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1.
Psychopharmacology (Berl) ; 190(2): 157-70, 2007 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-17115136

RESUMEN

RATIONALE: Nicotine produces behavioural effects that are potentially related to its interaction with diverse nicotinic acetylcholine receptor populations. Evidence from gene deletion studies suggests that the interoceptive stimulus properties of nicotine are mediated by heteromeric high-affinity receptors containing alpha4beta2 subunits. Mice lacking beta2 subunits do not discriminate nicotine (Shoaib et al., Neuropharmacology, 42:530-539, 2002), and nicotine does not elicit dopamine release in these animals (Grady et al., J Neurochem, 76:258-268, 2001). The stimulus properties of nicotine can be detected in rats using a two-lever operant drug discrimination paradigm, allowing them to be classified pharmacologically using ligands with selectivity for receptors containing alpha4beta2, alpha3beta4 or alpha7 subunits. MATERIALS AND METHODS: Rats trained to discriminate 0.4 mg/kg nicotine from vehicle were given the nicotinic receptor agonists, cytisine, varenicline, TC2559, ABT-594, A-85380 (all having high affinity but varying selectivity for alpha4beta2-containing receptors), and WO 03/062224 and WO 01/60821A1 (selective for beta4- and alpha7-containing receptors, respectively). In separate studies, WO 03/062224 was used as the training stimulus. RESULTS: Nicotine, TC-2559, A-85380 and ABT-594 showed dose-dependent and complete stimulus substitution, whilst WO 03/062224 and WO 01/60821A1 were completely without effect. Cytisine and varenicline showed partial generalisation, consistent with their partial agonist activity at nicotinic receptors eliciting dopamine release in rat striatal slices. After almost 50 training sessions with WO 03/062224, there was no clear evidence that an alpha3beta4 receptor agonist could sustain a discriminable stimulus. CONCLUSION: Substitution to the nicotine discriminative stimulus required high-affinity and high intrinsic activity at beta2 but not at beta4- or at alpha7-containing nicotinic receptors.


Asunto(s)
Aprendizaje Discriminativo/fisiología , Motivación , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Receptores Nicotínicos/efectos de los fármacos , Receptores Nicotínicos/fisiología , Tabaquismo/fisiopatología , Animales , Conducta Apetitiva/efectos de los fármacos , Conducta Apetitiva/fisiología , Azetidinas/farmacología , Benzazepinas/farmacología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/fisiopatología , Cistina/farmacología , Aprendizaje Discriminativo/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Masculino , Piridinas/farmacología , Quinoxalinas/farmacología , Ratas , Ratas Endogámicas , Vareniclina , Receptor Nicotínico de Acetilcolina alfa 7
2.
Neuropharmacology ; 49(1): 59-72, 2005 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-15992581

RESUMEN

The presynaptic nicotinic modulation of glutamatergic transmission in the CNS has been associated with activation of the alpha7 subtype of nicotinic acetylcholine receptor (nAChR) in sub-cortical regions, whereas in the frontal cortex, non-alpha7 nAChRs have been implicated. The aim of this investigation was to directly characterise nAChR-evoked release of excitatory amino acids from rat frontal cortex, by monitoring the release of [3H]D-aspartate from superfused synaptosomes or minces. Co-administration of a nAChR agonist with a depolarising stimulus enhanced [3H]D-aspartate release above the effect of depolarising agent alone. This enhancement was blocked by the nicotinic antagonist mecamylamine. Other experiments revealed that in the absence of a depolarising stimulus, the nAChR agonists nicotine, epibatidine and anatoxin-a could evoke the release of [3H]D-aspartate in a Ca2+- and concentration-dependant manner. Differential sensitivity to the alpha7- and beta2*-selective nAChR antagonists alpha-bungarotoxin (alpha-Bgt) and dihydro-beta-erythroidine (DHbetaE) implicated two nAChR subtypes (alpha7 and beta2*), and this was supported by using the subtype-selective agonists choline (10 mM; alpha7 selective, blocked by alpha-Bgt but not by DHbetaE) and 5-Iodo-A-85380 (10 nM; beta2*-selective, blocked by DHbetaE but not by alpha-Bgt). Immunocytochemistry showed that alpha-Bgt labelling was associated with structures immunopositive for vesicular glutamate transporters, in both frontal cortex sections and synaptosome preparations, supporting the presence of alpha7 nAChR on glutamatergic terminals in rat frontal cortex.


