RESUMEN
Rats were twice daily (2 x 10 mg/kg, i.p.) treated for three weeks with the peripheral benzodiazepine (BZ) receptor ligands Ro 5-4864 (4'-chlorodiazepam) and PK 11,195 (1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carbox ami de). After the first injection there were no differences between the drug-treated and control animals in behavioral tests. After 10 days treatment, the number of sniffings was increased in Ro 5-4864-treated rats. After the last injection, sniffings and ambulations were decreased in PK 11,195-treated animals. The number of rearings and groomings remained unchanged throughout the treatment, and there were no changes in the results in the elevated plus-maze test. Apparently these compounds are devoid of anxiolytic and anxiogenic effects at moderate doses. The effect of 72 a h withdrawal from the above mentioned chronic treatment on peripheral and central BZ receptors as well as on GABAA receptors was studied with receptor binding techniques using 3H-Ro 5-4864, 3H-flumazenil and 3H-muscimol, respectively, as ligands. The number of GABAA and central BZ receptors was lower after Ro 5-4864 treatment, as was the effect of progesterone-induced stimulation of 3H-muscimol binding. The number of peripheral BZ receptors was decreased after Ro 5-4864 and PK 11,195 treatments in the olfactory bulb but not in the cerebral cortex. The chronic treatment with peripheral BZ receptor ligands Ro 5-4864 and PK 11,195 produced only little behavioral effects. Ro 5-4864, often presented as an agonist of peripheral BZ receptors, was behaviorally inactive.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Conducta Animal/efectos de los fármacos , Benzodiazepinonas/farmacología , Convulsivantes/farmacología , Isoquinolinas/farmacología , Receptores de GABA-A/efectos de los fármacos , Animales , Benzodiazepinonas/efectos adversos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Inyecciones Intraperitoneales , Isoquinolinas/efectos adversos , Masculino , Muscimol/metabolismo , Ratas , Ratas Wistar , Receptores de GABA-A/metabolismo , Síndrome de Abstinencia a SustanciasRESUMEN
Two groups of rats were selected from a small animal population on the basis of their exploratory activity in an elevated plus-maze model of anxiety. One group had a considerably lower and the other one a higher exploratory activity than the average total population. These subgroups were termed "anxious" and "non-anxious", respectively. In both groups central benzodiazepine binding sites in various brain structures were labelled with 3H-flunitrazepam. Peripheral benzodiazepine binding sites labelled in vitro with different tritiated ligands were also studied in several peripheral organs including blood platelets and lymphocytes. "Anxious" animals had a significantly lower number of 3H-flunitrazepam binding sites in the cerebral cortex but not in the hippocampus and cerebellum. In this subgroup 3H-Ro 5-4864 binding to peripheral benzodiazepine recognition sites was also lower than in the other one in adrenals, kidneys, platelets and lymphocytes. In the heart no differences of 3H-Ro 5-4864 binding between subgroups studied were found. Although in "anxious" rats 3H-diazepam and 3H-PK 11195 binding was significantly lower only in lymphocytes, a somewhat decreased binding to these ligands was also present in platelets. No significant differences in the affinity were found between the two groups throughout the experiments described. The results indicate that behavioral anxiety in rats is correlated not only with the lower number of central benzodiazepine receptors but also with a lower density of peripheral benzodiazepine binding sites in several peripheral organs including platelets and lymphocytes.
Asunto(s)
Conducta Animal/fisiología , Receptores de GABA-A/metabolismo , Glándulas Suprarrenales/metabolismo , Animales , Benzodiazepinonas/metabolismo , Plaquetas/metabolismo , Encéfalo/metabolismo , Convulsivantes/metabolismo , Flunitrazepam/metabolismo , Riñón/metabolismo , Linfocitos/metabolismo , Masculino , Miocardio/metabolismo , Ratas , TritioRESUMEN
Forced swimming stress caused a significant increase in the density of central type benzodiazepine binding sites in rat cerebral cortex and hippocampus. The number of peripheral type benzodiazepine binding sites was also enhanced on blood platelets. The affinity of neither central nor peripheral type benzodiazepine binding sites was changed considerably after swimming stress. Pretreatment of rats with beta-(phenyl)GABA (100 mg/kg), a GABAB agonist, almost completely eliminated the described changes of the both types of benzodiazepine binding sites caused by swimming stress. In an elevated plus-maze model of anxiety beta-(phenyl)GABA itself was inactive but like diazepam effectively counteracted the behavioural effects of DMCM, a beta-carboline derivative with anxiogenic properties. The possible involvement of benzodiazepine receptors in the mechanism of action of beta-(phenyl)GABA is discussed.