RESUMEN
Studies have shown that both aging and dopaminergic dysfunction affected spatial learning and memory. Systematic dopaminergic inhibition, by dopamine receptor (DR) antagonist treatment, impaired spatial delayed-response (SDR) performance, which mostly requires self/body centered egocentric reference frame, in rhesus monkeys. However, the influence of DR blocking on large scale maze learning, which mainly involves world centered allocentric reference frame, remains unclear. Moreover, the effects of aging on the process also remain unknown. Present study investigated the issues, using large scale mazes composed of 8 maze units. Maze No. 1 was used for adaptation and training. Mazes No. 2-4 were used to investigate influence of aging, by comparing learning performance between young and aged rhesus monkeys. Mazes No. 5-8 were used to investigate the effects of DR antagonist treatment, SKF-83566 (0.02, 0.2 mg/kg) and haloperidol (0.001, 0.01 mg/kg). The result showed similar learning performance between young and aged monkeys in mazes No. 2-4. In mazes No. 5-8, we also found similar learning performance after acute DR antagonist injection, compared with pre-treatment baseline performance in mazes No. 2-4, in both young and aged groups. The result showed similar maze learning performance between young and aged monkeys in mazes (No. 2-4), suggesting no significant influence of aging on allocentric spatial learning. We also found similar maze performance in both groups, after dopamine receptor antagonist treatment in mazes (No. 5-8) compared with pre-treatment baseline performance in mazes (No. 2-4), suggesting no significant influence of dopaminergic inhibition on allocentric spatial learning. Together, the present study potentially suggested insensitivity of allocentric spatial learning to cognitive aging and acute systematic dopaminergic inhibition.
Asunto(s)
Envejecimiento/psicología , Antagonistas de Dopamina/farmacología , Aprendizaje por Laberinto/efectos de los fármacos , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/administración & dosificación , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/análogos & derivados , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Administración Intravenosa , Animales , Haloperidol/administración & dosificación , Haloperidol/farmacología , Macaca mulatta , Masculino , Desempeño Psicomotor/efectos de los fármacos , Desempeño Psicomotor/fisiología , Navegación EspacialRESUMEN
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⯵g/site) or quinpirole (0, 1.0, 2.0, and 3.0⯵g/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⯵g/site) and quinpirole (1.0⯵g/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.
Asunto(s)
2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Quinpirol/farmacología , Receptores Dopaminérgicos/metabolismo , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/administración & dosificación , Animales , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Dopamina/metabolismo , Agonistas de Dopamina/administración & dosificación , Agonistas de Dopamina/farmacología , Locomoción/efectos de los fármacos , Locomoción/fisiología , Masculino , Actividad Motora/efectos de los fármacos , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Trastornos Parkinsonianos/tratamiento farmacológico , Trastornos Parkinsonianos/fisiopatología , Quinpirol/administración & dosificación , Ratas , Ratas Wistar , Receptores Dopaminérgicos/efectos de los fármacos , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D2/metabolismoRESUMEN
BACKGROUND: SKF83959, an atypical dopamine (DA) D1 receptor agonist, has been used to test the functions of DA-related receptor complexes in vitro, but little is known about its impact on conditioned behavior. The present study examined the effects of SKF83959 on operant behaviors and assayed the neurochemical mechanisms involved. METHODS: Male rats were trained and maintained on either a fixed-interval 30-second (FI30) schedule or a differential reinforcement of low-rate response 10-second (DRL10) schedule of reinforcement. After drug treatment tests, western blotting assayed the protein expressions of the calcium-/calmodulin-dependent protein kinase II (CaMKII) and the transcription factor cyclic AMP response element binding protein (CREB) in tissues collected from 4 selected DA-related areas. RESULTS: SKF83959 disrupted the performance of FI30 and DRL10 behaviors in a dose-dependent manner by reducing the total number of responses in varying magnitudes. Moreover, the distinct profiles of the behavior altered by the drug were manifested by analyzing qualitative and quantitative measures on both tasks. Western-blot results showed that phospho-CaMKII levels decreased in the nucleus accumbens and the dorsal striatum of the drug-treated FI30 and DRL10 subjects, respectively, compared with their vehicle controls. The phospho-CREB levels decreased in the nucleus accumbens and the hippocampus of drug-treated FI30 subjects but increased in the nucleus accumbens of drug-treated DRL10 subjects. CONCLUSIONS: Our results provide important insight into the neuropsychopharmacology of SKF83959, indicating that the drug-altered operant behavior is task dependent and related to regional-dependent changes of CaMKII-CREB signaling in the mesocorticolimbic DA systems.
