RESUMO
The auditory mismatch negativity (MMN) has been proposed as a biomarker of NMDA receptor (NMDAR) dysfunction in schizophrenia. Such dysfunction may be caused by aberrant interactions of different neuromodulators with NMDARs, which could explain clinical heterogeneity among patients. In two studies (N = 81 each), we used a double-blind placebo-controlled between-subject design to systematically test whether auditory mismatch responses under varying levels of environmental stability are sensitive to diminishing and enhancing cholinergic vs. dopaminergic function. We found a significant drug × mismatch interaction: while the muscarinic acetylcholine receptor antagonist biperiden delayed and topographically shifted mismatch responses, particularly during high stability, this effect could not be detected for amisulpride, a dopamine D2/D3 receptor antagonist. Neither galantamine nor levodopa, which elevate acetylcholine and dopamine levels, respectively, exerted significant effects on MMN. This differential MMN sensitivity to muscarinic versus dopaminergic receptor function may prove useful for developing tests that predict individual treatment responses in schizophrenia.
Assuntos
Dopamina , Potenciais Evocados Auditivos , Acetilcolina/farmacologia , Estimulação Acústica , Colinérgicos , Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Eletroencefalografia , Potenciais Evocados Auditivos/fisiologia , Humanos , Antagonistas Muscarínicos/farmacologia , Receptores DopaminérgicosRESUMO
Current therapies for gastroparesis metoclopramide and domperidone carry risks of extrapyramidal symptoms and life-threatening cardiac arrhythmias. Trazpiroben, a novel, potent dopamine D2/D3 receptor antagonist, has low brain permeation and very low affinity for human ether-à-go-go-related gene (hERG) channel inhibition, potentially improving on safety profiles of existing therapies. Trazpiroben demonstrated the following receptor affinities: high for D2 and D3, moderate for D4, and minimal for D1 and D5 It demonstrated moderate affinity for adrenergic α 1B (α 1B) and 5-hydroxytryptamine (5HT) 2A receptors and low potential for off-target adverse events (AEs). Trazpiroben potently inhibited dopamine-activated D2L receptor activation of cognate G-proteins in human embryonic kidney 293 cell membranes and was a neutral D2L receptor antagonist. In vivo, trazpiroben dose-dependently increased prolactin release in orally dosed rat (0.1-1 mg/kg). Additionally, multiple oral doses in the rat (100 mg/kg) and dog (50 mg/kg) for 3 days produced robust plasma exposures and prolactin increases in both species. Trazpiroben inhibited retching/vomiting in the dog with apomorphine-induced emesis with a potency (0.1-1 mg/kg) like that of trazpiroben-mediated prolactin increases in rat. Oral trazpiroben (1, 10, and 30 mg/kg) did not affect rat rotarod performance, suggesting low brain penetration. Trazpiroben concentrations were low in cerebrospinal fluid versus plasma after multiple oral doses for 4 days in rat and dog. Trazpiroben weakly inhibited the hERG channel current (concentration causing half-maximal inhibition of control-specific binding of 15.6 µM), indicating little potential for disrupting cardiac rhythm. Overall, trazpiroben is a potent D2/D3 receptor antagonist designed to avoid the serious potential AEs associated with current gastroparesis therapies. SIGNIFICANCE STATEMENT: Trazpiroben is a novel, potent dopamine D2/D3 selective receptor antagonist designed to avoid adverse effects associated with the current pharmacological therapies metoclopramide and domperidone. Preclinical studies have demonstrated low brain penetration and weak affinity for the hERG channel, indicating that trazpiroben is not expected to be associated with central nervous system or cardiovascular safety issues. With these pharmacological properties, trazpiroben may represent a viable new treatment option for gastroparesis because of a potentially improved safety profile relative to existing therapies.
