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1.
J Mol Neurosci ; 53(3): 345-51, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24214104

RESUMEN

The locus coeruleus (LC) is an important brainstem area involved in cocaine addiction. However, evidence to elucidate how cocaine modulates the activity of LC neurons remains incomplete. Here, we performed whole recordings in brain slices to evaluate the effects of cocaine on the sodium (Na(+)), potassium (K(+)), calcium (Ca(2+)) channels, and glutamatergic synaptic transmission in the locus coeruleus neurons. Local application of cocaine significantly and reversibly reduced the spontaneous firing rate but did not affect action potential amplitude, rising time, decay time, or half width of noradrenergic locus coeruleus neurons. Moreover, cocaine attenuated the sodium current but did not affect potassium and calcium currents. The N-methyl-D-aspartate receptor mediated excitatory postsynaptic currents were reduced by neuropeptide galanin but not cocaine. All those data demonstrate that cocaine has inhibitory effect on the spontaneous activities and sodium current in locus coeruleus neurons. Therefore, neuromodulation of sodium channel in locus coeruleus neurons may play an important role in drug addiction.


Asunto(s)
Cocaína/farmacología , Potenciales Postsinápticos Excitadores , Canales Iónicos/metabolismo , Locus Coeruleus/efectos de los fármacos , Neuronas/efectos de los fármacos , Animales , Calcio/metabolismo , Epinefrina/metabolismo , Galanina/farmacología , Ácido Glutámico/metabolismo , Locus Coeruleus/fisiología , Neuronas/metabolismo , Neuronas/fisiología , Potasio/metabolismo , Ratas , Ratas Sprague-Dawley , Sodio/metabolismo
2.
Neuroscience ; 190: 270-88, 2011 Sep 08.
Artículo en Inglés | MEDLINE | ID: mdl-21672612

RESUMEN

The behavioral phenotype of a transgenic mouse overexpressing a galanin receptor 2 (GalR2)-enhanced, green fluorescent protein (EGFP)-construct under the platelet-derived growth factor-B promoter, and of controls, was assessed in various behavioral tests, such as the Porsolt forced swim test, as well as the open field, elevated plus maze and passive avoidance tests. In addition, the distribution of GalR2-EGFP expressing cell bodies and processes was studied in the brain of these mice using histochemical methods. Three age groups of the transgenic mice demonstrated decreased levels of immobility in the forced swim test, indicative of antidepressive-like behavior and/or increased stress resistance. Anxiety-like behaviors, measured in two different tests, did not differ between the GalR2-overexpressing and the wild-type mice, nor did motor activity levels, emotional learning or memory behaviors. High levels of GalR2 mRNA and protein expression were observed in the presubiculum, subiculum, cingulate cortex, retrosplenial granular and agranular cortices, subregions of prefrontal cortex, and the olfactory bulb, regions which are directly or indirectly implicated in depression-like behavior. These results may contribute to the understanding of the pathophysiology of major depressive disorder and the role of GalR2 in the regulation of mood, and suggest a potential therapeutic effect by targeting the GalR2 for treatment of depressive disorders.


Asunto(s)
Depresión/genética , Hipocampo/metabolismo , Actividad Motora/genética , Receptor de Galanina Tipo 2/genética , Animales , Ansiedad/genética , Ansiedad/metabolismo , Conducta Animal/fisiología , Encéfalo/metabolismo , Depresión/metabolismo , Modelos Animales de Enfermedad , Masculino , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Transgénicos , Fenotipo , Receptor de Galanina Tipo 2/metabolismo , Natación
3.
Proc Natl Acad Sci U S A ; 105(7): 2717-22, 2008 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-18272487

