RESUMEN
Phosphodiesterase 5 (PDE5) inhibitors have recently been reported to exert beneficial effects against ischemia-reperfusion injury in several organs but their neuroprotective effects in brain stroke models are scarce. The present study was undertaken to assess the effects of sildenafil against cell death caused by intrastriatal injection of malonate, an inhibitor of succinate dehydrogenase; which produces both energy depletion and lesions similar to those seen in cerebral ischemia. Our data demonstrate that sildenafil (1.5mg/kg by mouth (p.o.)), given 30min before malonate (1.5µmol/2µL), significantly decreased the lesion volume caused by this toxin. This protective effect can be probably related to the inhibition of excitotoxic pathways. Thus, malonate induced the activation of the calcium-dependent protease, calpain and the cyclin-dependent kinase 5, cdk5; which resulted in the hyperphosphorylation of tau and the cleavage of the protective transcription factor, myocyte enhancer factor 2, MEF2. All these effects were also significantly reduced by sildenafil pre-treatment, suggesting that sildenafil protects against malonate-induced cell death through the regulation of the calpain/p25/cdk5 signaling pathway. Similar findings were obtained using inhibitors of calpain or cdk5, further supporting our contention. Sildenafil also increased MEF2 phosphorylation and Bcl-2/Bax and Bcl-xL/Bax ratios, effects that might as well contribute to prevent cell death. Finally, sildenafil neuroprotection was extended not only to rat hippocampal slices subjected to oxygen and glucose deprivation when added at the time of reoxygenation, but also, in vivo when administered after malonate injection. Thus, the therapeutic window for sildenafil against malonate-induced hypoxia was set at 3h.
Asunto(s)
Calpaína/metabolismo , Quinasa 5 Dependiente de la Ciclina/metabolismo , Hipoxia Encefálica , Malonatos/toxicidad , Fármacos Neuroprotectores/farmacología , Inhibidores de Fosfodiesterasa 5/farmacología , Piperazinas/farmacología , Sulfonas/farmacología , Animales , Hipoxia Encefálica/inducido químicamente , Hipoxia Encefálica/metabolismo , Hipoxia Encefálica/patología , Hipoxia Encefálica/prevención & control , Masculino , Fosforilación/efectos de los fármacos , Purinas/farmacología , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Citrato de Sildenafil , Proteína X Asociada a bcl-2/metabolismo , Proteína bcl-X/metabolismo , Proteínas tau/metabolismoRESUMEN
The aim of the present study was to investigate whether late pre-conditioning using 3-nitropropionic acid (3NP) prevents the 5-hydroxytryptamine (5-HT) deficits caused by the amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA) in the rat. For this purpose we administered 3NP 24 h before MDMA (3 x 5 mg/kg i.p., every 2 h) and rats were killed 7 days later. Pre-treatment of 3NP afforded complete protection against MDMA-induced 5-HT deficits independent of any effect on MDMA-induced hyperthermia or 5-HT transporter activity. To identify the transductional mechanisms responsible for the neuroprotective effect of 3NP, we first examined the involvement of nitric oxide (NO) by using selective inhibitors of all three nitric oxide synthase isoforms. Inhibition of endothelial and neuronal nitric oxide synthase, but not inducible nitric oxide synthase, reversed 3NP-induced pre-conditioning. The NO donor S-Nitroso-N-acetylpenicilamine mimicked 3NP effects further suggesting the involvement of NO in mediating 3NP protection. To investigate the involvement of NOS/soluble guanylate cyclase (sGC)/protein kinase G/mitochondrial ATP-sensitive potassium channels (mitoK(ATP)) signaling pathway we examined the effect of 5-hydroxydecanoate (5-HD), a selective mitoK(ATP) blocker, and 1H-(1,2,4)oxadiazolo[4,3-a]quinoxaline-1-one, a potent inhibitor of sGC, on 3NP-induced tolerance. 5-hydroxydecanoate, but not 1H-(1,2,4)oxadiazolo[4,3-a]quinoxaline-1-one, suppressed 3NP-mediated protection suggesting that mitoK(ATP) opening, but not NO-mediated activation of sGC, participates in the mechanism underlying tolerance to MDMA. Our data also showed that the protective effect of 3NP was abolished by cycloheximide, supporting the involvement of de novo protein synthesis. In conclusion, 3NP-induced delayed tolerance against 5-HT deficits caused by MDMA occurs via NO production.