Assuntos
Antagonistas dos Receptores de Dopamina D2/uso terapêutico , Gastroparesia/tratamento farmacológico , Receptores de Dopamina D3/antagonistas & inibidores , Triazóis/uso terapêutico , Animais , Antieméticos/farmacologia , Antieméticos/uso terapêutico , Células CHO , Cricetinae , Cricetulus , Cães , Domperidona/análogos & derivados , Domperidona/farmacologia , Domperidona/uso terapêutico , Antagonistas de Dopamina/química , Antagonistas de Dopamina/farmacologia , Antagonistas de Dopamina/uso terapêutico , Antagonistas dos Receptores de Dopamina D2/química , Antagonistas dos Receptores de Dopamina D2/farmacologia , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Células HEK293 , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Triazóis/farmacologiaRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Dopamine receptors are long-standing primary targets in the treatment of mental diseases and there is growing evidence that suggests relationships between obesity and the dopamine system, especially dopamine D1 and D2 receptors. Leaves of Nelumbo nucifera Gaertn. (lotus leaves) have been medically used for helping long-term maintenance of weight loss. Whether and how components of lotus leaves function through the dopamine receptors remains unclear. AIM OF THE STUDY: This work aimed to discover dopamine receptor-active alkaloids isolated from the lotus leaves, to evaluate their potencies and to analyze their structure activity relationship. MATERIALS AND METHODS: Dried lotus leaves were prepared and total extract was divided into alkaloids and flavones. Eight alkaloids were separated and characterized by a combination of high-performance liquid chromatography, quadrupole time-of-flight mass spectrometry and nuclear magnetic resonance, and assayed by a fluorometric imaging plate reader platform. Human embryonic kidney 239 cell lines expressing dopamine D1, D2 and serotonin 2A (5-HT2A) receptors, respectively, were cultured and used in the assay. RESULTS: Alkaloids in the lotus leaves were the bioactive phytochemicals and inhibited dopamine from accessing the D1 and D2 receptors. All eight compounds functioned as D1-receptor antagonists and except N-nornuciferine, seven alkaloids functioned as D2-receptor antagonists. (S)-coclaurine and (R)-coclaurine are optical isomers and antagonized both D1 and D2 with equivalent potencies, suggesting that the optical rotation of the methylene linker in the monobenzyl isoquinoline backbone did not influence their activity. Among the eight alkaloids, O-nornuciferine was the potent antagonist to both receptors (the lowest IC50 values, D1: 2.09 ± 0.65 µM and D2: 1.14 ± 0.10 µM) while N-nornuciferine was found to be the least potent as it moderately antagonized D1 and was inactive on D2. O-nornuciferine was also a 5-HT2A antagonist (IC50~20 µM) while N-nornuciferine had no activity. These hinted the importance of a methyl group attached to the nitrogen atom in the aporphine backbone. Armepavine showed a nearly 10-fold selectivity to D2. CONCLUSIONS: In this work, eight alkaloids were isolated from the leaves of Nelumbo nucifera Gaertn. and assayed on the D1 and D2 receptors. They were D1/D2 antagonists with IC50 values in the mid- to low-micromolar range and O-nornuciferine was the most potent alkaloid among the eight. This family of alkaloids was biochemically evaluated on the dopamine receptors by the same platform for the first time.
Assuntos
Alcaloides/farmacologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Nelumbo/química , Extratos Vegetais/química , Folhas de Planta/química , Receptores de Dopamina D1/antagonistas & inibidores , Alcaloides/química , Dopamina , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Haloperidol , Humanos , Compostos Fitoquímicos , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismoRESUMO
OBJECTIVES: We investigated effect of the ventromedial hypothalamus (VMH) dopamine D2 receptor inhibition on food intake and plasma ghrelin following chronic free or scheduled meal with different caloric intakes. METHODS: Male Wistar rats (220-250 g) were fed diets containing free (control) or three scheduled diets of standard, restricted and high-fat for 1 month. The animals stereotaxically received an intra VMH single dose of sulpiride (0.005 µg)/or saline (0.5 µL) before meal time. Thirty minutes later, food intake and circulating ghrelin were measured. RESULTS: Sulpiride significantly reduced food intake and ghrelin concentration in freely fed and scheduled-standard diet (p<0.05), while increased food intake, with ghrelin level on fasted level in scheduled-restricted group (p<0.01) compared to control. Food intake and ghrelin concentration between scheduled-high fat and freely fed or scheduled-standard diets did not show significant changes. CONCLUSIONS: The VMH D2 receptors are possibly involved in controlling scheduled eating behavior, depending on energy balance context.
