Effects of serotonin (5-HT)1A and 5-HT2A receptor agonists on schedule-controlled responding in rats: drug combination studies

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-HT(1A) 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-HT(2A) 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-HT(1A) receptor antagonist; 0.01-0.1 mg/kg) attenuated the rate-decreasing effects of 8-OH-DPAT and F13714 while MDL100907 (5-HT(2A) 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.

Fig. 1

Effects of F13714, 8-OH-DPAT, DOM and DPT on schedule-controlled responding in rats. Abscissa, drug in milligrams per kilogram body weight. Ordinate, response rate in responses per second. All entries represent the mean (± SEM) from 8 rats; entries above “V” represent response rate after vehicle administration.

Fig. 2

Upper four panels: effects of 8-OH-DPAT, F13714, DOM and DPT alone or in combination with the 5-HT_1A receptor antagonist WAY100635 or the 5-HT_2A receptor antagonist MDL100907. See Fig 1 for other details. Bottom two panels: Schild plots constructed from the same data shown in the upper and middle panels. Abscissae, negative log of the dose of antagonist in moles per kilogram of body weight. Ordinates, log of the dose ratio – 1.

Fig. 3

Composite additive curves from a representative rat for three mixtures (1:3, 1:1, and 3:1) of 8-OH-DPAT and DOM. Abscissae, log dose of the drug mixture in milligrams per kilogram body weight. Ordinate, response rate expressed as a percentage of the control (vehicle) rate.

Fig. 4

Ratios of observed (experimentally determined) ED₅₀ values (Z_mix) and expected (additive) ED₅₀ values (Z_add) for different proportions of drug mixtures. Ordinates, ratio of Z_mix and Z_add. Abscissae, proportion ratios of each pair of the drug