Repeated Exposure to the “Spice” Cannabinoid JWH-018 Induces Tolerance and Enhances Responsiveness to 5-HT1A Receptor Stimulation in Male Rats
Joshua S. Elmore, Michael H. Baumann
Frontiers in Psychiatry February 27, 2018 DOI: 10.3389/fpsyt.2018.00055 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Male Sprague-Dawley rats |
| Interventions | JWH-018 DOI 8-OH-DPAT |
| Dose | 1.0 mg/kg, sc (JWH-018); 0.1 mg/kg, sc (DOI); 0.3 mg/kg, sc (8-OH-DPAT) |
| Duration | 7 consecutive days of repeated treatment, with challenges at 1 and 7 days after the final repeated treatment |
| Topics | Serotonin |
| Keywords | Catalepsy 5-ht1a receptor Hypothermia Synthetic cannabinoids Cannabinoid receptor Stimulation Endocrinology 8-oh-dpat Pharmacology Partial agonist 5-HT Receptor Dopamine |
| Citations | 26 |
| Key findings | Repeated JWH-018 treatment produces tolerance to its hypothermic and cataleptic effects and transiently enhances 5-HT1A receptor sensitivity, but does not alter 5-HT2A/2C receptor-mediated behaviors. |
Abstract
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.
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 3
- Positive Allosteric Modulation of the 5-HT1A Receptor by Indole-Based Synthetic Cannabinoids Abused by Humans ACS Chemical Neuroscience April 23, 2020
- 5‐HT 2A receptor agonism by tert ‐leucinamide and valinamide synthetic cannabinoids: In vitro and in vivo evidence British Journal of Pharmacology May 5, 2026
- Novel behavioral assays of spontaneous and precipitated THC withdrawal in mice. Drug and Alcohol Dependence October 1, 2018
Cites 11
- Traditional marijuana, high‐potency cannabis and synthetic cannabinoids: increasing risk for psychosis World Psychiatry September 22, 2016
- Cognitive Impairment Induced by Delta9-tetrahydrocannabinol Occurs through Heteromers between Cannabinoid CB1 and Serotonin 5-HT2A Receptors PLoS Biology July 9, 2015
- Synthetic cannabinoids found in "spice" products alter body temperature and cardiovascular parameters in conscious male rats. Drug and Alcohol Dependence October 1, 2017
- Cannabis, psychosis and schizophrenia: unravelling a complex interaction. Addiction September 1, 2017
- Repeated administration of phytocannabinoid Δ(9)-THC or synthetic cannabinoids JWH-018 and JWH-073 induces tolerance to hypothermia but not locomotor suppression in mice, and reduces CB1 receptor expression and function in a brain region-specific manner. Pharmacological Research December 2015
and 6 more in the library