RESUMO
Perinatal testosterone, or its metabolite estradiol, organize the brain toward a male phenotype. Male rodents with insufficient testosterone during this period fail to display sexual behavior and partner preference for receptive females in adulthood. However, cohabitation with non-reproductive conspecifics under the influence of a D2 agonist facilitates the expression of conditioned partner preference via Pavlovian learning in gonadally intact male rats. In the present experiment, three groups of neonatal PD1 males (N = 12/group) were either gonadectomized (GDX), sham-GDX, or left intact and evaluated for social preferences and sexual behaviors as adults. We then examined whether the effects of GDX could be reversed by conditioning the males via cohabitation with receptive females under the effects of the D2 agonist quinpirole (QNP) or saline, along with the size of some brain regions, such as the sexually dimorphic nucleus of the preoptic area (SDN-POA), suprachiasmatic nucleus (SCN), posterior dorsal medial amygdala (MeApd) and ventromedial hypothalamus (VMH). Results indicated that neonatal GDX resulted in the elimination of male-typical sexual behavior, an increase in same-sex social preference, and a reduction of the area of the SDN-POA. However, GDX-QNP males that underwent exposure to receptive females in adulthood increased their social preference for females and recovered the size in the SDN-POA. Although neonatal GDX impairs sexual behavior and disrupts partner preference and brain dimorphism in adult male rats, Pavlovian conditioning under enhanced D2 agonism ameliorates the effects on social preference and restores brain dimorphism in the SDN-POA without testosterone.
Assuntos
Área Pré-Óptica , Caracteres Sexuais , Gravidez , Ratos , Animais , Masculino , Feminino , Área Pré-Óptica/metabolismo , Encéfalo , Quimpirol/farmacologia , Castração , Testosterona/farmacologia , Testosterona/metabolismoRESUMO
Huntington's disease (HD) is a progressive neurodegenerative disease characterized by neuropsychiatric disturbance, cognitive impairment, and locomotor dysfunction. In the early stage (chorea) of HD, expression of dopamine D2 receptors (D2R) is reduced, whereas dopamine (DA) levels are increased. Contrary, in the late stage (bradykinesia), DA levels and the expression of D2R and dopamine D1 receptors (D1R) are reduced. 3-Nitropropionic acid (3-NPA) is a toxin that may replicate HD behavioral phenotypes and biochemical aspects. This study assessed the neurotransmitter levels, dopamine receptor gene expression, and the effect of acute exposure to quinpirole (D2R agonist) and eticlopride (D2R antagonist) in an HD model induced by 3-NPA in adult zebrafish. Quinpirole and eticlopride were acutely applied by i.p. injection in adult zebrafish after chronic treatment of 3-NPA (60 mg/kg). 3-NPA treatment caused a reduction in DA, glutamate, and serotonin levels. Quinpirole reversed the bradykinesia and memory loss induced by 3-NPA. Together, these data showed that 3-NPA acts on the dopaminergic system and causes biochemical alterations similar to late-stage HD. These data reinforce the hypothesis that DA levels are linked with locomotor and memory deficits. Thus, these findings may suggest that the use of DA agonists could be a pharmacological strategy to improve the bradykinesia and memory deficits in the late-stage HD.
Assuntos
Dopamina , Doenças Neurodegenerativas , Nitrocompostos , Propionatos , Salicilamidas , Animais , Dopamina/metabolismo , Quimpirol/farmacologia , Peixe-Zebra/metabolismo , Hipocinesia , Receptores de Dopamina D2/metabolismo , Agonistas de Dopamina/farmacologia , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Receptores de Dopamina D1/metabolismoRESUMO
Adolescence is a phase of substantial changes in the brain, characterized by maturational remodeling of many systems. This remodeling allows functional plasticity to adapt to a changing environment. The dopaminergic system is under morphological and physiological changes during this phase. In the present study, we investigated if changes in the dopaminergic tone alter mice behavior in a receptor and sex-specific manner, specifically at the beginning of the puberty period. We administered L-Dopa, SKF-38393 (D1 dopamine receptor agonist), and Quinpirole (D2 dopamine receptor agonist) and tested male and female mice's motor, anxiety- and depressive-like behavior. While females displayed an impaired exploratory drive, males presented an intense depressive-like response. Our results provide insights into the function of dopaminergic development in adolescent behavior and highlight the importance of studies in this time window with male and female subjects.
