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1.
Addict Biol ; 27(2): e13133, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35032086

RESUMO

Circadian genes, including Per1, in the medial shell region of nucleus accumbens (mNAcSh), regulate binge alcohol consumption. However, the upstream mechanism regulating circadian genes-induced alcohol consumption is not known. Since activation of dopamine D2 receptors (D2R) increases Per1 gene expression, we hypothesised that local infusion of quinpirole, a D2R agonist, by increasing Per1 gene expression in the mNAcSh, will increase binge alcohol consumption in mice. We performed two experiments on male C57BL/6J mice, instrumented with bilateral guide cannulas above the mNAcSh, and exposed to a 4-day drinking-in-dark (DID) paradigm. The first experiment determined the effects of bilateral infusion of quinpirole (100 ng/300 nl/site) or DMSO (Vehicle group) in the mNAcSh on Per1 gene expression and alcohol consumption. The second experiment determined the effect of antisense-induced downregulation of Per1 in the mNAcSh on the quinpirole-induced increase in alcohol consumption. Control experiments were performed by exposing the animals to sucrose (10% w/v). After the experiment, animals were euthanised, brains removed and processed for localisation of injection sites and analysis of Per1 gene expression in the mNAcSh. As compared with the DMSO, local bilateral infusion of quinpirole significantly increased the expression of Per1 in the mNAcSh along with an increase in the amount of alcohol consumed in mice exposed to DID paradigm. In addition, local antisense-induced downregulation of Per1 significantly attenuated the effects of intro-accumbal infusion of quinpirole on alcohol consumption. Our results suggest that Per1 in the mNAcSh mediates D2R activation-induced increase in alcohol consumption.


Assuntos
Núcleo Accumbens , Receptores de Dopamina D2 , Consumo de Bebidas Alcoólicas/genética , Animais , Agonistas de Dopamina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Quimpirol/farmacologia , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo
2.
Am J Physiol Cell Physiol ; 322(3): C327-C337, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-34986020

RESUMO

In vivo administration of dopamine (DA) receptor (DR)-related drugs modulate gastric pepsinogen secretion. However, DRs on gastric pepsinogen-secreting chief cells and DA D2 receptor (D2R) on somatostatin-secreting D cells were subsequently acquired. In this study, we aimed to further investigate the local effect of DA on gastric pepsinogen secretion through DRs expressed on chief cells or potential D2Rs expressed on D cells. To elucidate the modulation of DRs in gastric pepsinogen secretion, immunofluorescence staining, ex vivo incubation of gastric mucosa isolated from normal and D2R-/- mice were conducted, accompanied by measurements of pepsinogen or somatostatin levels using biochemical assays or enzyme-linked immunosorbent assays. D1R, D2R, and D5R-immunoreactivity (IR) were observed on chief cells in mouse gastric mucosa. D2R-IR was widely distributed on D cells from the corpus to the antrum. Ex vivo incubation results showed that DA and the D1-like receptor agonist SKF38393 increased pepsinogen secretion, which was blocked by the D1-like receptor antagonist SCH23390. However, D2-like receptor agonist quinpirole also significantly increased pepsinogen secretion, and D2-like receptor antagonist sulpiride blocked the promotion of DA. Besides, D2-like receptors exerted an inhibitory effect on somatostatin secretion, in contrast to their effect on pepsinogen secretion. Furthermore, D2R-/- mice showed much lower basal pepsinogen secretion but significantly increased somatostatin release and an increased number of D cells in gastric mucosa. Only SKF38393, not quinpirole, increased pepsinogen secretion in D2R-/- mice. DA promotes gastric pepsinogen secretion directly through D1-like receptors on chief cells and indirectly through D2R-mediated suppression of somatostatin release.


Assuntos
Celulas Principais Gástricas/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Pepsinogênio A/metabolismo , Quimpirol/farmacologia , Receptores de Dopamina D2/agonistas , Células Secretoras de Somatostatina/efeitos dos fármacos , Somatostatina/metabolismo , Animais , Celulas Principais Gástricas/metabolismo , Antagonistas de Dopamina/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Via Secretória , Células Secretoras de Somatostatina/metabolismo
3.
Exp Neurol ; 347: 113920, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34762921

RESUMO

Parkinson's disease (PD) is a complex multisystem, chronic and so far incurable disease with significant unmet medical needs. The incidence of PD increases with aging and the expected burden will continue to escalate with our aging population. Since its discovery in the 1961 levodopa has remained the gold standard pharmacotherapy for PD. However, the progressive nature of the neurodegenerative process in and beyond the nigrostriatal system causes a multitude of side effects, including levodopa-induced dyskinesia within 5 years of therapy. Attenuating dyskinesia has been a significant challenge in the clinical management of PD. We report on a small molecule that eliminates the expression of levodopa-induced dyskinesia and significantly improves PD-like symptoms. The lead compound PD13R we discovered is a dopamine D3 receptor partial agonist with high affinity and selectivity, orally active and with desirable drug-like properties. Future studies are aimed at developing this lead compound for treating PD patients with dyskinesia.