Asunto(s)
Ácido Aspártico/metabolismo , Lóbulo Frontal/metabolismo , Receptores Nicotínicos/fisiología , Receptores Presinapticos/fisiología , Animales , Animales Recién Nacidos , Ácido Aspártico/farmacología , Azetidinas/farmacología , Toxinas Bacterianas/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Bungarotoxinas/metabolismo , Bungarotoxinas/farmacología , Calcio/farmacología , Colina/metabolismo , Toxinas de Cianobacterias , Ácidos Dicarboxílicos/farmacología , Dopamina beta-Hidroxilasa/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Estimulación Eléctrica/métodos , Lóbulo Frontal/citología , Lóbulo Frontal/efectos de los fármacos , Lóbulo Frontal/efectos de la radiación , Inmunohistoquímica/métodos , Técnicas In Vitro , Masculino , Toxinas Marinas/farmacología , Mecamilamina/farmacología , Microcistinas , Microscopía Confocal/métodos , Inhibidores de la Captación de Neurotransmisores/farmacología , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Antagonistas Nicotínicos/farmacología , Fosfopiruvato Hidratasa/metabolismo , Cloruro de Potasio/farmacología , Piridinas/farmacología , Pirrolidinas/farmacología , Ratas , Ratas Sprague-Dawley , Receptores Presinapticos/clasificación , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo , Sinaptosomas/efectos de la radiación , Factores de Tiempo , Tritio/metabolismo , Tropanos , Receptor Nicotínico de Acetilcolina alfa 7
3.
Neuropharmacology ; 47(6): 848-59, 2004 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-15527819

RESUMEN

The novel compound 5-iodo-A-85380 binds with higher affinity to alpha4beta2* nicotinic acetylcholine receptors (nAChR), compared with other nAChR subtypes (Mukhin et al., 2000). In the present study, we have confirmed that in competition binding assays for three major nAChR subtypes, 5-iodo-A-85380 is 850 and 27,000-fold more potent at rat brain alpha4beta2* binding sites than at alpha3beta4 and alpha7 subtypes, respectively. In functional assays, 5-iodo-A-85380 potently activated (EC50 12-35 nM) both alpha-CTx-MII-sensitive and -insensitive components of [3H]dopamine release from rat striatal synaptosomes, corresponding to alpha6beta2* and alpha4beta2* nAChR, respectively. 5-Iodo-A-85380 was markedly less potent at eliciting [3H]ACh release from rat interpeduncular nucleus synaptosomes, [3H]noradrenaline release from rat hippocampal slices, and Ca2+ increases in a cell line expressing rat alpha3beta4 nAChR (EC50 = 5, 3.2, 1.6 microM, respectively). As predicted by ligand binding studies, 5-iodo-A-85380 is a more discriminating agonist than the parent compound epibatidine. However, it is not specific for alpha4beta2* nAChR as it also potently activates alpha6beta2* nAChR.


Asunto(s)
Azetidinas/farmacología , Agonistas Nicotínicos/farmacología , Piridinas/farmacología , Receptores Nicotínicos/efectos de los fármacos , Receptores Presinapticos/efectos de los fármacos , Acetilcolina/metabolismo , Animales , Unión Competitiva/efectos de los fármacos , Calcio/metabolismo , Línea Celular , Dopamina/metabolismo , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fluorometría , Indicadores y Reactivos , Ratones , Neostriado/efectos de los fármacos , Neostriado/metabolismo , Antagonistas Nicotínicos/metabolismo , Antagonistas Nicotínicos/farmacología , Norepinefrina/metabolismo , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo
4.
Brain Res ; 941(1-2): 34-42, 2002 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-12031545

