the inhibitory effects could be reversed by dopamine D1 receptor antagonist SCH23390. Besides, FEN impacted the white blood cell increase caused by breast cancer disease showing decreased neutrophils but increased lymphocytes. Drug safety was verified in aspects of body weight, organ index and tissue section. In conclusion, dopamine D1 receptor agonists FEN and l-SPD showed efficacy in inhibiting metastasis along with good safety in breast cancer, thus providing an alternative for anti-metastasis therapy in the future. Furthermore, this study also indicates that dopamine D1 receptor may be a possible target for metastatic breast cancer treatment and even other cancers at a late stage.


Assuntos
Berberina/análogos & derivados , Neoplasias da Mama/patologia , Agonistas de Dopamina/farmacologia , Fenoldopam/farmacologia , Neoplasias Pulmonares/secundário , Células-Tronco Neoplásicas/patologia , Receptores de Dopamina D1/metabolismo , Animais , Berberina/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/prevenção & controle , Camundongos , Mucina-1/efeitos dos fármacos , Células-Tronco Neoplásicas/efeitos dos fármacos
10.
Spectrochim Acta A Mol Biomol Spectrosc ; 222: 117185, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31177005

RESUMO

Density functional theory is one of the most popular accepted computational quantum mechanical techniques used in the analysis of molecular structure and vibrational spectra. Experimental and theoretical investigations of the molecular structure, electronic and vibrational characteristics of 4-[2-(Dipropylamino) ethyl]-1,3-dihydro-2H-indol-2-one are presented in this work. The title compound was characterized using FT-IR, FT-Raman and UV-Vis spectroscopic techniques. The results were compared with the theoretical calculations obtained using DFT/B3LYP with 6-311++G(d,p) as basis sets and was found to be in good agreement. The complete optimization of the molecular geometry of the title compound was carried out. Further, the vibrational assignments and calculation of potential energy distribution (PED) were reported. NLO has emerged as a key factor in recent researches. Materials showing nonlinear optical properties form the basis of nonlinear optics and development of such materials plays an important role in the present scenario. The current work provides sufficient justification for the title compound to be selected as a good non-linear optical (NLO) candidate. The electronic properties were reported using TD-DFT approach. The HOMO (EHOMO = -5.96 eV), LUMO (ELUMO = -0.80 eV) energies, energy gap and electrophilicity (2.22) was calculated in order to understand the stability, reactivity and bioactivity of the compound under investigation. To comprehend the bonding interactions we have performed the total (TDOS), partial (PDOS) and overlap population or COOP (Crystal Orbital Overlap Population) density of states. The drug likeness values were analyzed to evaluate the potential of the title compound to be an active pharmaceutical component. As a positive proof the paper further explains the molecular docking studies of the said compound. In addition, the stereochemistry of the protein structure was checked using Ramachandran plot. The title compound is a directly acting dopamine D2 agonist. In order to establish relationship between molecular descriptors of compound and its biological activity, QSAR studies have been done within the framework of DFT for 10 dopamine agonist including the title compound. Hence, the research exploration provides requisite information pertaining to the geometry, stability, reactivity and bioactivity of the compound through spectroscopic and quantum chemical methods.


Assuntos
Agonistas de Dopamina/química , Agonistas de Dopamina/farmacologia , Oxindois/química , Oxindois/farmacologia , Receptores de Dopamina D2/metabolismo , Teoria da Densidade Funcional , Humanos , Simulação de Acoplamento Molecular , Relação Quantitativa Estrutura-Atividade , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral Raman
11.
Anim Reprod Sci ; 207: 73-82, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31208851

RESUMO

A dopamine type-2 receptor (DRD2) SNP, previously found to be correlated with serum prolactin (PRL) concentrations in cattle, was evaluated for impact on growth traits, serum prolactin concentration, and semen quality. Over a four-year period, yearling beef bulls were allowed diets containing or lacking ergot alkaloids (EA). Every 21 or 28 d semen was collected for semen motility and morphology assessment and blood samples were collected to measure serum PRL concentrations. In addition, body condition score and scrotal circumference were evaluated. Serum PRL concentrations were assessed using a radioimmunoassay. In the first year, all bulls were sacrificed at the end of a 126-day study. Testicles and epididymis were collected at the end of the study or 60 days after removal from treatment. Immunohistochemistry was performed on testis, epididymis, and sperm cells, incubated with or without a primary antibody for DRD2 and counterstained with DAPI. Isolation of DNA was performed on sperm pellets using DNAzol (Thermo Fisher Scientific, Waltham, MA, USA) methods. Polymerase chain reaction was performed to amplify the region of the DRD2 gene containing the SNP of interest. The products were subjected to restriction fragment length polymorphism analysis. Further, all samples were subjected to genotyping using a custom Taqman genotyping assay (Applied Biosystems, Foster city, CA, USA). The presence of DRD2 was detected in the testis, epididymis, and sperm cells. The DRD2 genotype was not associated with semen quality, serum PRL, or growth traits. Consumption of EA resulted in lesser PRL serum concentrations but had no effect on values for other variable examined.


