RESUMEN
Starting from a benzazepine sulfonamide 5-HT(6) receptor antagonist lead with limited brain penetration, application of a strategy of conformational constraint and reduction of hydrogen bond donor count led to a novel series of tricyclic derivatives with high 5-HT(6) receptor affinity and excellent brain:blood ratios.
Asunto(s)
Antidepresivos Tricíclicos/síntesis química , Encéfalo/efectos de los fármacos , Química Farmacéutica/métodos , Receptores de Serotonina/química , Antagonistas de la Serotonina/síntesis química , Animales , Antidepresivos Tricíclicos/farmacología , Barrera Hematoencefálica/efectos de los fármacos , Citocromo P-450 CYP3A , Sistema Enzimático del Citocromo P-450/química , Humanos , Enlace de Hidrógeno , Microsomas/efectos de los fármacos , Modelos Químicos , Conformación Molecular , Isoformas de Proteínas , Ratas , Antagonistas de la Serotonina/farmacologíaRESUMEN
A beam-walking apparatus has been evaluated for its ability to detect motor impairments in mice acutely treated with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 30 mg/kg, s.c., single or double administration). Mice subjected to MPTP lesioning showed deficits in motor performance on the beam-walking task, for up to 6 days post-MPTP administration, as compared to saline-treated controls. In addition, MPTP-treated mice were detected to have a marked depletion in striatal dopamine levels and a concomitant reduction in substantia nigra (SN) tyrosine hydroxylase (TH) immunoreactivity, at 7 days post-MPTP administration, indicative of dopaminergic neuronal loss. Pre-administration of the potent MAO-B inhibitor R-(-)-deprenyl at 3 or 10 mg/kg, 30 min, s.c, significantly inhibited the MPTP-induced reduction in SN TH-immunoreactivity, striatal dopamine depletions and impairments in mouse motor function. The data described in the present study provides further evidence that functional deficits following an acute MPTP dosing schedule in mice can be quantified and are related to nigro-striatal dopamine function.
Asunto(s)
Encéfalo/fisiopatología , Dopamina/deficiencia , Etología/instrumentación , Trastornos Neurológicos de la Marcha/diagnóstico , Neurofarmacología/instrumentación , Trastornos Parkinsonianos/diagnóstico , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/efectos adversos , Animales , Encéfalo/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/patología , Cuerpo Estriado/fisiopatología , Relación Dosis-Respuesta a Droga , Etología/métodos , Trastornos Neurológicos de la Marcha/fisiopatología , Trastornos Neurológicos de la Marcha/prevención & control , Masculino , Ratones , Ratones Endogámicos C57BL , Inhibidores de la Monoaminooxidasa/uso terapéutico , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/metabolismo , Vías Nerviosas/fisiopatología , Neurofarmacología/métodos , Trastornos Parkinsonianos/fisiopatología , Trastornos Parkinsonianos/prevención & control , Valor Predictivo de las Pruebas , Selegilina/uso terapéutico , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismo , Sustancia Negra/fisiopatología , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
The automated behavioural apparatus, LABORAS (Laboratory Animal Behaviour Observation, Registration and Analysis System), has been further validated with respect to the ability of the system to detect behavioural impairments in mice, following various dopaminergic manipulations. Initially data were obtained from mice administered with amphetamine, haloperidol, SCH23390, apomorphine and L-DOPA, with the focus on locomotor and grooming activities. The data recorded by LABORAS on administration of these pharmacological tool compounds, is comparable with published findings using standard LMA systems and conventional observer methods. In addition the home cage behaviour of mice administered with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) using an acute dosing regimen was also investigated. In LABORAS, mice subjected to MPTP lesioning showed deficits in spontaneous motor activity at day 6-7 post-MPTP administration, over a 24 h test period, as compared to saline treated controls. The data captured and analysed using LABORAS, suggests that the automated system is able to detect both pharmacologically and lesion-induced changes in behaviour of mice, reliably and efficiently.
