In vivo administration of the 5-HT1A receptor agonist 8-OH-DPAT interferes with brain GABA(A)/benzodiazepine receptor complexes.
In the present study the influence of in vivo administration, or in vitro addition, of the prototypic 5-HT1A receptor agonist 8-OH-DPAT on in vitro characteristics of GABA(A)/benzodiazepine receptor complexes was examined. In vivo administration of 8-OH-DPAT at a dose (32 microg/kg, s.c. -10') that has been reported to produce anxiolytic-like effects in the elevated plus-maze doubled the Kd for in vitro binding of 3H-flunitrazepam to rat cortical membranes (Bmax was unchanged) and enhanced GABA-stimulated (3, 10, 30 and 100 microM) 36Cl- influx in corticohippocampal synaptoneurosomes. In synaptoneurosomes from vehicle treated rats, diazepam (1, 3 and 10 microM) potentiated GABA-stimulated (3 microM) 36Cl- influx. No such effect was observed in tissue from 8-OH-DPAT treated rats, in which the GABA-stimulated (3 microM) 36Cl- influx was similar to that caused by GABA + diazepam in tissue from vehicle treated rats. When added in vitro, 8-OH-DPAT failed to alter basal or GABA-stimulated 36Cl- uptake. In vivo administration of a low "anxiolytic" dose of 8-OH-DPAT thus appears to interfere with GABA(A)/benzodiazepine receptor complexes, whereas in vitro application does not. The underlying mechanism remains to be elucidated but could involve in vivo release of positive modulators of GABA(A)/benzodiazepine receptor complexes, e.g. GABA, endozepines or neurosteroids.
Söderpalm
B
B
Institute of Physiology and Pharmacology, Department of Pharmacology, Göteborg University, Sweden. bo.soderpalm@pharm.gu.se
Andersson
G
G
Enerbäck
C
C
Engel
J A
JA
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology*; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D003975:Diazepam / Q000494:pharmacology; D005445:Flunitrazepam / Q000378:metabolism; D018757:GABA Modulators / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D002712:Chlorides; D018757:GABA Modulators; D011963:Receptors, GABA-A; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; D005680:gamma-Aminobutyric Acid; D005445:Flunitrazepam; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D003975:Diazepam