Behavioral and neurochemical pharmacology of six psychoactive substituted phenethylamines: mouse locomotion, rat drug discrimination and in vitro receptor and transporter binding and function - PubMed (original) (raw)

Behavioral and neurochemical pharmacology of six psychoactive substituted phenethylamines: mouse locomotion, rat drug discrimination and in vitro receptor and transporter binding and function

Amy J Eshleman et al. Psychopharmacology (Berl). 2014 Mar.

Abstract

Rationale: Psychoactive-substituted phenethylamines 2,5-dimethoxy-4-chlorophenethylamine (2C-C); 2,5-dimethoxy-4-methylphenethylamine (2C-D); 2,5-dimethoxy-4-ethylphenethylamine (2C-E); 2,5-dimethoxy-4-iodophenethylamine (2C-I); 2,5-dimethoxy-4-ethylthiophenethylamine (2C-T-2); and 2,5-dimethoxy-4-chloroamphetamine (DOC) are used recreationally and may have deleterious side effects.

Objectives: This study compares the behavioral effects and the mechanisms of action of these substituted phenethylamines with those of hallucinogens and a stimulant.

Methods: The effects of these compounds on mouse locomotor activity and in rats trained to discriminate dimethyltryptamine, (-)-DOM, (+)-LSD, (±)-MDMA, and S(+)-methamphetamine were assessed. Binding and functional activity of the phenethylamines at 5-HT1A, 5-HT2A, 5-HT2C receptors and monoamine transporters were assessed using cells heterologously expressing these proteins.

Results: The phenethylamines depressed mouse locomotor activity, although 2C-D and 2C-E stimulated activity at low doses. The phenethylamines except 2C-T-2 fully substituted for at least one hallucinogenic training compound, but none fully substituted for (+)-methamphetamine. At 5-HT1A receptors, only 2C-T-2 and 2C-I were partial-to-full very low potency agonists. In 5-HT2A arachidonic acid release assays, the phenethylamines were partial to full agonists except 2C-I which was an antagonist. All compounds were full agonists at 5-HT2A and 5-HT2C receptor inositol phosphate assays. Only 2C-I had moderate affinity for, and very low potency at, the serotonin transporter.

Conclusions: The discriminative stimulus effects of 2C-C, 2C-D, 2C-E, 2C-I, and DOC were similar to those of several hallucinogens, but not methamphetamine. Additionally, the substituted phenethylamines were full agonists at 5-HT2A and 5-HT2C receptors, but for 2C-T-2, this was not sufficient to produce hallucinogen-like discriminative stimulus effects. Additionally, the 5-HT2A inositol phosphate pathway may be important in 2C-I's psychoactive properties.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest.

All authors declare that they have no conflicts of interest.

Figures

Fig. 1

Fig. 1

Structures of 2C-C, 2C-D, 2C-E, 2C-I, 2C-T-2 and DOC

Fig. 2

Fig. 2

Average horizontal activity counts/10 min (ambulation counts) as a function of time (0–8 hr) and dose of test compound. Data for the vehicle and the dose which produced peak depressant effects are shown in each panel. 2C-D and DOC also produced stimulant effects, and data for the dose which produced peak stimulant effects are also shown. N=8 for each treatment.

Fig. 3

Fig. 3

[3H]AA release from HEK-5-HT2A cells. Experiments were conducted as described in methods. Data presented are means ± sem. (A) Agonist assay. Basal activity is subtracted, and data are normalized to the maximal stimulation by serotonin on each experimental day. n=3–5 except n=2 for 2C-I. (B) Antagonist assay. Nonspecific release, measured in the presence of 30 μM ketanserin, is subtracted from all data and data are normalized to the maximal release stimulated by serotonin. n=3–4.

Fig. 4

Fig. 4

Stimulation of IP-1 formation in HEK-5-HT2A and HEK-5-HT2C cells. Experiments were conducted as described in methods. A. HEK-5-HT2A cells. All compounds are full or partial agonists. The average maximal stimulation by serotonin was 565 ± 46 nM IP1. n=3–8. B. HEK-5-HT2C cells. All compounds are full agonists. The average maximal stimulation by serotonin was 1390 ± 180 nM. n=4–7.

Similar articles

Cited by

References

    1. Acuna-Castillo C, Villalobos C, Moya PR, Saez P, Cassels BK, Huidobro-Toro JP. Differences in potency and efficacy of a series of phenylisopropylamine/phenylethylamine pairs at 5-HT(2A) and 5-HT(2C) receptors. Br J Pharmacol. 2002;136:510–519. - PMC - PubMed
    1. Backstrom JR, Chang MS, Chu H, Niswender CM, Sanders-Bush E. Agonist-directed signaling of serotonin 5-HT2C receptors: differences between serotonin and lysergic acid diethylamide (LSD) Neuropsychopharmacology. 1999;21:77S–81S. - PubMed
    1. Baker LE, Broadbent J, Michael EK, Matthews PK, Metosh CA, Saunders RB, West WB, Appel JB. Assessment of the discriminative stimulus effects of the optical isomers of ecstasy (3,4-methylenedioxymethamphetamine; MDMA) Behav Pharmacol. 1995;6:263–275. - PubMed
    1. Berg KA, Maayani S, Goldfarb J, Scaramellini C, Leff P, Clarke WP. Effector pathway-dependent relative efficacy at serotonin type 2A and 2C receptors: evidence for agonist-directed trafficking of receptor stimulus. Mol Pharmacol. 1998;54:94–104. - PubMed
    1. Bosak A, Lovecchio F, Levine M. Recurrent Seizures and Serotonin Syndrome Following “2C-I” Ingestion. J Med Toxicol 2013 - PMC - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources