Behavioural and biochemical evidence for a long-lasting decrease in GABAergic function elicited by chronic administration of FG 7142.
Chronic treatment with the beta-carboline derivative FG 7142 (15 mg/kg i.p. twice a day for 10 consecutive days) produced a long-lasting enhancement of shock-induced suppression of drinking in rats, without affecting unpunished behaviour. This proconflict effect was observed up to 15 days after withdrawal from FG 7142. A significant sensitization to seizures induced by isoniazid, a drug known to inhibit GABAergic transmission, was also found to occur after long-term (25 days) withdrawal. Moreover, the density of low-affinity GABA receptors was decreased by 30% in the cerebral cortex of rats repeatedly injected with FG 7142 at 5 and 15 days after withdrawal. The capacity of high-affinity GABA receptors, as well as the apparent dissociation constants for both high- and low-affinity GABA receptors were unchanged. Similar modifications in [3H]GABA binding were also observed in the cerebellum. The enhancement of punishment suppressed behaviour, the sensitization to isoniazid-induced convulsions and the decrease in the density of low-affinity GABA receptors suggest that chronic administration of FG 7142 induces a persistent down-regulation of GABAergic transmission in the central nervous system.
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects*; D002243:Carbolines / Q000008:administration & dosage / Q000494:pharmacology*; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007538:Isoniazid / Q000494:pharmacology; D008297:Male; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000502:physiology*
D002243:Carbolines; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; C035874:FG 7142; D007538:Isoniazid