Assuntos
Antiparkinsonianos/toxicidade , Dopaminérgicos/toxicidade , Discinesia Induzida por Medicamentos/metabolismo , Levodopa/toxicidade , Transtornos Parkinsonianos/metabolismo , Receptores de Dopamina D3/metabolismo , Animais , Callithrix , Agonistas de Dopamina/farmacologia , Agonistas de Dopamina/uso terapêutico , Discinesia Induzida por Medicamentos/prevenção & controle , Células HEK293 , Humanos , Ligantes , Transtornos Parkinsonianos/prevenção & controle , Primatas , Estrutura Secundária de Proteína , Quimpirol/farmacologia , Quimpirol/uso terapêutico , Receptores de Dopamina D3/agonistas , Receptores de Dopamina D3/química
4.
Pharmacol Biochem Behav ; 213: 173314, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34919902

RESUMO

Dysfunction of the central dopamine D2-receptor-related network has been proposed to play a critical role in dopamine-related diseases, such as schizophrenia and drug dependence. Generally, the stimulation of dopamine D2-receptors on medium spiny neurons (MSN) induces several behavioral effects, such as sedation, hallucination, aversion and motivation. Furthermore, such physiological responses through dopamine D2-receptor-containing MSN (D2-MSN) may be synchronized with the activity of dopamine D1-receptor-containing MSN (D1-MSN), or both may exhibit dual agonistic/antagonistic innervation. In the present study, we characterized the discriminative stimulus effect of the selective dopamine D2-receptor agonist quinpirole to further investigate the "D1/D2-MSN" interaction using dopamine-related agents, hallucinogens and sedatives in rats. Among dopamine receptor agonists, only selective dopamine D2-receptor agonists substituted for the discriminative stimulus effects of quinpirole. Neither the δ-opioid receptor agonist SNC80 nor the adenosine A2A-receptor antagonist istradefylline, both of which may act on D2-MSNs, substituted for the discriminative stimulus effects of quinpirole. Interestingly, the dopamine D1-receptor antagonist SCH23390 and the GABAB-receptor agonist baclofen, but not hallucinogens or sedatives, substituted for the discriminative stimulus effects of quinpirole. These results suggest that stimulation of central dopamine D2-receptors exerts a distinct discriminative stimulus effect, and blockade of dopamine D1-receptors and agonistic modulation of GABAB-receptors may share the discriminative stimulus effect via the activation of central dopamine D2-receptors.


Assuntos
Dopamina , Receptores de Dopamina D1 , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina , Animais , Dopamina/farmacologia , Agonistas de Dopamina/farmacologia , Ergolinas/farmacologia , Quimpirol/farmacologia , Ratos , Receptores de Dopamina D2/agonistas
5.
Invest Ophthalmol Vis Sci ; 62(15): 30, 2021 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-34967855

RESUMO

Purpose: The development of myopia in guinea pigs can be inhibited by attenuating scleral hypoxia by increasing choroidal blood perfusion (ChBP). In this study, we reduced ChBP through surgical and pharmacological methods to determine the effect on myopia development. We also determined whether ChBP was reduced by quinpirole, a drug that enhances form-deprivation myopia (FDM). Methods: ChBP was reduced in the right eyes of guinea pigs via transection of the temporal ciliary arteries or daily injections of phenylephrine into the inferior peribulbar space for one week during normal ocular growth. Other guinea pigs were subjected to two weeks of monocular FDM-with facemasks, along with daily injections of quinpirole, a dopamine D2 receptor agonist, to enhance the FDM. Changes in refraction, axial length, ChBP, and choroidal thickness (ChT) were measured in both treated and fellow eyes of the treatment and control groups. Scleral hypoxia labeling with pimonidazole adducts and α-smooth muscle actin (α-SMA) protein were also measured. Results: Surgical and pharmacological reduction of ChBP induced myopia development in the treated eyes. These treatments rendered the scleral hypoxia and increased scleral α-SMA expression. Furthermore, quinpirole injections, which increased the magnitude of myopia, augmented the FDM-associated reductions in ChBP and ChT and increased the levels of scleral hypoxia and α-SMA protein. Conclusions: Decreased ChBP in guinea pigs leads to scleral hypoxia and scleral myofibroblast transdifferentiation with increased α-SMA expression, ultimately resulting in myopia development. In future clinical trials, ChBP reduction can serve as a potential biomarker for early detection of myopia development.


Assuntos
Corioide/irrigação sanguínea , Miopia/fisiopatologia , Fluxo Sanguíneo Regional/fisiologia , Actinas/metabolismo , Animais , Comprimento Axial do Olho , Velocidade do Fluxo Sanguíneo , Western Blotting , Corioide/efeitos dos fármacos , Corioide/patologia , Artérias Ciliares/cirurgia , Angiografia por Tomografia Computadorizada , Modelos Animais de Doenças , Agonistas de Dopamina/farmacologia , Eletrorretinografia , Cobaias , Hipóxia/metabolismo , Músculo Liso/metabolismo , Miopia/metabolismo , Fenilefrina/farmacologia , Quimpirol/farmacologia , Receptores de Dopamina D2/metabolismo , Refração Ocular/fisiologia , Esclera/metabolismo , Tomografia de Coerência Óptica
6.
Neurobiol Learn Mem ; 186: 107538, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34737042

