RESUMEN
Stimulation of α2-adrenoceptor/I1-imidazoline receptors in the rostral ventrolateral medulla decreases the blood pressure via sympathoinhibition. However, alteration of receptor responses in genetically hypertensive rats remains unclear. We examined cardiovascular responses of α2-adrenoceptor/I1-imidazoline receptor agonist and antagonists microinjected into the rostral ventrolateral medulla of conscious spontaneously hypertensive rats and normotensive Wistar Kyoto rats. Injection of 2-nmol clonidine-an α2-adrenoceptor/I1-imidazoline receptor agonist-unilaterally into the rostral ventrolateral medulla decreased the blood pressure, heart rate, and renal sympathetic nerve activity; the responses were significantly enhanced in spontaneously hypertensive rats than in Wistar Kyoto rats. Co-injection of 2-nmol 2-methoxyidazoxan (a selective α2-adrenoceptor antagonist) or 2-nmol efaroxan (an I1-receptor antagonist) with 2 nmol of clonidine attenuated the hypotensive and bradycardic effects of clonidine-only injection. Injection of 2-methoxyidazoxan alone increased the blood pressure and heart rate in spontaneously hypertensive rats, but not in Wistar Kyoto rats. These results suggest enhanced responsiveness of α2-adrenoceptor/I1-imidazoline receptors in the rostral ventrolateral medulla of spontaneously hypertensive rats.
Asunto(s)
Receptores de Imidazolina/fisiología , Bulbo Raquídeo/fisiología , Receptores Adrenérgicos alfa 2/fisiología , Animales , Antihipertensivos/farmacología , Benzofuranos/farmacología , Presión Sanguínea/efectos de los fármacos , Determinación de la Presión Sanguínea , Clonidina/farmacología , Estado de Conciencia/fisiología , Frecuencia Cardíaca/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Idazoxan/análogos & derivados , Idazoxan/farmacología , Imidazoles/farmacología , Masculino , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Sistema Nervioso Simpático/efectos de los fármacosRESUMEN
Effects of stress on the reward system are well established in the literature. Although previous studies have revealed that stress can reinstate extinguished addictive behaviors related to cocaine, the effects of stress on the rewarding memory of cocaine are not fully understood. Here, we provide evidence that stress potentiates the expression of rewarding memory of cocaine via the activation of brainstem-reward circuitry using a cocaine-induced conditioned place preference (CPP) paradigm combined with restraint stress in rats. The rats exposed to 30-minute restraint stress immediately before posttest exhibited significantly larger CPP scores compared with non-stressed rats. Intra-laterodorsal tegmental nucleus (LDT) microinjection of a ß or α2 adrenoceptor antagonist attenuated the stress-induced enhancement of cocaine CPP. Consistent with this observation, intra-LDT microinjection of a ß or α2 adrenoceptor agonist before posttest increased cocaine CPP. Additionally, intra-ventral tegmental area (VTA) microinjection of antagonists for the muscarinic acetylcholine, nicotinic acetylcholine or glutamate receptors attenuated the stress-induced enhancement of cocaine CPP. Finally, intra-medial prefrontal cortex (mPFC) microinjection of a D1 receptor antagonist also reduced the stress-induced enhancement of cocaine CPP. These findings suggest a mechanism wherein the LDT is activated by noradrenergic input from the locus coeruleus, leading to the activation of VTA dopamine neurons via both cholinergic and glutamatergic transmission and the subsequent excitation of the mPFC to enhance the memory of cocaine-induced reward value.
Asunto(s)
Cocaína/farmacología , Inhibidores de Captación de Dopamina/farmacología , Memoria/efectos de los fármacos , Recompensa , Neuronas Adrenérgicas/efectos de los fármacos , Antagonistas Adrenérgicos alfa/farmacología , Animales , Tronco Encefálico/efectos de los fármacos , Condicionamiento Psicológico/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Idazoxan/análogos & derivados , Idazoxan/farmacología , Masculino , Ratas Sprague-Dawley , Receptores Adrenérgicos alfa 2/fisiología , Receptores Adrenérgicos beta/fisiología , Restricción Física , Estrés Psicológico/fisiopatología , Tegmento Mesencefálico/efectos de los fármacos , Timolol/farmacologíaRESUMEN
Among vertebrate ectotherms, air breathing frequency is generally constrained across warmer temperatures, but decreases during cooling. The brainstem mechanisms that give rise to this ventilatory strategy are unclear. Neuromodulation has recently been shown to stabilize motor circuit output across temperatures. Therefore, we tested the hypothesis that an important neuromodulatory system in respiratory control network, norepinephrine, produces this pattern of respiratory motor activity across temperatures. To this end, we used in vitro brainstem-spinal cord preparations from adult bullfrogs, Lithobates catesbeianus, to assess the role of noradrenergic signaling in shaping the frequency response of the respiratory network during temperature changes. We identified that noradrenergic signaling through the α1 adrenergic receptor constrains motor output from the respiratory network across warm temperatures. In contrast, the α2 adrenergic receptor actively inhibits respiratory motor output during cooling. These results indicate that noradrenergic tuning, rather than passive thermal responses, produces temperature responses of the respiratory circuits.