Asunto(s)
1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Conducta Animal/efectos de los fármacos , Dopaminérgicos , Neostriado/patología , Degeneración Nerviosa/patología , Psicología Experimental/instrumentación , Sustancia Negra/patología , Anfetamina/toxicidad , Animales , Apomorfina/farmacología , Automatización , Benzazepinas/farmacología , Química Encefálica/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Agonistas de Dopamina/farmacología , Antagonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Electroquímica , Haloperidol/farmacología , Hipercinesia/inducido químicamente , Hipercinesia/psicología , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Reproducibilidad de los ResultadosRESUMEN
1. Although an important regulatory role for serotonin (5-HT) in seizure activation and propagation is well established, relatively little is known of the function of specific 5-HT receptor subtypes on seizure modulation. 2. The aim of the present study was to investigate the role of 5-HT(1A, 1B and 1D) receptors in modulating generalised seizures in the rat maximal electroshock seizure threshold (MEST) test. 3. The mixed 5-HT receptor agonists SKF 99101 (5-20 mg kg(-1) i.p.) and RU 24969 (1-5 mg kg(-1) i.p.), 0.5 h pretest, both produced marked dose-related increases in seizure threshold. These agents share high affinity for 5-HT(1A, 1B and 1D) receptors. 4. Antiseizure effects induced by submaximal doses of these agonists were maintained following p-chlorophenylalanine (150 mg kg(-1) i.p. x 3 days)-induced 5-HT depletion. 5. The anticonvulsant action of both SKF 99101 (15 mg kg(-1) i.p.) and RU 24969 (2.5 mg kg(-1) i.p.) was dose-dependently abolished by the selective 5-HT1B receptor antagonist SB-224289 (0.1-3 mg kg(-1) p.o., 3 h pretest) but was unaffected by the selective 5-HT1A receptor antagonist WAY 100635 (0.01-0.3 mg kg(-1) s.c., 1 h pretest). This indicates that 5-HT1B receptors are primarily involved in mediating the anticonvulsant properties of these agents. 6. In addition, the ability of the 5-HT(1B/1D) receptor antagonist GR 127935 (0.3-3 mg kg(-1) s.c., 60 min pretest) to dose-dependently inhibit SKF 99101-induced elevation of seizure threshold also suggests possible downstream involvement of 5-HT1D receptors in the action of this agonist, although confirmation awaits the identification of a selective 5-HT1D receptor antagonist. 7. Overall, these data demonstrate that stimulation of postsynaptic 5-HT1B receptors inhibits electroshock-induced seizure spread in rats.
Asunto(s)
Indoles/farmacología , Receptor de Serotonina 5-HT1B/efectos de los fármacos , Convulsiones/tratamiento farmacológico , Agonistas de Receptores de Serotonina/farmacología , Animales , Electrochoque , Masculino , Piperidonas/farmacología , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptor de Serotonina 5-HT1D/efectos de los fármacos , Agonistas del Receptor de Serotonina 5-HT1 , Antagonistas del Receptor de Serotonina 5-HT1 , Antagonistas de la Serotonina/farmacología , Compuestos de Espiro/farmacologíaRESUMEN
Following stroke, patients suffer a wide range of disabilities including motor impairment, anxiety and depression. However, to date, characterisation of rodent stroke models has concentrated mainly on the investigation of motor deficits. The aim of the present studies was therefore to investigate home cage behaviour (as assessed by a recently developed automatic behavioural classification system, LABORAS) and social behaviour (as a measure of anxiety) in rats following transient middle cerebral artery occlusion (tMCAO). Rats subjected to tMCAO (90 min) showed deficits in general home cage behaviours including locomotion, rearing, grooming and drinking for up to 7 weeks post occlusion, as compared with sham operated controls. In addition, a significant decrease in the total duration of social interaction was also observed in occluded rats compared with shams. The data shows that in addition to motor deficits, animals display changes in home cage behaviour and decreased social behaviour which, in contrast to motor function, are prolonged over time. Transient MCAO in rats may therefore provide a pre-clinical model to investigate agents offering symptomatic relief for ischaemia-induced motor deficits and anxiety over time following injury.
Asunto(s)
Conducta Animal , Infarto de la Arteria Cerebral Media/fisiopatología , Conducta Social , Animales , Ansiedad/fisiopatología , Ansiedad/psicología , Infarto de la Arteria Cerebral Media/psicología , Masculino , Actividad Motora , Examen Neurológico , Ratas , Ratas Sprague-Dawley , Pérdida de PesoRESUMEN
A newly developed apparatus for automated behavioural analysis, Laboratory Animal Behaviour Observation, Registration and Analysis System (LABORAS), has been further validated with respect to the ability of the system to detect the pharmacodynamic effects of standard pharmacological tools. Data were obtained from rats administered with mCPP (reversal with SB242084), 8-OH-DPAT (reversal with WAY100635), amphetamine (reversal with haloperidol) and angiotensin, with the focus on locomotor activity, feeding and drinking behaviours. The data captured and analysed by LABORAS, suggests that the automated system is able to detect pharmacologically induced changes in behaviour, reliably and efficiently, with a significant reduction in the number of animals required, and reduced operator input.