Assuntos
Bovinos , Agonistas de Dopamina/farmacologia , Crescimento e Desenvolvimento , Polimorfismo de Nucleotídeo Único , Prolactina/sangue , Receptores de Dopamina D2/genética , Sêmen/efeitos dos fármacos , Animais , Constituição Corporal/genética , Bovinos/sangue , Bovinos/genética , Bovinos/crescimento & desenvolvimento , Dopamina/sangue , Genótipo , Crescimento e Desenvolvimento/efeitos dos fármacos , Crescimento e Desenvolvimento/genética , Masculino , Sêmen/metabolismo , Sêmen/fisiologia , Análise do Sêmen/veterinária , Motilidade Espermática/efeitos dos fármacos , Motilidade Espermática/genética
12.
Psychopharmacology (Berl) ; 236(8): 2325-2336, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31201476

RESUMO

RATIONALE: Patients with obsessive-compulsive disorder (OCD) have been found to show exaggerated error responses and prediction error learning signals in a variety of EEG and fMRI tasks, with data converging on the anterior cingulate cortex as a key locus of dysfunction. Considerable evidence has linked prediction error processing to dopaminergic function. OBJECTIVE: In this study, we investigate potential dopaminergic dysfunction during reward processing in the context of OCD. METHODS: We studied OCD patients (n = 18) and controls (n = 18) whilst they learned probabilistic associations between abstract stimuli and monetary rewards in the fMRI scanner involving administration (on separate visits) of a dopamine receptor agonist, pramipexole 0.5 mg; a dopamine receptor antagonist, amisulpride 400 mg; and placebo. We fitted a Q-learning computational model to fMRI prediction error responses; group differences were examined in anterior cingulate and nucleus accumbens regions of interest. RESULTS: There were no significant group, drug, or interaction effects in the number of correct choices; computational modeling suggested a marginally significant difference in learning rates between groups (p = 0.089, partial ƞ2 = 0.1). In the imaging results, there was a significant interaction of group by drug (p = 0.013, partial ƞ2 = 0.13). OCD patients showed abnormally strong cingulate signaling of prediction errors during omission of an expected reward, with unexpected reduction by both pramipexole and amisulpride (p = 0.014, partial ƞ2 = 0.26, 1-ß error probability = 0.94). Exaggerated cingulate prediction error signaling to omitted reward in placebo was related to trait subjective difficulty in self-regulating behavior in OCD. CONCLUSIONS: Our data support cingulate dysfunction during reward processing in OCD, and bidirectional remediation by dopaminergic modulation, suggesting that exaggerated cingulate error signals in OCD may be of dopaminergic origin. The results help to illuminate the mechanisms through which dopamine receptor antagonists achieve therapeutic benefit in OCD. Further research is needed to disentangle the different functions of dopamine receptor agonists and antagonists during bidirectional modulation of cingulate activation.


Assuntos
Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Giro do Cíngulo/efeitos dos fármacos , Giro do Cíngulo/diagnóstico por imagem , Transtorno Obsessivo-Compulsivo/diagnóstico por imagem , Recompensa , Adulto , Dopamina/metabolismo , Método Duplo-Cego , Feminino , Previsões , Giro do Cíngulo/metabolismo , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Núcleo Accumbens/diagnóstico por imagem , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Transtorno Obsessivo-Compulsivo/metabolismo , Estimulação Luminosa/métodos
13.
Neurol Sci ; 40(9): 1917-1923, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31111272