RESUMEN

This study examined the influence of brain-derived neurotrophic factor (BDNF) on the basal and depolarisation-induced release of the neurotransmitters GABA, dopamine and serotonin from rat striatal brain slices in vitro. BDNF potentiated the potassium or veratrine-stimulated release of GABA, dopamine and serotonin. This potentiation was shown to be dependent on activation of the high-affinity tyrosine kinase-linked receptor TrkB, as K252a (a potent TrkB antagonist) largely prevented the effects. BDNF potentiated the release of each neurotransmitter to similar extents irrespective of the type of depolarising stimulus used. In all cases the potentiation of neurotransmitter release caused by BDNF was dependent on membrane depolarisation as BDNF alone was incapable of causing potentiation. These results, obtained using striatal slices in vitro, suggest that BDNF may be acting via the specific receptor TrkB to modulate synaptic performance in the corpus striatum in vivo.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Serotonina/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/farmacología , Carbazoles/farmacología , Cuerpo Estriado/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Femenino , Alcaloides Indólicos , Ratas , Ratas Sprague-Dawley
5.
Brain Res ; 967(1-2): 201-9, 2003 Mar 28.
Artículo en Inglés | MEDLINE | ID: mdl-12650981

RESUMEN

The depolarisation-induced release of brain-derived neurotrophic factor (BDNF) from adult rat striatal slices was studied in vitro. The slices were preloaded with [125I]BDNF and exposed to depolarising stimulation with varying concentrations of veratrine (up to 50 microM) and potassium (up to 50 mM) which caused activity-dependent short-term release of [125I]BDNF. The results indicate that this stimulated release of [125I]BDNF is not regulated by a feedback mechanism mediated via the TrkB receptor. The release of [125I]BDNF was found to be dependent on the concentrations of both extracellular and intracellular calcium, since BDNF release was modulated by the addition of both EGTA and BAPTA-AM, agents chelating either external or internal Ca(2+), respectively. BDNF release also proved to be dependent on activation of IP(3) mediated Ca(2+) release from intracellular stores. [125I]BDNF release was also modulated by 5HT(3) receptor ligands and by receptors coupled to adenylate cyclase. Taken together, these results indicate that [125I]BDNF release is activity dependent, and is modulated by changes in Ca(2+) levels. Moreover the release occurs via a mechanism involving cAMP.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Cuerpo Estriado/metabolismo , Animales , Cuerpo Estriado/efectos de los fármacos , AMP Cíclico/metabolismo , Femenino , Humanos , Técnicas In Vitro , Radioisótopos de Yodo , Ratas , Ratas Sprague-Dawley
6.
Brain Res ; 968(1): 156-61, 2003 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-12644273

RESUMEN

Brain-derived neurotrophic factor (BDNF) has been shown to modulate synaptic plasticity in the corpus striatum in vitro by activation of the tyrosine kinase linked receptor, TrkB. However, the signalling pathways that mediate this modulation of plasticity are poorly understood. Three proteins mediating signalling pathways are activated by the binding of BDNF to TrkB: phosphoinositol-3 kinase (PI3K); Ras-MEK and phospholipase C-gamma (PLCgamma). The present study investigates which of these pathways are necessary for BDNF-mediated potentiation of synaptic output of dopamine from slices and synaptosomes of rat corpus striatum. The results indicate that activation of the PI3K and Ras-MEK pathways, but not PLCgamma, are involved. Inhibitors of transcription and translation had no effect on the potentiation of depolarisation-stimulated (15 mM KCl) dopamine release mediated by BDNF.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/farmacología , Cuerpo Estriado/efectos de los fármacos , Dopamina/metabolismo , Proteínas Tirosina Quinasas , Transducción de Señal/efectos de los fármacos , Animales , Carbazoles/farmacología , Cromonas/farmacología , Cuerpo Estriado/metabolismo , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Inhibidores Enzimáticos/farmacología , Femenino , Flavonoides/farmacología , Humanos , Técnicas In Vitro , Alcaloides Indólicos , Glicoproteínas de Membrana/metabolismo , Morfolinas/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Cloruro de Potasio/farmacología , Biosíntesis de Proteínas , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/metabolismo , Transducción de Señal/fisiología , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo , Transcripción Genética
7.
Eur J Pharmacol ; 493(1-3): 85-93, 2004 Jun 16.
Artículo en Inglés | MEDLINE | ID: mdl-15189767