Asunto(s)
Tronco Encefálico/fisiología , Norepinefrina/farmacología , Respiración , Temperatura , Potenciales de Acción/efectos de los fármacos , Antagonistas Adrenérgicos alfa/farmacología , Análisis de Varianza , Animales , Tronco Encefálico/citología , Tronco Encefálico/efectos de los fármacos , Femenino , Idazoxan/análogos & derivados , Idazoxan/farmacología , Técnicas In Vitro , Neuronas Motoras/efectos de los fármacos , Prazosina/farmacología , Rana catesbeiana , Respiración/efectos de los fármacos , Médula Espinal/citología , Médula Espinal/efectos de los fármacos , Médula Espinal/fisiologíaRESUMEN
Social play behaviour is a vigorous, highly rewarding social activity abundant in the young of most mammalian species, including humans. Social play is thought to be important for social, emotional and cognitive development, yet its neural underpinnings are incompletely understood. We have previously shown that low doses of methylphenidate suppress social play behaviour through a noradrenergic mechanism of action, and that methylphenidate exerts its effect within the prefrontal cortex, amygdala and habenula. In the present study, we sought to reveal whether these regions work in parallel or in series to mediate the play-suppressant effect of methylphenidate. To that aim, we tested whether infusion of the α2-adrenoceptor antagonist RX821002 into the anterior cingulate cortex, infralimbic cortex, basolateral amygdala or habenula prevents the effect of methylphenidate on social play behaviour, or the psychomotor stimulant effect of methylphenidate. We found that the social play-suppressant effect of methylphenidate was not prevented by infusion of the α2-adrenoceptor antagonist into either region, or by infusion of RX821002 into both the anterior cingulate and infralimbic cortex. By contrast, RX821002 infusion into the anterior cingulate modestly enhanced social play, and infusion of the antagonist into the infralimbic cortex attenuated the psychomotor stimulant effect of methylphenidate. We conclude that there is redundancy in the neural circuitry that mediates the play-suppressant effect of methylphenidate, whereby prefrontal cortical and subcortical limbic mechanisms act in parallel. Moreover, our data support the notion that prefrontal noradrenergic mechanisms contribute to the locomotor enhancing effect of psychostimulant drugs.
Asunto(s)
Estimulantes del Sistema Nervioso Central/farmacología , Corteza Cerebral/efectos de los fármacos , Habénula/efectos de los fármacos , Metilfenidato/farmacología , Receptores Adrenérgicos alfa 2/metabolismo , Conducta Social , Antagonistas Adrenérgicos alfa/farmacología , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Corteza Cerebral/metabolismo , Conducta Exploratoria/efectos de los fármacos , Conducta Exploratoria/fisiología , Habénula/metabolismo , Idazoxan/análogos & derivados , Idazoxan/farmacología , Masculino , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/metabolismo , Ratas Wistar , RecompensaRESUMEN
Tapentadol is an analgesic that acts as an agonist of µ opioid receptors (MOR) and that inhibits noradrenaline reuptake. Data from healthy rats show that tapentadol inhibits neuronal activity in the locus coeruleus (LC), a nucleus regulated by both the noradrenergic and opioid systems. Thus, we set out to investigate the effect of tapentadol on LC activity in streptozotocin (STZ)-induced diabetic rats, a model of diabetic polyneuropathy, by analyzing single-unit extracellular recordings of LC neurons. Four weeks after inducing diabetes, tapentadol dose-response curves were obtained from animals pre-treated with RX821002 or naloxone (alpha2-adrenoceptors and opioid receptors antagonists, respectively). In STZ rats, the spontaneous activity of LC neurons (0.9⯱â¯0.1â¯Hz) was lower than in naïve animals (1.5⯱â¯0.1â¯Hz), and tapentadol's inhibitory effect was also weaker. Alpha2-adrenoceptors blockade by RX821002 (100⯵g/kg i.v.) in STZ animals significantly increased the spontaneous activity (from 0.8⯱â¯0.1 to 1.4⯱â¯0.2â¯Hz) and it dampened the inhibition of LC neurons produced by tapentadol. However, opioid receptors blockade following naloxone pre-treatment (5â¯mg/kg i.v.) did not alter the spontaneous firing rate (0.9⯱â¯0.2 vs 0.9⯱â¯0.2â¯Hz) or the inhibitory effect of tapentadol on LC neurons in STZ animals. Thus, diabetic polyneuropathy appears to exert neuroplastic changes in LC neurotransmission, enhancing the sensitivity of alpha2-adrenoceptors and dampening opioid receptors expression. Tapentadol's activity seems to be predominantly mediated through its noradrenergic effects rather than its influence on opioid receptors in the STZ model of diabetic polyneuropathy.