Asunto(s)
N-Metil-3,4-metilenodioxianfetamina/farmacología , Fármacos Neuroprotectores/farmacología , Nitrocompuestos/farmacología , Propionatos/farmacología , Serotonina/deficiencia , Animales , Masculino , N-Metil-3,4-metilenodioxianfetamina/administración & dosificación , Fármacos Neuroprotectores/administración & dosificación , Óxido Nítrico/biosíntesis , Óxido Nítrico/fisiología , Donantes de Óxido Nítrico/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Óxido Nítrico Sintasa/metabolismo , Nitrocompuestos/administración & dosificación , Propionatos/administración & dosificación , Inhibidores de la Síntesis de la Proteína/farmacología , Ratas , Ratas Wistar , Serotonina/toxicidad , Serotoninérgicos/administración & dosificación , Serotoninérgicos/farmacologíaRESUMEN
BACKGROUND AND PURPOSE: 3,4-methylenedioxymethamphetamine (MDMA) causes a persistent loss of dopaminergic cell bodies in the substantia nigra of mice. Current evidence indicates that such neurotoxicity is due to oxidative stress but the source of free radicals remains unknown. Inhibition of mitochondrial electron transport chain complexes by MDMA was assessed as a possible source. EXPERIMENTAL APPROACH: Activities of mitochondrial complexes after MDMA were evaluated spectrophotometrically. In situ visualization of superoxide production in the striatum was assessed by ethidium fluorescence and striatal dopamine levels were determined by HPLC as an index of dopaminergic toxicity. KEY RESULTS: 3,4-methylenedioxymethamphetamine decreased mitochondrial complex I activity in the striatum of mice, an effect accompanied by an increased production of superoxide radicals and the inhibition of endogenous aconitase. alpha-Lipoic acid prevented superoxide generation and long-term toxicity independent of any effect on complex I inhibition. These effects of alpha-lipoic acid were also associated with a significant increase of striatal glutathione levels. The relevance of glutathione was supported by reducing striatal glutathione content with L-buthionine-(S,R)-sulfoximine, which exacerbated MDMA-induced dopamine deficits, effects suppressed by alpha-lipoic acid. The nitric oxide synthase inhibitor, N(G)-nitro-L-arginine, partially prevented MDMA-induced dopamine depletions, an effect reversed by L-arginine but not D-arginine. Finally, a direct relationship between mitochondrial complex I inhibition and long-term dopamine depletions was found in animals treated with MDMA in combination with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. CONCLUSIONS AND IMPLICATIONS: Inhibition of mitochondrial complex I following MDMA could be the source of free radicals responsible for oxidative stress and the consequent neurotoxicity of this drug in mice.
Asunto(s)
Complejo I de Transporte de Electrón/antagonistas & inhibidores , Alucinógenos/toxicidad , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Síndromes de Neurotoxicidad/etiología , Animales , Antioxidantes/farmacología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Radicales Libres/metabolismo , Masculino , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ácido Tióctico/farmacologíaRESUMEN
Phosphodiesterase 5 (PDE5) inhibitors are often used in combination with club drugs such as 3,4-methylenedioxymethamphetamine (MDMA or ecstasy). We investigated the consequences of such combination in the serotonergic system of the rat. Oral administration of sildenafil citrate (1.5 or 8 mg/kg) increased brain cGMP levels and protected in a dose-dependent manner against 5-hydroxytryptamine depletions caused by MDMA (3 x 5 mg/kg, i.p., every 2 h) in the striatum, frontal cortex and hippocampus without altering the acute hyperthermic response to MDMA. Intrastriatal administration of the protein kinase G (PKG) inhibitor, KT5823 [(9S, 10R, 12R)-2,3,9,10,11,12-Hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid, methyl ester)], suppressed sildenafil-mediated protection. By contrast, the cell permeable cGMP analogue, 8-bromoguanosine cyclic 3',5'-monophosphate, mimicked sildenafil effects further suggesting the involvement of the PKG pathway in mediating sildenafil protection. Because mitochondrial ATP-sensitive K(+) channels are a target for PKG, we next administered the specific mitochondrial ATP-sensitive K(+) channel blocker, 5-hydroxydecanoic acid, 30 min before sildenafil. 5-hydroxydecanoic acid completely reversed the protection afforded by sildenafil, thereby implicating the involvement of mitochondrial ATP-sensitive K(+) channels. Sildenafil also increased Akt phosphorylation, and so the possible involvement of the Akt/endothelial nitric oxide synthase (eNOS)/sGC signalling pathway was analysed. Neither the phosphatidylinositol 3-kinase inhibitor, wortmannin, nor the selective eNOS inhibitor, L-N5-(1-iminoethyl)-L-ornithine dihydrochloride, reversed the protection afforded by sildenafil, suggesting that Akt/eNOS/sGC cascade does not participate in the protective mechanisms. Our data also show that the protective effect of sildenafil can be extended to vardenafil, another PDE5 inhibitor. In conclusion, sildenafil protects against MDMA-induced long-term reduction of indoles by a mechanism involving increased production of cGMP and subsequent activation of PKG and mitochondrial ATP-sensitive K(+) channel opening.
