RESUMEN

Dopamine D1-like and D2-like receptors are expressed in the pulmonary arteries, however there is a little information about their effect on vascular tone in pulmonary circulation, even the vascular effect of activation of the dopamine D3 and D4 subtypes in physiological and pathological conditions such as pulmonary hypertension is unknown. The objective of this study was to evaluate the vascular response of trunk pulmonary artery rings from saline and monocrotaline-treated rats in the presence of selective dopamine receptor agonists. In trunk pulmonary artery rings with intact and denuded endothelium, cumulative concentration-response curves were performed for phenylephrine, acetylcholine, and dopamine receptor agonists (apomorphine-D2-like, SKF38393-D1, quinpirole-D2/D3, 7-OH-DPATD3, and PD168077-D4) alone and in the presence of corresponding selective dopamine receptor antagonists (SCH23390-D1, raclopride-D2/D3, U99194 maleate-D3, and L-745,870-D4). Contractile and relaxant effects generated during the activation with phenylephrine and acetylcholine, respectively, were significantly reduced in intact and denuded endothelium trunk pulmonary artery rings from monocrotaline rats in comparison with control rats. All dopamine receptor agonists, except the 7-OH-DPAT, produced significant vascular relaxation in intact trunk pulmonary artery rings precontracted with phenylephrine in both experimental groups. Also, the vascular relaxation of SKF38393, and particularly apomorphine and PD168077 was significant in denuded endothelium trunk pulmonary artery rings from control and monocrotaline groups. Furthermore, the vasorelaxation induced by these dopamine agonists was significantly reduced in pulmonary preparations from monocrotaline-treated rats in comparison to that recorded in preparations from control rats. The effect of dopamine receptor agonists decreased significantly in the presence of the corresponding antagonist in both experimental groups. The results support that dopamine D4 receptor agonist induces significant vascular relaxation, whereas dopamine D3 receptor agonist induces vasoconstriction in intact and denuded endothelium trunk pulmonary artery rings in control and monocrotaline-induced pulmonary arterial hypertension rats.

Asunto(s)

Agonistas de Dopamina , Dopamina , Ratas , Animales , Agonistas de Dopamina/farmacología , Apomorfina/farmacología , Receptores de Dopamina D2/fisiología , Arteria Pulmonar , Monocrotalina/farmacología , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina , Acetilcolina/farmacología , Fenilefrina

RESUMEN

SUMMARY STATEMENT: A2A receptor required previous D2 receptor activation to modulate Ca2+ currents. Istradefylline decreases pramipexole modulation on Ca2+ currents. Istradefylline reduces A2A + neurons activity in striatial microcircuit, but pramipexole failed to further reduce neuronal activity.

Asunto(s)

Dopamina , Trastornos Parkinsonianos , Adenosina , Animales , Trastornos Parkinsonianos/tratamiento farmacológico , Pramipexol , Receptores de Dopamina D2/fisiología , Roedores

RESUMEN

Fear extinction (FExt) is used to treat patients with posttraumatic stress disorder (PTSD). However, fear related to traumatic events can be persistent and return even after successful extinction. The neurochemical control of extinction seems to be performed by several neurotransmitters, including dopamine (DA), through D1 and D2 receptors. Recently, we showed that intranasally applied DA (IN-DA) facilitated the FExt, but the mechanisms by which it promoted this effect are still unknown. This study focused on investigating whether these effects are mediated by the action of DA on D2-like receptors since these receptors seem to be related to neurochemical and molecular changes underlying extinction. Also, we investigated whether IN-DA treatment would affect conditioned fear-induced antinociception (Fear-IA). Rats treated with IN-DA (1 mg/kg) twenty-five minutes after sulpiride (SUL; 40 mg/kg, i.p., D2-antagonist) were subjected to the extinction of contextual fear. IN-DA applied before the extinction session induced the FExt and prevented Fear-IA. These effects were impaired by pre-treatment with SUL, suggesting that the IN-DA effects are mediated by DA on D2-like receptors. SUL per se also facilitated the FExt but did not affect Fear-IA. These data suggest IN-DA as a promising pharmacological tool to supplement the psychotherapy of patients suffering from PTSD.

Asunto(s)

Condicionamiento Psicológico/fisiología , Antagonistas de los Receptores de Dopamina D2/farmacología , Dopamina/farmacología , Extinción Psicológica/fisiología , Miedo/fisiología , Receptores de Dopamina D2/fisiología , Sulpirida/farmacología , Administración Intranasal , Animales , Condicionamiento Psicológico/efectos de los fármacos , Dopaminérgicos/farmacología , Extinción Psicológica/efectos de los fármacos , Masculino , Ratas , Sulpirida/antagonistas & inhibidores