Assuntos
Antagonistas dos Receptores de Dopamina D2/farmacologia , Ingestão de Alimentos , Grelina , Hipotálamo/efeitos dos fármacos , Sulpirida/farmacologia , Animais , Grelina/sangue , Masculino , Ratos , Ratos Wistar , Receptores de Dopamina D2RESUMO
BACKGROUND: The reticular thalamus gates thalamocortical information flow via finely tuned inhibition of thalamocortical cells in the mediodorsal thalamus. Brain imaging studies in humans show that the psychedelic lysergic acid diethylamide (LSD) modulates activity and connectivity within the cortico-striato-thalamo-cortical (CSTC) circuit, altering consciousness. However, the electrophysiological effects of LSD on the neurons in these brain areas remain elusive. METHODS: We employed in vivo extracellular single-unit recordings in anesthetized adult male mice to investigate the dose-response effects of cumulative LSD doses (5-160 µg/kg, intraperitoneal) upon reticular thalamus GABAergic neurons, thalamocortical relay neurons of the mediodorsal thalamus, and pyramidal neurons of the infralimbic prefrontal cortex. RESULTS: LSD decreased spontaneous firing and burst-firing activity in 50% of the recorded reticular thalamus neurons in a dose-response fashion starting at 10 µg/kg. Another population of neurons (50%) increased firing and burst-firing activity starting at 40 µg/kg. This modulation was accompanied by an increase in firing and burst-firing activity of thalamocortical neurons in the mediodorsal thalamus. On the contrary, LSD excited infralimbic prefrontal cortex pyramidal neurons only at the highest dose tested (160 µg/kg). The dopamine D2 receptor (D2) antagonist haloperidol administered after LSD increased burst-firing activity in the reticular thalamus neurons inhibited by LSD, decreased firing and burst-firing activity in the mediodorsal thalamus, and showed a trend towards further increasing the firing activity of neurons of the infralimbic prefrontal cortex. CONCLUSION: LSD modulates firing and burst-firing activity of reticular thalamus neurons and disinhibits mediodorsal thalamus relay neurons at least partially in a D2-mediated fashion. These effects of LSD on thalamocortical gating could explain its consciousness-altering effects in humans.
Assuntos
Relação Dose-Resposta a Droga , Fenômenos Eletrofisiológicos , Dietilamida do Ácido Lisérgico/farmacologia , Córtex Pré-Frontal , Tálamo , Animais , Transtornos da Consciência/induzido quimicamente , Transtornos da Consciência/metabolismo , Antagonistas dos Receptores de Dopamina D2/farmacologia , Alucinógenos/farmacologia , Masculino , Camundongos , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Receptores de Dopamina D2/metabolismo , Tálamo/efeitos dos fármacos , Tálamo/metabolismoRESUMO
RATIONALE: Levo-tetrahydropalmatine (l-THP), an active ingredient of Corydalis yanhusuo, has been reported to be a partial agonist for dopamine D1 receptors (D1R) and an antagonist for D2R. Although it has been safely used clinically in China for decades as an analgesic with sedative/hypnotic properties, there are few studies that address the mechanisms by which l-THP exerts its beneficial effects in chronic pain-induced sleep disturbance. OBJECTIVES: To investigate the effects and mechanisms of l-THP on sleep disturbance in a neuropathic pain-like condition. METHODS: A mouse model of chronic neuropathic pain induced by partial sciatic nerve ligation (PSNL) was employed. The antinociceptive and hypnotic effects of l-THP were evaluated by measurement of mechanical allodynia, thermal hyperalgesia, and electroencephalogram (EEG) recordings in PSNL mice. Pharmacological approaches and c-Fos expression were used to clarify the mechanisms of l-THP. RESULTS: Intraperitoneal injection of l-THP at 5 and 10 mg/kg not only significantly increased the mechanical threshold by 134.4% and 174.8%, and prolonged the thermal latency by 49.4% and 69.2%, but also increased non-rapid eye movement sleep by 17.5% and 29.6%, and decreased sleep fragmentation in PSNL mice, compared with the vehicle control. Moreover, the antinociceptive effect of l-THP was prevented by D1R antagonist SCH23390 or D2R agonist quinpirole; meanwhile, the hypnotic effect of l-THP was blocked by quinpirole rather than by SCH23390. Immunohistochemistry demonstrated that l-THP inhibited c-Fos overexpression induced by PSNL in the cingulate cortex and the periaqueductal gray. CONCLUSIONS: These findings indicated that l-THP exerted analgesic effects by agonism D1R and antagonism D2R, and the antagonism of D2R mediated the hypnotic effect of l-THP in PSNL mice.