Asunto(s)
Alucinógenos/antagonistas & inhibidores , Alucinógenos/toxicidad , N-Metil-3,4-metilenodioxianfetamina/antagonistas & inhibidores , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Inhibidores de Fosfodiesterasa 5 , Inhibidores de Fosfodiesterasa/farmacología , Piperazinas/farmacología , Serotonina/deficiencia , Sulfonas/farmacología , Animales , Western Blotting , Temperatura Corporal/efectos de los fármacos , Química Encefálica/efectos de los fármacos , GMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de GMP Cíclico/metabolismo , Ácido Hidroxiindolacético/metabolismo , Imidazoles/farmacología , Canales KATP/efectos de los fármacos , Masculino , Microinyecciones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Neostriado/efectos de los fármacos , Purinas/farmacología , Ratas , Ratas Wistar , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Transducción de Señal/efectos de los fármacos , Citrato de Sildenafil , Triazinas/farmacología , Diclorhidrato de VardenafilRESUMEN
The mechanisms underlying 3,4-methylenedioxymethamphetamine (MDMA)-induced serotonergic (5-HT) toxicity remain unclear. It has been suggested that MDMA depletes 5-HT by increasing brain tyrosine levels, which via non-enzymatic hydroxylation leads to DA-derived free radical formation. Because this hypothesis assumes the pre-existence of hydroxyl radicals, we hypothesized that MDMA metabolism into pro-oxidant compounds is the limiting step in this process. Acute hyperthermia, plasma tyrosine levels and concentrations of MDMA and its main metabolites were higher after a toxic (15 mg/kg i.p.) vs. a non-toxic dose of MDMA (7.5mg/kg i.p.). The administration of a non-toxic dose of MDMA in combination with l-tyrosine (0.2 mmol/kg i.p.) produced a similar increase in serum tyrosine levels to those found after a toxic dose of MDMA; however, brain 5-HT content remained unchanged. The non-toxic dose of MDMA combined with a high dose of tyrosine (0.5 mmol/kg i.p.), caused long-term 5-HT depletions in rats treated at 21.5 degrees C but not in those treated at 15 degrees C, conditions known to decrease MDMA metabolism. Furthermore, striatal perfusion of MDMA (100 microM for 5h) combined with tyrosine (0.5 mmol/kg i.p.) in hyperthermic rats did not cause 5-HT depletions. By contrast, rats treated with the non-toxic dose of MDMA under heating conditions or combined with entacapone or acivicin, which interfere with MDMA metabolism or increase brain MDMA metabolite availability respectively, showed significant reductions of brain 5-HT content. Altogether, these data indicate that although tyrosine may contribute to MDMA-induced toxicity, MDMA metabolism appears to be the limiting step.