RESUMO

Continuous subcutaneous apomorphine infusion (CSAI) is a well-recognized therapeutic option for the management of motor fluctuations in Parkinson's disease (PD), although clinical experience suggests that most patients discontinue CSAI after a variable amount of time due to several causes and circumstances. The objective of the present study was to evaluate the reasons of CSAI discontinuation and to investigate which treatment was adopted afterwards. Two independent raters retrospectively reviewed the electronic medical record of 114 patients treated with CSAI for at least 6 months. The records were reviewed regarding efficacy, safety, and evolution of CSAI treatment. Most of PD patients on CSAI had a significant improvement in their clinical condition. Lack of improvement of dyskinesia was the most frequent causes of treatment discontinuation. The second reason for CSAI discontinuation was cognitive deterioration. At CSAI discontinuation, younger patients were more likely to undergo deep brain stimulation (DBS), while older patients and patients with cognitive impairment were more likely switched to oral therapy alone (OTA). CSAI is an effective treatment that unfortunately must be discontinued in a great number of patients with advanced PD. As older age is the main limiting factor for accessing second-level therapies at CSAI discontinuation, CSAI treatment should not be postponed to older age. CSAI might be considered a good first-line and fast strategy in patients undergoing rapid deterioration of their quality of life while waiting for DBS or levodopa/carbidopa intestinal gel therapy.


Assuntos
Apomorfina/farmacologia , Agonistas de Dopamina/farmacologia , Infusões Subcutâneas , Adesão à Medicação , Doença de Parkinson/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Apomorfina/administração & dosagem , Apomorfina/efeitos adversos , Carbidopa/administração & dosagem , Disfunção Cognitiva , Estimulação Encefálica Profunda , Agonistas de Dopamina/administração & dosagem , Agonistas de Dopamina/efeitos adversos , Combinação de Medicamentos , Substituição de Medicamentos , Registros Eletrônicos de Saúde , Feminino , Humanos , Levodopa/administração & dosagem , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/fisiopatologia , Estudos Retrospectivos
14.
Behav Pharmacol ; 30(4): 370-375, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31085944

RESUMO

Consuming a high fat diet can lead to many negative health consequences, such as obesity, insulin resistance, and enhanced sensitivity to drugs acting on dopamine systems. It has recently been demonstrated that dietary supplementation with fish oil, which is rich in omega-3 fatty acids, can prevent this high fat diet-induced enhanced sensitivity to dopaminergic drugs from developing. However, it is not known whether fish oil supplementation can reverse this effect once it has already developed. To test the hypothesis that dietary supplementation with fish oil will reverse high fat diet-induced enhanced sensitivity to quinpirole, a dopamine D2/D3 receptor agonist, male Sprague-Dawley rats were fed either standard chow (17% kcal from fat), high fat chow (60% kcal from fat), standard chow, or high fat chow supplemented with 20% (w/w) fish oil. Body weight, food consumption, and sensitivity to quinpirole-induced (0.0032-0.32 mg/kg) penile erections were examined throughout the course of the experiment. Eating high fat chow enhanced sensitivity of rats to quinpirole-induced penile erections (i.e. resulted in a leftward shift of the ascending limb of the dose-response curve). Dietary supplementation with fish oil successfully treated this effect, as dose-response curves were not different for rats eating standard chow and rats eating high fat chow with fish oil. These results suggest that in addition to preventing the negative health consequences of eating a high fat diet, fish oil can also reverse some of these consequences once they have developed.


Assuntos
Comportamento Animal/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Óleos de Peixe/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Suplementos Nutricionais , Dopaminérgicos/metabolismo , Agonistas de Dopamina/farmacologia , Resistência à Insulina/fisiologia , Masculino , Obesidade/tratamento farmacológico , Ereção Peniana/efeitos dos fármacos , Quimpirol/metabolismo , Quimpirol/farmacologia , Ratos , Receptores de Dopamina D2 , Receptores de Dopamina D3
15.
Neuroscience ; 410: 76-96, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31078685