RESUMO

We evaluated interactions between dopamine D2 receptor and nitric oxide (NO) actions on the regulation of anxiety and memory in the 6-hydroxydopamine (6-OHDA) mouse model of Parkinson's disease (PD). A unilateral guide cannula was stereotaxically implanted over the right striatum. Elevated plus-maze test (EPM) test-retest protocol was employed to evaluate anxiety and memory in mice. The results revealed that injection of L-NAME (9 mg/kg) induced anxiolytic and amnesic effects, while L-arginine (9 mg/kg) produced anxiogenic and memory-improvement effects in the 6-OHDA mouse model of PD. Administration of sulpiride (20 mg/kg) induced anxiogenic and memory-improvement effects, whereas quinpirole (20 mg/kg) caused anxiolytic and amnesic effects in PD mice. Co-injection of sulpiride (5, 10, and 20 mg/kg) plus L-NAME (3 mg/kg) induced anxiolytic and amnesic effects. Co-injection of sulpiride (20 mg/kg) plus L-arginine (3 mg/kg) induced anxiogenic and memory-improvement effects. Co-administrations of quinpirole (20 mg/kg) and L-NAME (3 mg/kg) induced anxiolytic effect, but co-administration of quinpirole (20 mg/kg) plus L-arginine (3 mg/kg) caused anxiogenic and memory-improvement effects. The isobologram analysis revealed that there is a synergistic effect between sulpiride and L-arginine as well as quinpirole and L-NAME upon induction of anxiogenic and anxiolytic effects, respectively in PD mice. Our results suggested: (1) NO and dopamine D2 receptor mechanisms affect anxiety and memory in PD mice; (2) L-NAME reversed anxiogenic and memory-improvement effect induced by sulpiride; (3) Anxiolytic and amnesic effects induced by quinpirole reversed by L-arginine; (4) There is a synergistic effect between dopamine D2 receptor and NO systems on the modulation of anxiety and memory.


Assuntos
Arginina/farmacologia , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Inibidores Enzimáticos/farmacologia , Doença de Parkinson/fisiopatologia , Quimpirol/farmacologia , Sulpirida/farmacologia , Adrenérgicos/farmacologia , Animais , Ansiedade/tratamento farmacológico , Ansiedade/fisiopatologia , Modelos Animais de Doenças , Antagonistas dos Receptores de Dopamina D2/farmacologia , Quimioterapia Combinada , Masculino , Memória/efeitos dos fármacos , Memória/fisiologia , Camundongos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/farmacologia , Oxidopamina/farmacologia , Receptores de Dopamina D2/fisiologia
7.
Pharmacol Biochem Behav ; 211: 173292, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34710401

RESUMO

This study analyzed whether the positive allosteric modulator of metabotropic glutamate receptor type 5 (mGlu5) 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB) would alleviate deficits in prepulse inhibition (PPI) and affect dopamine (DA) D2 signaling in the dorsal striatum and prefrontal cortex (PFC) in the neonatal quinpirole (NQ) model of schizophrenia (SZ). Male and female Sprague-Dawley rats were neonatally treated with either saline (NS) or quinpirole HCL (1 mg/kg; NQ), a DAD2 receptor agonist, from postnatal days (P) 1-21. Rats were raised to P44 and behaviorally tested on PPI from P44-P48. Before each trial, rats were subcutaneous (sc) administered saline or CDPPB (10 mg/kg or 30 mg/kg). On P50, rats were given a spontaneous locomotor activity test after CDPPB or saline administration. On P51, the dorsal striatum and PFC were evaluated for both arrestin-2 (ßA-2) and phospho-AKT protein levels. NQ-treated rats demonstrated a significant deficit in PPI, which was alleviated to control levels by the 30 mg/kg dose of CDPPB. There were no significant effects of CDPPB on locomotor activity. NQ treatment increased ßA-2 and decreased phospho-AKT in both the dorsal striatum and PFC, consistent with an increase DAD2 signaling. The 30 mg/kg dose of CDPPB significantly reversed changes in ßA-2 in the dorsal striatum and PFC and phospho-AKT in the PFC equivalent to controls. Both doses of CDPPB produced a decrease of phospho-AKT in the PFC compared to controls. This study revealed that a mGlu5 positive allosteric modulator was effective to alleviate PPI deficits and striatal DAD2 signaling in the NQ model of SZ.


Assuntos
Benzamidas/farmacologia , Pirazóis/farmacologia , Quimpirol/farmacologia , Receptor de Glutamato Metabotrópico 5/metabolismo , Receptores de Dopamina D2/metabolismo , Esquizofrenia/tratamento farmacológico , Filtro Sensorial/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Comportamento Animal/efeitos dos fármacos , Corpo Estriado/metabolismo , Agonistas de Dopamina/farmacologia , Feminino , Locomoção/efeitos dos fármacos , Masculino , Córtex Pré-Frontal/metabolismo , Inibição Pré-Pulso/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Esquizofrenia/metabolismo
8.
Neurotoxicol Teratol ; 88: 107034, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34600099