Asunto(s)
Encéfalo/efectos de los fármacos , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Síndromes de Neurotoxicidad/metabolismo , Serotonina/metabolismo , Tirosina/metabolismo , Análisis de Varianza , Animales , Antimetabolitos/farmacología , Área Bajo la Curva , Temperatura Corporal/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Catecoles/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Inhibidores Enzimáticos/farmacología , Ácido Hidroxiindolacético/metabolismo , Isoxazoles/farmacología , Masculino , Síndromes de Neurotoxicidad/etiología , Nitrilos/farmacología , Unión Proteica/efectos de los fármacos , Ratas , Ratas Wistar , Factores de Tiempo , Tirosina/farmacologíaRESUMEN
Preconditioning has emerged as a valid strategy against different neurotoxic insults. Although the mechanisms underlying preconditioning are not fully understood, the activation of ATP-sensitive potassium (KATP) channels has been proposed to play a pivotal role in neuronal preconditioning. In the present work we examine whether minoxidil a KATP channel activator protects against the long-term toxicity caused by the amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA) in rats. Our data show that intrastriatal administration of minoxidil prevents MDMA-induced long-term indole depletions in the rat striatum. This effect was not related to an effect on core temperature, as pre-treatment with minoxidil did not significantly alter MDMA-induced hyperthermia. Taking into account that minoxidil opens both sarcolemmal and mitochondrial KATP channels, we examined the role of each type of channels in the protective effects of minoxidil using specific inhibitors. The administration of HMR-1098, a blocker of the sarcolemmal KATP channels, along with minoxidil did not affect the protection afforded by the latter. On the contrary the selective mitochondrial KATP channel blocker 5-hydroxydecanoic acid completely reversed the protection afforded by minoxidil, thereby implicating the involvement of mitochondrial (but not sarcolemmal) KATP channels. Furthermore our data show the participation of Akt and extracellular signal-regulated kinases in minoxidil-afforded protection. Intrastriatal administration of wortmannin or PD98059 (inhibitors of phosphatidylinositol-3-kinase and mitogen-activated protein kinase/extracellular regulated protein kinase, respectively), along with minoxidil abolished the protective effect of minoxidil against the serotonergic toxicity caused by MDMA. These results demonstrate that minoxidil by opening mitochondrial KATP channels completely prevents MDMA toxicity and that Akt and MAP kinases are involved in minoxidil-afforded neuroprotection.
Asunto(s)
Quinasas MAP Reguladas por Señal Extracelular/fisiología , Canales KATP/fisiología , Minoxidil/farmacología , N-Metil-3,4-metilenodioxianfetamina/farmacología , Proteínas Proto-Oncogénicas c-akt/fisiología , Serotonina/deficiencia , Animales , Masculino , Mitocondrias/efectos de los fármacos , Mitocondrias/fisiología , N-Metil-3,4-metilenodioxianfetamina/antagonistas & inhibidores , Canales de Potasio/fisiología , Ratas , Ratas Wistar , Serotonina/metabolismoRESUMEN
RATIONALE: A close relationship appears to exist between 3,4-methylenedioxymethamphetamine (MDMA)-induced changes in core body temperature and long-term serotonin (5-HT) loss. OBJECTIVE: We investigated whether changes in core body temperature affect MDMA metabolism. MATERIALS AND METHODS: Male Wistar rats were treated with MDMA at ambient temperatures of 15, 21.5, or 30 degrees C to prevent or exacerbate MDMA-induced hyperthermia. Plasma concentrations of MDMA and its main metabolites were determined for 6 h. Seven days later, animals were killed and brain indole content was measured. RESULTS: The administration of MDMA at 15 degrees C blocked the hyperthermic response and long-term 5-HT depletion found in rats treated at 21.5 degrees C. At 15 degrees C, plasma concentrations of MDMA were significantly increased, whereas those of three of its main metabolites were reduced when compared to rats treated at 21.5 degrees C. By contrast, hyperthermia and indole deficits were exacerbated in rats treated at 30 degrees C. Noteworthy, plasma concentrations of MDMA metabolites were greatly enhanced in these animals. Instrastriatal perfusion of MDMA (100 microM for 5 h at 21 degrees C) did not potentiate the long-term depletion of 5-HT after systemic MDMA. Furthermore, interfering in MDMA metabolism using the catechol-O-methyltransferase inhibitor entacapone potentiated the neurotoxicity of MDMA, indicating that metabolites that are substrates for this enzyme may contribute to neurotoxicity. CONCLUSIONS: This is the first report showing a direct relationship between core body temperature and MDMA metabolism. This finding has implications on both the temperature dependence of the mechanism of MDMA neurotoxicity and human use, as hyperthermia is often associated with MDMA use in humans.