Assuntos
Analgésicos não Narcóticos/uso terapêutico , Alcaloides de Berberina/uso terapêutico , Hipnóticos e Sedativos/uso terapêutico , Neuralgia/tratamento farmacológico , Receptores de Dopamina D1/fisiologia , Receptores de Dopamina D2/fisiologia , Analgésicos não Narcóticos/farmacologia , Animais , Alcaloides de Berberina/farmacologia , Modelos Animais de Doenças , Antagonistas dos Receptores de Dopamina D2/farmacologia , Antagonistas dos Receptores de Dopamina D2/uso terapêutico , Eletroencefalografia/efeitos dos fármacos , Hipnóticos e Sedativos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuralgia/fisiopatologia , Receptores de Dopamina D1/agonistasRESUMO
The typical compounds of Aurantii fructus (AF) reported in previous research were screened for their high antagonistic ability on the D2 dopamine receptor (D2R) in silico, and then bioactivity-guided separation was undertaken on the potential D2R antagonists from AF using high-speed counter-current chromatography (HSCCC). Three flavanones, two polymethoxyflavonoids, and three coumarins were effectively isolated from ethanol extracts of Aurantii fructus (AF) by the use of a two-step HSCCC method, and their chemical structures were identified by mass spectrometry, ¹H-NMR, and 13C-NMR and compared with published data. Firstly, crude extract of 70% ethanol eluent (150 mg) was isolated by HSCCC using an n-hexane-ethyl acetate-n-butanol-methanol-0.05% acetic acid (1:3:1.8:1:5, v/v/v/v/v) solvent system, and compounds 1 (naringin, 28 mg), 2 (neohesperidin, 13 mg), 3 (meranzin, 5 mg) and 4 (poncirin, 3 mg) were successfully isolated with 98.5%, 95.1%, 97.7%, and 92.4% purity, respectively. Then, the crude extract of 95% ethanol eluent (120 mg) was isolated by n-hexane-n-butanol-ethanol (methanol)-0.05% acetic acid (2:0.6:1:3, v/v/v/v) solvent system and compounds 3 (meranzin, 3 mg), 5 (meranzin hydrate, 4 mg), 6 (isomeranzin, 6 mg), 7 (nobiletin, 10 mg), and 8 (tangeretin, 7 mg) were successfully isolated with 95.8%, 98.5%, 95.1%, 92.4%, and 97.7% purity, respectively. Naringenin, a parent structure of naringin with the excellent binding score of -9.3 kcal/mol, was completely in conjunction with the active site of D2R, indicating that it is critical for the treatment of gastrointestinal dysfunction. The results indicated that the bioactivity-guided method is practical for the effective separation of active compounds from natural resources.