Asunto(s)
2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/análogos & derivados , Conducta Animal/efectos de los fármacos , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/efectos de los fármacos , Condicionamiento Operante/efectos de los fármacos , Agonistas de Dopamina/farmacología , Neostriado/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/administración & dosificación , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Animales , Agonistas de Dopamina/administración & dosificación , Masculino , Ratas , Ratas Wistar , Receptores de Dopamina D1/agonistasRESUMEN
Steroid sex hormones produce physiological effects in reproductive and non-reproductive tissues, such as the brain. In the brain, sex hormones receptors are expressed in cortical, limbic and midbrain areas modulating memory, arousal, fear and motivation between other behaviors. One neurotransmitters system regulated by sex hormones is dopamine (DA), where during adulthood, sex hormones promote neurophysiological and behavioral effects on DA systems such as tuberoinfundibular (prolactin secretion), nigrostriatal (motor circuit regulation) and mesocorticolimbic (driving of motivated behavior). However, the long-term effects induced by neonatal exposure to sex hormones on DA release induced by D1 receptor activation and its expression in nucleus accumbens (NAcc) have not been fully studied. To answer this question, neurochemical, cellular and molecular techniques were used. The data show sex differences in NAcc DA extracellular levels induced by D1 receptor activation and protein content of this receptor in male and female control rats. In addition, neonatal programming with a single dose of TP increases the NAcc protein content of D1 receptors of adult male and female rats. Our results show new evidence related with sex differences that could explain the dependence to drug of abuse in males and females, which may be associated with increased reinforcing effects of drugs of abuse.
Asunto(s)
Dopamina/metabolismo , Ácido Glutámico/metabolismo , Hormonas Esteroides Gonadales/farmacología , Núcleo Accumbens/metabolismo , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismo , Ácido gamma-Aminobutírico/metabolismo , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/administración & dosificación , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Envejecimiento , Animales , Animales Recién Nacidos , Agonistas de Dopamina/administración & dosificación , Agonistas de Dopamina/farmacología , Estradiol/administración & dosificación , Estradiol/farmacología , Femenino , Hormonas Esteroides Gonadales/administración & dosificación , Inyecciones , Masculino , Núcleo Accumbens/efectos de los fármacos , Ratas Sprague-Dawley , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/efectos de los fármacos , Factores Sexuales , Propionato de Testosterona/administración & dosificación , Propionato de Testosterona/farmacología , TiempoRESUMEN
Depression and anxiety are more common among females than males and represent a leading cause of disease-related disability in women. Since the dopamine D1-D2 heteromer is involved in depression- and anxiety-like behavior, the possibility that the receptor complex may have a role in mediating sex differences in such behaviors and related biochemical signaling was explored.In non-human primate caudate nucleus and in rat striatum, females expressed higher density of D1-D2 heteromer complexes and a greater number of D1-D2 expressing neurons compared to males. In rat, the sex difference in D1-D2 expression levels occurred even though D1 receptor expression was lower in female than in male with no difference in D2 receptor expression. In behavioral tests, female rats showed faster latency to depressive-like behavior and a greater susceptibility to the pro-depressive and anxiogenic-like effects of D1-D2 heteromer activation by low doses of SKF 83959, all of which were ameliorated by the selective heteromer disrupting peptide, TAT-D1. The sex difference observed in the anxiety test correlated with differences in low-frequency delta and theta oscillations in the nucleus accumbens. Analysis of signaling pathways revealed that the sex difference in D1-D2 heteromer expression led to differences in basal and heteromer-stimulated activities of two important signaling pathways, BDNF/TrkB and Akt/GSK3/ß-catenin.These results suggest that the higher D1-D2 heteromer expression in female may significantly increase predisposition to depressive-like and anxiety-like behavior in female animals.