Asunto(s)
Temperatura Corporal/fisiología , Alucinógenos/metabolismo , Alucinógenos/toxicidad , N-Metil-3,4-metilenodioxianfetamina/metabolismo , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Síndromes de Neurotoxicidad/psicología , Animales , Temperatura Corporal/efectos de los fármacos , Química Encefálica/efectos de los fármacos , Catecol O-Metiltransferasa/metabolismo , Inhibidores de Catecol O-Metiltransferasa , Catecoles/farmacología , Interpretación Estadística de Datos , Sinergismo Farmacológico , Inhibidores Enzimáticos/farmacología , Fiebre/inducido químicamente , Ácido Hidroxiindolacético/metabolismo , Masculino , Microdiálisis , Nitrilos/farmacología , Ratas , Ratas Wistar , Serotonina/metabolismo , Tirosina/sangreRESUMEN
Amiloride and several of its congeners known to block the Na(+)/Ca(2+) and/or Na(+)/H(+) antiporters potentiate methamphetamine-induced neurotoxicity without altering methamphetamine-induced hyperthermia. We now examine whether amiloride also exacerbates 3,4-methylenedioxymethamphetamine (MDMA)-induced long-term serotonin (5-HT) loss in rats. Amiloride (2.5 mg/kg, every 2 h x 3, i.p.) given at ambient temperature 30 min before MDMA (5 mg/kg, every 2 h x 3, i.p.), markedly exacerbated long-term 5-HT loss. However, in contrast to methamphetamine, amiloride also potentiated MDMA-induced hyperthermia. Fluoxetine (10 mg/kg i.p.) completely protected against 5-HT depletion caused by the MDMA/amiloride combination without significantly altering the hyperthermic response. By contrast, the calcium channel antagonists flunarizine or diltiazem did not afford any protection. Findings with MDMA and amiloride were extended to the highly selective Na(+)/H(+) exchange inhibitor dimethylamiloride, suggesting that the potentiating effects of amiloride are probably mediated by the blockade of Na(+)/H(+) exchange. When the MDMA/amiloride combination was administered at 15 degrees C hyperthermia did not develop and brain 5-HT concentrations remained unchanged 7 days later. Intrastriatal perfusion of MDMA (100 microM for 8 h) in combination with systemic amiloride caused a small depletion of striatal 5-HT content in animals made hyperthermic but not in the striatum of normothermic rats. These data suggest that enhancement of MDMA-induced 5-HT loss caused by amiloride or dimethylamiloride depends on their ability to enhance MDMA-induced hyperthermia. We hypothesise that blockade of Na(+)/H(+) exchange could synergize with hyperthermia to render 5-HT terminals more vulnerable to the toxic effects of MDMA.
Asunto(s)
Amilorida/farmacología , Alucinógenos/farmacología , N-Metil-3,4-metilenodioxianfetamina/farmacología , Serotoninérgicos/farmacología , Serotonina/metabolismo , Bloqueadores de los Canales de Sodio/farmacología , Amilorida/análogos & derivados , Animales , Temperatura Corporal/efectos de los fármacos , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Sinergismo Farmacológico , Fiebre/inducido químicamente , Masculino , Ratas , Ratas Wistar , Intercambiadores de Sodio-Hidrógeno/antagonistas & inhibidores , Intercambiadores de Sodio-Hidrógeno/efectos de los fármacos , Intercambiadores de Sodio-Hidrógeno/fisiologíaRESUMEN
The amphetamine derivative 3,4-methylenedioxymethamphetamine (MDMA) produces long-term toxicity to serotonin (5-HT) neurones in rats, which is exacerbated when combined with the mitochondrial inhibitor malonate. Moreover, MDMA, which does not produce dopamine depletion in the rat, potentiates malonate-induced striatal dopamine toxicity. Because the malonate/MDMA combination acutely causes a synergistic increase of 5-HT and dopamine release, in this study we sought to determine whether pharmacological blockade of MDMA- and/or malonate-induced dopamine release prevents neurotoxicity. Fluoxetine, given 30 min prior to the malonate/MDMA combination, afforded complete protection against 5-HT depletion and reversed MDMA-induced exacerbation of dopamine toxicity found in the malonate/MDMA treated rats. Protection afforded by fluoxetine was not related to changes in MDMA-induced hyperthermia. Similarly, potentiation of malonate-induced dopamine toxicity caused by MDMA was not observed in p-chlorophenylalanine-5-HT depleted rats. Finally, the dopamine transporter inhibitor GBR 12909 completely prevented dopamine neurotoxicity caused by the malonate/MDMA combination and reversed the exacerbating toxic effects of malonate on MDMA-induced 5-HT depletion without significantly altering the hyperthermic response. Overall, these results suggest that the synergic release of dopamine caused by the malonate/MDMA combination plays an important role in the long-term toxic effects. A possible mechanism of neurotoxicity and protection is proposed.
