RESUMEN
Reinforcing effects mediated by accumbal CB(1) receptors (CB(1)R) are controversial, as well as their role in the rewarding effects of cocaine. Accumbal glutamate and glutamate receptors have been proposed to be involved in CB(1)R-mediated effects on cocaine reward. Rewarding effects of cocaine can be evaluated with the conditioned place preference or CPP test. Rimonabant, a cannabinoid CB(1)R ligand, lentiviruses aimed at silencing CB(1)R, and selective glutamatergic ligands are good tools for studying the function of accumbal CB(1) and glutamate receptors. The objectives of the present study were (i) to discern the CPP effects of in vivo gene silencing of accumbal CB(1) receptors by means of lentiviruses containing siRNAs; (ii) to discern the CPP effects of intra-accumbens infusions of the cannabinoid CB(1)R ligand rimonabant, and to evaluate whether effects are due to receptor blockade or inverse agonism; (iii) to discern the role of CB(1)R located within the nucleus accumbens shell in the rewarding effects of cocaine, by means of local infusions of rimonabant, and (iv) to discern the role of glutamate receptors (AMPAR, NMDAR, mGluR2/3) in rimonabant-induced effects on CPP in cocaine-treated rats. The findings revealed that in vivo silencing of accumbal CB(1) receptors with Lenti-CB(1)R-siRNAs induced place aversion to cocaine, but intra-accumbal rimonabant induced place preference in its own right, indicating that this compound seems to act as inverse agonist on the CPP. Glutamate receptors participate in rimonabant-mediated place preference because it was abolished after blocking AMPA glutamate receptors, but not NMDAR or mGluR2/3. Finally, in cocaine-treated rats, local rimonabant induced place aversion to the drug (not place preference), and this effect was mediated by glutamate neurotransmission because it was abolished after blockade of AMPA, NMDA or mGlu2/3 receptors, even though only the blockade of mGlu2/3 autoreceptors restored the emergence of place preference to cocaine.
Asunto(s)
Reacción de Prevención/efectos de los fármacos , Cocaína/farmacología , Núcleo Accumbens/efectos de los fármacos , Piperidinas/farmacología , Pirazoles/farmacología , Receptor Cannabinoide CB1/genética , Receptores de Glutamato/fisiología , Recompensa , Animales , Condicionamiento Clásico/efectos de los fármacos , Agonismo Inverso de Drogas , Silenciador del Gen , Lentivirus/genética , Ligandos , Núcleo Accumbens/metabolismo , Ratas , Ratas Wistar , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptor Cannabinoide CB1/fisiología , RimonabantRESUMEN
Drug addiction is viewed as a form of neural plasticity, and neurotrophic factors have been implicated in many forms of plasticity in the adult nervous system. Here we show that the fibroblast growth factor-1 (FGF-1), that is expressed on dopamine and GABA neurons of the ventral tegmental area (VTA), is involved in the sensitizing effects of morphine. The receptor FGFR-1 is expressed on VTA astrocytes, as well as dopamine and GABA neurons. FGF-1 or anti-FGF-1 infusions into the VTA during the induction (not expression) phase of sensitization advanced or blocked morphine's activating motor effects respectively, in a dose-dependent manner. Infusions into the adjacent substantia nigra, whose neurons also express FGF-1 and FGFR-1, did not modify normal morphine-induced sensitization. Biochemical traits related to morphine's sensitizing effects were altered by intra-VTA anti-FGF-1 because morphine-induced upregulation of both tyrosine hydroxylase (TH) and N-methyl d-aspartate glutamate receptor 1 (NMDAR1) in the VTA was blocked after anti-FGF-1. Changes in the activation state of VTA calcium/calmodulin-dependent kinase type II seem to participate in FGF-1-induced effects as well. We conclude that the FGF-1 system of the ventral tegmental area is required for biochemical and behavioral sensitization to this drug.