Asunto(s)
Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/fisiopatología , Neuropatías Diabéticas/complicaciones , Neuropatías Diabéticas/fisiopatología , Locus Coeruleus/citología , Inhibición Neural/efectos de los fármacos , Tapentadol/farmacología , Potenciales de Acción/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Idazoxan/análogos & derivados , Idazoxan/farmacología , Masculino , Naloxona/farmacología , Neuronas/fisiología , Dimensión del Dolor/efectos de los fármacos , Ratas , Tapentadol/antagonistas & inhibidoresRESUMEN
The poor norepinephrine innervation and high density of Gi/o-coupled α2A- and α2C-adrenoceptors in the striatum and the dense striatal dopamine innervation have prompted the possibility that dopamine could be an effective adrenoceptor ligand. Nevertheless, the reported adrenoceptor agonistic properties of dopamine are still inconclusive. In this study, we analyzed the binding of norepinephrine, dopamine, and several compounds reported as selective dopamine D2-like receptor ligands, such as the D3 receptor agonist 7-OH-PIPAT and the D4 receptor agonist RO-105824, to α2-adrenoceptors in cortical and striatal tissue, which express α2A-adrenoceptors and both α2A- and α2C-adrenoceptors, respectively. The affinity of dopamine for α2-adrenoceptors was found to be similar to that for D1-like and D2-like receptors. Moreover, the exogenous dopamine receptor ligands also showed high affinity for α2A- and α2C-adrenoceptors. Their ability to activate Gi/o proteins through α2A- and α2C-adrenoceptors was also analyzed in transfected cells with bioluminescent resonance energy transfer techniques. The relative ligand potencies and efficacies were dependent on the Gi/o protein subtype. Furthermore, dopamine binding to α2-adrenoceptors was functional, inducing changes in dynamic mass redistribution, adenylyl cyclase activity, and ERK1/2 phosphorylation. Binding events were further studied with computer modeling of ligand docking. Docking of dopamine at α2A- and α2C-adrenoceptors was nearly identical to its binding to the crystallized D3 receptor. Therefore, we provide conclusive evidence that α2A- and α2C-adrenoceptors are functional receptors for norepinephrine, dopamine, and other previously assumed selective D2-like receptor ligands, which calls for revisiting previous studies with those ligands.
Asunto(s)
Dopamina/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Receptores Dopaminérgicos/metabolismo , Adenilil Ciclasas/metabolismo , Animales , Corteza Cerebral/metabolismo , Clonidina/farmacología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Proteínas de Unión al GTP/metabolismo , Células HEK293 , Humanos , Idazoxan/análogos & derivados , Idazoxan/farmacología , Ligandos , Neostriado/metabolismo , Norepinefrina/metabolismo , Fosforilación/efectos de los fármacos , Quinpirol/farmacología , Ovinos , Tetrahidronaftalenos/farmacologíaRESUMEN
The activation of GABA, opioid or α2 adrenergic mechanisms in the lateral parabrachial nucleus (LPBN) facilitates hypertonic NaCl intake in rats. In the present study, we combined opioid or α2 adrenergic antagonists with GABA agonists into the LPBN in order to investigate if NaCl intake caused by GABAergic activation in normohydrated rats depends on opioid or α2-adrenergic mechanisms in this area. Male Holtzman rats with stainless steel cannulas implanted bilaterally in the LPBN were used. Bilateral injections of muscimol or baclofen (GABAA and GABAB agonists, respectively, 0.5â¯nmol/0.2⯵l) into the LPBN induced strong ingestion of 0.3â¯M NaCl (45.8⯱â¯7.3 and 21.8⯱â¯4.8â¯ml/240â¯min, respectively) and water intake (22.7⯱â¯3.4 and 6.6⯱â¯2.5â¯ml/240â¯min, respectively). Naloxone (opioid antagonist, 150â¯nmol/0.2⯵l) into the LPBN abolished 0.3â¯M NaCl and water intake to muscimol (2.0⯱â¯0.6 and 0.9⯱â¯0.2â¯ml/240â¯min, respectively) or baclofen (2.3⯱â¯1.1 and 0.8⯱â¯0.4â¯ml/240â¯min, respectively). RX 821002 (α2 adrenoceptor antagonist, 10â¯nmol/0.2⯵l) into the LPBN reduced 0.3â¯M NaCl intake induced by the injections of muscimol or baclofen (26.6⯱â¯8.0 and 10.1⯱â¯4.9â¯ml/240â¯min, respectively). RX 821002 reduced water intake induced by muscimol (7.7⯱â¯2.9â¯ml/240â¯min), not by baclofen. The results suggest that sodium intake caused by gabaergic activation in the LPBN in normohydrated rats is totally dependent on the activation of opioid mechanisms and partially dependent on the activation of α2 adrenergic mechanisms in the LPBN.