Assuntos
Citrus/química , Distribuição Contracorrente/métodos , Antagonistas dos Receptores de Dopamina D2/isolamento & purificação , Antagonistas dos Receptores de Dopamina D2/farmacologia , Simulação de Acoplamento Molecular , Cromatografia Líquida de Alta Pressão , Antagonistas dos Receptores de Dopamina D2/química , Avaliação Pré-Clínica de Medicamentos , Flavanonas/química , Extratos Vegetais/farmacologiaRESUMO
An in-depth study of the pharmacological properties of 4-[4-oxo-(4h)-quinazolin-3-yl]-benzoic acid as an analgesic agent established that it had a sufficiently high analgesic effect on models of somatic and neuropathic pain syndromes. Study objective was to study the mechanisms of analgesic action of PK-66 compound in rats using the pharmacological analysis. We evaluated the mechanisms of analgesic effect of PK-66 (1 mg/kg, intraperitoneal) compound on the thermal irritation model on Hours 1, 2, 4 and 6 after administration of study compounds. To evaluate the mechanisms of PK-66 compound pain killing, we determined the changes in its efficacy against the effects of pharmacological analyzers - Naloxon, Tramadolum, Clophelinum (Clonidine), Yohimbine, Noraepinephrine, Reserpinum, Chlorpromazine (Aminazin), Levodopa, Diazepam, and Memantine). The anti-nociceptive effect of PK-66 compound was virtually unchanged during all study terms with underlying administration of Naloxon, an opioid receptor antagonist. The results of administration of Reserpinum in rats and the concomitant administration of Noradrenaline, Clophelinum, Yohimbine and quinazoline derivative demonstrated that the adrenergic system, in particular alpha-2 adrenergic receptors, was involved in the mechanisms of PK-66 activity. Changes in the PK-66 compound effect with underlying previous administration of Levodopa and Chlorpromazine suggested that the dopaminergic system was unquestionably involved in the analgesic activity of the compound. Further study of the involvement of inhibitory and exhilarating amino acids, GABA and glutamate, showed that administration of Diazepam potentiated and extended the PK-66 analgesic effect on the thermal nociception models throughout the experiment. At the same time, increased antinociception with underlying Memantine administration preceding PK-66 was observed only in the first hours of the experiment. Therefore, the studies conducted have shown that the adrenergic system, in particular alpha-2 adrenergic receptors, dopaminergic and GABAergic systems, is involved in the mechanisms of analgesic action of 4-[4-oxo-(4h) -quinazolin-3-yl]-benzoic acid (PK-66) without any effect of PK-66 on opioid receptors.
Assuntos
Antagonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Analgésicos/uso terapêutico , Benzoatos/uso terapêutico , Antagonistas dos Receptores de Dopamina D2/uso terapêutico , Hiperalgesia/tratamento farmacológico , Dor/tratamento farmacológico , Quinazolinas/uso terapêutico , Administração Oral , Antagonistas de Receptores Adrenérgicos alfa 2/química , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Analgésicos/química , Analgésicos/farmacologia , Animais , Benzoatos/farmacologia , Antagonistas dos Receptores de Dopamina D2/química , Antagonistas dos Receptores de Dopamina D2/farmacologia , Avaliação Pré-Clínica de Medicamentos , Temperatura Alta , Injeções Intraperitoneais , Masculino , Quinazolinas/química , Quinazolinas/farmacologia , Ratos WistarRESUMO
This study aimed to explain how prolonged inhibition of central dopaminergic activity affects the cellular processes governing gonadotrophin-releasing hormone (GnRH) and LH secretion in anoestrous sheep. For this purpose, the study included two experimental approaches: first, we investigated the effect of infusion of sulpiride, a dopaminergic D2 receptor antagonist (D2R), on GnRH and GnRH receptor (GnRHR) biosynthesis in the hypothalamus and on GnRHR in the anterior pituitary using an immunoassay. This analysis was supplemented by analysis of plasma LH levels by radioimmunoassay. Second, we used real-time polymerase chain reaction to analyse the influence of sulpiride on the levels of kisspeptin (Kiss1) mRNA in the preoptic area and ventromedial hypothalamus including arcuate nucleus (VMH/ARC), and RFamide-related peptide-3 (RFRP-3) mRNA in the paraventricular nucleus (PVN) and dorsomedial hypothalamic nucleus. Sulpiride significantly increased plasma LH concentration and the levels of GnRH and GnRHR in the hypothalamic-pituitary unit. The abolition of dopaminergic activity resulted in a significant increase in transcript level of Kiss1 in VMH/ARC and a decrease of RFRP-3 in PVN. The study demonstrates that dopaminergic neurotransmission through D2R is involved in the regulatory pathways of GnRH and GnRHR biosynthesis in the hypothalamic-pituitary unit of anoestrous sheep, conceivably via mechanisms in which Kiss1 and RFRP-3 participate.