Asunto(s)
Ansiedad/metabolismo , Núcleo Caudado/metabolismo , Depresión/metabolismo , Núcleo Accumbens/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Caracteres Sexuales , Transducción de Señal , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/administración & dosificación , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/análogos & derivados , Animales , Ansiedad/fisiopatología , Conducta Animal , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Núcleo Caudado/efectos de los fármacos , Chlorocebus aethiops , Depresión/fisiopatología , Femenino , Glucógeno Sintasa Quinasa 3/metabolismo , Masculino , Núcleo Accumbens/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Sprague-Dawley , Receptor trkB/metabolismo , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D2/agonistas , Transducción de Señal/efectos de los fármacos , beta Catenina/metabolismoRESUMEN
The aim of this study was to investigate the relationship of dopamine D1 receptor (D1R) and its downstream factors with morphine withdrawal symptoms in rats. Rats were injected intraperitoneally with morphine in a dose-escalating manner. The midbrain periaqueductal gray (PAG) area was microinjected with D1R antagonist SCH23390 or D1R agonist SKF38393. Rats were intraperitoneally injected with naloxone (4â¯mg/kg) after the last morphine injection, and the withdrawal response was observed. The D1R antagonist reduced the withdrawal response in morphine-exposed rats and decreased the expression of Ca2+/calmodulin-dependent protein kinase II (CaMKII), phosphorylated extracellular signal-regulated kinase (p-ERK) and cAMP response element-binding protein (CREB) in the PAG. However, the ability of SKF38393 to increase the withdrawal response was weak and limited. Taken together, the results suggest that D1R antagonist decreased the withdrawal response in morphine-exposed rats by downregulating the downstream factors, CaMKII, p-ERK and CREB.
Asunto(s)
Benzazepinas/farmacología , Morfina/efectos adversos , Sustancia Gris Periacueductal/metabolismo , Síndrome de Abstinencia a Sustancias/prevención & control , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/administración & dosificación , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Animales , Benzazepinas/administración & dosificación , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Regulación hacia Abajo/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Masculino , Microinyecciones , Morfina/antagonistas & inhibidores , Naloxona/farmacología , Ratas , Receptores de Dopamina D1/antagonistas & inhibidoresRESUMEN
The D1 dopamine receptor agonist, SKF-38393, induces cytotoxicity in striatal dopaminergic neurons via an extracellular signal-regulated kinase (ERK) signaling cascade. However, the underlying mechanism remains unclear. We hypothesized that repeated activation of dopaminergic receptors by agonists could lead to neuronal cell death. This study investigated the effects of SKF-38393 on dopaminergic neuronal cell death in a 6-hydroxydopamine-lesioned rat model of Parkinson's disease (PD) and PC12 cells. In the PD model, SKF-38393 administration (3 and 10 mg/kg per day, s.c.) for 8 weeks significantly increased the number of tyrosine hydroxylase-immunopositive neuronal cells in nigrostriatal regions. SKF-38393 administration for 8 weeks induced phosphorylation of sustained ERK1/2 and Bad (Bcl-2-associated death promoter) at Ser155 (BadSer155), and augmented Bax (Bcl-2-associated X protein) expression. However, SKF-38393 only increased Bad phosphorylation at Ser112 (BadSer112) when administered for 4 weeks. In PC12 cells, toxic levels of SKF-38393 (20 and 50 µM) rapidly induced formation of neurite-like processes, but not in the presence of an adenylyl cyclase inhibitor (MDL-12330 A). SKF-38393 (20 and 50 µM) induced sustained ERK1/2 and BadSer155 phosphorylation as well as caspase-3 activation. At a non-toxic level (5 µM), SKF-38393 produced only transient ERK1/2 and BadSer112 phosphorylation. Repeated treatments with SKF-38393 (5 µM) for 1-3 days activated BadSer112. Repeated treatments for 4-7 days induced sustained ERK1/2 and BadSer155 phosphorylation as well as Bax and caspase-3 activation. These results suggest that SKF-38393 induces neurotoxicity by activation of the sustained ERK-Bad-Bax system. These findings contribute to an understanding of the adverse effects of D1 dopamine receptor agonists in patients with PD.
Asunto(s)
2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Muerte Celular/efectos de los fármacos , Agonistas de Dopamina/farmacología , Neuronas Dopaminérgicas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Células PC12/efectos de los fármacos , Enfermedad de Parkinson Secundaria , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/administración & dosificación , Adrenérgicos/farmacología , Animales , Modelos Animales de Enfermedad , Agonistas de Dopamina/administración & dosificación , Masculino , Oxidopamina/farmacología , Fosforilación , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D1/agonistasRESUMEN
Many works have been performed to understand the mechanisms of the formation and persistence of memory. However, it is not fully understood whether the decay of long-term memory can be modulated by the activation of dopamine D1 receptor. A Barnes maze task was employed to measure long-term spatial memory. We observed that the spatial memory acquired through 3 trials per session for 4â¯days had begun to fade out by the 14th day and had completely disappeared by 21â¯days after the first probe test. The intraperitoneal administration of SKF 38393 (a dopamine D1 receptor agonist) for 7â¯days beginning on the 14th day after the first probe test prevented natural memory forgetting, and the intraperitoneal administration of SCH 23390 (a dopamine D1 receptor antagonist) prevented this memory persistence. In the Western blotting, the administration of SKF 38393 increased the phosphorylation levels of PKA, ERK1/2, CaMKII, and CREB in the hippocampus. In addition, such increased levels were decreased by the corresponding antagonist (SCH 23390). Moreover, the inhibition of PKA could completely reverse the preservation of spatial memory induced by dopamine D1 receptor activation. These results suggest that the activation of the dopamine D1 receptor plays a critical role in the persistence of long-term spatial memory through the PKA signaling pathway.