RESUMO

Parkinson's disease (PD) is a neurodegenerative illness presenting motor and non-motor symptoms due to the loss of dopaminergic terminals in basal ganglia, most importantly, the striatum. L-DOPA relieves many motor signs. Unfortunately, in the long term, L-DOPA use causes motor disabilities by itself and does not act in comorbid conditions such as depression. These deficiencies have led to search for drugs such as dopamine (DA) receptor agonists (DA-agonists) that allow the reduction of L-DOPA dose. Previously, we have identified the attributes of non-stimulated (resting) and cortical stimulated (active) striatal microcircuits following the activity of dozens of neurons simultaneously using calcium imaging in brain slices. We also have characterized the changes that take place in DA-depleted microcircuits in vitro. In control conditions, there is low spontaneous activity. After cortical stimulation (CtxS) sequences and alternation of neuronal ensembles activity occur, including reverberations. In contrast, DA-deprived circuits exhibit high spontaneous activity at rest, and a highly recurrent ensemble curtails alternation. Interestingly, CtxS briefly relieves these Parkinsonian signs in DA-depleted tissue. Here we compare the actions of some DA-agonists used in PD therapeutics on the pathological dynamics of DA-depleted microcircuits at rest and with CtxS; taking L-DOPA as reference. D2-class agonists better reduce the excessive spontaneous activity of DA-depleted microcircuits. All DA-agonists tend to maintain ensemble alternation seen in control circuits after CtxS. However, quantitative analyses suggest differences in their actions: in general, DA-agonists only approximate L-DOPA actions. Nonetheless no treatment, including L-DOPA, completely restores microcircuit dynamics to control conditions.


Assuntos
Corpo Estriado/metabolismo , Agonistas de Dopamina/farmacologia , Dopamina/metabolismo , Levodopa/farmacologia , Rede Nervosa/metabolismo , Animais , Corpo Estriado/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Rede Nervosa/efeitos dos fármacos , Técnicas de Cultura de Órgãos
16.
Int J Mol Sci ; 20(10)2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31137460

RESUMO

The ghrelin system has received substantial recognition as a potential target for novel anti-seizure drugs. Ghrelin receptor (ghrelin-R) signaling is complex, involving Gαq/11, Gαi/o, Gα12/13, and ß-arrestin pathways. In this study, we aimed to deepen our understanding regarding signaling pathways downstream the ghrelin-R responsible for mediating anticonvulsive effects in a kindling model. Mice were administered the proconvulsive dopamine 1 receptor-agonist, SKF81297, to gradually induce a kindled state. Prior to every SKF81297 injection, mice were treated with a ghrelin-R full agonist (JMV-1843), a Gαq and Gα12 biased ligand unable to recruit ß-arrestin (YIL781), a ghrelin-R antagonist (JMV-2959), or saline. Mice treated with JMV-1843 had fewer and less severe seizures compared to saline-treated controls, while mice treated with YIL781 experienced longer and more severe seizures. JMV-2959 treatment did not lead to differences in seizure severity and number. Altogether, these results indicate that the Gαq or Gα12 signaling pathways are not responsible for mediating JMV-1843's anticonvulsive effects and suggest a possible involvement of ß-arrestin signaling in the anticonvulsive effects mediated by ghrelin-R modulation.


Assuntos
Encéfalo/metabolismo , Excitação Neurológica , Receptores de Grelina/agonistas , Animais , Benzazepinas/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Agonistas de Dopamina/farmacologia , Glicina/análogos & derivados , Glicina/farmacologia , Indóis/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Piperidinas/farmacologia , Quinazolinonas/farmacologia , Receptores de Grelina/antagonistas & inibidores , Triazóis/farmacologia , Triptofano/análogos & derivados , Triptofano/farmacologia , beta-Arrestinas/farmacologia
17.
Neuropharmacology ; 155: 1-9, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31085186

RESUMO

Medications that enhance dopaminergic neurotransmission can be useful in the pharmacotherapy of posttraumatic stress disorder (PTSD), which manifests as fearful memory retrieval, anxiety and depression. We examined the effects of subchronic (15 days) treatment with select dopaminergic medications, including bromocriptine, modafinil, dihydrexidine, rotigotine and pramipexole, in a mouse model of PTSD induced by single prolonged stress (mSPS). The potential antidepressant-like and anxiolytic effects of the medications were measured by the forced swim test (FST) and the elevated plus maze (EPM) test, respectively. In addition, we studied the effects of these medications on memory retrieval in an auditory fear conditioning (FC) test, on ultrasonic vocalizations (USVs) induced by restraint stress, and on spontaneous locomotor activity (SLA). We report that a single exposure to a severe and complex set of stressors several days before testing increased immobility time in the FST and freezing in the FC paradigm and reduced the time spent in the open arms of the EPM. The stressed mice also displayed increased USVs, especially the short type. While none of the tested dopamine-mimetics exhibited anxiolytic-like effects, rotigotine produced antidepressant-like activity specifically in the mSPS-exposed animals. Moreover, both rotigotine and pramipexole shortened the duration of freezing in the fear conditioning test, but only in the mSPS-exposed mice. This study supports the hypothesis that the activation of dopaminergic D2/D3 receptors may be a promising pharmacotherapy for PTSD.


