piperidines and dipropyltryptamine

Although many drugs act by indirectly stimulating multiple receptors (e.g., reuptake inhibitors), relatively little is known about interactions between agonism at different receptors. This study compared the effect of serotonin (5-HT)(1A) receptor agonists with the discriminative stimulus effects of the 5-HT(2A) receptor agonist 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) in rats and rhesus monkeys. Eight rats discriminated 0.56 mg/kg i.p. DOM and responded under a fixed ratio (FR) 10 schedule of food presentation, whereas three rhesus monkeys discriminated 0.32 mg/kg s.c. DOM and responded under an FR 5 schedule of stimulus shock termination. DOM and the 5-HT(2A) receptor agonists 2,5-dimethoxy-4-n-propylthiophenethylamine (2C-T-7) and dipropyltryptamine (DPT), but not the 5-HT(1A) receptor agonists 8-hydroxy-2-(di-n-propylamino) tetralin hydrochloride (8-OH-DPAT) and 3-chloro-4-fluorophenyl-(4-fluoro-4-([(5-methyl-6-methylaminopyridin-2-ylmethyl) amino) methyl] piperidin-1-yl) methanone (F13714), occasioned responding on the DOM-associated lever in rats and monkeys. Both 8-OH-DPAT and F13714 attenuated the discriminative stimulus effects of DOM in monkeys but not in rats; these effects of 8-OH-DPAT and F13714 were prevented by the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide (WAY 100635). DPT and 2C-T-7 enhanced the discriminative stimulus effects of DOM in rats and monkeys in an additive manner. Taken together, the results suggest that the DOM discriminative stimulus is pharmacologically similar and mediated by 5-HT(2A) receptors in rats and monkeys; however, the ability of 5-HT(1A) receptor agonists to modify the effects of DOM is markedly different between these species. These results indicate possible differences in the neurobiology of 5-HT systems that could be important for studying drugs that have multiple mechanisms of action (e.g., reuptake inhibitors that indirectly stimulate multiple receptors).

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Aminopyridines; Animals; Discrimination, Psychological; DOM 2,5-Dimethoxy-4-Methylamphetamine; Drug Interactions; Macaca mulatta; Male; Phenethylamines; Piperidines; Rats; Rats, Sprague-Dawley; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Agonists; Tryptamines

N,N-dipropyltryptamine (DPT) is a synthetic tryptamine hallucinogen which has been used psychotherapeutically in humans, but has been studied preclinically only rarely. In the present studies, DPT was tested in a drug-elicited head-twitch assay in mice, and in rats trained to discriminate lysergic acid diethylamide (LSD), N,N-dimethyl-4-phosphoryloxytryptamine (psilocybin), or 3,4-methylenedioxymethamphetamine (MDMA). A separate group of rats was also trained to recognize DPT itself as a discriminative stimulus, and in all cases, the behavioral effects of DPT were challenged with the selective serotonin (5-HT)2A antagonist M100907, the 5-HT1A selective antagonist WAY-100635, or their combination. In the head-twitch assay, DPT elicited dose-dependent effects, producing a biphasic dose-effect curve. WAY-100635 produced a parallel rightward shift in the dose-effect curve for head twitches, indicative of surmountable antagonism, but the antagonist effects of M100907 were functionally insurmountable. DPT produced partial to full substitution when tested in rats trained to discriminate LSD, psilocybin or MDMA, and served as a discriminative stimulus. In all cases, the antagonist effects of M100907 were more profound than were those of WAY-100635. DPT is thus active in two rodent models relevant to 5-HT2 agonist activity. The effectiveness with which M100907 antagonizes the behavioral actions of this compound strongly suggest that the 5-HT2A receptor is an important site of action for DPT, but the modulatory actions of WAY-100635 also imply a 5-HT1A-mediated component to the actions of this compound.

Topics: Animals; Data Interpretation, Statistical; Discrimination Learning; Dose-Response Relationship, Drug; Fluorobenzenes; Hallucinogens; Lysergic Acid Diethylamide; Male; Mice; N-Methyl-3,4-methylenedioxyamphetamine; Piperazines; Piperidines; Psilocybin; Pyridines; Rats; Rats, Inbred F344; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2A; Serotonin Antagonists; Tryptamines

These studies investigated the role of serotonin-1A (5-HT1A) and 5-HT2A receptors in the behavioral effects of dipropyltryptamine (DPT). Eight rats discriminated 0.56 mg/kg 2,5-dimethoxy-4-methylamphetamine (DOM) from saline and responded under a fixed ratio 5 schedule of food presentation; 12 other rats were used for observational studies. DOM and DPT increased responding on the DOM lever with 3.2 mg/kg DPT producing greater than 95% responding on the DOM lever; this effect of DPT was antagonized by the 5-HT2A receptor antagonist MDL100907. In another study, the 5-HT1A and 5-HT7 receptor agonist 8-OH-DPAT produced lower-lip retraction and, at larger doses, flat body posture; DPT alone produced flat body posture and not lower-lip retraction; MDL100907 alone did not produce either effect. Pretreatment with DPT blocked 8-OH-DPAT-elicited lower-lip retraction, suggesting antagonist activity of DPT at 5-HT1A receptors; however, in the presence of MDL100907 DPT produced not only flat body posture but also lower-lip retraction, suggesting that agonist activity of DPT at 5-HT2A receptors masked agonist activity at 5-HT1A receptors. Lower-lip retraction and flat body posture by DPT in the presence of MDL100907 were attenuated by the 5-HT1A receptor antagonist WAY100635. These findings suggest that DPT has agonist activity at 5-HT1A and 5-HT2A receptors and that effects at 5-HT2A receptors mask effects at 5-HT1A receptors.

Topics: Animals; Behavior, Animal; Discrimination Learning; Drug Interactions; Fluorobenzenes; Male; Piperazines; Piperidines; Posture; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Tryptamines