Synthetic cannabinoid JWH-073 alters both acute behavior and in vivo/vitro electrophysiological responses in mice

Mario Barbieri; Micaela Tirri; Sabrine Bilel; Raffaella Arfè; Giorgia Corli; Beatrice Marchetti; Lorenzo Caruso; Marie Soukupova; Virginia Cristofori; Giovanni Serpelloni; Matteo Marti

doi:10.3389/fpsyt.2022.953909

Synthetic cannabinoid JWH-073 alters both acute behavior and in vivo/vitro electrophysiological responses in mice

Front Psychiatry. 2022 Oct 21:13:953909. doi: 10.3389/fpsyt.2022.953909. eCollection 2022.

Authors

Affiliations

¹ Department of Neuroscience and Rehabilitation, University of Ferrara, Ferrara, Italy.
² Department of Translational Medicine, Section of Legal Medicine and Laboratory for Technologies of Advanced Therapies (LTTA) Centre, University of Ferrara, Ferrara, Italy.
³ Department of Environment and Prevention Sciences, University of Ferrara, Ferrara, Italy.
⁴ Department of Chemistry and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy.
⁵ Neuroscience Clinical Center and Transcranial Magnetic Stimulation (TMS) Unit, Verona, Italy.
⁶ Department for Anti-Drug Policies, Collaborative Center of the National Early Warning System, Presidency of the Council of Ministers, Rome, Italy.

Abstract

JWH-073 is a synthetic cannabinoid (SCB) that is illegally marketed within an "herbal blend", causing psychoactive effects more intense than those produced by Cannabis. Users report that JWH-073 causes less harmful effects than other SCBs, misrepresenting it as a "safe JWH-018 alternative", which in turn prompts its recreational use. The present study is aimed to investigate the in vivo pharmacological activity on physiological and neurobehavioral parameters in male CD-1 mice after acute 1 mg/kg JWH-073 administration. To this aim we investigate its effect on sensorimotor (visual, acoustic, and tactile), motor (spontaneous motor activity and catalepsy), and memory functions (novel object recognition; NOR) in mice coupling behavioral and EEG data. Moreover, to clarify how memory function is affected by JWH-073, we performed in vitro electrophysiological studies in hippocampal preparations using a Long-Term Potentiation (LTP) stimulation paradigm. We demonstrated that acute administration of JWH-073 transiently decreased motor activity for up to 25 min and visual sensorimotor responses for up to 105 min, with the highest effects at 25 min (~48 and ~38%, respectively), while the memory function was altered up to 24 h (~33%) in treated-mice as compared to the vehicle. EEG in the somatosensory cortex showed a maximal decrease of α (~23%) and γ (~26%) bands at 15 min, β (~26%) band at 25 min, a maximal increase of θ (~14%) band at 25 min and δ (~35%) band at 2 h, and a significant decrease of θ (~18%), α (~26%), and β (~10%) bands during 24 h. On the other hand, EEG in the hippocampus showed a significant decrease of all bands from 10 min to 2 h, with the maximal effect at 30 min for θ (~34%) and γ (~26%) bands and 2 h for α (~36%), β (~29%), and δ (~15%) bands. Notably, the δ band significant increase both at 5 min (~12%) and 24 h (~19%). Moreover, in vitro results support cognitive function impairment (~60% of decrease) by interfering with hippocampal synaptic transmission and LTP generation. Our results suggest that JWH-073 deeply alters brain electrical responsiveness with minor behavioral symptoms. Thus, it poses a subtle threat to consumers who mistakenly consider it safer than other SCBs.

Keywords: JWH-018; JWH-073; NOR; NPS; cortex; electrophysiology; hippocampus; synthetic cannabinoids.