RESUMO

The human brain matures into a complex structure, and to reach its complete development, connections must occur along exact paths. If at any stage, the processes are altered, interrupted, or inhibited, the consequences can be permanent. Dopaminergic signaling participates in the control of physiological functions and behavioral processes, and alterations in this signaling pathway are related to the pathogenesis of several neurological disorders. For this reason, the use of pharmacological agents able to interact with the dopaminergic signaling may elucidate the biological bases of such disorders. We investigated the long-lasting behavioral effects on adult zebrafish after quinpirole (a dopamine D2/D3 receptor agonist) exposure during early life stages of development (24 h exposure at 5 days post-fertilization, dpf) to better understand the mechanisms underlying neurological disorders related to the dopaminergic system. Quinpirole exposure at the early life stages of zebrafish led to late behavioral alterations. When evaluated at 120 dpf, zebrafish presented increased anxiety-like behaviors. At the open tank test, fish remained longer at the bottom of the tank, indicating anxiety-like behavior. Furthermore, quinpirole-treated fish exhibited increased absolute turn angle, likely an indication of elevated erratic movements and a sign of increased fear or anxiety. Quinpirole-treated fish also showed altered swimming patterns, characterized by stereotypic swimming. During the open tank test, exposed zebrafish swims from corner to corner in a repetitive manner at the bottom of the tank. Moreover, quinpirole exposure led to memory impairment compared to control fish. However, quinpirole administration had no effects on social and aggressive behavior. These findings demonstrate that dopaminergic signaling altered by quinpirole administration in the early life stages of development led to late alterations in behavioral parameters of adult zebrafish.


Assuntos
Agonistas de Dopamina/farmacologia , Dopamina/metabolismo , Quimpirol/farmacologia , Comportamento Estereotipado/efeitos dos fármacos , Animais , Ansiedade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Antagonistas de Dopamina/farmacologia , Atividade Motora/efeitos dos fármacos , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D2/metabolismo , Tempo , Peixe-Zebra/metabolismo
9.
Eur J Pharmacol ; 912: 174517, 2021 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-34555394

RESUMO

Dopamine (DA) is an important modulator in nociception and analgesia. Spinal DA receptors are involved in descending modulation of the nociceptive transmission. Genetic variations within DA neurotransmission have been associated with altered pain sensitivity and development of chronic pain syndromes. The variant rs6277 in dopamine receptor 2 a (drd2a) has been associated with a decreased D2 receptor availability and increased nociception. The aim of this study is to further characterize the role of DA neurotransmission in nociception and the anti-nociceptive function of drd2a. The phenotype caused by rs6277 was modelled in zebrafish larvae using morpholino's and the effect on nociception was tested using a validated behavioural assay. The anti-nociceptive role of drd2a was tested using pharmacological intervention of D2 agonist Quinpirole. The experiments demonstrate that a decrease in drd2a expression results in a pro-nociceptive behavioural phenotype (P = 0.016) after a heat stimulus. Furthermore, agonism of drd2a with agonist Quinpirole (0.2 µM) results in dose-dependent anti-nociception (P = 0.035) after a heat stimulus. From these results it is concluded that the dopamine receptor drd2a is involved in anti-nociceptive behaviour in zebrafish. The model allows further screening and testing of genetic variation and treatment involved in nociception.


Assuntos
Dopamina/fisiologia , Nociceptividade/fisiologia , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/fisiologia , Transmissão Sináptica/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Temperatura Alta , Modelos Animais , Morfolinos/farmacologia , Nociceptividade/efeitos dos fármacos , Quimpirol/farmacologia , Receptores de Dopamina D2/agonistas , Transmissão Sináptica/efeitos dos fármacos , Peixe-Zebra
10.
Psychopharmacology (Berl) ; 238(11): 3143-3153, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34313801

RESUMO

RATIONALE: Palatability and incentive value influence animal food choice. Dopamine D2/3 receptor signaling may mediate the effects of palatability and incentive value on choice. Dopamine signaling is disrupted in attention-deficit hyperactivity disorder (ADHD). Investigating behavioral choice processes under D2/3 receptor agonists will help elucidate behavioral and pharmacological correlates of ADHD. OBJECTIVES: To determine (1) how changes in incentive value affects choice of actions for outcomes that differ in palatability; (2) the effects of the D2/3 agonist quinpirole on choice based on palatability and incentive value; (3) how choice differs in spontaneously hypertensive rats (SHR; ADHD model) compared with control strains. METHODS: Rats responded instrumentally for two food outcomes (chocolate and grain pellets) that differed in palatability. Following specific satiety of one outcome, rats underwent a choice test. Prior to the choice test, rats were given intra-peritoneal quinpirole (0.01-0.1 mg/kg) body weight. These manipulations were conducted in three strains of rats: SHR rats; the normotensive Wistar-Kyoto (WKY) controls; and Wistar outbred (WIS) controls. RESULTS: All rat strains responded more vigorously for chocolate pellets compared with grain pellets. Quinpirole reduced the effects of palatability and dose-dependently increased the effects of incentive value on choice. SHR rats were the least influenced by incentive value, whereas WKY rats were the least influenced by palatability. CONCLUSIONS: These results show that D2/3 signaling modulates choice based on palatability and incentive value. Disruption of this process in SHR rats may mirror motivational impairments observed in ADHD.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Animais , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Modelos Animais de Doenças , Dopamina , Agonistas de Dopamina/farmacologia , Motivação , Quimpirol/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Roedores
11.
J Psychiatr Res ; 141: 124-135, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34198193