Assuntos
Agonistas de Dopamina , Levodopa , Humanos , Camundongos , Masculino , Feminino , Animais , Adolescente , Quimpirol/farmacologia , Levodopa/farmacologia , 2,3,4,5-Tetra-Hidro-7,8-Di-Hidroxi-1-Fenil-1H-3-Benzazepina/farmacologia , Agonistas de Dopamina/farmacologia , Dopaminérgicos/farmacologia , Ergolinas/farmacologia , Receptores de Dopamina D1 , Dopamina , Ansiedade/tratamento farmacológicoRESUMO
Dopamine D2 receptor (D2R) is expressed in striatopallidal neurons and decreases forskolin-stimulated cyclic adenine monophosphate (cAMP) accumulation and gamma-aminobutyric acid (GABA) release. Dopamine D3 receptor (D3R) mRNA is expressed in a population of striatal D2R-expressing neurons. Also, D3R protein and binding have been reported in the neuropil of globus pallidus. We explore whether D2R and D3R colocalize in striatopallidal terminals and whether D3R modulates the D2R effect on forskolin-stimulated [3H]cAMP accumulation in pallidal synaptosomes and high K+ stimulated-[3H]GABA release in pallidal slices. Previous reports in heterologous systems indicate that calmodulin (CaM) and CaMKII modulate D2R and D3R functions; thus, we study whether this system regulates its functional interaction. D2R immunoprecipitates with CaM, and pretreatment with ophiobolin A or depolarization of synaptosomes with 15 mM of K+ decreases it. Both treatments increase the D2R inhibition of forskolin-stimulated [3H]cAMP accumulation when activated with quinpirole, indicating a negative modulation of CaM on D2R function. Quinpirole also activates D3R, potentiating D2R inhibition of cAMP accumulation in the ophiobolin A-treated synaptosomes. D2R and D3R immunoprecipitate in pallidal synaptosomes and decrease after the kainic acid striatal lesion, indicating the striatal origin of the presynaptic receptors. CaM-kinase II alfa (CaMKIIα) immunoprecipitates with D3R and increases after high K+ depolarization. In the presence of KN62, a CaMKIIα blocker, D3R potentiates D2R effects on cAMP accumulation in depolarized synaptosomes and GABA release in pallidal slices, indicating D3R function regulation by CaMKIIα. Our data indicate that D3R potentiates the D2R effect on cAMP accumulation and GABA release at pallidal terminals, an interaction regulated by the CaM-CaMKIIα system.
Assuntos
Calmodulina , Receptores de Dopamina D3 , Sesterterpenos , Receptores de Dopamina D3/metabolismo , Quimpirol/farmacologia , Calmodulina/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Colforsina , Receptores de Dopamina D2/metabolismo , Ácido gama-Aminobutírico/metabolismoRESUMO
There is evidence about the importance of sex in pain. The purpose of this study was to investigate the effect of sex in the antiallodynic activity of spinal dopamine D1-and D2-like receptors in a model of fibromyalgia-type pain in rats. Reserpine induced the same extent of tactile allodynia in female and male rats. Intrathecal injection of SCH-23390 (3-30 nmol, D1-like receptor antagonist), pramipexole (0.15-15 nmol) or quinpirole (1-10 nmol D2-like receptor agonists) increased withdrawal threshold in reserpine-treated female rats. Those drugs induced a greater antiallodynic effect in female rats. Sex-difference was also observed in a nerve injury model. Ovariectomy abated the antiallodynic effect of SCH-23390 (30 nmol) in reserpine-treated rats, while systemic reconstitution of 17ß-estradiol levels or intrathecal injection of estrogen receptor-α agonist protopanaxatriol in ovariectomized reserpine-treated females restored the antiallodynic effect of SCH-23390. Intrathecal administration of ICI-182,780 (estrogen receptor-α/ß antagonist) or methyl-piperidino-pyrazole hydrate (estrogen receptor-α antagonist) abated 17ß-estradiol-restored antiallodynic effect of SCH-23390 in rats. In contrast, ovariectomy slightly reduced the effect of pramipexole (15 nmol) or quinpirole (10 nmol) in reserpine-treated rats, whereas systemic reconstitution of 17ß-estradiol levels did not modify the antiallodynic effect of both drugs. Combination 17ß-estradiol/progesterone, but not 17ß-estradiol nor progesterone alone, restored the antiallodynic effect of pramipexole and quinpirole in the rats. Mifepristone (progesterone receptor antagonist) abated 17ß-estradiol + progesterone restoration of the antiallodynic effect of pramipexole and quinpirole. These data suggest that the antiallodynic effect of dopamine D1-and D2-like receptors in fibromyalgia-type pain depends on spinal 17ß-estradiol/estrogen receptor-α and progesterone receptors, respectively.