Asunto(s)
Analgésicos Opioides/metabolismo , Agonistas del GABA/farmacología , Núcleos Parabraquiales/efectos de los fármacos , Receptores Adrenérgicos alfa 2/metabolismo , Sodio/metabolismo , Antagonistas Adrenérgicos alfa/farmacología , Animales , Baclofeno/farmacología , Ingestión de Líquidos/efectos de los fármacos , Conducta de Ingestión de Líquido/efectos de los fármacos , Interacciones Farmacológicas , Idazoxan/análogos & derivados , Idazoxan/farmacología , Masculino , Muscimol/farmacología , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Ratas , Factores de TiempoRESUMEN
Exposure to drug-associated cues evokes drug-seeking behavior and is regarded as a major cause of relapse. Conditional stimulus upregulates noradrenaline (NA) system activity, but the drug-seeking behavior depends particularly on phasic dopamine signaling downstream from the ventral tegmental area (VTA). The VTA dopamine-ergic activity is regulated via the signaling of alpha1 -adrenergic and alpha2 -adrenergic receptors (α1 -ARs and α2 -ARs); thus, the impact of the conditional stimulus on drug-seeking behavior might involve NAergic signaling in the VTA. To date, the role of VTA ARs in regulating cocaine seeking was not studied. We found that cocaine seeking under extinction conditions in male Sprague-Dawley rats was attenuated by intra-VTA prazosin or terazosin-two selective α1 -AR antagonists. In contrast, cocaine seeking was facilitated by intra-VTA administration of the selective α1 -AR agonist phenylephrine as well as α2 -AR antagonist RX 821002, whereas the selective ß-AR antagonist propranolol had no effects. In addition, blockade of α1 -AR in the VTA prevented α2 -AR antagonist-induced enhancement of cocaine seeking. Importantly, the potential non-specific effects of the VTA AR blockade on cocaine seeking could be excluded, because none of the AR antagonists influenced sucrose seeking under extinction conditions or locomotor activity in the open field test. These results demonstrate that NAergic signaling potently and selectively regulates cocaine seeking during early cocaine withdrawal via VTA α1 -AR and α2 -AR but not ß-AR. Our findings provide new insight into the NAergic mechanisms that underlie cocaine craving.
Asunto(s)
Agonistas de Receptores Adrenérgicos alfa 1/farmacología , Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Conducta Animal/efectos de los fármacos , Cocaína/administración & dosificación , Inhibidores de Captación de Dopamina/administración & dosificación , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Área Tegmental Ventral , Antagonistas Adrenérgicos beta/farmacología , Animales , Condicionamiento Operante , Ansia , Idazoxan/análogos & derivados , Idazoxan/farmacología , Masculino , Fenilefrina/farmacología , Prazosina/análogos & derivados , Prazosina/farmacología , Propranolol/farmacología , Ratas , Ratas Sprague-Dawley , AutoadministraciónRESUMEN
The study examined the dose-dependent effects of selective antagonists of α2A/D-, α2B-, and α2C- adrenoceptors applied in concentrations of 10-9-10-5 M on atrial and ventricular contractility of rat myocardium in vitro. Selective blockade of each α2-adrenoceptor subtype affected the contractile force of the atrial and ventricular strips. Various concentrations of α2A/D- and α2C-adrenoceptor antagonists produced positive inotropic effect on ventricular strips and negative effect on atrial strips. α2B-Adrenoceptor blocker in the majority of the tested concentrations produced a positive inotropic effect in both atria and ventricles.
Asunto(s)
Acridinas/farmacología , Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Idazoxan/análogos & derivados , Imidazoles/farmacología , Contracción Miocárdica/efectos de los fármacos , Piperazinas/farmacología , Receptores Adrenérgicos alfa 2/metabolismo , Animales , Animales no Consanguíneos , Relación Dosis-Respuesta a Droga , Atrios Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/efectos de los fármacos , Idazoxan/farmacología , Contracción Miocárdica/fisiología , Ratas , Receptores Adrenérgicos alfa 2/clasificación , Técnicas de Cultivo de TejidosRESUMEN
RATIONALE: Fas-associated death domain (FADD) is an adaptor of death receptors that can also induce anti-apoptotic actions through its phosphorylated form (p-FADD). Activation of monoamine receptors, indirect targets of classic anti-depressant drugs (ADs), reduced FADD and increased p-FADD and p-FADD/FADD ratio in brain. OBJECTIVES: To ascertain whether ADs, which indirectly regulate monoamine receptors, modulate FADD protein forms to promote anti-apoptotic actions. METHODS: The effects of selected norepinephrine transporter (NET), serotonin transporter (SERT), monoamine oxidase (MAO) inhibitors, atypical ADs, and electroconvulsive shock (ECS) or behavioral procedures (forced swim test, FST) on FADD forms and pro-survival FADD-like interleukin-1ß-converting enzyme-inhibitory protein (FLIP-L) and phosphoprotein enriched in astrocytes of 15 kDa (p-PEA-15) contents were assessed in rat brain cortex by western blot analysis. RESULTS: Acute NET (e.g., nisoxetine) but not SERT (e.g., fluoxetine) inhibitors decreased cortical FADD (up to 37 %) and increased p-FADD/FADD ratio (up to 1.9-fold). Nisoxetine effects were prevented by α2-antagonist RX-821002, suggesting the involvement of presynaptic α2-autoreceptors. Immobility time in the FST correlated with increases of pro-apoptotic FADD and decreases of anti-apoptotic p-FADD. The MAO-A/B inhibitor phenelzine decreased FADD (up to 33 %) and increased p-FADD (up to 65 %) and p-FADD/FADD (up to 2.4-fold). Other MAO inhibitors (clorgyline, Ro 41-1049, rasagiline), atypical ADs (ketamine and mirtazapine), or ECS did not modulate cortical FADD. Chronic (14 days) desipramine and fluoxetine, but not phenelzine, increased p-FADD (up to 59 %), p-FADD/FADD ratio (up to 1.8-fold), and pro-survival p-PEA-15 (up to 46 %) in rat brain cortex. CONCLUSIONS: Multifunctional FADD protein, through an increased p-FADD/FADD ratio, could participate in the mechanisms of anti-apoptotic actions induced by ADs.