RESUMO

Anxiety disorders, which have a noticeable global prevalence and may be caused by many factors, include a spectrum of disorders that share features of excessive fear- and anxiety-related behavioral disturbances. Different brain areas and neurotransmitter systems have been under investigation for anxiety-related disorders. In this study, we investigated the possible interaction between the dopaminergic and nitric oxide (NO) neurotransmitter systems in the medial septal nucleus and their roles in anxiety-like behaviors using elevated plus-maze (EPM) test in male rats. Our results showed that: (i) both D1-and D2-like receptor agonists, SKF-38393 and quinpirole, augmented anxiety-like behaviors at their two highest applied doses in the EPM test; (ii) both D1-and D2-like receptor antagonists, SCH- 23390 and sulpiride, reduced anxiety-like behaviors at their two highest applied doses in the EPM test; (iii) L-Arginine, a NO precursor, increased anxiety-like behaviors, but L-NAME, a non-specific nitric oxide synthase (NOS) inhibitor, reduced them in the EPM test; (iv) L-NAME could not reverse the anxiety-like parameters produced by SKF-38393, but it significantly reduced the anxiety-like behaviors induced by quinpirole; (v) Neither SCH- 23390 nor sulpiride changed anxiety-related behaviors induced by L-Arginine. It can be concluded that both dopaminergic and nitric oxide systems in the medial septal nucleus are involved in modulating anxiety-like behaviors. While NO has an involvement in the exerted effects by the D2-like agonist, such effects were not observed at the applied range of the doses for D1-and D2-like antagonists.


Assuntos
Núcleos Septais , Animais , Ansiedade/tratamento farmacológico , Dopamina , Masculino , Óxido Nítrico , Quimpirol/farmacologia , Ratos , Receptores de Dopamina D1
12.
J Psychopharmacol ; 35(10): 1188-1203, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34291671

RESUMO

BACKGROUND/AIMS: Neonatal quinpirole (NQ) treatment to rats increases dopamine D2 (DAD2) receptor sensitivity in adult animals. We investigated if increased DAD2 sensitivity would be passed to the next (F1) generation, and if these animals demonstrated sensorimotor gating deficits and enhanced behavioral responses to nicotine. METHODS: Male and female rats were intraperitoneal (IP) administered quinpirole (1 mg/kg) or saline (NS) from postnatal day (P)1-21. Animals were either behaviorally tested (F0) or raised to P60 and mated, creating F1 offspring. RESULTS: Experiment 1 revealed that F1 generation animals that were the offspring of at least one NQ-treated founder increased yawning behavior, a DAD2-mediated behavioral event, in response to acute quinpirole (0.1 mg/kg). F1 generation rats also demonstrated increased striatal ß arrestin-2 and decreased phospho-AKT signaling, consistent with increased G-protein independent DAD2 signaling, which was equal to F0 NQ-treated founders, although this was not observed in all groups. RNA-Seq analysis revealed significant gene expression changes in the F1 generation that were offspring of both NQ-treated founders compared to F0 NQ founders and controls, with enrichment in sensitivity to stress hormones and cell signaling pathways. In Experiment 2, all F1 generation offspring demonstrated sensorimotor gating deficits compared to controls, which were equivalent to F0 NQ-treated founders. In Experiment 3, all F1 generation animals demonstrated enhanced nicotine behavioral sensitization and nucleus accumbens (NAcc) brain-derived neurotrophic factor (BDNF) protein. Further, F1 generation rats demonstrated enhanced adolescent nicotine conditioned place preference equivalent to NQ-treated founders conditioned with nicotine. CONCLUSIONS: This represents the first demonstration of transgenerational effects of increased DAD2 sensitivity in a rodent model.


Assuntos
Nicotina/farmacologia , Quimpirol/farmacologia , Receptores de Dopamina D2/metabolismo , Filtro Sensorial/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Agonistas de Dopamina/farmacologia , Feminino , Masculino , Núcleo Accumbens/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
13.
Neurobiol Dis ; 157: 105429, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34153463

RESUMO

L-DOPA-induced dyskinesia (LID) is a significant complication of dopamine replacement therapy in Parkinson's disease (PD), and the specific role of different dopamine receptors in this disorder is poorly understood. We set out to compare patterns of dyskinetic behaviours induced by the systemic administration of L-DOPA and D1 or D2 receptor (D1R, D2R) agonists in mice with unilateral 6-hydroxydopamine lesions. Mice were divided in four groups to receive increasing doses of L-DOPA, a D1R agonist (SKF38393), a D2/3 agonist (quinpirole), or a selective D2R agonist (sumanirole). Axial, limb and orofacial abnormal involuntary movements (AIMs) were rated using a well-established method, while dystonic features were quantified in different body segments using a new rating scale. Measures of abnormal limb and trunk posturing were extracted from high-speed videos using a software for markerless pose estimation (DeepLabCut). While L-DOPA induced the full spectrum of dyskinesias already described in this mouse model, SKF38393 induced mostly orofacial and limb AIMs. By contrast, both of the D2-class agonists (quinpirole, sumanirole) induced predominantly axial AIMs. Dystonia ratings revealed that these agonists elicited marked dystonic features in trunk/neck, forelimbs, and hindlimbs, which were overall more severe in sumanirole-treated mice. Accordingly, sumanirole induced pronounced axial bending and hindlimb divergence in the automated video analysis. In animals treated with SKF38393, the only appreciable dystonic-like reaction consisted in sustained tail dorsiflexion and stiffness. We next compared the effects of D1R or D2R selective antagonists in L-DOPA-treated mice, where only the D2R antagonist had a significant effect on dystonic features. Taken together these results indicate that the dystonic components of LID are predominantly mediated by the D2R.