Asunto(s)
Trastornos Relacionados con Anfetaminas/fisiopatología , Cuerpo Estriado/efectos de los fármacos , Alucinógenos/toxicidad , Malonatos/toxicidad , N-Metil-3,4-metilenodioxianfetamina/toxicidad , Serotoninérgicos/toxicidad , Animales , Regulación de la Temperatura Corporal/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cuerpo Estriado/fisiopatología , Dopamina/metabolismo , Inhibidores de Captación de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Fluoxetina/farmacología , Masculino , Neuronas/efectos de los fármacos , Piperazinas/farmacología , Ratas , Ratas Wistar , Serotonina/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacologíaRESUMEN
There is ample evidence that plastic changes in the nervous system require the excitatory amino acid transmission. This appears to be also the case for psychostimulant-induced behavioral sensitization. More specifically the glutamatergic input from the medial prefrontal cortex (mPFC) to the VTA and the NAc appears to be involved in behavioral sensitization processes. However, dissociations regarding the role of the mPFC with respect to the development and expression of sensitization, as well as with respect to the psychostimulant being studied (amphetamine versus cocaine) appear to exist. The present study examined the role of the dorsal mPFC in the development and expression of 3,4-methylenedioxymethamphetamine (MDMA)-induced sensitization. Bilateral ibotenic acid or sham lesions of the dorsal mPFC were performed 7 days prior to or 4 days after a context-dependent sensitization-inducing regimen of MDMA (15 mg/kg i.p.) or saline. Rats were then challenged with MDMA (5 mg/kg i.p.) after 12 days of withdrawal. Ibotenic acid lesions did not affect the activating effects of MDMA, but prevented the development and expression of MDMA sensitization. Thus, the distance traveled during the development phase of sensitization increased in sham-lesioned rats but not in ibotenic-lesioned animals. Similarly, sham-lesioned rats showed a sensitized response when challenged with MDMA after the withdrawal period, an effect not observed in ibotenic-lesioned animals. These data reinforce the view that the dorsal mPFC is involved in psychostimulant sensitization and more specifically they indicate that the dorsal mPFC plays a key role in the development and expression of MDMA-induced behavioral sensitization.
Asunto(s)
Inhibidores de Captación Adrenérgica/farmacología , Conducta Animal/efectos de los fármacos , Agonistas de Aminoácidos Excitadores/toxicidad , Ácido Iboténico/toxicidad , N-Metil-3,4-metilenodioxianfetamina/farmacología , Corteza Prefrontal/fisiología , Análisis de Varianza , Animales , Encefalopatías/fisiopatología , Interacciones Farmacológicas , Masculino , Actividad Motora/efectos de los fármacos , Inhibición Neural/efectos de los fármacos , Corteza Prefrontal/lesiones , Corteza Prefrontal/patología , Ratas , Factores de TiempoRESUMEN
Akin to what has been reported for cocaine, systemic administration of the dopamine D1 receptor antagonist, SCH 23390 ((R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride), blocks the expression but not the induction of 3,4-methylenedioxymethamphetamine (MDMA)-induced behavioral sensitization. Since the medial prefrontal cortex (mPFC) appears to regulate the expression of sensitization to cocaine, this study examined whether microinjection of SCH 23390 into the mPFC would alter the expression of MDMA sensitization. Saline or MDMA was administered for 5 consecutive days. After 12 days of withdrawal, rats received a bilateral intra-mPFC microinjection of SCH 23390 or saline followed by an intraperitoneal (i.p.) challenge dose of MDMA. While SCH 23390 enhanced locomotion in MDMA-naïve rats, it completely suppressed the expression of sensitization in MDMA-pretreated animals. Since, SCH 23390 has a fairly good affinity for 5-HT(2C) receptors, we went further to study the role of mPFC D1 and 5-HT(2C) receptors in this, apparently, paradoxical effect shown by SCH 23390. Thus, the microinjection of both SKF 81297 (R-(+)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide) and MK 212 (6-chloro-2-(1-piperazinyl)pyrazine hydrochloride), a D1 and 5-HT(2C) receptor agonist, respectively, blocked MDMA sensitization. By contrast, the 5-HT(2C) receptor antagonist, RS 102221 (8-[5-(2,4-dimethoxy-5-(4-trifluoromethylphenylsulfonamido)phenyl-5-oxopentyl]-1,3,8-triazaspiro[4,5]decane-2,4-dione hydrochloride), had no effect in MDMA-naïve or MDMA-sensitized animals, but reversed the effects of SCH 23390 in MDMA-pretreated rats. These results demonstrate that suppression of MDMA-induced sensitization by SCH 23390 is mediated by 5-HT(2C) receptor stimulation in the mPFC and not by the blockade of mPFC D1 receptors. Furthermore, these data indicate that stimulation of 5-HT(2C) receptors by SCH 23390 is not a minor issue and should be considered when interpreting future data.