RESUMEN

The present study investigated the role of the 5-hydroxytryptamine (5-HT, serotonin)1D receptor as a presynaptic autoreceptor in the guinea pig. In keeping with the literature, the 5-HT1B selective antagonist, 1'-methyl-5-[[2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydrospiro [furo[2,3-f]indole-3,4'-piperidine]oxalate (SB224289) potentiated [3H]5-HT outflow from pre-labelled slices of guinea pig cerebral cortex confirming its role as a presynaptic autoreceptor in this species. In addition, the 5-HT1D receptor-preferring antagonists, 1-[2-[4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-2H-pyridin-1-yl]-ethyl]-3-pyridin-4-yl-methyl-tetrahydro-pyrimidin-2-one (LY367642), (R)-1-[2-(4-(6-fluoro-1H-indol-3-yl-)-3,6-dihydro-1(2H)-pyridinyl)ethyl]-3,4-dihydro-1H-2-benzopyran-6-carboxamide (LY456219), (S)-1-[2-(4-(6-fluoro-1H-indol-3-yl-)-3,6-dihydro-1(2H)-pyridinyl)ethyl]-3,4-dihydro-1H-2-benzopyran-6-carboxamide (LY456220) and 1-[2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-ethyl]-3,3-dimethyl-1,2-dihydro-indol-2-one (LY310762), potentiated [3H]5-HT outflow from this preparation with potencies (EC50 values=31-140 nM) in the same range as their affinities for the guinea pig 5-HT1D receptor (Ki values=100-333 nM). The selective 5-HT1D receptor agonist, R-2-(4-fluoro-phenyl)-2-[1-[3-(5-[1,2,4]triazol-4-yl-1H-indol-3-yl)-propyl]-piperidin-4-ylamino]-ethanol dioxylate (L-772,405), inhibited [3H]5-HT outflow. In microdialysis studies, administration of either SB224289 or LY310762 at 10 mg/kg by the intraperitoneal (i.p.) route, potentiated the increase in extracellular 5-HT concentration produced by a maximally effective dose of the selective serotonin re-uptake inhibitor, fluoxetine (at 20 mg/kg i.p.). In addition, the 5-HT1D receptor-preferring antagonist and 5-HT transporter inhibitor, LY367642 (at 10 mg/kg i.p.), elevated extracellular 5-HT concentrations to a greater extent than a maximally effective dose of fluoxetine. It is concluded that the 5-HT1D receptor, like the 5-HT1B receptor, may be a presynaptic autoreceptor in the guinea pig.


Asunto(s)
Autorreceptores/fisiología , Receptores Presinapticos/fisiología , Animales , Corteza Cerebral/química , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/patología , Cromatografía Líquida de Alta Presión/métodos , Citalopram/farmacología , Fluoxetina/farmacología , Cobayas , Hipotálamo/química , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Indoles/farmacología , Masculino , Glicoproteínas de Membrana/metabolismo , Glicoproteínas de Membrana/farmacología , Proteínas de Transporte de Membrana/metabolismo , Proteínas de Transporte de Membrana/farmacología , Microdiálisis/métodos , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/farmacología , Piperidinas/farmacología , Piperidonas/farmacología , Pirimidinas/farmacología , Ratas , Ratas Endogámicas , Receptor de Serotonina 5-HT1B/fisiología , Receptor de Serotonina 5-HT1D/fisiología , Serotonina/metabolismo , Serotonina/farmacología , Agonistas del Receptor de Serotonina 5-HT1 , Antagonistas del Receptor de Serotonina 5-HT1 , Proteínas de Transporte de Serotonina en la Membrana Plasmática , Especificidad de la Especie , Compuestos de Espiro/farmacología , Fracciones Subcelulares/química , Fracciones Subcelulares/patología , Triazoles/farmacología , Tritio , Reino Unido
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