Asunto(s)
Antidepresivos/farmacología , Corteza Cerebral/efectos de los fármacos , Desipramina/farmacología , Proteína de Dominio de Muerte Asociada a Fas/efectos de los fármacos , Fluoxetina/farmacología , Antagonistas Adrenérgicos alfa/farmacología , Animales , Apoptosis , Autorreceptores/metabolismo , Western Blotting , Encéfalo/efectos de los fármacos , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD , Corteza Cerebral/metabolismo , Clorgilina/farmacología , Electrochoque , Antagonistas de Aminoácidos Excitadores/farmacología , Proteína de Dominio de Muerte Asociada a Fas/metabolismo , Fluoxetina/análogos & derivados , Idazoxan/análogos & derivados , Idazoxan/farmacología , Indanos/farmacología , Ketamina/farmacología , Masculino , Mianserina/análogos & derivados , Mianserina/farmacología , Mirtazapina , Inhibidores de la Monoaminooxidasa/farmacología , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Fenelzina/farmacología , Fosfoproteínas/efectos de los fármacos , Fosfoproteínas/metabolismo , Fosforilación/efectos de los fármacos , Proteínas de Unión al ARN/antagonistas & inhibidores , Ratas , Tiazoles/farmacologíaRESUMEN
Kinetic on and off rate constants for many receptor ligands are difficult to determine with regular radioligand binding technique since only few of the ligands are available in labeled form. Here we developed a new and simple radioligand binding method for determining the kinetic off-rate constant for unlabeled ligands, using whole cells expressing α2A- and α2C-adrenoceptors. The new method involves pre-incubation with unlabeled ligand, centrifugation of microtiter plates in order to adhere the cells to the bottom surface, and then upside-down centrifugation of the plates for few seconds to wash away the non-bound fraction of the pre-incubated ligand. The final on-reaction assay for the radioligand is then started by quick addition of a relatively fast-associating radioligand to the cells. The curve obtained is defined by a fairly simple mathematical formula that reflects the simultaneous dissociation of pre-incubated ligand and association of the radioligand. The method proved to produce highly reproducible results in determining the koff constants for various unlabeled ligands. The results show that the α2C-selectivity of MK912 depends mainly on a very slow off-rate at the α2C-adrenoceptor subtype. Regarding the markedly α2C- over α2A-selective compound spiroxatrine, its much faster on-rate at α2C- than α2A-adrenoceptors explains much of its exceptional α2C-selectivity. Several new techniques for determining the kinetic component of ligand-receptor interactions at molecular level are currently developing. As a reference, based on standard radioligand binding techniques, the present study describes a simple and robust experimental and mathematical procedure for determining koff constants of unlabeled drugs.
Asunto(s)
Ensayo de Unión Radioligante/métodos , Receptores Adrenérgicos alfa 2/metabolismo , Células HEK293 , Humanos , Idazoxan/análogos & derivados , Idazoxan/metabolismo , Cinética , Ligandos , Unión Proteica , Proteínas Recombinantes de Fusión/metabolismoRESUMEN
BACKGROUND: Synthesis and hypotensive properties of centrally acting imidazoline agents: 1-[(imidazolidin-2-yl)imino]-1H-indazole (Marsanidine) and 7-chloro-1-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-1H-indazole (TCS-80) were tested in rats. We have recently synthesized two novel Marsanidine analogues which decrease blood pressure and heart rate in rats: 1-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-1H-indole (TCS-54), and 7-chloro-1-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-1H-indole (TCS-213). Among all these analogues, compound TCS-80 exhibits the highest affinity to I1-imidazoline receptors and the lowest α2/I1 selectivity ratio. The observed cardiovascular effects of the compounds might be mediated through α2-adrenergic and I1-imidazoline receptors and subsequent decrease of the symphathetic nerve activity. The present studies were performed to determine whether α2-adrenergic and/or I1-imidazoline receptors are involved in the decrease of blood pressure and heart rate induced by Marsanidine, TCS-54, TCS-80, and TCS-213 in rats. METHODS: Anesthetized rats were infused iv with the tested compounds and selective α2-adrenoceptor antagonist, RX821002, or nonselective α2-adrenergic/I1-imidazoline receptor antagonist, Efaroxan. The mean arterial blood pressure and heart rate were monitored directly and continuously throughout the experiment. RESULTS: Efaroxan inhibited the hypotensive effect of TCS-80 stronger than RX821002. The degree of inhibition of the hypotensive effect of the remaining compounds was similar for both antagonists. The presence of Efaroxan and RX821002 diminished the heart rate decrease induced by all compounds administration, though the influence on the maximal chronotropic effect was attenuated significantly in the TCS-80 and TCS-213 treated animals only. CONCLUSION: Our results indicate that hypotensive and negative chronotropic activities of all tested compounds are mediated by both the α2-adrenergic and I1-imidazoline receptors. Moreover, the circulatory effect of TCS-80 might be mediated to relatively higher degree by the I1-imidazoline receptors than by the α2-adrenergic ones.