Asunto(s)
Conducta Animal/efectos de los fármacos , Benzazepinas/farmacología , Antagonistas de Dopamina/farmacología , Alucinógenos/farmacología , N-Metil-3,4-metilenodioxianfetamina/farmacología , Corteza Prefrontal/fisiología , Receptor de Serotonina 5-HT2C/efectos de los fármacos , Receptores de Dopamina D1/efectos de los fármacos , Animales , Benzazepinas/administración & dosificación , Antagonistas de Dopamina/administración & dosificación , Masculino , Microinyecciones , Actividad Motora/efectos de los fármacos , Pirazinas/farmacología , Ratas , Ratas Wistar , Agonistas de Receptores de Serotonina/farmacología , Compuestos de Espiro/farmacología , Sulfonamidas/farmacologíaRESUMEN
Minocycline has been shown to exert neuroprotection against a wide variety of toxic insults both in vitro and in vivo. However, contradictory results have recently been reported. We now report that minocycline affords no protection against the neurotoxicity caused by malonate or N-methyl-d-aspartate (NMDA). Rats were treated with minocycline (45 mg/kg i.p. x 7) every 12 h. Thirty minutes after the second dose of minocycline, an intrastriatal stereotaxic injection of malonate (1.5 mumol) or NMDA (0.1 mumol) was administered. Seven days later, the rats were killed, and lesion volumes were quantified using two different methods [triphenyltetrazolium chloride (TTC) staining or cytochrome oxidase histochemistry]. Our results show that minocycline does not prevent the lesions caused by either malonate or by NMDA. On the contrary, the putative NMDA receptor antagonist, MK-801, blocked the toxicity caused by both toxins indicating that, although by different mechanisms, excitotoxicity is mediating neuronal death. We conclude that minocycline, at least under our experimental conditions, is not neuroprotective against excitotoxicity caused by either malonate or NMDA.
Asunto(s)
Malonatos/toxicidad , Minociclina/farmacología , N-Metilaspartato/toxicidad , Neostriado/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Neurotoxinas/toxicidad , Animales , Maleato de Dizocilpina/farmacología , Vías de Administración de Medicamentos , Esquema de Medicación , Masculino , Neostriado/patología , Síndromes de Neurotoxicidad/patología , Síndromes de Neurotoxicidad/prevención & control , Ratas , Ratas Wistar , Resultado del TratamientoRESUMEN
RATIONALE: There is a large body of evidence indicating that the mesoaccumbens dopamine pathway is critically involved in the expression of behavioral sensitization to amphetamine and cocaine, but its role in the development of sensitization to psychostimulants is not that sound. Very few studies, however, have examined the role of dopamine transmission in 3,4-methylenedioxymethamphetamine (MDMA)-induced sensitization. OBJECTIVES: The effects of the D1 receptor antagonist SCH 23390 on the development and expression of MDMA-induced behavioral sensitization were investigated in rats. METHODS: During the development phase of sensitization, SCH 23390 was administered 15 min before every administration of MDMA. After 12 days of withdrawal, a MDMA challenge dose was given and locomotor activity was measured. In separate experiments, 15 min before the challenge injection of MDMA, SCH 23390 was administered either systemically or directly into the core of the nucleus accumbens (NAc) of MDMA-pretreated rats. RESULTS: SCH 23390 did not prevent the development of MDMA-induced behavioral sensitization but completely blocked the expression when given before the challenge dose of MDMA. The same results were obtained when SCH 23390 was locally applied into the core of the NAc. CONCLUSIONS: The present data suggest that D1 receptor stimulation is not critical for the development of long-term MDMA sensitization, in agreement with what has been reported for cocaine. By contrast, expression of sensitization depends on the activation of D1 receptors located in the NAc core.