Assuntos
Anestro/metabolismo , Antagonistas dos Receptores de Dopamina D2/farmacologia , Hormônio Liberador de Gonadotropina/biossíntese , Kisspeptinas/metabolismo , Neuropeptídeos/metabolismo , Receptores LHRH/biossíntese , Sulpirida/farmacologia , Animais , Feminino , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Hormônio Luteinizante/sangue , Adeno-Hipófise/efeitos dos fármacos , Adeno-Hipófise/metabolismo , OvinosRESUMO
The aim of the present study was to clarify the relationship between hypothalamic dopamine (DA) and salsolinol (SAL) for the secretion of prolactin (PRL) in goats. SAL or thyrotropin-releasing hormone (TRH) was intravenously injected into female goats treated with or without the D2 DA receptor antagonist haloperidol (Hal), which crosses the blood-brain barrier, and the PRL-releasing response to SAL was compared with that to TRH. PRL-releasing responses to SAL, Hal, and Hal plus SAL were also examined after a pretreatment to augment central DA using carbidopa (Carbi) and L-dopa. The PRL-releasing response to Hal alone was greater than that to SAL or TRH alone. The PRL-releasing response to Hal plus SAL was similar to that of Hal alone. In contrast, the PRL-releasing response to Hal plus TRH was greater than that to TRH or Hal alone. The treatment with Carbi plus L-dopa inhibited SAL- and Hal-induced PRL secretion. The inhibition of the PRL-releasing response to SAL disappeared when SAL was injected with Hal. These results indicate that the mechanisms underlying the SAL-induced PRL response differ from those of TRH, and suggest that hypothalamic DA and its synthesis is associated in part with SAL-induced PRL secretion in goats.
Assuntos
Dopamina/fisiologia , Cabras/metabolismo , Cabras/fisiologia , Hipotálamo , Isoquinolinas/farmacologia , Prolactina/metabolismo , Animais , Carbidopa/farmacologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Combinação de Medicamentos , Feminino , Haloperidol/farmacologia , Injeções Intravenosas , Isoquinolinas/administração & dosagem , Levodopa/farmacologia , Hormônio Liberador de Tireotropina/administração & dosagem , Hormônio Liberador de Tireotropina/farmacologiaRESUMO
Parkinson's disease (PD) consists of a neurodegenerative pathology that has received a considerable amount of attention because of its clinical manifestations. The most common treatment consists of administering the drugs levodopa and biperiden, which reduce the effectiveness of the disease and the progress of its symptoms. However, phytotherapy treatment of PD has shown great potential in retarding the loss of dopaminergic neurons and minimizing the behavioral abnormalities. The aim of this study is to systematically review the use of supplemental herbal plants with cellular protective effect and behavioral activity in in vivo and in vitro experimental models. A total of 20 studies were summarized, where the effectiveness of herbal extracts and their isolated bioactive compounds was observed in animal models for PD. The main neurochemical mechanisms found in these studies are schematically represented. The herbal extracts and their biocompounds have antioxidant, anti-apoptotic, and antiinflammatory properties, which contribute to avoiding neuronal loss. Reports show that besides acting on the biosynthesis of dopamine and its metabolites, these compounds prevent D2 receptors' hypersensitivity. It is suggested that further studies need be conducted to better understand the mechanisms of action of the bioactive compounds distributed in these plants. Copyright © 2017 John Wiley & Sons, Ltd.
Assuntos
Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Fitoterapia , Extratos Vegetais/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Dopamina/biossíntese , Antagonistas dos Receptores de Dopamina D2/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , HumanosRESUMO
The pattern of prolactin (PRL) secretion depends on the physiological state. Due to insufficient detection sensitivity of existing assays, the precise description of these patterns in mice is lacking. We described an ultrasensitive ELISA assay that can detect mouse PRL in small fractions of whole blood, allowing longitudinal studies of PRL secretion profiles in freely moving mice. Over a 24-hour period, males displayed no oscillation in PRL levels, whereas virgin and lactating females showed large pulses. Peaks of PRL secretion reached 30-40 ng/mL in lactating female mice and rarely exceeded 10 ng/mL in virgin females. These pulses of PRL in lactating females were associated with suckling. The return of pups after an experimental 12-hour weaning induced a pulse of PRL release, reaching 100 ng/mL. This approach also enabled us to assess the inhibitory tone from hypothalamic dopamine neurons on PRL secretion. We used a dopamine D2 receptor antagonist to relieve pituitary lactotrophs from the tuberoinfundibular dopaminergic inhibitory tone and demonstrate a D2-induced PRL rise that can be used to evaluate both the secretory capacity of lactotrophs and the magnitude of the inhibitory tone on pituitary PRL release. We demonstrate that, although lactotroph function is altered to enhance chronic PRL output, their secretory response to acute stimulus is not modified during lactation and that chronic hyperprolactinemia is linked to a lower inhibitory tone. The combination of a sensitive PRL ELISA and administration of D2 receptor antagonist provide a unique opportunity to investigate the function and plasticity of the lactotroph axis in freely moving mice.