Asunto(s)
Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Hipocampo/metabolismo , Memoria a Largo Plazo/fisiología , Receptores de Dopamina D1/metabolismo , Memoria Espacial/fisiología , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/administración & dosificación , Animales , Agonistas de Dopamina , Masculino , Aprendizaje por Laberinto/fisiología , Ratones , Transducción de SeñalRESUMEN
fMRI was used to study late effects of dopamine D1/5 receptor activation on hippocampal signal processing and signal propagation to several target regions. The dopamine D1/5 receptor agonists SKF83959 and SKF38393 were intraperitoneally applied without, immediately before or 7 days after electrical stimulation of the right perforant pathway with bursts of high-frequency pulses. Control animals received a 0.9% NaCl solution. One day after D1/5 receptor activation, the perforant pathway was stimulated and the induced BOLD responses in the right hippocampus and its target regions, left hippocampus (l-HC) and medial prefrontal cortex (mPFC), were measured. Depending on the temporal relation between dopamine receptor activation and the first perforant pathway stimulation the induced BOLD response pattern differed. When applied without concurrent perforant pathway stimulation, the agonists caused region-selective increases in the induced BOLD responses: the effect of SKF83959 was evident in the mPFC whereas that of SKF38393 was confined to the l-HC. When applied in conjunction with perforant pathway stimulation, either agonist caused increased BOLD responses in both regions. In contrast, when applied 7 days after perforant pathway stimulation, neither SKF83959 nor SKF38393 modified the BOLD responses in the mPFC or l-HC 1day later. These findings suggest that (i) activation of dopamine D1/5 receptors alone is sufficient to modify stimulus-induced BOLD responses in target regions of the right hippocampus 24h later, and (ii), the history of previous stimulations crucially affects the impact of dopamine receptor activation on stimulus-induced BOLD responses.
Asunto(s)
Hipocampo/fisiología , Receptores de Dopamina D1/fisiología , Receptores de Dopamina D5/fisiología , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/administración & dosificación , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/análogos & derivados , Animales , Mapeo Encefálico , Agonistas de Dopamina/administración & dosificación , Estimulación Eléctrica , Hipocampo/efectos de los fármacos , Imagen por Resonancia Magnética , Masculino , Vía Perforante/fisiología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/fisiología , Ratas Wistar , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D5/agonistasRESUMEN
Deficits in social interaction are hallmarks of neurological and psychiatric disorders. However, its underlying mechanism is still unclear. Here, we show that the loss of dendritic cell factor 1 (Dcf1) in the nervous system of mice induces social interaction deficiency, autism-like behaviour, and influences social interaction via the dopamine system. Dopamine receptor D1 agonist rescues this social cognition phenotype, and improves short-term plasticity. Together, this study presents a new genetic mechanism that affects social interaction and may provide a new way to improve positive social interaction and treat autism spectrum disorders.
Asunto(s)
Relaciones Interpersonales , Proteínas de la Membrana/fisiología , Proteínas del Tejido Nervioso/fisiología , Receptores de Dopamina D1/fisiología , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/administración & dosificación , Animales , Dopamina/administración & dosificación , Dopamina/metabolismo , Agonistas de Dopamina/administración & dosificación , Potenciales Postsinápticos Excitadores , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/fisiología , Masculino , Proteínas de la Membrana/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas del Tejido Nervioso/genética , Plasticidad Neuronal , Receptores de Dopamina D1/metabolismoRESUMEN
External control over rapid and precise release of chemicals in the brain potentially provides a powerful interface with neural activity. Optical manipulation techniques, such as optogenetics and caged compounds, enable remote control of neural activity and behavior with fine spatiotemporal resolution. However, these methods are limited to chemicals that are naturally present in the brain or chemically suitable for caging. Here, we demonstrate the ability to interface with neural functioning via a wide range of neurochemicals released by stimulating loaded liposomal nanostructures with femtosecond lasers. Using a commercial two-photon microscope, we released inhibitory or excitatory neurochemicals to evoke subthreshold and suprathreshold changes in membrane potential in a live mouse brain slice. The responses were repeatable and could be controlled by adjusting laser stimulation characteristics. We also demonstrate the release of a wider range of chemicals-which previously were impossible to release by optogenetics or uncaging-including synthetic analogs of naturally occurring neurochemicals. In particular, we demonstrate the release of a synthetic receptor-specific agonist that exerts physiological effects on long-term synaptic plasticity. Further, we show that the loaded liposomal nanostructures remain functional for weeks in a live mouse. In conclusion, we demonstrate new techniques capable of interfacing with live neurons, and extendable to in vivo applications.
