Receptor reserve for 5-hydroxytryptamine1A-mediated inhibition of serotonin synthesis: possible relationship to anxiolytic properties of 5-hydroxytryptamine1A agonists.
The irreversible receptor antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) was used to determine the relationship between receptor occupancy and response at central 5-hydroxytryptamine1A (5-HT1A) serotonin receptors mediating the inhibition of serotonin synthesis in rat cortex and hippocampus. Rats were treated with vehicle or EEDQ (2 or 6 mg/kg) and 24 hr later dose-response curves were constructed for inhibition of 5-hydroxytrytophan (5-HTP) accumulation (after decarboxylase inhibition with NSD-1015) by the selective 5-HT1A agonists 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) (0.01-3 mg/kg), buspirone (0.1-7.5 mg/kg), and ipsapirone (0.1-6.25 mg/kg) and the 5-HT1A agonist/antagonist BMY 7378 (0.015-5 mg/kg). In vehicle-pretreated rats, a similar maximal inhibition of 5-HT synthesis (range, 52-59%) was observed in both brain areas with 8-OH-DPAT, buspirone, and ipsapirone. These three agonists were also more potent in reducing 5-HTP accumulation in the cortex than in the hippocampus (ED50, 8-OH-DPAT, 14 and 30 microgram/kg; buspirone, 0.42 and 0.63 mg/kg; ipsapirone, 0.44 and 1.26 mg/kg, respectively). In the cortex, EEDQ treatment shifted the dose-response curves for 8-OH-DPAT, buspirone, and ipsapirone 8.6-, 2.0-, and 2.8-fold to the right, respectively. Corresponding rightward shifts in the hippocampus were smaller, 6.0-, 1.6-, and 2.1-fold, respectively. The EEDQ-induced shifts in the dose-response curves were accompanied by reductions in maximal response. In contrast, whereas the maximal inhibition of cortical 5-HTP accumulation by BMY 7378 (55%) was similar to that obtained with the agonists, maximal response in the hippocampus was much smaller (32%). Furthermore, in both brain regions EEDQ reduced the maximal response to BMY 7378 without shifting the dose-response curves. Analysis of the data by the double-reciprocal method of Furchgott, followed by calculation of fractional receptor occupancy for each dose of agonist, revealed a nonlinear relationship between receptor occupancy and response for 8-OH-DPAT, buspirone, and ipsapirone in both brain regions, demonstrating the presence of a large receptor reserve. For BMY 7378, in contrast, linear relationships were obtained. Because 5-HT1A receptor-mediated regulation of 5-HT synthesis appears to be mediated by somatodendritic autoreceptors on 5-HT neurons in the midbrain raphé nuclei, the results suggest that these autoreceptors possess a large receptor reserve for agonists. The relevance of these findings for the mechanism of action of nonbenzodiazepine anxiolytics is discussed.
Meller
E
E
Millhauser Laboratories, Department of Psychiatry, New York University Medical Center, New York 10016.
Goldstein
M
M
Bohmaker
K
K
D006916:5-Hydroxytryptophan / Q000378:metabolism; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism / Q000494:pharmacology*; D002065:Buspirone / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000502:physiology; D011985:Receptors, Serotonin / Q000145:classification / Q000187:drug effects / Q000502:physiology*; D012701:Serotonin / Q000096:biosynthesis*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
D014151:Anti-Anxiety Agents; D010879:Piperazines; D011743:Pyrimidines; D011804:Quinolines; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D013764:Tetrahydronaphthalenes; D012701:Serotonin; C000470:EEDQ; C043077:ipsapirone; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D006916:5-Hydroxytryptophan; C053428:BMY 7378; D002065:Buspirone