Assuntos
Dopamina , Fibromialgia , Ratos , Masculino , Feminino , Animais , Quimpirol/farmacologia , Fibromialgia/tratamento farmacológico , Pramipexol/farmacologia , Pramipexol/uso terapêutico , Progesterona , Reserpina/farmacologia , Receptores de Estrogênio , Dor/tratamento farmacológico , Estradiol/farmacologia , Estradiol/uso terapêutico , Estrogênios/uso terapêutico , Receptores de Dopamina D1 , Modelos TeóricosRESUMO
The dopaminergic neurotransmitter system is implicated in several brain functions and behavioral processes. Alterations in it are associated with the pathogenesis of several human neurological disorders. Pharmacological agents that interact with the dopaminergic system allow the investigation of dopamine-mediated cellular and molecular responses and may elucidate the biological bases of such disorders. Zebrafish, a translationally relevant biomedical research organism, has been successfully employed in prior psychopharmacology studies. Here, we evaluated the effects of quinpirole (dopamine D2/D3 receptor agonist) in adult zebrafish on behavioral parameters, brain-derived neurotrophic factor (BDNF) and neurotransmitter levels. Zebrafish received intraperitoneal injections of 0.5, 1.0, or 2.0 mg/kg quinpirole or saline (control group) twice with an inter-injection interval of 48 h. All tests were performed 24 h after the second injection. After this acute quinpirole administration, zebrafish exhibited decreased locomotor activity, increased anxiety-like behaviors and memory impairment. However, quinpirole did not affect social and aggressive behavior. Quinpirole-treated fish exhibited stereotypic swimming, characterized by repetitive behavior followed by immobile episodes. Moreover, quinpirole treatment also decreased the number of BDNF-immunoreactive cells in the zebrafish brain. Analysis of neurotransmitter levels demonstrated a significant increase in glutamate and a decrease in serotonin, while no alterations were observed in dopamine. These findings demonstrate that dopaminergic signaling altered by quinpirole administration results in significant behavioral and neuroplastic changes in the central nervous system of zebrafish. Thus, we conclude that the use of quinpirole administration in adult zebrafish may be an appropriate tool for the analysis of mechanisms underlying neurological disorders related to the dopaminergic system.
Assuntos
Agonistas de Dopamina , Peixe-Zebra , Animais , Humanos , Agonistas de Dopamina/farmacologia , Quimpirol/farmacologia , Receptores de Dopamina D3 , Dopamina/farmacologia , Fator Neurotrófico Derivado do Encéfalo , Atividade MotoraRESUMO
BACKGROUND: Diabetes mellitus is associated with abnormalities in peripheral/central catecholaminergic systems, including changes in catecholamine levels and receptor expression. OBJECTIVE: Since quinpirole-induced cardiac sympathetic inhibition is greater in diabetic than in normoglycemic rats, this study pharmacologically investigated the dopamine D2 -like receptor subtypes that mediate cardiac sympathetic inhibition in diabetic (streptozotocin [STZ]-pretreated) pithed rats. METHODS: Fifty male Wistar rats were pretreated with STZ, pithed and conditioned for spinal stimulation (C7 -T1 ) of the tachycardic sympathetic tone. The resulting increases in heart rate were evaluated following i.v. blocking doses of antagonists at D2 , D3 and D4 receptors during a continuous i.v. infusion of quinpirole (an agonist at D2 -like receptors) or saline (vehicle). RESULTS: With this experimental approach, the cardiac sympathetic inhibition produced by quinpirole in diabetic rats was: (i) unchanged after administration of vehicles and; (ii) abolished by the antagonists L-741,626 (D2 ), SB-277011-A (D3 ) or L-745,870 (D4 ). CONCLUSION: These findings in diabetic pithed rats imply that: (i) the cardiac sympathetic inhibition by quinpirole involves activation of D2/3/4 dopamine receptors; and (ii) there is a differential stimulation of these receptors compared to normoglycemic rats. These D2/3/4 receptor subtypes could be a novel drug target for the therapy of typical cardiac complications of diabetes.
Assuntos
Diabetes Mellitus Experimental , Agonistas de Dopamina , Animais , Dopamina , Agonistas de Dopamina/farmacologia , Masculino , Quimpirol/farmacologia , Ratos , Ratos Wistar , Receptores de Dopamina D1 , Receptores de Dopamina D2/metabolismo , EstreptozocinaRESUMO
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/metabolismoRESUMO
Brain mechanisms of sexual attraction toward reproductive partners develop from a systematic interrelationship between biology (nature) and learning (nurture). However, the causes of attraction toward non-reproductive partners are poorly understood. Here, we explored the role of Pavlovian learning under dopaminergic agonism on the development of sexual preference and brain activation for young male rats. During conditioning, adult sexually naïve males received either Saline (Saline-Paired) or the D2-receptor agonist quinpirole (QNP-Paired) and cohabited in contingency, or out of contingency (QNP-Unpaired) during 24 h with an almond-scented prepubertal juvenile male (PD25). Conditioning occurred every 4 days for three trials. Social and sexual responses were assessed four days after the last conditioning trial in a drug-free test, and males chose freely between a scented young male (PD37) and a novel receptive female. Four days later, males were exposed to the conditioned odor only and brain Fos-IR and serum testosterone were analyzed. Saline-Paired and QNP-Unpaired males displayed more non-contact erections (NCEs) and genital investigations for females, whereas QNP-Paired males expressed more NCEs and genital investigations for young males. In the QNP-Paired group, exposure to the young male-paired odor evoked more Fos-IR in limbic, hypothalamic and cortical areas, but no differences in serum testosterone were observed. Cohabitation with juvenile males during enhanced D2 agonism results in atypical appetitive sexual responses and a higher pattern of brain response for the young male-paired odor, with no changes in serum testosterone. We discuss the potential implications for the development of pedophilic disorder and perhaps other paraphilias.
Assuntos
Agonistas de Dopamina , Comportamento Sexual Animal , Animais , Agonistas de Dopamina/farmacologia , Feminino , Humanos , Masculino , Odorantes , Quimpirol , Ratos , Receptores de Dopamina D2RESUMO
The dysfunction of dopaminergic signaling is associated with several neurological disorders. The use of pharmacological agents that interact with this signaling system may be employed to understand mechanisms underlying such disorders. Nutritional status can impact dopamine reuptake, receptor affinity, transporter activity, and the effects of drugs that bind to dopamine receptors or interact with dopaminergic system. Here we evaluated the effects of quinpirole (a dopamine D2/D3 receptor agonist) exposure on fed and non-fed zebrafish larvae. Zebrafish larvae (6 days post-fertilization, dpf) were exposed to quinpirole (5.5, 16.7, and 50.0 µM) or water (control group) for one hour. To evaluate the effect of feeding status on quinpirole exposure, the experiments were performed on fed and non-fed animals, a between subject experimental design. Both fed and non-fed quinpirole treated larvae exhibited increased erratic movements compared to controls in an open tank exploration task. No alterations were observed on the main parameters of exploratory behavior and swim activity for non-fed larvae treated with quinpirole compared to controls. However, fed animals exposed to quinpirole exhibited increased locomotor activity, anxiety-like behavior, and repetitive circular movements when compared to controls and non-fed exposed animals. In addition, we observed quinpirole exposure to have no effects on morphological parameters and heartbeat, but to impair optomotor responses in both fed and non-fed larvae compared to control. We also found quinpirole effects to interact with feeding status, as quinpirole-treated fed larvae improved while quinpirole treated non-fed larvae impaired their avoidance reaction towards an aversive stimulus. These results indicate that the behavioral effects of quinpirole exposure depended upon feeding status. They showed that consumption of food, a naturally rewarding stimulus known to engage the dopaminergic system, made this neurotransmitter system more susceptible to quinpirole's effects.