RESUMEN

The dopaminergic system plays an essential role in maintaining homeostasis between the central nervous system (CNS) and the immune system. Previous studies have associated imbalances in the dopaminergic system to the pathogenesis of multiple sclerosis (MS). Here, we examined the protein levels of dopaminergic receptors (D1R and D2R) in different phases of the experimental autoimmune encephalomyelitis (EAE) model. We also investigated if the treatment with pramipexole (PPX)-a dopamine D2/D3 receptor-preferring agonist-would be able to prevent EAE-induced motor and mood dysfunction, as well as its underlying mechanisms of action. We report that D2R immunocontent is upregulated in the spinal cord of EAE mice 14 days post-induction. Moreover, D1R and D2R immunocontents in lymph nodes and the oxidative damage in the spinal cord and striatum of EAE animals were significantly increased during the chronic phase. Also, during the pre-symptomatic phase, axonal damage in the spinal cord of EAE mice could already be found. Surprisingly, therapeutic treatment with PPX failed to inhibit the progression of EAE. Of note, PPX treatment inhibited EAE-induced depressive-like while failed to inhibit anhedonic-like behaviors. We observed that PPX treatment downregulated IL-1ß levels and increased BNDF content in the spinal cord after EAE induction. Herein, we show that a D2/D3 receptor-preferred agonist mitigated EAE-induced depressive-like behavior, which could serve as a new possibility for further clinical trials on treating depressive symptoms in MS patients. Thus, we infer that D2R participates in the crosstalk between CNS and immune system during autoimmune and neuroinflammatory response induced by EAE, mainly in the acute and chronic phase of the disease.

Asunto(s)

Encefalomielitis Autoinmune Experimental/metabolismo , Receptores de Dopamina D1/fisiología , Receptores de Dopamina D2/fisiología , Anhedonia/efectos de los fármacos , Anhedonia/fisiología , Animales , Axones/patología , Factor Neurotrófico Derivado del Encéfalo/biosíntesis , Factor Neurotrófico Derivado del Encéfalo/genética , Cuerpo Estriado/metabolismo , Depresión/etiología , Depresión/prevención & control , Progresión de la Enfermedad , Evaluación Preclínica de Medicamentos , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/psicología , Femenino , Interleucina-1beta/biosíntesis , Interleucina-1beta/genética , Ganglios Linfáticos/metabolismo , Ratones , Ratones Endogámicos C57BL , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/metabolismo , Estrés Oxidativo , Fragmentos de Péptidos/biosíntesis , Fragmentos de Péptidos/genética , Pramipexol/farmacología , Pramipexol/uso terapéutico , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D3/agonistas , Método Simple Ciego , Médula Espinal/metabolismo , Médula Espinal/patología

RESUMEN

Ketamine has addictive potential, a troublesome fact due to its promising use as a therapeutic drug. An important phenomenon associated with drug addiction is behavioral sensitization, usually characterized as augmented locomotion. However, other behaviors may also be susceptible to sensitization, and/or interfere with locomotor activity. Thus, this study drew a comprehensive behavioral 'profiling' in an animal model of repeated administration of ketamine. Adult Swiss mice received single daily ketamine injections (30 or 50 mg/Kg, i.p.), which were followed by open field testing for 7 days (acquisition period, ACQ). A ketamine challenge (sensitization test, ST) was carried out after a 5-day withdrawal. Locomotion, rearing, grooming, rotation and falling were assessed during ACQ and ST. All behaviors were affected from the first ACQ day onwards, with no indication of competition between locomotion and the other behaviors. Only locomotion in response to 30 mg/Kg of ketamine both escalated during ACQ and expressed increased levels at ST, evidencing development and expression of locomotor sensitization. Considering the involvement of serotonin 5HT(2) and dopamine D(2) receptors on addiction mechanisms, we further tested the involvement of these receptors in ketamine-induced sensitization. Ketanserin (5HT2 antagonist, 3 mg/Kg, s.c.) prevented ketamine-evoked development of locomotor sensitization. However, ketanserin pretreatment during ACQ failed to inhibit its expression during ST. Raclopride (D2 antagonist, 0.5 mg/Kg, s.c.) evoked less robust reductions in locomotion but prevented the development of ketamine-evoked sensitization. Pretreatment during ACQ further inhibited the expression of sensitization during ST. These results indicate that a partial overlap in serotonergic and dopaminergic mechanisms underlies ketamine-induced locomotor sensitization.

Asunto(s)

Sensibilización del Sistema Nervioso Central/efectos de los fármacos , Ketamina/farmacología , Locomoción/efectos de los fármacos , Receptores de Dopamina D2/fisiología , Receptores de Serotonina 5-HT2/fisiología , Animales , Relación Dosis-Respuesta a Droga , Femenino , Ketamina/antagonistas & inhibidores , Ketanserina/farmacología , Masculino , Ratones , Racloprida/farmacología , Conducta Estereotipada/efectos de los fármacos