Asunto(s)
Rayos Láser , Liposomas , Nanoestructuras , Neuronas/efectos de los fármacos , Neurotransmisores/administración & dosificación , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/administración & dosificación , Animales , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/fisiología , Sistemas de Liberación de Medicamentos , Compuestos de Oro , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Masculino , Potenciales de la Membrana/efectos de los fármacos , Ratones Endogámicos C57BL , Ratones Transgénicos , Microscopía , Muscimol/administración & dosificación , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Neuronas/fisiología , Técnicas de Placa-Clamp , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismo , Técnicas de Cultivo de TejidosRESUMEN
Levodopa (L-dopa) is the dominating therapy drug for exogenous dopaminergic substitution and can alleviate most of the manifestations of Parkinson's disease (PD), but long-term therapy is associated with the emergence of L-dopa-induced dyskinesia (LID). Evidence points towards an involvement of Glycogen Synthase Kinase-3ß (GSK-3ß) in development of LID. In the present study, we found that animals rendered dyskinetic by L-dopa treatment, administration of TDZD8 (2mg/kg) obviously prevented the severity of AIM score, as well as improvement in motor function (P < 0.05). Moreover, the TDZD8-induced reduction in dyskinetic behavior correlated with a reduction in molecular correlates of LID. TDZD8 reduced the phosphorylation levels of tau, DARPP32, ERK and PKA protein, which represent molecular markers of LID, as well as reduced L-dopa-induced FosB mRNA and PPEB mRNA levels in the lesioned striatum. In addition, we found that TDZD8 antidyskinetic properties were overcome by D1 receptor, as pretreatment with SKF38393 (5 mg/kg, 10 mg/kg, respectively), a D1 receptor agonist, blocked TDZD8 antidyskinetic actions. This study supported the hypothesis that GSK-3ß played an important role in the development and expression of LID. Inhibition of GSK-3ß with TDZD8 reduced the development of ALO AIM score and associated molecular changes in 6-OHDA-lesioned rats.
Asunto(s)
Discinesia Inducida por Medicamentos/prevención & control , Glucógeno Sintasa Quinasa 3 beta/antagonistas & inhibidores , Levodopa/toxicidad , Trastornos Parkinsonianos/complicaciones , Tiadiazoles/administración & dosificación , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/administración & dosificación , Animales , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Fosfoproteína 32 Regulada por Dopamina y AMPc/metabolismo , Discinesia Inducida por Medicamentos/etiología , Discinesia Inducida por Medicamentos/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Oxidopamina , Fosforilación , Ratas , Receptores de Dopamina D1/agonistas , Tirosina 3-Monooxigenasa/metabolismo , Proteínas tau/metabolismoRESUMEN
Dopamine is critical for many processes that drive learning and memory, including motivation, prediction error, incentive salience, memory consolidation, and response output. Theories of dopamine's function in these processes have, for the most part, been developed from behavioral approaches that examine learning mechanisms in appetitive tasks. A parallel and growing literature indicates that dopamine signaling is involved in consolidation of memories into stable representations in aversive tasks such as fear conditioning. Relatively little is known about how dopamine may modulate memories that form during extinction, when organisms learn that the relation between previously associated events is severed. We investigated whether fear and reward extinction share common mechanisms that could be enhanced with dopamine D1/5 receptor activation. Pharmacological activation of dopamine D1/5 receptors (with SKF 81297) enhanced extinction of both cued and contextual fear. These effects also occurred in the extinction of cocaine-induced conditioned place preference, suggesting that the observed effects on extinction were not specific to a particular type of procedure (aversive or appetitive). A cAMP/PKA biased D1 agonist (SKF 83959) did not affect fear extinction, whereas a broadly efficacious D1 agonist (SKF 83822) promoted fear extinction. Together, these findings show that dopamine D1/5 receptor activation is a target for the enhancement of fear or reward extinction.