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Imidazoles/farmacología , Indazoles/farmacología , Animales , Benzofuranos/farmacología , Hipotensión , Idazoxan/análogos & derivados , Idazoxan/farmacología , Imidazoles/antagonistas & inhibidores , Imidazoles/síntesis química , Imidazolidinas/antagonistas & inhibidores , Imidazolidinas/farmacología , Receptores de Imidazolina/efectos de los fármacos , Imidazolinas/antagonistas & inhibidores , Imidazolinas/síntesis química , Imidazolinas/farmacología , Indazoles/antagonistas & inhibidores , Indazoles/síntesis química , Masculino , Ratas , Receptores Adrenérgicos alfa 2/efectos de los fármacosRESUMEN
Social play behavior, abundant in the young of most mammalian species, is thought to be important for social and cognitive development. Social play is highly rewarding, and as such, the expression of social play depends on its pleasurable and motivational properties. Since the motivational properties of social play have only sporadically been investigated, we developed a setup in which rats responded for social play under a progressive ratio schedule of reinforcement. Dopaminergic neurotransmission plays a key role in incentive motivational processes, and both dopamine and noradrenaline have been implicated in the modulation of social play behavior. Therefore, we investigated the role of dopamine and noradrenaline in the motivation for social play. Treatment with the psychostimulant drugs methylphenidate and cocaine increased responding for social play, but suppressed its expression during reinforced play periods. The dopamine reuptake inhibitor GBR-12909 increased responding for social play, but did not affect its expression, whereas the noradrenaline reuptake inhibitor atomoxetine decreased responding for social play as well as its expression. The effects of methylphenidate and cocaine on responding for social play, but not their play-suppressant effects, were blocked by pretreatment with the dopamine receptor antagonist α-flupenthixol. In contrast, pretreatment with the α2-adrenoceptor antagonist RX821002 prevented the play-suppressant effect of methylphenidate, but left its effect on responding for social play unaltered. In sum, the present study introduces a novel method to study the incentive motivational properties of social play behavior in rats. Using this paradigm, we demonstrate dissociable roles for dopamine and noradrenaline in social play behavior: dopamine stimulates the motivation for social play, whereas noradrenaline negatively modulates the motivation for social play behavior and its expression.
Asunto(s)
Dopamina/metabolismo , Motivación/fisiología , Norepinefrina/metabolismo , Conducta Social , Inhibidores de Captación Adrenérgica/farmacología , Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Animales , Clorhidrato de Atomoxetina/farmacología , Cocaína/farmacología , Condicionamiento Operante/efectos de los fármacos , Condicionamiento Operante/fisiología , Antagonistas de Dopamina/farmacología , Inhibidores de Captación de Dopamina/farmacología , Flupentixol/farmacología , Idazoxan/análogos & derivados , Idazoxan/farmacología , Masculino , Metilfenidato/farmacología , Motivación/efectos de los fármacos , Pruebas Neuropsicológicas , Piperazinas/farmacología , Distribución Aleatoria , Ratas Wistar , Receptores Adrenérgicos alfa 2/metabolismo , Receptores Dopaminérgicos/metabolismoRESUMEN
Norepinephrine is a neurotransmitter that signals by stimulating the α1, α2 and ß adrenergic receptor (AR). We determined the role of these receptors in regulating the immediate early genes, Activity Regulated Cytoskeleton Associated Protein (Arc) and Zif268 in the rat cerebral cortex. RX821002, an α2-AR antagonist, produced Arc and Zif268 elevations across cortical layers. Next we examined the effects of delivering RX821002 with an α1-AR antagonist, prazosin, and a ß-AR antagonist, propranolol. RX821002 given with a prazosin and propranolol cocktail, or with each of these antagonists individually, decreased Arc and Zif268 to saline-treated control levels in most cortical layers. Arc and Zif268 levels were also similar to saline-treated control levels when rats were given a prazosin and propranolol cocktail alone, or when each of these antagonists were delivered individually. Taken together, these data reveal that α2-AR uniquely exert a tonic inibitory regulation of both Arc and Zif268 compared to α1 and ß-AR. However, the ability of RX821002 to increase Arc and Zif268 is interdependent with α1 and ß-AR signaling.