RESUMEN

Galanin is a neuropeptide with a wide range of effects in the nervous and endocrine systems, mediated through three G protein-coupled receptor subtypes (GalR1-3). Interestingly, galanin and its receptors are also expressed in certain tumors. Here we studied the effects of galanin in rat pheochromocytoma (PC12) cells stably transfected with GFP-tagged GalR2. Galanin at 100 nM inhibited cell proliferation in both nontransfected and transfected cells. Conversly, both galanin and the GalR2(R3)-agonist AR-M1896 induced caspase-dependent apoptotic cell death only in GalR2-transfected cells. Western-blot analyses of downstream mediators of the G(q/11)-type G protein showed down-regulation of pAkt and pBad in galanin-exposed transfected cells. Also, the specific PI3 kinase inhibitor LY-294002 increased the level of pBad and decreased activation of caspases. In addition, p21(cip1) levels were up-regulated in galanin-exposed PC12 cells and down-regulated in galanin-exposed GalR2-transfected cells. In agreement, FACS analyses of galanin exposed cells showed occurrence of cell cycle arrest in PC12 cells and cell death in transfected cells. Finally, as shown with real-time PCR, galanin and its receptors were expressed at very high levels in human pheochromocytoma tissues as compared with normal adrenal medulla. These findings point to GalR2 as a possible target for therapeuthic interventions in pheochromocytoma.


Asunto(s)
Apoptosis/efectos de los fármacos , Galanina/farmacología , Receptor de Galanina Tipo 2/metabolismo , Animales , Caspasas/metabolismo , Proliferación Celular/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Galanina/genética , Regulación de la Expresión Génica , Humanos , Células PC12 , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Receptor de Galanina Tipo 1/genética , Receptor de Galanina Tipo 2/genética , Transducción de Señal/efectos de los fármacos
4.
Acta Physiol (Oxf) ; 190(1): 39-45, 2007 May.
Artículo en Inglés | MEDLINE | ID: mdl-17428231

RESUMEN

G protein-coupled receptors (GPCRs) mediate cellular responses to diverse extracellular stimuli to play a vital role in the control of physiology and behaviour. GPCR trafficking is of fundamental importance for the regulation of GPCRs signaling. In this mini review, we will discuss some of the recent findings on the mechanisms that regulate GPCR trafficking, which include (i) large dense-core vesicle (LDCV)-associated GPCR delivery which could be a general cell biological mechanism for rapid modulation of membrane receptors in response to certain stimuli; (ii) lateral diffusion of GPCRs in the plasma membrane for rapid change of the number of neurotransmitter receptors during synaptic plasticity and (iii) constitutive internalization of GPCRs, that contributes to receptor resensitization and distribution, including axonal polarization.


Asunto(s)
Transporte de Proteínas/fisiología , Receptores Acoplados a Proteínas G/fisiología , Animales , Membrana Celular/fisiología , Endocitosis/fisiología , Humanos , Receptores de Superficie Celular/fisiología
5.
Proc Natl Acad Sci U S A ; 104(4): 1401-6, 2007 Jan 23.
Artículo en Inglés | MEDLINE | ID: mdl-17227848

RESUMEN

The locus coeruleus (LC) harbors a compact group of noradrenergic cell bodies projecting to virtually all parts of the central nervous system. By using combined measurements of amperometry and patch-clamp, quantal vesicle release of noradrenaline (NA) was detected as amperometric spikes, after depolarization of the LC neurons. After a pulse depolarization, the average latency of amperometric spikes was 1,870 ms, whereas the latency of glutamate-mediated excitatory postsynaptic currents was 1.6 ms. A substantial fraction of the depolarization-induced amperometric spikes originated from the somata. In contrast to glutamate-mediated excitatory postsynaptic currents, NA secretion was strongly modulated by the action potential frequency (0.5-50 Hz). Somatodendritic NA release from LC upon enhanced cell activity produced autoinhibition of firing and of NA release. We conclude that, in contrast to classic synaptic transmission, quantal NA release from LC somata is characterized by a number of distinct properties, including long latency and high sensitivity to action potential frequency.


Asunto(s)
Locus Coeruleus/metabolismo , Neuronas/metabolismo , Neurotransmisores/metabolismo , Puente/metabolismo , Potenciales de Acción , Animales , Calcio/metabolismo , Ácido Glutámico/metabolismo , Técnicas In Vitro , Locus Coeruleus/citología , Locus Coeruleus/fisiología , Técnicas de Placa-Clamp , Puente/fisiología , Ratas , Ratas Sprague-Dawley
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