Assuntos
Discinesia Induzida por Medicamentos/fisiopatologia , Distonia/fisiopatologia , Movimento/efeitos dos fármacos , Transtornos Parkinsonianos/fisiopatologia , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Animais , Antiparkinsonianos/efeitos adversos , Benzimidazóis/farmacologia , Discinesia Induzida por Medicamentos/etiologia , Discinesia Induzida por Medicamentos/metabolismo , Distonia/induzido quimicamente , Distonia/metabolismo , Camundongos , Oxidopamina/toxicidade , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Quimpirol/farmacologia , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D2/agonistas
14.
Neuropharmacology ; 193: 108607, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34023337

RESUMO

Dreams appear intermittently during phasic rapid eye movement sleep (REMS). Although reasonable progress has been made about neuro-physio-pharmacological mechanism of appearance of REMS, appearance of dreams is a mystery. Isolated studies have reported that substantia nigra (SN) withdraws inhibition from pedunculo-pontine tegmentum (PPT) acetylcholine (ACh)-ergic REM-ON neurons to trigger REMS; some REM-ON neurons become phasically active during REMS; amygdala (Amyg), a limbic structure associated with emotions, may be related with dreaming like state; Amyg receives projections from both SN-Dopamine (DA)-ergic and PPT-ACh-ergic neurons. Collating these isolated findings, we proposed that on the background of REMS, SN-DA-ergic and PPT-ACh-ergic inputs phasically activate Amyg-neurons to manifest dreams. In the absence of better criteria, we recorded electrophysiological characteristics of REMS as the closest objective read-out for dreams in surgically prepared, chronic, freely moving rats. Microinjection of either DA-ergic or ACh-ergic agonist [Quinpirole (Qnp) or Carbachol (Carb)] bilaterally into Amyg increased, while antagonists [Haloperidol (Hal) or Scopolamine (Scop)] reduced REMS. Electrical stimulation of either bilateral SN or PPT increased REMS, which however, was prevented when stimulated in presence of Hal or Scop, respectively into the Amyg. These findings confirm and support our contention that SN-DA-ergic and PPT-ACh-ergic inputs integrate in Amyg for REMS regulation. Further, subject to confirmation in humans, we propose that on the background of REMS, some phasic PPT-ACh-ergic-REM-ON neurons intermittently trigger some neurons in Amyg, the area known to be associated with memory and emotions, causing intermittent appearance of REMS-associated dreams and in REMS behavior disorder.


Assuntos
Tonsila do Cerebelo/fisiologia , Neurônios Dopaminérgicos/fisiologia , Tegmento Pontino/fisiologia , Sono REM/fisiologia , Substância Negra/fisiologia , Vigília/fisiologia , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Carbacol/farmacologia , Neurônios Colinérgicos , Estimulação Elétrica , Haloperidol/farmacologia , Masculino , Tegmento Pontino/efeitos dos fármacos , Quimpirol/farmacologia , Ratos , Ratos Wistar , Escopolamina/farmacologia , Sono REM/efeitos dos fármacos , Substância Negra/efeitos dos fármacos , Vigília/efeitos dos fármacos
15.
Behav Brain Res ; 411: 113339, 2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-33945831

RESUMO

Dopamine (DA) in the striatum is essential to influence motor behavior and may lead to movement impairment in Parkinson's disease (PD). The present study examined the different functions of the DA D1 receptor (D1R) and DA D2 receptor (D2R) by intrastriatal injection of the D1R agonist SKF38393 and the D2R agonist quinpirole in 6-hydroxydopamine (6-OHDA)-lesioned and control rats. All rats separately underwent dose-response behavior testing for SKF38393 (0, 0.5, 1.0, and 1.5 µg/site) or quinpirole (0, 1.0, 2.0, and 3.0 µg/site) to determine the effects of the optimal modulating threshold dose. Two behavior assessment indices, the time of latency to fall and the number of steps on a rotating treadmill, were used as reliable readouts of motor stimulation variables for quantifying the motor effects of the drugs. The findings indicate that at threshold doses, SKF38393 (1.0 µg/site) and quinpirole (1.0 µg/site) produce a dose-dependent increase in locomotor activity compared to vehicle injection. The ameliorated behavioral responses to either SKF38393 or quinpirole in lesioned rats were greater than those in unlesioned control rats. Moreover, the dose-dependent increase in locomotor capacity for quinpirole was greater than that for SKF38393 in lesioned rats. These results can clarify several key issues related to DA receptors directly and may provide a basis for exploring the potential of future selective dopamine therapies for PD in humans.