Asunto(s)
Extinción Psicológica/fisiología , Miedo/fisiología , Receptores de Dopamina D1/fisiología , Receptores de Dopamina D5/fisiología , Recompensa , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/administración & dosificación , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/análogos & derivados , Animales , Benzazepinas/administración & dosificación , Cocaína/administración & dosificación , Condicionamiento Clásico/efectos de los fármacos , AMP Cíclico/metabolismo , Extinción Psicológica/efectos de los fármacos , Miedo/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D5/agonistas , beta-Arrestinas/metabolismoRESUMEN
The zebrafish (Danio rerio) has been shown to be an insatiable rival for mammalian model organisms, in many research areas including behavioral neuroscience. Despite a growing body of evidence on successful performance of zebrafish in learning paradigms, little progress has been made toward elucidating the role of neuromodulatory systems in regulation of cognitive functions in this species. Here, we investigated the modulatory effect of dopamine, one of the major neurotransmitters of importance in the brain, on cognitive performance of zebrafish. To this end, a plus maze associative learning paradigm was employed where fish trained to associate a conditioned visual stimulus with the sight of conspecifics as the rewarding unconditioned stimulus. Experimental fish were exposed to dopaminergic agonists (SKF-38393 and quinpirole) and antagonists (SCH-23390 and eticlopride) immediately before training, after training, and just before probe. Pre- and post-training administration of SKF-38393 and SCH-23390 enhanced learning and memory performance of zebrafish in the maze but not when given immediately before the probe trial. Quinpirole also enhanced probe trial performance when administered immediately before training and before the probe but not when given after training. Furthermore, fish that received eticlopride before training, after training or before the probe showed impairment in associative learning performance. Taken together, our results shed first light on modulatory role of dopamine receptors in different aspects of learning and memory in zebrafish.
Asunto(s)
Aprendizaje por Asociación/fisiología , Aprendizaje por Laberinto/fisiología , Receptores Dopaminérgicos/fisiología , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/administración & dosificación , Animales , Aprendizaje por Asociación/efectos de los fármacos , Benzazepinas/administración & dosificación , Agonistas de Dopamina/administración & dosificación , Antagonistas de Dopamina/administración & dosificación , Femenino , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Recuerdo Mental/efectos de los fármacos , Recuerdo Mental/fisiología , Quinpirol/administración & dosificación , Salicilamidas/administración & dosificación , Pez CebraRESUMEN
The ankyrin repeat and kinase domain containing 1 (ANKK1) TaqIA polymorphism has been extensively studied as a marker of the gene for dopamine receptor D2 (DRD2) in addictions and other dopamine-associated traits. In vitro mRNA and protein studies have shown a potential connection between ANKK1 and the dopaminergic system functioning. Here, we have investigated whether Ankk1 expression in the brain is regulated by treatment with dopaminergic agonists. We used quantitative RT-PCR of total brain and Western blots of specific brain areas to study Ankk1 in murine brain after dopaminergic treatments. We found that Ankk1 mRNA was upregulated after activation of D1R-like dopamine receptors with SKF38393 (2.660 ± 1.035-fold; t: 4.066, df: 11, P = 0.002) and apomorphine (2.043 ± 0.595-fold; t: 3.782, df: 8, P = 0.005). The D2R-like agonist quinelorane has no effect upon Ankk1 mRNA (1.004 ± 0.580-fold; t: 0.015, df: 10, P = 0.9885). In contrast, mice treatment with the D2R-like agonists 7-OH-DPAT and aripiprazole caused a significant Ankk1 mRNA downregulation (0.606 ± 0.057-fold; t: 2.786, df: 10, P = 0.02 and 0.588 ± 0.130-fold; t: 2.394, df: 11, P = 0.036, respectively). With respect the Ankk1 proteins profile, no effects were found after SKF38393 (t: 0.54, df: 2, P = 0.643) and Quinelorane (t: 0.286, df: 8, P = 0.782) treatments. In contrast, the D2R-like agonist 7-OH-DPAT (±) caused a significant increment of Ankk1 in the striatum (t: 2.718, df: 7; P = 0.03) when compared to the prefrontal cortex. The activation of D1R-like and D2-R-like leads to opposite transcriptional regulation of Ankk1 by specific pathways.
