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The neurobehavioral effects of the designer drug naphyrone – an experimental investigation with pharmacokinetics and concentration/effect relationship in mice

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Abstract

Rationale

The recreational use of naphyrone, a potent synthetic cathinone with a pyrovalerone structure, has raised questions about possible deleterious neurobehavioral consequences.

Objective

To investigate naphyrone-induced neurobehavioral effects and alterations in brain monoamines using two patterns of abuse, i.e., single and repeated (binge) use.

Methods

We studied naphyrone dose/induced locomotor activity relationship at 3, 10, 30, and 100 mg/kg in mice. We investigated the effects of single (30 mg/kg; acute injection) versus repeated (30 mg/kg ×3/day for 3 days; binge injection) intraperitoneal naphyrone administration on locomotor activity, anxiety-like behavior, spatial recognition memory, anhedonia, behavioral despair, and social interaction. We measured post-mortem prefrontal cortex levels of monoamines and modeled naphyrone pharmacokinetics and concentration/locomotor effect relationship.

Results

Both naphyrone administration patterns induced time-dependent increases in locomotor activity (p < 0.001 and p < 0.0001, respectively) and social interaction (p < 0.05 and p < 0.001, respectively) but did not alter spatial recognition memory or anhedonia. Acute naphyrone injection induced anxiety-like behavior (p < 0.01) and reduced resignation (p < 0.01) whereas binge administration induced non-anxiety-like behavior (p < 0.05) and did not alter behavioral despair. Both patterns increased the prefrontal cortex dopamine (p < 0.0001) and norepinephrine (p < 0.05 and p < 0.01, respectively) but not serotonin content. Naphyrone pharmacokinetics followed a two-compartment model with an overall elimination half-life of 0.3 h. The naphyrone concentration/locomotor effect relationship was described by an additive Emax model with an EC50 of 672 μg/L.

Conclusions

Single naphyrone administration increases locomotor activity according to a direct concentration/effect relationship. The neurobehavioral effects after binge differs from those after single administration and are not explained by drug accumulation given the relatively fast elimination.

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Acknowledgments

The authors would like to thank the Animal Platform, CRP2 - UMS 3612 CNRS - US25 Inserm -IRD - Faculté de Pharmacie de Paris, Université Paris Descartes, Paris, France, for their technical assistance.

Funding

Funding support was provided solely from institutional and departmental sources from the Institut national de la santé et de la recherche médicale (INSERM).

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Authors and Affiliations

  1. Inserm, UMR-S 1144, Paris University, Paris, France

    Bruno Mégarbane, Camille Gamblin, Olivier Roussel, Elodie Bouaziz-Amar, Lucie Chevillard, Jacques Callebert, Gilles Morineau, Jean-Louis Laplanche & Nadia Benturquia

  2. Department of Medical and Toxicological Critical Care, Lariboisière Hospital, Paris, France

    Bruno Mégarbane

  3. Toxicology Department, Institut de Recherche Criminelle de la Gendarmerie Nationale, Rosny sous-Bois, France

    Olivier Roussel

  4. CNRS, UMR8601, Laboratory of Chemistry and Pharmacological and Toxicological Biochemistry, CBNIT, Paris-Descartes University, Paris, France

    Huixiong Chen & Mélanie Etheve-Quelquejeu

  5. Division of Clinical Pharmacology and Toxicology, University Hospital Basel and University of Basel, Basel, Switzerland

    Matthias E. Liechti

  6. Faculté de Pharmacie de Paris, Paris University, 4 avenue de l’Observatoire, 75006, Paris, France

    Nadia Benturquia

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  1. Bruno Mégarbane
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  2. Camille Gamblin
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  3. Olivier Roussel
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  5. Lucie Chevillard
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  7. Huixiong Chen
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  12. Nadia Benturquia
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Correspondence to Nadia Benturquia.

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Mégarbane, B., Gamblin, C., Roussel, O. et al. The neurobehavioral effects of the designer drug naphyrone – an experimental investigation with pharmacokinetics and concentration/effect relationship in mice. Psychopharmacology 237, 1943–1957 (2020). https://doi.org/10.1007/s00213-020-05510-2

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