Asunto(s)
Corteza Cerebral/metabolismo , Proteínas del Citoesqueleto/metabolismo , Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Receptores Adrenérgicos/metabolismo , Antagonistas Adrenérgicos/farmacología , Animales , Proteínas del Citoesqueleto/genética , Proteína 1 de la Respuesta de Crecimiento Precoz/genética , Idazoxan/análogos & derivados , Idazoxan/farmacología , Proteínas del Tejido Nervioso/genética , Prazosina/farmacología , Propranolol/farmacología , ARN Mensajero/metabolismo , Ratas Sprague-Dawley , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Receptores Adrenérgicos beta/metabolismoRESUMEN
Repeated exposure to cocaine is known to dysregulate the norepinephrine system, and norepinephrine has also been implicated as having a role in abstinence and withdrawal. The goal of this study was to determine the effects of exposure to cocaine self-administration and subsequent abstinence on regulatory elements of the norepinephrine system in the nonhuman primate brain. Rhesus monkeys self-administered cocaine (0.3 mg/kg/injection, 30 reinforcers/session) under a fixed-interval 3-min schedule of reinforcement for 100 sessions. Animals in the abstinence group then underwent a 30-day period during which no operant responding was conducted, followed by a final session of operant responding. Control animals underwent identical schedules of food reinforcement and abstinence. This duration of cocaine self-administration has been shown previously to increase levels of norepinephrine transporters (NET) in the ventral noradrenergic bundle terminal fields. In contrast, in the current study, abstinence from chronic cocaine self-administration resulted in elevated levels of [(3)H]nisoxetine binding to the NET primarily in dorsal noradrenergic bundle terminal field structures. As compared to food reinforcement, chronic cocaine self-administration resulted in decreased binding of [(3)H]RX821002 to α2-adrenoceptors primarily in limbic-related structures innervated by both dorsal and ventral bundles, as well as elevated binding in the striatum. However, following abstinence from responding for cocaine binding to α2-adrenoceptors was not different than in control animals. These data demonstrate the dynamic nature of the regulation of norepinephrine during cocaine use and abstinence, and provide further evidence that the norepinephrine system should not be overlooked in the search for effective pharmacotherapies for cocaine dependence.
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Encéfalo/metabolismo , Trastornos Relacionados con Cocaína/metabolismo , Cocaína/administración & dosificación , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 2/administración & dosificación , Animales , Autorradiografía , Encéfalo/diagnóstico por imagen , Fluoxetina/administración & dosificación , Fluoxetina/análogos & derivados , Idazoxan/administración & dosificación , Idazoxan/análogos & derivados , Macaca mulatta , Masculino , Vías Nerviosas/metabolismo , Esquema de Refuerzo , AutoadministraciónRESUMEN
Binge-eating disorder is a common psychiatric disorder affecting ~2% of adults. Binge-eating was initiated in freely-fed, lean, adult, female rats by giving unpredictable, intermittent access to ground, milk chocolate over four weeks. The rats avidly consumed chocolate during 2 hr binge sessions, with compensatory reductions of normal chow intake in these sessions and the days thereafter. Bodyweights of binge-eating rats were normal. The model's predictive validity was explored using nalmefene (0.1-1.0mg/kg), R-baclofen (1.0-10mg/kg) and SB-334867 (3.0-30 mg/kg) (orexin-1 antagonist), which all selectively decreased chocolate bingeing without reducing chow intake. Sibutramine (0.3-5.0mg/kg) non-selectively reduced chocolate and chow consumption. Olanzapine (0.3-3.0mg/kg) was without effect and rolipram (1.0-10mg/kg) abolished all ingestive behaviour. The pro-drug, lisdexamfetamine (LDX; 0.1-1.5mg/kg), dose-dependently reduced chocolate bingeing by ⩽ 71% without significantly decreasing normal chow intake. Its metabolite, D-amphetamine (0.1-1.0mg/kg), dose-dependently and preferentially decreased chocolate bingeing ⩽ 56%. Using selective antagonists to characterize LDX's actions revealed the reduction of chocolate bingeing was partially blocked by prazosin (α1-adrenoceptor; 0.3 and 1.0mg/kg) and possibly by SCH-23390 (D1; 0.1mg/kg). RX821002 (α2-adrenoceptor; 0.1 and 0.3mg/kg) and raclopride (D2; 0.3 and 0.5mg/kg) were without effect. The results indicate that LDX, via its metabolite, d-amphetamine, reduces chocolate bingeing, partly by indirect activation of α1-adrenoceptors and perhaps D1 receptors.
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Conducta Animal/efectos de los fármacos , Bulimia/tratamiento farmacológico , Conducta Alimentaria/efectos de los fármacos , Dimesilato de Lisdexanfetamina/farmacología , Animales , Baclofeno/farmacología , Benzazepinas/farmacología , Benzodiazepinas/farmacología , Peso Corporal/efectos de los fármacos , Modelos Animales de Enfermedad , Ingestión de Alimentos/efectos de los fármacos , Femenino , Idazoxan/análogos & derivados , Idazoxan/farmacología , Naltrexona/análogos & derivados , Naltrexona/farmacología , Olanzapina , Prazosina/farmacología , Profármacos/farmacología , Racloprida/farmacología , Ratas , Ratas Wistar , Rolipram/farmacologíaRESUMEN
We studied the effects of selective blockade of various subtypes of α2-adrenoceptors on cardiac chronotropy in newborn rats. This period in rats is characterized by the absence of adrenergic regulation of heart function. Blockade of α2A/D- and α2B-adrenoceptors in 1-weekold rats provoked tachycardia. In contrast, blockade of α2C-adrenoceptors in newborn rats had no effect on heart rate.
