RESUMEN
A previous study showed that N-[1-(2-benzo[b]thiophenyl)cyclohexyl]piperidin-3-ol (3-OH-pip-BTCP), an active metabolite of the potent dopamine reuptake inhibitor N-[1-(2-benzo[b]thiophenyl)cyclohexyl]piperidine (BTCP), exhibits stimulant effects in rats (i.e. increases dopamine levels in the nucleus accumbens and increases locomotion). The present study sought to further characterize the behavioral profile of 3-OH-pip-BTCP, specifically, its interaction with cocaine-maintained behavior. Cocaine self-administration was examined in 3-OH-pip-BTCP pretreated rats. 3-OH-pip-BTCP (0-20 mg/kg, i.p.) dose-dependently decreased cocaine self-administration. Additionally, 3-OH-pip-BTCP (10 mg/kg) shifted the cocaine dose-response to the left. Together, these results suggest that 3-OH-pip-BTCP shares similar reinforcing effects with cocaine and therefore may serve as a substitutive drug and possible agonist therapy for cocaine addiction.
Asunto(s)
Cocaína/farmacología , Inhibidores de Captación de Dopamina/metabolismo , Fenciclidina/análogos & derivados , Fenciclidina/metabolismo , Fenciclidina/farmacología , Animales , Cocaína/antagonistas & inhibidores , Inhibidores de Captación de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Masculino , Ratas , Ratas Wistar , AutoadministraciónRESUMEN
Disruption of glutamate homeostasis frequently leads to oxidative stress and to the release of hydroxyl radicals (radical OH). Here, we investigated, via a microdialysis approach, the possible involvement of metabotropic glutamate receptors in the glutamate-induced release of hydroxyl radicals in adult rat striatum. Glutamate was applied at low amount, resulting in a moderate release that was not inhibited by dizocilpine (MK-801), a specific NMDA receptor antagonist. (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG), a broad spectrum metabotropic antagonist, that does not exert any effect on the basal release of radical OH suppressed their response to glutamate. (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (t-ACPD), a non-selective metabotropic glutamate receptors agonist, promoted an radical OH release almost similar to that observed after glutamate, which was similarly impaired by co-infusion with MCPG. By contrast, infusion of (RS)-3,5-dihydroxyphenylglycine (DHPG), a more specific group I metabotropic glutamate receptors agonist, did not result in any appreciable radical OH response. Thus, beside NMDA receptors, some metabotropic glutamate receptors may also be involved in the glutamate-induced release of hydroxyl radicals.
Asunto(s)
Cuerpo Estriado/metabolismo , Cicloleucina/análogos & derivados , Radical Hidroxilo/metabolismo , Metoxihidroxifenilglicol/análogos & derivados , Receptores de Glutamato Metabotrópico/metabolismo , Análisis de Varianza , Animales , Cuerpo Estriado/efectos de los fármacos , Cicloleucina/farmacología , Maleato de Dizocilpina/farmacología , Interacciones Farmacológicas , Antagonistas de Aminoácidos Excitadores/farmacología , Ácido Glutámico/farmacología , Glicina/análogos & derivados , Glicina/farmacología , Masculino , Metoxihidroxifenilglicol/farmacología , Ratas , Ratas Wistar , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Factores de TiempoRESUMEN
Prenatal infection constitutes an important risk factor for brain injury, in both premature and full-term infants. Unfortunately, as the mechanisms involved are far from understood, no therapeutic strategy emerges to prevent the damage. We tested the hypothesis that administration of lipopolysaccharide (LPS) to gravid female rats enhanced glutamate-induced oxidative stress in brain of pups. A microdialysis probe was implanted into the striatum of 14-day-old animals and the release of hydroxyl radicals (.OH) in the perfusion medium was evaluated. Glutamate promoted a delayed.OH release in the offspring of dams given LPS, contrasting with the.OH decreases observed in control animals. A similar response occurred after infusion of (R,S)-3,5-dihydroxyphenylglycine (DHPG), a Group I metabotropic glutamate receptor (mGluR) agonist. This response was not consecutive to a remote activation of N-methyl-D-aspartate (NMDA) receptors, as it was unaffected by an NMDA receptor antagonist. Furthermore, the response to NMDA itself decreased in the offspring of dams given LPS. Massive amounts of DHPG, however, likely internalizing the mGlu receptor, still blunted the response to NMDA, as in controls. No quantitative variation occurred in mGluR1, mGluR5, or the NR1 subunit of the NMDA receptor between controls and neonates born from LPS-treated dams. Direct LPS injection into age-matched pups, by contrast, affected the response to neither glutamate nor DHPG. These results confirm that normally during perinatal development, the brain is protected from any oxidative stress resulting from excess glutamate, and the results support the hypothesis that maternal infection before delivery may lead to critical brain damage via the release of toxic free radicals.
