Abstract
It is well established that repeated administration of both 5-hydroxytryptamine2 (5-HT2) receptor agonists and antagonists decreases the density of 5-HT2A and 5-HT2C receptors. However, the regulation of these two receptors has not been studied in the same tissue. Therefore, we examined the effects of repeated daily injections of the 5-HT2 receptor agonists (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) and d-lysergic acid diethylamide (LSD) and the antagonistsd-2-bromolysergic acid diethylamide hydrogen tartrate (BOL) and α-phenyl-2-(2-phenylethyl)-4-piperidinemethanol (MDL 11,939) on rabbit cortical 5-HT2A and 5-HT2Creceptors. Repeated administration of DOI, LSD, or BOL decreased cortical 5-HT2A receptor density but had no effect on the density of cortical 5-HT2C receptors. Repeated administration of the selective 5-HT2A receptor antagonist MDL 11,939 significantly increased 5-HT2A receptor density. This unexpected outcome also occurred without any change in cortical 5-HT2C receptor density. The down-regulation of 5-HT2A receptors produced by chronic administration of BOL was associated with a decrease in DOI-elicited head bobs, whereas 5-HT2A receptor up-regulation produced by MDL 11,939 was associated with an increase in DOI-elicited head bobs compared with controls. These studies demonstrate that 5-HT2A receptor antagonists can both down- and up-regulate the density of cortical 5-HT2A receptors and these changes in receptor density have functional consequences for 5-HT2A receptor-mediated behaviors. Furthermore, because DOI, LSD, and BOL have approximately equal affinities for the 5-HT2A and 5-HT2Creceptors, these results suggest that different mechanisms regulate 5-HT2A and 5-HT2C receptor density, in that chronic occupation of 5-HT2C receptors does not modulate their density in rabbit frontal cortex.
Footnotes
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This research was supported by U.S. Public Health Service Grant MH16841 from the National Institute for Mental Health and by Grant DA11164 from the National Institute on Drug Abuse.
- Abbreviations:
- 5-HT2
- 5-hydroxytryptamine2
- DOI
- (±)-2,5-dimethoxy-4-iodoamphetamine
- BOL
- d-2-bromolysergic acid diethylamide hydrogen tartrate
- LSD
- d-lysergic acid diethylamide
- SR 46349B
- trans-4-[(3Z)3-(2-dimethylaminoethyl) oxyimino-3-(2-fluorophenyl) propen-1-yl] phenol
- MDL 11,939
- α-phenyl-2-(2-phenylethyl)-4-piperidinemethanol
- RS 102221
- α-benzenesulfonamide of 8-[5-(5-amino-2,4-dimethoxyphenyl) 5-oxopentyl]-1,3,8-triazaspiro[4.5]decane-2,4-dione
- Gpp(NH)p
- 5-guanylylimidodiphosphate
- Received July 25, 2001.
- Accepted September 7, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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