Abstract
Rationale
Indirect-acting serotonin (5-HT) receptor agonists (e.g., selective 5-HT reuptake inhibitors [SSRI]) stimulate multiple 5-HT receptors, although the role of particular receptors as well as interaction(s) among different receptors in the therapeutic effects of SSRIs is not fully understood.
Objectives
Relatively few studies have systematically examined direct-acting agonists in combination. This study examined the 5-HT1A receptor agonists 8-hydroxy-2-(di-n-propylamino) tetralin hydrochloride (8-OH-DPAT; 0.01–10.0 mg/kg) and 3-chloro-4-fluorophenyl-4-fluoro-4-([(5-methyl-6-methylamino-pyridin-2-ylmethyl)-amino]-methyl)-piperidin-1-yl-methanone (F13714; 0.01–1.0 mg/kg) and the 5-HT2A receptor agonists 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM; 0.32–10.0 mg/kg) and dipropyltryptamine (DPT; 1.0–32.0 mg/kg), alone and in combination, in rats responding under a fixed ratio schedule of food presentation.
Results
When administered alone, each drug decreased the rate of responding in a dose-related manner with the potency order being F13714 > 8-OH-DPAT > DOM > DPT. WAY100635 (5-HT1A receptor antagonist; 0.01–0.1 mg/kg) attenuated the rate-decreasing effects of 8-OH-DPAT and F13714 while MDL100907 (5-HT2A receptor antagonist; 0.01–0.1 mg/kg) attenuated the rate-decreasing effects of DOM and DPT. Dose addition analysis showed that the interaction between 8-OH-DPAT and F13714, as well as the interaction between DOM and DPT, was additive. In contrast, the interaction between 8-OH-DPAT and DOM, as well as the interaction between F13714 and DOM, was infra-additive.
Conclusions
This study shows that for some dose combinations, agonist actions at one 5-HT receptor subtype attenuate agonist actions at another 5-HT receptor subtype; thus, the combined neuropharmacological actions and therapeutic effects of indirect-acting agonists are not likely to be adequately characterized by examining in isolation activity at particular 5-HT receptor subtypes.
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Acknowledgments
The authors thank Christopher Cruz, Sonia Cano, Margarita Gardea, and Jennifer Kite for excellent technical assistance.
CPF is supported by a Senior Scientist Award from the National Institute on Drug Abuse, National Institutes of Health (K05 DA17918). This research was supported, in part, by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the views of the National Institute on Drug Abuse or the National Institutes of Health.
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Li, JX., Crocker, C., Koek, W. et al. Effects of serotonin (5-HT)1A and 5-HT2A receptor agonists on schedule-controlled responding in rats: drug combination studies. Psychopharmacology 213, 489–497 (2011). https://doi.org/10.1007/s00213-010-2136-9
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DOI: https://doi.org/10.1007/s00213-010-2136-9