RESUMEN

The prevalence of anxiety disorders in patients with Attention Deficit/Hyperactivity Disorder (ADHD) is around 15-40%, three times higher than in the general population. The dopaminergic system, classically associated with ADHD, interacts directly with the adenosinergic system through adenosine A2A receptors (A2A) and dopamine D2 receptors (D2) forming A2A-D2 heterodimers. Both dopaminergic and adenosinergic systems are implicated in anxiety disorders. Therefore, the aims of this study were: a) to investigate the main effects of ADORA2A and DRD2 gene variants on anxiety disorders in an ADHD sample of children and adolescents; b) to test potential synergism between ADORA2A and DRD2 genes on the same outcome; c) to explore ADORA2A variants functionality using an in silico approach. The sample consists of 478 children and adolescents with ADHD and their parents, totalizing 1.239 individuals. An association between the ADORA2A rs2298383 TT genotype with the presence of anxiety disorders (P = .004) and an interaction between ADORA2A-DRD2 risk haplotypes with the same outcome (P = .005) was detected. The in silico analyses showed that rs2298383 has the highest score for regulatory function among all variants in the ADORA2A gene described up to date. Altogether, the present findings suggested that the ADORA2A gene and the interaction of ADORA2A and DRD2 genes may play a role in anxiety disorders in children and adolescents with ADHD.

Asunto(s)

Trastornos de Ansiedad/genética , Trastorno por Déficit de Atención con Hiperactividad/genética , Predisposición Genética a la Enfermedad/genética , Receptor de Adenosina A2A/genética , Receptores de Dopamina D2/genética , Adolescente , Trastornos de Ansiedad/etiología , Trastorno por Déficit de Atención con Hiperactividad/complicaciones , Niño , Femenino , Haplotipos , Humanos , Masculino , Polimorfismo de Nucleótido Simple/genética , Receptor de Adenosina A2A/fisiología , Receptores de Dopamina D2/fisiología

RESUMEN

Membrane progesterone receptors are known to mediate rapid nongenomic progesterone effects in different cell types. Recent evidence revealed that mPRα is highly expressed in the rat pituitary, being primarily localized in lactotrophs, acting as an intermediary of P4-inhibitory actions on prolactin secretion. The role of mPRs in prolactinoma development remains unclear. We hypothesize that mPR agonists represent a novel tool for hyperprolactinemia treatment. To this end, pituitary expression of mPRs was studied in three animal models of prolactinoma. Expression of mPRs and nuclear receptor was significantly decreased in tumoral pituitaries compared to normal ones. However, the relative proportion of mPRα and mPRß was highly increased in prolactinomas. Interestingly, the selective mPR agonist (Org OD 02-0) significantly inhibited PRL release in both normal and tumoral pituitary explants, displaying a more pronounced effect in tumoral tissues. As P4 also regulates PRL secretion indirectly, by acting on dopaminergic neurons, we studied mPR involvement in this effect. We found that the hypothalamus has a high expression of mPRs. Interestingly, both P4 and OrgOD 02-0 increased dopamine release in hypothalamus explants. Moreover, in an in vivo treatment, that allows both, pituitary and hypothalamus actions, the mPR agonist strongly reduced the hyperprolactinemia in transgenic females carrying prolactinoma. Finally, we also found and interesting gender difference: males express higher levels of pituitary mPRα/ß, a sex that does not develop prolactinoma in these mice models. Taken together, these findings suggest mPRs activation could represent a novel tool for hyperprolactinemic patients, especially those that present resistance to dopaminergic drugs.

Asunto(s)

Neoplasias Hipofisarias/prevención & control , Progesterona/farmacología , Prolactina/metabolismo , Prolactinoma/prevención & control , Receptores de Dopamina D2/fisiología , Receptores de Progesterona/agonistas , Animales , Gonadotropina Coriónica Humana de Subunidad beta/genética , Gonadotropina Coriónica Humana de Subunidad beta/metabolismo , Femenino , Humanos , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Neoplasias Hipofisarias/etiología , Neoplasias Hipofisarias/patología , Prolactinoma/etiología , Prolactinoma/patología , Ratas , Transducción de Señal

RESUMEN

Excessive dopamine neurotransmission underlies psychotic episodes as observed in patients with some types of bipolar disorder and schizophrenia. The dopaminergic hypothesis was postulated after the finding that antipsychotics were effective to halt increased dopamine tone. However, there is little evidence for dysfunction within the dopaminergic system itself. Alternatively, it has been proposed that excessive afferent activity onto ventral tegmental area dopaminergic neurons, particularly from the ventral hippocampus, increase dopamine neurotransmission, leading to psychosis. Here, we show that selective dopamine D2 receptor deletion from parvalbumin interneurons in mouse causes an impaired inhibitory activity in the ventral hippocampus and a dysregulated dopaminergic system. Conditional mutant animals show adult onset of schizophrenia-like behaviors and molecular, cellular, and physiological endophenotypes as previously described from postmortem brain studies of patients with schizophrenia. Our findings show that dopamine D2 receptor expression on parvalbumin interneurons is required to modulate and limit pyramidal neuron activity, which may prevent the dysregulation of the dopaminergic system.