Assuntos
Agonistas de Dopamina/uso terapêutico , Receptores de Dopamina D2 , Receptores de Dopamina D3/agonistas , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Transtornos de Estresse Pós-Traumáticos/psicologia , Animais , Agonistas de Dopamina/farmacologia , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Ratos , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Transtornos de Estresse Pós-Traumáticos/metabolismo , Estresse Psicológico/tratamento farmacológico , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia , Vocalização Animal/efeitos dos fármacos , Vocalização Animal/fisiologia
18.
Pharmacol Biochem Behav ; 181: 77-85, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31034853

RESUMO

Rats can emit 22-kHz or 50-kHz ultrasonic vocalizations (USVs) in negative, as well as positive contexts which index their emotional state. 22-kHz USVs are emitted during aversive contexts and can be initiated by activation of the ascending cholinergic pathways originating from the laterodorsal tegmental nucleus or initiated pharmacologically by injection of cholinergic agonists into target areas of these pathways (medial cholinoceptive vocalization strip). Conversely, 50-kHz USVs are emitted during positive pro-social contexts and can be initiated by stimulation of ascending dopaminergic pathways originating from the ventral tegmental area or by injection of dopamine agonists into target areas of these pathways (nucleus accumbens shell). Recently, we have shown an inhibitory effect a positive emotional state has on the emission of carbachol-induced 22-kHz USVs from the anterior hypothalamic/medial preoptic area. However, this structure is a fragment of that cholinoceptive vocalization strip. We wanted to examine if we could observe similar effect when the aversive state is induced from the lateral septum, the most rostral division of the cholinoceptive vocalization strip. The results supported previous findings. First, microinjection of the dopamine agonist R-(-)-apomorphine into the nucleus accumbens shell resulted in increased emission of frequency modulated (FM) 50-kHz USVs that are regarded as signals expressing a positive emotional state in rats. Second, FM 50-kHz USVs and not flat (F) 50-kHz USVs were able to decrease 22-kHz USVs induced by microinjections of carbachol into the lateral septum. This research provides further support to the hypothesis that the initiation of a positive emotional state functionally antagonizes initiation of a negative emotional state in rats.


Assuntos
Apomorfina/farmacologia , Carbacol/farmacologia , Agonistas Colinérgicos/farmacologia , Agonistas de Dopamina/farmacologia , Emoções/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Núcleos Septais/efeitos dos fármacos , Ondas Ultrassônicas , Vocalização Animal/efeitos dos fármacos , Análise de Variância , Animais , Apomorfina/administração & dosagem , Carbacol/administração & dosagem , Agonistas Colinérgicos/administração & dosagem , Agonistas de Dopamina/administração & dosagem , Masculino , Microinjeções , Núcleo Accumbens/metabolismo , Ratos , Núcleos Septais/metabolismo , Ultrassom/métodos
19.
Drugs ; 79(7): 693-703, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30968290

RESUMO

Dopamine agonists (DAs) represent an excellent treatment option for patients with Parkinson's disease, in both the early and advanced stages of the disease, improving motor symptoms, lowering the incidence of motor complications, and addressing several non-motor symptoms. Indeed, each of these compounds have different pharmacokinetic and pharmacodynamic properties, resulting in a unique efficacy and safety profile. Comorbidities, prominent non-motor symptoms and individual subjects' clinical characteristics should guide the choice of a specific DA, allowing better management of the patient by optimizing the DA benefit/risk ratio. In this article we discuss brain distribution of dopamine receptors and their role in each of the dopaminergic pathways, the pharmacological profile of non-ergoline DAs and class-related adverse effects, as reported from post-marketing studies.


Assuntos
Antiparkinsonianos/química , Agonistas de Dopamina/química , Doença de Parkinson/tratamento farmacológico , Receptores Dopaminérgicos/metabolismo , Antiparkinsonianos/farmacologia , Encéfalo , Dopamina/metabolismo , Agonistas de Dopamina/farmacologia , Desenho de Drogas , Humanos , Estrutura Molecular , Transdução de Sinais , Relação Estrutura-Atividade
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