Assuntos
2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Quimpirol/farmacologia , Receptores Dopaminérgicos/metabolismo , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/administração & dosagem , Animais , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Agonistas de Dopamina/administração & dosagem , Agonistas de Dopamina/farmacologia , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Atividade Motora/efeitos dos fármacos , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/fisiopatologia , Quimpirol/administração & dosagem , Ratos , Ratos Wistar , Receptores Dopaminérgicos/efeitos dos fármacos , Receptores de Dopamina D1/efeitos dos fármacos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D2/metabolismo
16.
ACS Chem Neurosci ; 12(11): 1873-1884, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-33974399

RESUMO

A dopamine D2 receptor mutation was recently identified in a family with a novel hyperkinetic movement disorder. Compared to the wild type D2 receptor, the novel allelic variant D2-I212F activates a Gαi1ß1γ2 heterotrimer with higher potency and modestly enhanced basal activity in human embryonic kidney (HEK) 293 cells and has decreased capacity to recruit arrestin3. We now report that omitting overexpressed G protein-coupled receptor kinase-2 (GRK2) decreased the potency and efficacy of quinpirole for arrestin recruitment. The relative efficacy of quinpirole for arrestin recruitment to D2-I212F compared to D2-WT was considerably lower without overexpressed GRK2 than with added GRK2. D2-I212F exhibited higher basal activation of GαoA than Gαi1 but little or no increase in the potency of quinpirole relative to D2-WT. Other signs of D2-I212F constitutive activity for G protein-mediated signaling, in addition to basal activation of Gαi/o, were enhanced basal inhibition of forskolin-stimulated cyclic AMP accumulation that was reversed by the inverse agonists sulpiride and spiperone and a ∼4-fold increase in the apparent affinity of D2-I212F for quinpirole, determined from competition binding assays. In mouse midbrain slices, inhibition of tonic current by the inverse agonist sulpiride in dopamine neurons expressing D2-I212F was consistent with our hypothesis of enhanced constitutive activity and sensitivity to dopamine relative to D2-WT. Molecular dynamics simulations with D2 receptor models suggested that an ionic lock between the cytoplasmic ends of the third and sixth α-helices that constrains many G protein-coupled receptors in an inactive conformation spontaneously breaks in D2-I212F. Overall, these results confirm that D2-I212F is a constitutively active and signaling-biased D2 receptor mutant and also suggest that the effect of the likely pathogenic variant in a given brain region will depend on the nature of G protein and GRK expression.


Assuntos
Receptores de Dopamina D2 , Transdução de Sinais , Animais , AMP Cíclico , Agonistas de Dopamina/farmacologia , Células HEK293 , Humanos , Camundongos , Quimpirol/farmacologia , Receptores de Dopamina D2/genética
17.
Neuroreport ; 32(7): 555-561, 2021 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-33850083

RESUMO

l-dopa and dopamine D2 receptor (D2R) agonists are commonly used to relieve the motor deficits of Parkinson's disease. However, long-term treatment with l-dopa or D2R agonists can induce adverse effects such as abnormal involuntary movements (AIMs), which are major limiting factors in achieving long-term control of parkinsonian syndromes. The pathophysiological mechanisms involved in the development of dopaminergic agonist-induced adverse effects are not well understood. Here, we examined the role of two D2R isoforms, D2S and D2L, in l-dopa-induced AIMs using dopamine D2L knockout (D2L KO) mice (expressing purely D2S) and wild-type mice (expressing predominantly D2L). We found that D2L KO mice displayed markedly enhanced AIMs in response to chronic treatment of l-dopa compared to wild-type mice. The l-dopa-induced enhancement of AIMs in D2L KO mice was significantly reduced by the D2R antagonist eticlopride. D2L KO mice also displayed markedly enhanced AIMs in response to chronic treatment with quinpirole, a preferential D2R agonist. These results suggest that D2S contributes more than D2L to dopaminergic agonist-induced AIMs. Our findings may uncover a new factor that contributes to the pathophysiology of dopaminergic drug-induced AIMs, a characteristic manifestation of dyskinesia and also present in psychosis. There is a possibility that the increased ratio of D2S to D2L in the brain plays a significant role in the development of AIM side effects induced by l-dopa or D2R agonists. See Video Abstract, http://links.lww.com/WNR/A622.


Assuntos
Discinesia Induzida por Medicamentos/metabolismo , Levodopa/efeitos adversos , Atividade Motora/efeitos dos fármacos , Isoformas de Proteínas/metabolismo , Receptores de Dopamina D2/metabolismo , Animais , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Masculino , Camundongos , Camundongos Knockout , Quimpirol/farmacologia , Receptores de Dopamina D2/genética , Salicilamidas/farmacologia
18.
Neurochem Res ; 46(6): 1487-1501, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33710536

RESUMO

Activation of dopamine (DA) neurons is essential for the transition from sleep to wakefulness and maintenance of awakening, and sufficient to accelerate the emergence from general anesthesia in animals. Dopamine receptors (DR) are involve in arousal mediation. In the present study, we showed that the olfactory tubercle (OT) was active during emergence from isoflurane anesthesia, local injection of dopamine D1 receptor (D1R) agonist chloro-APB (1 mg/mL) and D2 receptor (D2R) agonist quinpirole (1 mg/mL) into OT enhanced behavioural and cortical arousal from isoflurane anesthesia, while D1R antagonist SCH-23390 (1 mg/mL) and D2R antagonist raclopride (2.5 mg/mL) prolonged recovery time. Optogenetic activation of DAergic terminals in OT also promoted behavioural and cortical arousal from isoflurane anesthesia. However, neither D1R/D2R agonists nor D1R/D2R antagonists microinjection had influences on the induction of isoflurane anesthesia. Optogenetic stimulation on DAergic terminals in OT also had no impact on the anesthesia induction. Our results indicated that DA signals in OT accelerated emergence from isoflurane anesthesia. Furthermore, the induction of general anesthesia, different from the emergence process, was not mediated by the OT DAergic pathways.