Asunto(s)
Encéfalo/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/administración & dosificación , Animales , Apomorfina , Aripiprazol , Encéfalo/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Serina-Treonina Quinasas/genética , Quinolinas , ARN Mensajero/metabolismo , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D2/agonistas , Tetrahidronaftalenos , Regulación hacia Arriba/efectos de los fármacosRESUMEN
The mesolimbic dopaminergic system (MLDS) originating from the ventral tegmental area has important role in the regulation of motivation, learning and memory. The ventral pallidum (VP), innervated by the MLDS, is involved in the regulation of adaptive behavior, but its exact role is not known in inhibitory avoidance learning. The VP contains both D1 and D2 dopamine receptors, but the density of the former subtype is more excessive. Therefore, in our present experiments, the role of D1 dopamine receptors of the VP in one trial step-through inhibitory avoidance paradigm was investigated. In the conditioning trial, animals were shocked 3 times with 0.5 mA current for 1s, and subsequently were microinjected bilaterally with D1 dopamine receptor agonist SKF38393 into the VP in three doses (0.1 µg, 1.0 µg or 5.0 µg in 0.4 µl saline). To clarify whether the agonist effect was specific, we also applied the D1 dopamine receptor antagonist SCH23390 (5.0 µg in 0.4 µl saline) 15 min prior the agonist treatment. The D1 dopamine receptor agonist, in a dose-dependent manner, significantly increased the step-through latency during the test trials: retention was significant relative to the controls even after 2 weeks of conditioning. The D1 dopamine receptor antagonist SCH23390 pretreatment eliminated SKF38393 effects in the ventral pallidum. Our results show that D1 dopamine receptor mediated mechanisms in the VP facilitate learning and memory in inhibitory avoidance paradigm and this facilitation is specific because it can be eliminated by D1 dopamine receptor antagonist.
Asunto(s)
Reacción de Prevención/efectos de los fármacos , Prosencéfalo Basal/efectos de los fármacos , Inhibición Psicológica , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Dopamina D1/metabolismo , Retención en Psicología/efectos de los fármacos , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/administración & dosificación , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Animales , Benzazepinas/administración & dosificación , Benzazepinas/farmacología , Agonistas de Dopamina/administración & dosificación , Agonistas de Dopamina/farmacología , Antagonistas de Dopamina/administración & dosificación , Antagonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Masculino , Ratas , Ratas WistarRESUMEN
Histamine H3 receptors (H3Rs) co-localize with dopamine (DA) D1 receptors (D1Rs) on striatal medium spiny neurons and functionally antagonize D1R-mediated responses. The intra-striatal administration of D1R agonists reduces DA release whereas D1R antagonists have the opposite effect. In this work, a microdialysis method was used to study the effect of co-activating D1 and H3 receptors on the release of DA from the rat dorsal striatum. Infusion of the D1R agonist SKF-38393 (0.5 and 1 µM) significantly reduced DA release (26-58%), and this effect was prevented by co-administration of the H3R agonist immepip (10 µM). In turn, the effect of immepip was blocked by the H3R antagonist thioperamide (10 µM). Our results indicate that co-stimulation of post-synaptic D1 and H3 receptors may indirectly regulate basal DA release in the rat striatum and provide in vivo evidence for a functional interaction between D1 and H3 receptors in the basal ganglia.
Asunto(s)
Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Antagonistas de los Receptores Histamínicos H3/farmacología , Receptores de Dopamina D1/fisiología , Receptores Histamínicos H3/fisiología , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/administración & dosificación , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/antagonistas & inhibidores , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Animales , Cuerpo Estriado/efectos de los fármacos , Agonistas de Dopamina/administración & dosificación , Agonistas de Dopamina/farmacología , Interacciones Farmacológicas , Agonistas de los Receptores Histamínicos/administración & dosificación , Agonistas de los Receptores Histamínicos/farmacología , Imidazoles/administración & dosificación , Imidazoles/antagonistas & inhibidores , Imidazoles/farmacología , Masculino , Microdiálisis , Microinyecciones , Piperidinas/administración & dosificación , Piperidinas/antagonistas & inhibidores , Piperidinas/farmacología , Ratas , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiologíaRESUMEN
RATIONALE: Mathematical models can assist the interpretation of the effects of interventions on schedule-controlled behaviour and help to differentiate between processes that may be confounded in traditional performance measures such as response rate and the breakpoint in progressive ratio (PR) schedules. OBJECTIVE: The effects of a D1-like dopamine receptor antagonist, 8-bromo-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol hydrobromide (SKF-83566), and a D2-like receptor antagonist, haloperidol, on rats' performance on PR schedules maintained by sucrose and corn oil reinforcers were assessed using a new model derived from Killeen's (Behav Brain Sci 17:105-172, 1994) Mathematical Principles of Reinforcement. METHOD: Separate groups of rats were trained under a PR schedule using sucrose or corn oil reinforcers. SKF-83566 (0.015 and 0.03 mg kg(-1)) and haloperidol (0.05 and 0.1 mg kg(-1)) were administered intraperitoneally (five administrations of each treatment). Running and overall response rates in successive ratios were analysed using the new model, and estimates of the model's parameters were compared between treatments. RESULTS: Haloperidol reduced a (the parameter expressing incentive value) in the case of both reinforcers, but did not affect the parameters related to response time and post-reinforcement pausing. SKF-83566 reduced a and k (the parameter expressing sensitivity of post-reinforcement pausing to the prior inter-reinforcement interval) in the case of sucrose, but did not affect any of the parameters in the case of corn oil. CONCLUSIONS: The results are consistent with the hypothesis that blockade of both D1-like and D2-like receptors reduces the incentive value of sucrose, whereas the incentive value of corn oil is more sensitive to blockade of D2-like than D1-like receptors.
