Changes in GABAergic transmission induced by stress, anxiogenic and anxiolytic beta-carbolines.
The cerebral cortex of unstressed (handling-habituated) rats has a higher number of low affinity GABA receptors than stressed (naive) rats. Foot shock stress delivered to unstressed rats decreases the density of cortical low affinity GABA receptors to the level found in the naive animals. The effect of stress on GABA receptors is mimicked by anxiogenic beta-carbolines, both after in vitro addition (10(-6) M) to cortical membrane preparations or after the in vivo administration (20 mg/kg IP) to unstressed rats. Vice versa, benzodiazepines or anxiolytic beta-carbolines (ZK 93423, 10(-5) M) added to membranes from naive rats increase GABA binding to the level of unstressed rats and remove the decrease in the density of GABA receptors elicited by anxiogenic beta-carbolines. Rats chronically treated with the anxiogenic beta-carboline, FG 7142 (15 mg/kg IP twice a day for 10 consecutive days) have an enhanced sensitivity to punishment at 5 and 15 days after the last treatment. The behavioural effect is paralleled by a marked decrease in the total number of cortical low affinity GABA receptors. Both biochemical and behavioural effects elicited by chronic FG 7142 are prevented by the concurrent administration of the benzodiazepine antagonist Ro15-1788. These results suggest that (a) anxiolytic beta-carbolines, like benzodiazepines, increase the GABAergic transmission, (b) acute and chronic anxiogenic beta-carboline administration, like stress, decreases GABAergic transmission. Since all these effects are antagonized by the benzodiazepine receptor blocker Ro15-1788, it is tempting to speculate that stress releases an endogenous ligand for benzodiazepine recognition sites.
Biggio
G
G
Institute of Biology, University of Cagliari, Italy.
Concas
A
A
Mele
S
S
Corda
M G
MG
D000818:Animals; D001007:Anxiety / Q000187:drug effects*; D001665:Binding Sites; D002243:Carbolines / Q000008:administration & dosage*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D013312:Stress, Physiological / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D002243:Carbolines; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid