RESUMEN
Rats were trained to discriminate the low-efficacy benzodiazepine receptor inverse agonist RU 33965 from vehicle in a two-lever discrimination task on a fixed ratio (FR) 20 schedule. Consistent discrimination was obtained at 0.5 mg/kg PO RU 33965. Both leptazol and stronger inverse agonists (FG7142, S-135, RU 34000) substituted for the cue. The weak inverse agonists/antagonists RU 33094, RU 34030, Ro 15-1788, and ZK 93426 also substituted for the cue with the latter two compounds being particularly potent. The agonist and partial agonists diazepam, RU 33203, and RU 39419 did not substitute for the RU 33965 cue but RU 39419 antagonised it. The full agonists diazepam and loprazolam only consistently antagonised the cue when given IP 5 min pretest. These data suggest that the RU 33965 cue results from its weak inverse agonist activity at benzodiazepine receptors, but kinetic factors must be considered when interpreting drug effects in discrimination studies.
Asunto(s)
Discriminación en Psicología/efectos de los fármacos , Imidazoles/farmacología , Receptores de GABA-A/efectos de los fármacos , Animales , Ansiolíticos/farmacología , Conducta Animal/efectos de los fármacos , Benzodiazepinas , Señales (Psicología) , Masculino , Ratas , Esquema de RefuerzoRESUMEN
The effects of the imidazobenzodiazepine Ro 15-4513 in combination with three CNS depressants (ethanol, benzodiazepine agonists and pentobarbital) were examined in three different experiments. Full antagonism of classical benzodiazepines by Ro 15-4513 was seen in all three situations. Partial antagonism of ethanol occurred in the pull up test of muscle relaxation in rats, but not in the inhibition of ultrasounds produced in rat pups by mild stress. The depressant effect of ethanol on twitching of the urethane-anaesthetised rat suprahyoid muscles was reversed. No attenuation of the effects of pentobarbital was seen in any test.
Asunto(s)
Ansiolíticos/farmacología , Azidas/farmacología , Conducta Animal/efectos de los fármacos , Benzodiazepinas/farmacología , Etanol/farmacología , Pentobarbital/farmacología , Anestesia , Animales , Diazepam/farmacología , Interacciones Farmacológicas , Femenino , Flumazenil/farmacología , Masculino , Contracción Muscular/efectos de los fármacos , Músculos/efectos de los fármacos , Ratas , Ratas Endogámicas , Uretano , Vocalización Animal/efectos de los fármacosRESUMEN
Five members of a novel series of quinoline derivatives which all have similar activities on benzodiazepine receptor binding in vitro were compared in a food-motivated conflict and stress-induced ultrasounds models of anxiety and on suprahyoid muscle twitching in urethane-anaesthetised rats. RU 42382, RU 43028 and RU 39419 showed anxiolytic activity in both tests and RU 40410 was an antagonist. RU 40744 inhibited stress-induced ultrasounds but had little activity in the conflict test. Amphetamine-induced suprahyoid muscle twitching was only weakly inhibited by RU 42382 and RU 43028 in comparison with a classical benzodiazepine agonist. Ro15-1788 antagonised RU 42382 indicating that a major component of its action was agonism at benzodiazepine receptors. RU 39419 had no effect, RU 40744 tended to increase and RU 40410 evoked a small but statistically significant increase in twitching. The same rank order was observed in antagonism of a benzodiazepine in the muscle twitching model. RU 42382 was least effective as an antagonist and RU 40410 most effective. RU 39419 had no effect alone but antagonised the decrease of firing rate of cerebellar Purkinje cells induced by a benzodiazepine in urethane-anaesthetised rats. Comparison of in vivo occupancy of benzodiazepine receptors and efficacy in the conflict test in rats suggests a ranking of agonist intrinsic activity: RU 42382 greater than RU 43028 greater than RU 39419. A simple relationship between intrinsic activity at benzodiazepine receptors and structure of the compounds is proposed.
Asunto(s)
Quinolinas/farmacología , Receptores de GABA-A/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Animales , Conflicto Psicológico , Masculino , Células de Purkinje/efectos de los fármacos , Ratas , Ratas Endogámicas , Receptores de GABA-A/metabolismo , Espasmo/inducido químicamente , Estrés Fisiológico/fisiopatologíaRESUMEN
Compounds of different chemical classes, with affinity for central benzodiazepine receptors, were investigated for effects on handling-induced ultrasonic cries in rat pups. Diazepam and clobazam inhibited ultrasounds and impaired motor performance at higher doses. Suriclone showed a similar profile to diazepam but premazepam clearly separated ultrasound inhibition from motor impairment. ZK 91296, CGS 9896, RU 39419 and RU 43028 inhibited ultrasounds with a lower maximal response but induced little or no motor incoordination. CL 218872 inconsistently inhibited sounds with no motor impairment and PK 8165 and PK 9084 had no consistent effects. Benzodiazepine antagonists weakly inhibited (RU 40410) or did not affect (Ro 15-1788 or CGS 8216) ultrasounds alone but fully (Ro 15-1788 or CGS 8216) or partially (RU 40410) antagonised the effects of benzodiazepines. Inverse agonists FG 7142, methyl-beta-carboline-3-carboxylate (BCM) and DMCM tended to increase ultrasounds alone, particularly when less stressful handling stimuli were used, and antagonised benzodiazepines. This procedure detects the differing behavioural effects of benzodiazepines receptor ligands and is proposed as a simple model of anxiety.