Full substitution of the discriminative cue of a 5-HT1A/1B/2C agonist with the combined administration of a 5-HT1B/2C and a 5-HT1A agonist

Abstract

The present study examined whether animals attend to the individual components of the cue produced by a drug that stimulates different 5-hydroxytryptamine (5-HT) receptor populations, using a drug discrimination task based on the conditioned taste aversion (CTA) procedure. The training drug was indorenate (5-methoxytryptamine beta-methylcarboxylate) (INDO) that has been described as a 5-HT(1A/2C/1B) agonist able to exert discriminative control in both operant and CTA procedures. The principal objective was to examine generalization with the combined administration of agonists for the different receptor sites that may mimic the mechanism of action of the training drug. Male Wistar rats, deprived of water, were trained to discriminate INDO from saline; during the drug trials, the administration of INDO preceded saccharin-LiCl pairings, while, during the saline trials, the administration of saline preceded the saccharin-saline pairings. In generalization tests, INDO, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, a 5-HT(1A) agonist), 1-(3-trifluoromethylphenyl)piperazine (TFMPP, a 5-HT(1B) agonist), alpha-methyl-5-HT (a 5-HT(2C) agonist) or 2-methyl-5-HT (a 5-HT(3) agonist), were administered alone or in combination. The results showed that 8-OH-DPAT, TFMPP and alpha-methyl-5-HT produced dose-dependent generalization, up to 88% in the case of 8-OH-DPAT. The combined administration of the following pairs of drugs, 8-OH-DPAT+TFMPP or 8-OH-DPAT+ alpha-methyl-5-HT, at doses that produced only 15-55% generalization when administered alone, produced greater than 80% generalization to INDO. However, the single administration of 2-methyl-5-HT produced only saline-like responding and its combined administration with 8-OH-DPAT did not modify the generalization produced by the single administration of 8-OH-DPAT. These results suggest that animals attend to the individual components of the drug cue; in the case of INDO, which has three elements, each mediated by a different receptor subpopulation (5-HT(1A), 5-HT(1B) and 5-HT(2C) ), the separate stimulation of at least two receptor subpopulations was 'interpreted' by the subject as the presence of the training drug.

Determining the subjective and physiological effects of BZP combined with TFMPP in human males

“…TFMPP was, and still is, commonly used as a marker for 5-HT activity due to its non-selective agonist activity at all 5-HT receptor subtypes (Miranda et al 2002). It also causes presynaptic 5-HT transporter (SERT)-mediated 5-HT release (Auerbach et al 1991).…”

Determining the subjective effects of TFMPP in human males

“…The effects of TFMPP are almost exclusive to the serotonergic system; for that reason, it has been widely used as a biomarker of serotonin (5-HT) activity (Miranda et al 2002) and to study the pharmacology of the serotonergic pathway (Auerbach et al 1990). TFMPP is relatively selective for 5-HT 1 and 5-HT 2 receptors, with minimal affinity for 5-HT 3 receptors (Robertson et al 1992).…”

Subjective effects in humans following administration of party pill drugs BZP and TFMPP alone and in combination

“…In contrast, TFMPP bears little resemblance to dopaminergic stimulants,10, 11 it does not exert any adrenergic effects11 and its mechanism of action is almost exclusively serotonergic, resembling other serotonergic compounds such as lysergic acid diethylamide (LSD),12 1‐[3‐chlorophenyl]‐piperazine (mCPP)13 and fenfluramine 14. Hence, TFMPP was, and still is, commonly used as a marker for 5‐HT activity 15, 16…”