Asunto(s)

Antipsicóticos/farmacología , Resistencia a Medicamentos , Interneuronas/metabolismo , Parvalbúminas/metabolismo , Receptores de Dopamina D2/fisiología , Esquizofrenia/etiología , Animales , Masculino , Ratones , Ratones Noqueados , Parvalbúminas/genética , Fenotipo , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismo , Transmisión Sináptica

RESUMEN

Sleep disorders increase pain sensitivity and the risk of developing painful conditions; however, the underlying mechanisms are poorly understood. It has been suggested that nucleus accumbens (NAc) influences sleep-wake cycle by means of a balance between adenosine activity at A2A receptors and dopamine activity at D2 receptors. Because the NAc also plays an important role in pain modulation, we hypothesized that the NAc and its A2A and D2 receptors mediate the pronociceptive effect of rapid eye movement (REM) sleep deprivation (SD). We found that 24 hours of REM-SD induced an intense pronociceptive effect in Wistar rats, which decreases progressively over a sleep rebound period. Although the level of fecal glucocorticoid metabolites increased with SD within group, it did not differ between sleep-deprived group and control group, indicating a stress response with similar magnitude between groups. The pronociceptive effect of REM-SD was prevented by excitotoxic lesion (N-Methyl-D-aspartate, 5.5 µg) of NAc and reverted by its acute blockade (Qx-314, 2%). The administration of an A2A receptor antagonist (SCH-58261, 7 ng) or a D2 receptor agonist (piribedil, 6 µg) into the NAc increased home cage activity and blocked the pronociceptive effect of REM-SD. Complementarily, an A2A receptor agonist (CGS-21680, 24 ng) impaired the reversal of the pronociceptive effect and decreased home cage activity, as it did a D2 receptor antagonist (raclopride, 5 µg). Rapid eye movement SD did not affect the expression of c-Fos protein in NAc. These data suggest that SD increases pain by increasing NAc adenosinergic A2A activity and by decreasing NAc dopaminergic D2 activity.

Asunto(s)

Nocicepción/fisiología , Núcleo Accumbens/fisiopatología , Dolor/fisiopatología , Privación de Sueño/fisiopatología , Sueño REM/efectos de los fármacos , Adenosina/análogos & derivados , Adenosina/farmacología , Agonistas del Receptor de Adenosina A2/farmacología , Animales , Masculino , Actividad Motora , Nocicepción/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Fenetilaminas/farmacología , Piribedil/farmacología , Antagonistas de Receptores Purinérgicos P1/farmacología , Pirimidinas/farmacología , Ratas , Ratas Wistar , Receptor de Adenosina A2A/fisiología , Receptores de Dopamina D2/fisiología , Triazoles/farmacología

RESUMEN

Motor execution and planning are tightly regulated by dopamine D1 and D2 receptors present in basal ganglia circuits. Although stimulation of D1 receptors is known to enhance motor function, the global effect of D2 receptor (D2R) stimulation or blockade remains highly controversial, with studies showing increasing, decreasing or no changes in motor activity. Moreover, pharmacological and genetic attempts to block or eliminate D2R have led to controversial results that questioned the importance of D2R in motor function. In this study, we generated an inducible Drd2 null-allele mouse strain that circumvented developmental compensations found in constitutive Drd2-/- mice and allowed us to directly evaluate the participation of D2R in spontaneous locomotor activity and motor learning. We have found that loss of D2R during adulthood causes severe motor impairments, including hypolocomotion, deficits in motor coordination, impaired learning of new motor routines and spontaneous catatonia. Moreover, severe motor impairment, resting tremor and abnormal gait and posture, phenotypes reminiscent of Parkinson's disease, were evident when the mutation was induced in aged mice. Altogether, the conditional Drd2 knockout model studied here revealed the overall fundamental contribution of D2R in motor functions and explains some of the side effects elicited by D2R blockers when used in neurological and psychiatric conditions, including schizophrenia, bipolar disorder, Tourette's syndrome, dementia, alcohol-induced delusions and obsessive-compulsive disorder.

Asunto(s)

Destreza Motora/fisiología , Trastornos Parkinsonianos/metabolismo , Receptores de Dopamina D2/metabolismo , Técnicas de Ablación/métodos , Animales , Ganglios Basales/metabolismo , Cuerpo Estriado/metabolismo , Antagonistas de Dopamina/farmacología , Humanos , Aprendizaje/efectos de los fármacos , Locomoción/genética , Masculino , Ratones , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Trastornos Parkinsonianos/fisiopatología , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/fisiología

RESUMEN

Dopamine (DA) modulates glutamatergic synaptic transmission and its plasticity in the striatum; however it is not well known how DA modulates long-term plasticity of striatal GABAergic inhibitory synapses. This work focused on the analysis of both dopaminergic modulation of inhibitory synapses and the synaptic plasticity established between GABAergic afferents to medium spiny neurons (MSNs). Our results showed that low and high DA concentrations mainly reduced the amplitude of inhibitory synaptic response; however detailed analysis of the D1 and D2 participation in this modulation displayed a wide variability in synaptic response. Analyzing DA participation in striatal GABAergic plasticity we observed that high frequency stimulation (HFS) of GABAergic interneurons in the presence of DA at a low concentration (200 nM) favored the expression of inhibitory striatal LTD, whereas higher concentration of DA (20 µM) primarily induced LTP. Interestingly, the plasticity induced in an animal model of striatal degeneration mimicked that induced in the presence of DA at a high concentration, which was not abolished with D2 antagonist but was prevented by PKA blocker.