Asunto(s)
Encéfalo/metabolismo , Enfermedades Fetales/metabolismo , Ácido Glutámico/metabolismo , Radical Hidroxilo/metabolismo , Metoxihidroxifenilglicol/análogos & derivados , Efectos Tardíos de la Exposición Prenatal , Ácido 2,3-Dicetogulónico/metabolismo , Envejecimiento , Animales , Animales Recién Nacidos , Encéfalo/efectos de los fármacos , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Cromatografía Líquida de Alta Presión/métodos , Ciclohexanos/farmacología , Ciclohexenos , Femenino , Lateralidad Funcional , Lipopolisacáridos/toxicidad , Masculino , Metoxihidroxifenilglicol/farmacología , Fármacos Neuroprotectores/farmacología , Estrés Oxidativo , Piperidinas/farmacología , Embarazo , Ratas , Ratas Wistar , Receptores de Glutamato Metabotrópico/metabolismo , Fracciones Subcelulares/efectos de los fármacos , Fracciones Subcelulares/metabolismo , Factores de TiempoRESUMEN
TCP and its derivative gacyclidine (+/- GK11) are high-affinity non-competitive antagonists of N-methyl-D-aspartate (NMDA) receptors (NMDARs) and as such exhibit significant neuroprotective properties. These compounds also bind with a low affinity to binding sites whose pharmacological profiles are different from that of NMDARs. With the intention to develop new strategies of neuroprotection, we found it mandatory to investigate whether 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP) and gacyclidine low-affinity sites are similar. The effects of several drugs selective for either NMDARs or the [(3)H]TCP low-affinity site (or PCP(3) site) on (+), (-)[(3)H]GK11 and [(3)H]TCP specific binding were investigated. Competition experiments on cerebellum homogenates revealed substantial differences between the pharmacological profiles of the PCP(3) site and that of gacyclidine's enantiomers low-affinity sites. Under experimental conditions preventing the interaction of the radioligands with NMDARs, the autoradiographic study showed, however, that the distributions of both [(3)H]TCP and (-)[(3)H]GK11 specific binding were similar. The specific labelling was low and uniform in telencephalic structures, whereas in the cerebellum it was higher in the molecular than in the granular layer. Finally, the analysis of competition experiments performed on tissues slices demonstrated that PCP(3) selective ligands were unable to prevent [(3)H]TCP or (-)[(3)H]GK11 binding to "non-NMDA" binding sites. As a whole, our data suggest that: (1) the different pharmacological profiles of [(3)H]TCP and [(3)H]gacyclidine enantiomers on low-affinity sites are due to their selectivity for specific NMDARs subpopulations; (2) the pharmacological isolation of TCP and gacyclidine "non-NMDA" binding sites is the most appropriate way to further study the low-affinity component of their specific binding. Obtaining reliable and specific pharmacological tools for those binding sites is of particular interest, since it is likely that they play a substantial role in the low neurotoxicity, and therefore tolerability, of gacyclidine, a new neuroprotective drug currently evaluated in clinical trials for the treatment of brain and spinal cord injuries.