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

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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.

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Acknowledgments

Funding for this study was provided by National Institutes of Health National Institute on Drug Abuse/Veterans Affairs Interagency agreements (Y1 DA 5007–05, Y1-DA-0101-01), The Methamphetamine Abuse Research Center (P50 DA018165), the Veterans Affairs Research Career and Merit Review programs, and by the National Institute on Drug Abuse contracts (N01DA2-8822 and N01DA-7-8872). The NIDA project officers contributed to study design and had no further role in the collection, analysis, and interpretation of data, in the writing of the report, or in the decision to submit the paper for publication.

Conflict of interest

All authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Research Service, Portland Veterans Affairs Medical Center, 3710 SW US Veterans Hospital Rd., Portland, OR, USA

    Amy J. Eshleman, Katherine M. Wolfrum, Robert A. Johnson & Aaron Janowsky

  2. Department of Psychiatry, Oregon Health & Science University, Portland, OR, 97239, USA

    Amy J. Eshleman & Aaron Janowsky

  3. Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, 97239, USA

    Amy J. Eshleman

  4. Department of Pharmacology & Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA

    Michael J. Forster & Michael B. Gatch

  5. The Methamphetamine Abuse Research Center, Oregon Health & Science University, Portland, OR, 97239, USA

    Aaron Janowsky

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  1. Amy J. Eshleman
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  2. Michael J. Forster
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  3. Katherine M. Wolfrum
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Correspondence to Amy J. Eshleman.

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Eshleman, A.J., Forster, M.J., Wolfrum, K.M. et al. Behavioral and neurochemical pharmacology of six psychoactive substituted phenethylamines: mouse locomotion, rat drug discrimination and in vitro receptor and transporter binding and function. Psychopharmacology 231, 875–888 (2014). https://doi.org/10.1007/s00213-013-3303-6

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  • DOI: https://doi.org/10.1007/s00213-013-3303-6

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