Asunto(s)

Dopamina/fisiología , Potenciación a Largo Plazo/fisiología , Neostriado/fisiología , Plasticidad Neuronal/fisiología , Transmisión Sináptica/fisiología , Animales , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Dopamina/farmacología , Antagonistas de Dopamina/farmacología , Estimulación Eléctrica , Fenómenos Electrofisiológicos , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas Aferentes/fisiología , Inhibidores de Proteínas Quinasas , Receptores de Dopamina D1/efectos de los fármacos , Receptores de Dopamina D1/fisiología , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D2/fisiología , Sinapsis/fisiología , Ácido gamma-Aminobutírico/fisiología

RESUMEN

BACKGROUND: A reduction of dopamine release or D2 receptor blockade in the terminal fields of the mesolimbic system clearly reduces conditioned fear. Injections of haloperidol, a preferential D2 receptor antagonist, into the inferior colliculus (IC) enhance the processing of unconditioned aversive information. However, a clear characterization of the interplay of D2 receptors in the mediation of unconditioned and conditioned fear is still lacking. METHODS: The present study investigated the effects of intra-IC injections of the D2 receptor-selective antagonist sulpiride on behavior in the elevated plus maze (EPM), auditory-evoked potentials (AEPs) to loud sounds recorded from the IC, fear-potentiated startle (FPS), and conditioned freezing. RESULTS: Intra-IC injections of sulpiride caused clear proaversive effects in the EPM and enhanced AEPs induced by loud auditory stimuli. Intra-IC sulpiride administration did not affect FPS or conditioned freezing. CONCLUSIONS: Dopamine D2-like receptors of the inferior colliculus play a role in the modulation of unconditioned aversive information but not in the fear-potentiated startle response.

Asunto(s)

Miedo/fisiología , Colículos Inferiores/metabolismo , Receptores de Dopamina D2/fisiología , Animales , Condicionamiento Psicológico , Antagonistas de los Receptores de Dopamina D2/farmacología , Potenciales Evocados Auditivos , Haloperidol/farmacología , Masculino , Ratas Wistar , Reflejo de Sobresalto

RESUMEN

Currently, several studies addresses the novel link between sleep and dopaminergic neurotransmission, focusing most closely on the mechanisms by which Parkinson's disease (PD) and sleep may be intertwined. Therefore, variations in the activity of afferents during the sleep cycles, either at the level of DA cell bodies in the ventral tegmental area (VTA) and/or substantia nigra pars compacta (SNpc) or at the level of dopamine (DA) terminals in limbic areas may impact functions such as memory. Accordingly, we performed striatal and hippocampal neurochemical quantifications of DA, serotonin (5-HT) and metabolites of rats intraperitoneally treated with haloperidol (1.5 mg/kg) or piribedil (8 mg/kg) and submitted to REM sleep deprivation (REMSD) and sleep rebound (REB). Also, we evaluated the effects of REMSD on motor and cognitive parameters and SNpc c-Fos neuronal immunoreactivity. The results indicated that DA release was strongly enhanced by piribedil in the REMSD group. In opposite, haloperidol prevented that alteration. A c-Fos activation characteristic of REMSD was affected in a synergic manner by piribedil, indicating a strong positive correlation between striatal DA levels and nigral c-Fos activation. Hence, we suggest that memory process is severely impacted by both D2 blockade and REMSD and was even more by its combination. Conversely, the activation of D2 receptor counteracted such memory impairment. Therefore, the present evidence reinforce that the D2 receptor is a key player in the SNpc neuronal activation mediated by REMSD, as a consequence these changes may have direct impact for cognitive and sleep abnormalities found in patients with PD. This article is part of the Special Issue entitled 'The Synaptic Basis of Neurodegenerative Disorders'.