Asunto(s)
2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/análogos & derivados , Antagonistas de Dopamina/farmacología , Haloperidol/farmacología , Modelos Teóricos , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/administración & dosificación , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Animales , Conducta Animal/efectos de los fármacos , Condicionamiento Operante/efectos de los fármacos , Aceite de Maíz/administración & dosificación , Antagonistas de Dopamina/administración & dosificación , Antagonistas de los Receptores de Dopamina D2 , Relación Dosis-Respuesta a Droga , Femenino , Haloperidol/administración & dosificación , Inyecciones Intraperitoneales , Ratas , Ratas Wistar , Tiempo de Reacción/efectos de los fármacos , Receptores de Dopamina D1/antagonistas & inhibidores , Esquema de Refuerzo , Sacarosa/administración & dosificaciónRESUMEN
It has been proposed that distributed neuronal networks in the medial temporal lobe process different characteristics of a recognition event; the hippocampus has been associated with contextual recollection while the perirhinal cortex has been linked with familiarity. Here we show that D1 dopamine receptor activity in these two structures participates differentially in object recognition memory consolidation. The D1 receptor antagonist SCH23390 was infused bilaterally 15 min before a 5 min sample phase in either rats' perirhinal cortex or dorsal hippocampus, and they were tested 90 min for short-term memory or 24 h later for long-term memory. SCH23390 impaired long-term memory when infused in the perirhinal cortex but not when infused in the hippocampus. Conversely, when the D1 receptor agonist SKF38393 was infused 10 min before a 3 min sample phase in the perirhinal cortex, long-term memory was enhanced, however, this was not observed when the D1 agonist was infused in the hippocampus. Short-term memory was spared when SCH23390 or SKF38393 were infused in the perirhinal cortex or the dorsal hippocampus suggesting that acquisition was unaffected. These results suggest that dopaminergic transmission in these medial temporal lobe structures have a differential involvement in object recognition memory consolidation.
Asunto(s)
Hipocampo/metabolismo , Memoria a Largo Plazo/fisiología , Memoria a Corto Plazo/fisiología , Receptores de Dopamina D1/fisiología , Reconocimiento en Psicología/fisiología , Lóbulo Temporal/metabolismo , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/administración & dosificación , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Animales , Benzazepinas/administración & dosificación , Benzazepinas/farmacología , Hipocampo/efectos de los fármacos , Masculino , Memoria a Largo Plazo/efectos de los fármacos , Memoria a Corto Plazo/efectos de los fármacos , Ratas , Ratas Wistar , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/antagonistas & inhibidores , Reconocimiento en Psicología/efectos de los fármacos , Lóbulo Temporal/efectos de los fármacosRESUMEN
In Sprague-Dawley rats by means in vivo microdialysis combined with HPLC analysis in was shown that an infusion into the medial n. accumbens of the dopamine D1 receptor agonist SKF-38393 (100 microM) caused a rise of extracellular levels of citrulline (an NO co-product) in this brain area (the average 139 +/- 3%), which was prevented by intraacumbal infusion of 0.5 mM 7-nitroindazole, a neuronal NO-synthase inhibitor. The intraaccumbal infusion of dopamine D2 receptor agonist quinelorane (100, 500, 1000 microM) did not affect the extracellular citrulline level in this brain area. Combined infusions into the medial nucleus accumbens of SKF-38393 (100 microM) and quinelorane (100 microM) produced a significant rise in citrulline extracellular levels (the average 243 +/- 14%) which was prevented by intraacumbal infusion of 0.5 mM 7-nitroindazole. The data obtained indicate for the first time that the nitregic system of the medial nucleus accumbens is under synergetic regulation of dopamine D1 and D2 receptors.