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Front. Psychiatry | doi: 10.3389/fpsyt.2018.00055

Repeated exposure to the “spice” cannabinoid JWH-018 induces tolerance and enhances responsiveness to 5-HT1A receptor stimulation in male rats

  • 1Designer Drug Research Unit (DDRU), NIDA Intramural Research Program (IRP), United States

Naphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-018) is a synthetic compound found in psychoactive “spice” products that activates cannabinoid receptors. Preclinical evidence suggests that exposure to synthetic cannabinoids increases 5-HT2A/2C receptor function in the brain, an effect which might contribute to psychotic symptoms. Here, we hypothesized that repeated exposures to JWH-018 would enhance behavioral responsiveness to the 5-HT2A/2C receptor agonist DOI. Male Sprague-Dawley rats fitted with sc temperature transponders received daily injections of JWH-018 (1.0 mg/kg, sc) or its vehicle for 7 consecutive days. Body temperature and catalepsy scores were determined at 1, 2 and 4 h post-injection each day. At 1 and 7 days after the final repeated treatment, rats received a challenge injection of either DOI (0.1 mg/kg, sc) or the 5-HT1A receptor agonist 8-OH-DPAT (0.3 mg/kg, sc), then temperature and behavioral responses were assessed. Behaviors induced by DOI included wet dog shakes and back muscle contractions (i.e., skin jerks), while behaviors induced by 8-OH-DPAT included ambulation, forepaw treading and flat body posture. On the first day of repeated treatment, JWH-018 produced robust hypothermia and catalepsy which lasted up to 4 h, and these effects were significantly blunted by day 7 of treatment. Repeated exposure to JWH-018 did not affect behaviors induced by DOI, but behavioral and hypothermic responses induced by 8-OH-DPAT were significantly augmented 1 day after cessation of JWH-018 treatment. Collectively, our findings show that repeated treatment with JWH-018 produces tolerance to its hypothermic and cataleptic effects, which is accompanied by transient enhancement of 5-HT1A receptor sensitivity in vivo.

Keywords: 5-HT2A receptor, 5-HT1A receptor, JWH-018, psychotic symptoms, Schizophrenia, Spice, synthetic cannabinoids

Received: 17 Aug 2017; Accepted: 08 Feb 2018.

Edited by:

Aviv M. Weinstein, Ariel University, Israel

Reviewed by:

Fabrizio Schifano, University of Hertfordshire, United Kingdom
Maria Antonietta De Luca, Università degli studi di Cagliari, Italy
Magi Farre, Hospital Universitari Germans Trias i Pujol, Spain  

Copyright: © 2018 Baumann and Elmore. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Michael H. Baumann, NIDA Intramural Research Program (IRP), Designer Drug Research Unit (DDRU), 333 Cassell Drive, Suite 4400, Baltimore, 21224, Maryland, United States, mbaumann@mail.nih.gov