Asunto(s)

Neuronas/fisiología , Receptores de Dopamina D2/fisiología , Privación de Sueño/fisiopatología , Sustancia Negra/citología , Sustancia Negra/fisiología , Animales , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Agonistas de Dopamina/farmacología , Antagonistas de Dopamina/farmacología , Antagonistas de los Receptores de Dopamina D2 , Neuroimagen Funcional , Haloperidol/farmacología , Hipocampo/metabolismo , Masculino , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Piribedil/farmacología , Ratas , Receptores de Dopamina D2/agonistas , Reconocimiento en Psicología/efectos de los fármacos , Reconocimiento en Psicología/fisiología , Serotonina , Privación de Sueño/metabolismo , Sustancia Negra/efectos de los fármacos

RESUMEN

It has been suggested that N,N-di-n-propyl-dopamine (dopamine analogue) decreased heart rate in rats through stimulation of dopamine receptors. Nevertheless, the role of prejunctional dopamine D1/2-like receptors or even α2-adrenoceptors to mediate cardiac sympatho-inhibition induced by dopamine remains unclear. Hence, this study identified the pharmacological profile of the cardiac sympatho-inhibition to dopamine in pithed rats. Male Wistar rats were pithed and prepared to stimulate the cardiac sympathetic outflow or to receive i.v. bolus of exogenous noradrenaline. I.v. continuous infusions of dopamine (endogenous ligand) or quinpirole (D2-like agonist) dose-dependently inhibited the tachycardic responses to sympathetic stimulation, but not those to exogenous noradrenaline. In contrast, SKF-38393 (100 µg/kg∙min, D1-like agonist) failed to modify both of these responses. The sympatho-inhibition to dopamine (1.8 µg/kg∙min) or quinpirole (100 µg/kg∙min): i) remained unaltered after saline or the antagonists SCH-23390 (D1-like, 300 µg/kg) and rauwolscine (α2-adrenoceptors, 300 µg/kg); and ii) was significantly antagonized by raclopride (D2-like, 300 µg/kg). These antagonists, at the above doses, failed to modify the sympathetically-induced tachycardic responses. The above results suggest that the inhibition of the cardiac sympathetic outflow to dopamine and quinpirole is primarily mediated by prejunctional D2-like receptors but not D1-like receptors or α2-adrenoceptors.

Asunto(s)

Sistema Cardiovascular/efectos de los fármacos , Sistema Cardiovascular/fisiopatología , Estado de Descerebración/fisiopatología , Dopamina/farmacología , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D2/fisiología , Sistema Nervioso Simpático/fisiopatología , 2,3,4,5-Tetrahidro-7,8-dihidroxi-1-fenil-1H-3-benzazepina/farmacología , Animales , Benzazepinas/antagonistas & inhibidores , Benzazepinas/farmacología , Relación Dosis-Respuesta a Droga , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Quinpirol/farmacología , Racloprida/farmacología , Ratas , Ratas Wistar , Sistema Nervioso Simpático/efectos de los fármacos , Taquicardia/fisiopatología , Yohimbina/antagonistas & inhibidores , Yohimbina/farmacología

RESUMEN

Although dopaminergic systems are more commonly associated with the reinforcing effects of various stimuli, numerous reports have demonstrated a relationship between changes in dopaminergic transmission and aversive situations. In the present study, we examined the involvement of D1-like and D2-like receptors in the expression of conditioned freezing using the context as the conditioned stimulus. Intraperitoneal injections of the D1 agonist SKF38393 or the D1 antagonist SCH23390 did not change the conditioned freezing in rats subjected to the contextual fear paradigm. In contrast, intraperitoneal injections of the D2 agonist quinpirole and the D2 antagonist sulpiride caused a significant dose-dependent reduction in the expression of contextual conditioned freezing. As these data may reflect that the systemic manipulations acted on dopaminergic receptors in different brain areas, the effects of administration of quinpirole and sulpiride into the ventral tegmental area (VTA) and the basolateral amygdala complex (BLA) on the expression of contextual conditioned freezing were also evaluated. Intra-VTA quinpirole and intra-BLA sulpiride injections reduced the conditioned freezing response; intra-VTA sulpiride and intra-BLA quinpirole injections had no significant effects. These data suggest that D2-like receptors, but not D1-like receptors, play an important role in the expression of contextual conditioned freezing. Quinpirole may act at D2 presynaptic receptors located in the VTA, decreasing dopamine levels in the terminal fields of the mesolimbic pathway. The effects of sulpiride, in contrast, appear to be triggered by an action on postsynaptic dopaminergic receptors located in the BLA. However, it cannot be totally excluded that the injected solutions did not also affect neighboring amygdalar regions. Together with previous findings, the present data suggest the need to consider dopaminergic mechanisms in the mesolimbic circuit as novel targets for the pharmacological treatment of fear-related disorders, especially post-traumatic stress disorder.

Asunto(s)

Amígdala del Cerebelo/fisiología , Condicionamiento Psicológico/fisiología , Miedo , Receptores de Dopamina D2/fisiología , Área Tegmental Ventral/fisiología , Amígdala del Cerebelo/efectos de los fármacos , Animales , Condicionamiento Psicológico/efectos de los fármacos , Dopaminérgicos/farmacología , Electrochoque/efectos adversos , Conducta Exploratoria/fisiología , Miedo/efectos de los fármacos , Reacción Cataléptica de Congelación/efectos de los fármacos , Masculino , Microinyecciones , Ratas , Ratas Wistar , Área Tegmental Ventral/efectos de los fármacos

RESUMEN

Animal models have shown that the neural bases of social attachment, sexual preference and pair bonds, depend on dopamine D2-type receptor and oxytocin activity. In addition, studies have demonstrated that cohabitation can shape partner preference via conditioning. Herein, we used rats to explore the development of learned same-sex partner preferences in adulthood as a result of cohabitation during enhanced D2 activity. Experimental Wistar males (N=20), received saline or the D2 agonist (quinpirole) and were allowed to cohabitate during 24 h, with a stimulus male partner that bore almond scent on the back as conditioned stimulus. This was repeated every 4 days, for a total of three trials. Four days later they were drug-free tested for partner preference between the scented male partner and a sexually receptive female. Sexual partner preference was analyzed by measuring frequency and latency for appetitive and consummatory sexual behaviors, as well as non-contact erections. Social preference was also analyzed by measuring the frequency and latency of visits, body contacts and time spent together. Results indicated that only quinpirole-treated males displayed sexual and social preference for the scented male over the sexually receptive female. They spent more time together, displayed more body contacts, more female-like proceptive behaviors, and more non-contact erections. Accordingly, conditioned males appeared to be more sexually aroused and motivated by the known male than by a receptive female. We discuss the implications of this animal model on the formation of learned homosexual partner preferences.

Asunto(s)

Condicionamiento Clásico , Receptores de Dopamina D2/fisiología , Conducta Sexual Animal , Animales , Masculino , Ratas , Ratas Wistar

RESUMEN

Systemic administration of D2-like dopaminergic-receptor agonists increases yawning behavior. However, only a few studies have been done in animals with pathological conditions. The taiep rat is a myelin mutant with an initial hypomyelination followed by progressive demyelination, being the brainstem one of the most affected areas. In our experiments, we analyzed the effects of systemic administration of the D2-family agonists and antagonists on yawning behavior, and correlated them with the lipid myelin content in the brainstem and other areas in the central nervous system (CNS) in 8 month old male taiep and Sprague-Dawley rats. Subjects were maintained under standard conditions in Plexiglas cages with a 12:12 light-dark cycle, lights on at 0700 and free access to rodent pellets and tap water. Drugs were freshly prepared injected ip at 0800 and subjects were observed for 60 min. When antagonists were used it was administered 15 min before the agonist. Sprague-Dawley and taiep rats significantly increased their yawning frequency after systemic injection of (-)-quinpirole hydrochloride, R(+)-7-Hydroxy-2-(dipropylamino)tetralin hydrobromide (7-OH-DPAT) or trans-(±)-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano [4,3-b]-1,4-oxazin-9-ol hydrochloride ((±)-PD 128,907). Among D2-like agonists used higher effects are obtained with (-)-quinpirole. The effects caused by (-)-quinpirole can be reduced by (-)-sulpiride; and yawning caused by 7-OH-DPAT was decreased by tiapride only in taiep rats. In Sprague-Dawley only (-)-sulpiride is able to decrease (-)-quinpirole-caused yawning. In conclusion, dopaminergic D2-like agonists are still able to cause yawning despite the severe myelin loss in taiep rats. Similarly, patients with various CNS illnesses that affect myelin, such as stroke or multiple sclerosis, are able to yawn suggesting that trigger neurons are still able to command this innate behavior.

Asunto(s)

Enfermedades Desmielinizantes/genética , Agonistas de Dopamina/administración & dosificación , Hemiplejía/fisiopatología , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/fisiología , Bostezo/genética , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Enfermedades Desmielinizantes/metabolismo , Enfermedades Desmielinizantes/patología , Progresión de la Enfermedad , Agonistas de Dopamina/farmacología , Hemiplejía/genética , Hemiplejía/metabolismo , Humanos , Masculino , Vaina de Mielina/efectos de los fármacos , Vaina de Mielina/genética , Vaina de Mielina/patología , Ratas , Ratas Mutantes , Ratas Sprague-Dawley , Receptores de Dopamina D2/genética , Bostezo/efectos de los fármacos

RESUMEN

The role of dopamine (DA) in rewarding motivated actions is well established but its role in learning how to avoid aversive events is still controversial. Here we tested the role of D2-like DA receptors in the nucleus accumbens (NAc) and the dorsolateral striatum (DLS) of rats in the learning and performance of conditioned avoidance responses (CAR). Adult male Wistar rats received systemic, intra-NAc or intra-DLS (pre- or post-training) administration of a D2-like receptor agonist (quinpirole) or antagonist ((-)sulpiride) and were given two sessions in the two-way active avoidance task. The main effects observed were: (i) sulpiride and lower (likely pre-synaptic) doses of quinpirole decreased the number of CARs and increased the number of escape failures; (ii) higher doses of quinpirole (likely post-synaptic) increased inter-trial crossings and failures; (iii) pre-training administration of sulpiride decreased the number of CARs in both training and test sessions when infused into the NAc, but this effect was observed only in the test session when it was infused into the DLS; (iv) post-training administration of sulpiride decreased CARs in the test session when infused into the NAc but not DLS. These findings suggest that activation of D2 receptors in the NAc is critical for fast adaptation to responding to unconditioned and conditioned aversive stimuli while activation of these receptors in the DLS is needed for a slower learning of how to respond to the same stimuli based on previous experiences.