Asunto(s)
Factor 1 de Crecimiento de Fibroblastos/fisiología , Morfina/farmacología , Actividad Motora/efectos de los fármacos , Área Tegmental Ventral/fisiología , Animales , Anticuerpos/farmacología , Astrocitos/metabolismo , Células Cultivadas , Proteínas Quinasas Dependientes de AMP Cíclico/biosíntesis , Dopamina/metabolismo , Factor 1 de Crecimiento de Fibroblastos/inmunología , Factor 1 de Crecimiento de Fibroblastos/farmacología , Proteínas Quinasas JNK Activadas por Mitógenos/biosíntesis , Masculino , Proteína Quinasa 1 Activada por Mitógenos/biosíntesis , Proteína Quinasa 3 Activada por Mitógenos/biosíntesis , Neuronas/metabolismo , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Proteínas Proto-Oncogénicas c-akt/biosíntesis , Ratas , Ratas Wistar , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Receptores de N-Metil-D-Aspartato/biosíntesis , Tirosina 3-Monooxigenasa/biosíntesis , Área Tegmental Ventral/efectos de los fármacos , Ácido gamma-Aminobutírico/metabolismoRESUMEN
The extra-adrenal Zuckerkandl's paraganglion is used as a source of chromaffin cells for transplantation in parkinsonian animals. Aging can affect its viability, and this tissue needs further characterization for improving grafting procedures. The objectives were: (i) to compare the main morpho-functional characteristics of prepubertal and old Zuckerkandl's paraganglion (ZP), and (ii) to discern phenotypic changes after sub-chronic dexamethasone treatment in extra-adrenal tissue of prepubertal rats. For these purposes, immunostaining methods, stereology, voltammetry, cell culture, Western blotting, and ELISA were employed. The findings revealed that all paraganglia were composed of mesenchymal tissue and chromaffin cells. In prepubertal rats, chromaffin cells are arranged as large or small clusters. Large clusters (also known as "cell nests") contain densely packed chromaffin cells, and they are seen as fascicles in longitudinal sections. In old paraganglia, cell nests disappear, and chromaffin cells are found to be arranged as small cell clusters or dispersed throughout the mesenchyma. Paraganglionic chromaffin cells possess a rounded morphology with diameter ranging from 12 to 15 µm, with intracytoplasmic granules (100-500 nm in diameter) containing catecholamines. Prepubertal and old ZP chromaffin cells are mostly noradrenergics, and a few of them are dopaminergics. Aging reduces the amount of chromaffin tissue (28% in adult rats vs. 11% in old animals, both in relation to total volume of the paraganglion), and induces the presence of adrenergic cells and adrenaline. Both prepubertal and old cells express the neurotrophic factors GDNF and TGF-ß1, aging leading to reduced levels of both growth factors. Dexamethasone (50 µg/kg daily, 5 days) leads to the expression of phenylethanolamine-N-methyl-transferase in prepubertal paraganglia, and to a higher content and release of adrenaline.
Asunto(s)
Envejecimiento/fisiología , Células Cromafines/patología , Dexametasona/farmacología , Glucocorticoides/farmacología , Cuerpos Paraaórticos/patología , Envejecimiento/metabolismo , Envejecimiento/patología , Animales , Células Cromafines/efectos de los fármacos , Células Cromafines/metabolismo , Masculino , Cuerpos Paraaórticos/efectos de los fármacos , Cuerpos Paraaórticos/metabolismo , Ratas , Ratas WistarRESUMEN
Neuroinflammation of the CNS seems to participate in sensitizing effects of drugs of abuse such as psychostimulants and morphine. The nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR-alpha) plays a prominent role in several physiological processes including the inflammatory response, and its activation mediates a reduced production of pro-inflammatory factors. The objectives were to examine the involvement of nuclear PPAR-alpha in motor sensitization to morphine and cocaine, by using null mice (PPAR-alpha -/-mice), or the injection of a selective PPAR-alpha agonist, [[4-chloro-6-[(2,3-dimethylphenyl)amino]-2-pyrimidinyl] thio]acetic acid (WY14643), in morphine-treated mice. The findings indicate that PPAR-alpha plays an inhibitory role in the expression (not induction) of motor sensitization to morphine, but it is devoid of effects on sensitization to cocaine, suggesting that this nuclear receptor participates in motor activating effects of opiates but not psychostimulants. Furthermore, brain PPAR-alpha expression is upregulated after the highest dose of repeated morphine, but not chronic cocaine, suggesting that this receptor could play a homeostatic role. In accordance, systemic WY14643 was able to block sensitization to morphine, confirming that PPAR-alpha plays a homeostatic role opposing morphine-induced motor sensitization, likely through a reduction of inflammation-associated changes.
Asunto(s)
Cocaína/farmacología , Inhibidores de Captación de Dopamina/farmacología , Morfina/farmacología , Actividad Motora/efectos de los fármacos , Narcóticos/farmacología , PPAR alfa/metabolismo , Análisis de Varianza , Animales , Western Blotting , Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Fármacos del Sistema Nervioso Central/farmacología , Cocaína/administración & dosificación , Inhibidores de Captación de Dopamina/administración & dosificación , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Morfina/administración & dosificación , Actividad Motora/fisiología , Narcóticos/administración & dosificación , PPAR alfa/agonistas , PPAR alfa/genética , Pirimidinas/farmacología , Factores de TiempoRESUMEN
The objective was to discern the neuroregenerative effect of grafts of extra-adrenal cells of the Zuckerkandl's paraganglion (ZP) in the nigrostriatal circuit, by using the retrograde model of parkinsonism in rats. The antiparkinsonian efficacy of two types of grafting procedures was studied (cell aggregates vs. dispersed cells), and GDNF and TGFbeta(1) (dopaminotrophic factors) as well as dopamine presence in extra-adrenal tissue was analyzed. Extra-adrenal chromaffin cells are noradrenergics, tissue dopamine is low, and they express both GDNF and TGFbeta(1). Grafts of cell aggregates, not of dispersed cells, exerted a trophic regeneration of the host striatum, leading to amelioration of motor deficits. Sprouting of spared dopaminergic fibers within the striatum, reduction of dopamine axon degeneration, and/or enhanced phenotypic expression of TH would explain striatal regeneration. Grafted cells as aggregates showed a better survival rate than dispersed cells, and they express higher levels of GDNF. Higher survivability and GDNF content together with the neurorestorative and dopaminotrophic action of both GDNF and TGFbeta(1) could account for striatal recovery and functional amelioration after grafting ZP cell aggregates. Finally, nigral degeneration and partial degeneration of ventral tegmental area were not precluded after transplantation, indicating that the trophic effect of grafts was local within the host striatum.