Assuntos
Ritmo Circadiano , Dopamina/metabolismo , Lactação , Lactotrofos/metabolismo , Prolactina/metabolismo , Animais , Antagonistas dos Receptores de Dopamina D2/farmacologia , Neurônios Dopaminérgicos/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Hipotálamo/citologia , Lactotrofos/efeitos dos fármacos , Estudos Longitudinais , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Schizophrenia has been found to involve source-monitoring deficits, whereby perceptions that result from self-initiated motor output become attributed to outside sources. One example of this phenomenon are the so called passivity experiences, such as delusions of control, during which the individual feels that own actions are controlled remotely by someone else. To explain these phenomena, it has been proposed that this illness involves efference copy failure. In other words, brain mechanism that prepare perceptual processes for the sensory consequences of self-initiated actions are impaired leading to their misattribution and to psychosis. In earlier work, it was argued that efference copy failure in schizophrenia is related to thalamic abnormalities. Namely, the thalamus can be thought of as a hub for cortico-cortical interactions, and these transthalamic cortico-cortical interactions were found to play a part in internal motor monitoring. Cortico-cortical communication via the thalamus can be impaired in a number of ways. For example, one way to impair these interactions is by interfering with the ability of the thalamus to display bursts of firing. As the burst firing mode in the thalamus requires a preceding period of prolonged hyperpolarization (100ms), one way to reduce the burst propensity of thalamic neurons is to interfere with the ability to display prolonged hyperpolarizations. In this paper, we argue that elevated striatal dopaminergic activity in schizophrenia attenuates nigrothalamic GABAergic inputs, and thereby reduces burst propensity of the mediodorsal (MD) thalamic nucleus in schizophrenia, with the ultimate result of reduced transthalamic cortico-cortical communication, relative disconnection between functionally associated cortical areas and to psychosis. Conversely, dopamine D2 receptor blockers (antipsychotics) may help restore nigrothalamic GABAergic inputs, thereby increasing the burst propensity in the thalamus.
Assuntos
Corpo Estriado/metabolismo , Dopamina/metabolismo , Modelos Neurológicos , Esquizofrenia/fisiopatologia , Transmissão Sináptica/fisiologia , Tálamo/fisiopatologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , HumanosRESUMO
CONCLUSION: Our study demonstrates that the regulation of D2 receptors may be frequency specific. The reduction in cochlear microphonics (CM) and distortion product otoacoustic emission (DPOAE) amplitudes after perfusion with a D2 antagonist suggests that this receptor plays a role in the regulation of cochlear hair cell activation. OBJECTIVES: Dopaminergic terminals are subject to negative feedback from dopamine D2 receptors. In the present study we investigated whether the regulation of dopamine D2 receptor is frequency specific and evaluated changes in CM in guinea pig cochlea. METHODS: A total of 30 male guinea pigs were randomly assigned to 3 groups and perfused with artificial perilymph (AP), AP containing ethanol (0.1%), or a D2 antagonist (L741626) for 2 h. In each group, compound action potentials (CAPs) evoked by a 1, 2, 4, 8, 16 or 24 kHz tone pip, CM evoked by 4 kHz tone bursts, and DPOAEs were measured before and 2 h after perilymphatic perfusion. RESULTS: Perfusion with the D2 antagonist resulted in increased CAP thresholds compared with the other two groups at high frequencies (4, 8, 16, 24 kHz, p < 0.05); however, no significant increase was observed at low frequencies (1, 2 kHz, p > 0.05). There was a significant reduction in DPOAEs and CM amplitudes after the 2 h perfusion with the D2 antagonist. A CM input/output (I/O) function curve plotted with the stimulating level as input and the CM relative amplitude as output indicated obvious nonlinearity after the 2 h perfusion in all three groups.