Asunto(s)

Reacción de Prevención/fisiología , Condicionamiento Operante/fisiología , Cuerpo Estriado/fisiología , Neuronas/fisiología , Núcleo Accumbens/fisiología , Receptores de Dopamina D2/fisiología , Animales , Reacción de Prevención/efectos de los fármacos , Condicionamiento Operante/efectos de los fármacos , Cuerpo Estriado/efectos de los fármacos , Agonistas de Dopamina/farmacología , Antagonistas de Dopamina/farmacología , Masculino , Neuronas/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Quinpirol/farmacología , Ratas , Ratas Wistar , Sulpirida/farmacología

RESUMEN

It is well known that dopamine imbalances are associated with many psychiatric disorders and that the dopaminergic receptor D2 is the main target of antipsychotics. Recently it was shown that levels of two proteins implicated in dopaminergic signaling, Neuronal calcium sensor-1 (NCS-1) and DARPP-32, are altered in the prefrontal cortex (PFC) of both schizophrenic and bipolar disorder patients. NCS-1, which inhibits D2 internalization, is upregulated in the PFC of both patients. DARPP-32, which is a downstream effector of dopamine signaling, integrates the pathways of several neurotransmitters and is downregulated in the PFC of both patients. Here, we used PC12 cells stably overexpressing NCS-1 (PC12-NCS-1 cells) to address the function of this protein in DARPP-32 signaling pathway in vitro. PC12-NCS-1 cells displayed downregulation of the cAMP/PKA pathway, with decreased levels of cAMP and phosphorylation of CREB at Ser133. We also observed decreased levels of total and phosphorylated DARPP-32 at Thr34. However, these cells did not show alterations in the levels of D2 and phosphorylation of DARPP-32 at Thr75. These results indicate that NCS-1 modulates PKA/cAMP signaling pathway. Identification of the cellular mechanisms linking NCS-1 and DARPP-32 may help in the understanding the signaling machinery with potential to be turned into targets for the treatment of schizophrenia and other debilitating psychiatric disorders.

Asunto(s)

Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Proteínas Sensoras del Calcio Neuronal/genética , Neuropéptidos/genética , Animales , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Fosfoproteína 32 Regulada por Dopamina y AMPc/metabolismo , Regulación hacia Abajo/genética , Regulación hacia Abajo/fisiología , Proteínas Sensoras del Calcio Neuronal/metabolismo , Proteínas Sensoras del Calcio Neuronal/fisiología , Neuropéptidos/metabolismo , Neuropéptidos/fisiología , Células PC12 , Fosforilación , Ratas , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D2/fisiología , Transducción de Señal/genética , Transducción de Señal/fisiología , Transfección , Regulación hacia Arriba/genética

RESUMEN

UNLABELLED: Carvacrol (5-isopropyl-2-methylphenol) is a monoterpenic phenol present in the essential oil of many plants. It is the major component of the essential oil fraction of oregano and thyme. In this study, the effect of carvacrol was investigated in two behavioral models, the forced swimming and tail suspension tests in mice, to investigate the possible antidepressant effect of this substance. Additionally, the mechanisms involved in the antidepressant-like effect of carvacrol in mice were also assessed. Carvacrol (cvc) was administered orally at single doses of 12.5, 25 and 50 mg/kg. The acute treatment of cvc decreased the immobility time in the forced swimming and tail suspension tests without accompanying changes in ambulation in the open-field test. The anti-immobility effect of carvacrol (25 mg/kg) was not prevented by pretreatment of mice with p-chlorophenylalanine, prazosin and yohimbine. On the other hand, the pretreatment of mice with SCH23390 or sulpiride completely blocked the antidepressant-like effect of carvacrol (25 mg/kg) in the forced swimming test. These results show that carvacrol presents antidepressant effects in the forced swimming and tail suspension tests; this effect seems to be dependent on its interaction with the dopaminergic system, but not with the serotonergic and noradrenergic systems. KEYWORDS: Carvacrol; Antidepressant; Forced swimming; Tail suspension; Dopaminergic system.

Asunto(s)

Antidepresivos/farmacología , Conducta Animal/efectos de los fármacos , Depresión/tratamiento farmacológico , Dopamina/fisiología , Monoterpenos/farmacología , Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Animales , Benzazepinas/farmacología , Cimenos , Modelos Animales de Enfermedad , Antagonistas de los Receptores de Dopamina D2 , Fenclonina/farmacología , Suspensión Trasera , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Prazosina/farmacología , Receptores de Dopamina D2/fisiología , Sulpirida/farmacología , Natación , Yohimbina/farmacología