Unique modulation of central 5-HT2 receptor binding sites and 5-HT2 receptor-mediated behavior by continuous gepirone treatment.
The effect of continuous treatment with the selective 5-HT1A agonist gepirone upon 5-HT2-mediated behavior and cortical 5-HT2 receptor binding sites was examined in naive rats or rats receiving noradrenergic (DSP4) or serotonergic (5,7-DHT) lesions. Continuous administration of gepirone in non-lesioned rats for 3, 7, or 14 days enhanced the head shake response to the 5-HT agonist quipazine. This enhancement of 5-HT2-mediated behavior occurred despite concomitant down-regulation of cortical 5-HT2 binding sites. However, 28 days of gepirone administration significantly reduced behavioral responsiveness to quipazine. The gepirone-induced facilitation of 5-HT2-mediated behavior observed after 7 days of continuous treatment was blocked in both DSP4 and 5,7-DHT-lesioned rats. However, both noradrenergic and serotonergic denervation failed to modify the down-regulation of 5-HT2 receptor binding sites produced by continuous gepirone administration. These results suggest that the curious dissociation of behavioral and biochemical indices of 5-HT2 receptor function produced by continuous gepirone treatment may be the result of a dual yet separate action of the drug on central presynaptic noradrenergic and serotonergic mechanisms and postsynaptic 5-HT receptors. Furthermore, the postsynaptic action of gepirone which reduces the maximal number of cortical 5-HT2 receptor binding sites may be the result of gepirone's agonist action at postsynaptic 5-HT1A receptors.
CNS Pharmacology, Bristol-Myers Squibb Company, Wallingford, Connecticut 06492.
F D
FD
Yocca
A S
AS
Eison
D K
DK
Hyslop
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E
Ryan
D P
DP
Taylor
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G
Gianutsos
D000704:Analysis of Variance; D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation; D008297:Male; D009638:Norepinephrine / Q000502:physiology; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D011814:Quipazine / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects*; D013997:Time Factors
D014151:Anti-Anxiety Agents; D011743:Pyrimidines; D011985:Receptors, Serotonin; D011814:Quipazine; C039979:gepirone; D009638:Norepinephrine