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Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Sistema de Conducción Cardíaco/efectos de los fármacos , Receptores Adrenérgicos alfa 2/fisiología , Receptores Presinapticos/fisiología , Acridinas/farmacología , Animales , Animales Recién Nacidos , Corazón/crecimiento & desarrollo , Sistema de Conducción Cardíaco/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Idazoxan/análogos & derivados , Idazoxan/farmacología , Imidazoles/farmacología , Contracción Miocárdica/efectos de los fármacos , Piperazinas/farmacología , Ratas , Taquicardia/inducido químicamente , Taquicardia/fisiopatologíaRESUMEN
The effects of serotonin receptor activation (by serotonin) and inhibition (by mianserin) on the properties of the α1-, α2-adrenoreceptors, and muscarinic cholinergic receptors in subcellular membrane fractions from the rat cerebral cortex were studied. Experimental data on the kinetics of specific antagonists binding to adrenergic and muscarinic receptors were analyzed by graphical and mathematical methods. The results suggest the presence of allosteric (cross-talk) interaction. In the control, α1- and α2-adrenoreceptors were represented by a single pool, and muscarinic receptors, by two pools. Two pools of adrenoreceptors with different affinity were detected against the background of serotonin. It was found that mianserin induces the formation of two pools of only (α2-receptors and muscarinic receptors are represented by two pools differing in the main parameters, such as dissociation constants and adrenoreceptor concentrations, in the control and experimental groups. It was shown that the allosteric effect of serotonin and mianserin is manifested in the inhibition of muscarinic receptors. It was assumed that the adrenergic and cholinergic receptors exist as dimers. The interaction between the adrenergic, cholinergic, and serotonergic systems is likely to be implemented at the cell membrane level.
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Corteza Cerebral/efectos de los fármacos , Mianserina/farmacología , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Receptores Muscarínicos/metabolismo , Serotonina/farmacología , Antagonistas Adrenérgicos alfa/farmacología , Animales , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Corteza Cerebral/metabolismo , Idazoxan/análogos & derivados , Idazoxan/farmacología , Masculino , Ratas Wistar , Antagonistas de la Serotonina/farmacología , TritioRESUMEN
OBJECTIVES: Disturbances in the noradrenergic system, including alterations in the densities of α2-adrenoceptors, are posited to be involved in the pathophysiology of depression. In this study, we investigate the binding of α2-adrenoceptors in regions relevant to depression in an animal model of depression. METHODS: Using in vitro autoradiography techniques and the selective α2-ligand, [3H]RX 821002, we investigated the density of α2-adrenoceptors in female Flinders-sensitive line (FSL) rats, a validated model of depression, and in two traditional control groups - female Flinders-resistant line (FRL) and Sprague-Dawley (SD) rats. RESULTS: The α2-adrenoceptor density was increased in most regions of the FSL rat brain when compared with SD rats (10% across regions). Moreover, the α2-adrenoceptor density was further increased in the FRL rats compared with both FSL (10% across regions) and SD rats (24% across regions). CONCLUSIONS: The increase in α2-adrenoceptor binding in cortical regions in the FSL strain compared with the SD control strain is in accord with α2-adrenoceptor post-mortem binding data in suicide victims with untreated major depression. However, the differences in binding observed in the two control groups were unexpected and suggest the need for further studies in a larger cohort of animals of both sexes.
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Neuronas Adrenérgicas/metabolismo , Encéfalo/metabolismo , Depresión/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Antagonistas Adrenérgicos alfa/química , Animales , Autorradiografía/métodos , Modelos Animales de Enfermedad , Femenino , Idazoxan/análogos & derivados , Idazoxan/química , Unión Proteica , Ratas , Ratas Sprague-DawleyRESUMEN
Despite years of drug development, electroconvulsive therapy (ECT) remains the most effective treatment for severe depression. The exact therapeutic mechanism of action of ECT is still unresolved and therefore we tested the hypothesis that the beneficial effect of ECT could in part be the result of increased noradrenergic neurotransmission leading to a decrease in α2-adrenoceptor binding. We have previously shown that both the Flinders sensitive line (FSL) and Flinders resistant line (FRL) rats had altered α2-adrenoceptor binding compared to control Sprague-Dawley (SD) rats. In this study, we treated female FSL, FRL and SD rats with electroconvulsive shock (ECS), an animal model of ECT, or sham stimulation for 10 days before brains were removed and cut into 20µm thick sections. Densities of α2-adrenoceptors were measured by quantitative autoradiography in the hippocampus, thalamic nucleus, hypothalamus, amygdala, frontal cortex, insular cortex, and perirhinal cortex using the α2-adrenoceptor antagonist, [(3)H]RX 821002. ECS decreased the binding of α2-adrenoceptors in cortical regions in the FSL and cortical and amygdaloid regions in the control FRL rats compared to their respective sham treated group. The normal SD controls showed no significant response to ECS treatment. Our data suggest that the therapeutic effect of ECS may be mediated through a decrease of α2-adrenoceptors, probably due to a sustained increase in noradrenaline release. These data confirm the importance of the noradrenergic system and the α2-adrenoceptor in depression and in the mechanism of antidepressant treatments.