Assuntos
Anestésicos Inalatórios/farmacologia , Nível de Alerta/fisiologia , Isoflurano/farmacologia , Tubérculo Olfatório/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Animais , Nível de Alerta/efeitos dos fármacos , Benzazepinas/farmacologia , Agonistas de Dopamina/farmacologia , Antagonistas dos Receptores de Dopamina D2/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Quimpirol/farmacologia , Racloprida/farmacologia , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D2/agonistas
19.
Sci Rep ; 11(1): 3501, 2021 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-33568753

RESUMO

The development of functionally selective or biased ligands is a promising approach towards drugs with less side effects. Biased ligands for G protein-coupled receptors can selectively induce G protein activation or ß-arrestin recruitment. The consequences of this selective action on cellular functions, however, are not fully understood. Here, we investigated the impact of five biased and balanced dopamine D2 receptor agonists and antagonists on the global protein expression in HEK293T cells by untargeted nanoscale liquid chromatography-tandem mass spectrometry. The proteome analysis detected 5290 protein groups. Hierarchical clustering and principal component analysis based on the expression levels of 1462 differential proteins led to a separation of antagonists and balanced agonist from the control treatment, while the biased ligands demonstrated larger similarities to the control. Functional analysis of affected proteins revealed that the antagonists haloperidol and sulpiride regulated exocytosis and peroxisome function. The balanced agonist quinpirole, but not the functionally selective agonists induced a downregulation of proteins involved in synaptic signaling. The ß-arrestin-preferring agonist BM138, however, regulated several proteins related to neuron function and the dopamine receptor-mediated signaling pathway itself. The G protein-selective partial agonist MS308 influenced rather broad functional terms such as DNA processing and mitochondrial translation.


Assuntos
Agonistas de Dopamina/farmacologia , Mitocôndrias/efeitos dos fármacos , Receptores de Dopamina D2/efeitos dos fármacos , beta-Arrestinas/metabolismo , Arrestinas/metabolismo , Dopamina/metabolismo , Proteínas de Ligação ao GTP/efeitos dos fármacos , Proteínas de Ligação ao GTP/metabolismo , Células HEK293 , Humanos , Mitocôndrias/metabolismo , Quimpirol/farmacologia , Receptores de Dopamina D2/metabolismo , Transdução de Sinais/efeitos dos fármacos
20.
Behav Pharmacol ; 32(1): 9-20, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33399293

RESUMO

Eating a high fat diet can lead to obesity, type 2 diabetes, and dopamine system dysfunction. For example, rats eating high fat chow are more sensitive than rats eating standard chow to the behavioral effects (e.g., locomotion and yawning) of dopaminergic drugs (e.g., quinpirole and cocaine). Daily dietary supplementation with 20% (w/w) fish oil prevents high fat diet-induced enhanced sensitivity to quinpirole-induced yawning and cocaine-induced locomotion; however, doctors recommend that patients take fish oil just two to three times a week. To test the hypothesis that intermittent (i.e., 2 days per week) dietary supplementation with fish oil prevents high fat diet-induced enhanced sensitivity to quinpirole and cocaine, rats eating standard chow (17% kcal from fat), high fat chow (60% kcal from fat), and rats eating standard or high fat chow with 20% (w/w) intermittent (e.g., 2 days per week) dietary fish oil supplementation were tested once weekly with quinpirole [0.0032-0.32 mg/kg, intraperitoneally (i.p.)] or cocaine (1.0-17.8 mg/kg, i.p.) using a cumulative dosing procedure. Consistent with previous reports, eating high fat chow enhanced sensitivity of rats to the behavioral effects of quinpirole and cocaine. Intermittent dietary supplementation of fish oil prevented high fat chow-induced enhanced sensitivity to dopaminergic drugs in male and female rats. Future experiments will focus on understanding the mechanism(s) by which fish oil produces these beneficial effects.


Assuntos
Cocaína/farmacologia , Dieta Hiperlipídica/efeitos adversos , Óleos de Peixe/farmacologia , Quimpirol/farmacologia , Animais , Cocaína/administração & dosagem , Suplementos Nutricionais , Agonistas de Dopamina/administração & dosagem , Agonistas de Dopamina/farmacologia , Inibidores da Captação de Dopamina/administração & dosagem , Inibidores da Captação de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Feminino , Óleos de Peixe/administração & dosagem , Locomoção/efeitos dos fármacos , Masculino , Quimpirol/administração & dosagem , Ratos , Ratos Sprague-Dawley , Bocejo/efeitos dos fármacos
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