Acute and residual effects in adolescent rats resulting from exposure to the novel synthetic cannabinoids AB-PINACA and AB-FUBINACA

Abstract

Synthetic cannabinoids (SCs) have rapidly proliferated as recreational drugs, and may present a substantial health risk to vulnerable populations. However, information on possible effects of long-term use is sparse. This study compared acute and residual effects of the popular indazole carboxamide SC compounds AB-PINACA and AB-FUBINACA in adolescent rats with ∆-tetrahydrocannabinol (THC) and control treatments. Albino Wistar rats were injected (i.p.) with AB-PINACA or AB-FUBINACA every second day (beginning post-natal day (PND) 31), first at a low dose (0.2 mg/kg on 6 days) followed by a higher dose (1 mg/kg on a further 6 days). THC-treated rats received equivalent doses of 6 × 1 mg/kg and 6 × 5 mg/kg. During drug treatment, THC, AB-PINACA, and AB-FUBINACA decreased locomotor activity at high and low doses, increased anxiety-like behaviours and audible vocalisations, and reduced weight gain. Two weeks after dosing was completed, all cannabinoid pre-treated rats exhibited object recognition memory deficits. These were notably more severe in rats pre-treated with AB-FUBINACA. However, social interaction was reduced in the THC pre-treated group only. Six weeks post-dosing, plasma levels of cytokines interleukin (IL)-1α and IL-12 were reduced by AB-FUBINACA pre-treatment, while cerebellar endocannabinoids were reduced by THC and AB-PINACA pre-treatment. The acute effects of AB-PINACA and AB-FUBINACA were broadly similar to those of THC, suggesting that acute SC toxicity in humans may be modulated by dose factors, including inadvertent overdose and product contamination. However, some lasting residual effects of these different cannabinoid receptor agonists were subtly different, hinting at recruitment of different mechanisms of neuroadaptation.

In vitro and in vivo pharmacokinetics and metabolism of synthetic cannabinoids CUMYL-PICA and 5F-CUMYL-PICA

“…These synthetic chemicals produce psychoactive “cannabimimetic” effects in humans and rodents [1–5], and their use as recreational drugs has been linked to a number of adverse health effects [6–9]. The molecular structures of these compounds are regularly altered in an attempt to evade drug detection and legislation [10], and consequently users of synthetic cannabinoids are frequently exposed to novel substances with unknown pharmacokinetic and pharmacodynamic properties.…”

Application of an activity‐based receptor bioassay to investigate the in vitro activity of selected indole‐ and indazole‐3‐carboxamide‐based synthetic cannabinoids at CB1 and CB2 receptors

“…This lack of knowledge has been addressed by making use of in vivo or in vitro assays based on different signaling pathways of the GPCRs, which has contributed to a better understanding regarding the pharmacology of these drugs and the structure–activity relationship at the CB receptors. Banister et al and Longworth et al have estimated the potency of a wide variety of SCs based on a Fluorometric Imaging Plate Reader (FLIPR ® ) membrane potential assay. Other studies carried out by Wiley et al and Nakajima et al investigated the activity of SCs at CB1 and CB2 measuring the [ 35 S] GTPγS binding to G α subunits .…”

Pharmaco‐toxicological effects of the novel third‐generation fluorinate synthetic cannabinoids, 5F‐ADBINACA, AB‐FUBINACA, and STS‐135 in mice. In vitro and in vivo studies

“…Preclinical studies showed that AB‐FUBINACA produces bradycardia and hypothermia in rats at doses of 0.3–3 mg/kg (Banister, Moir, et al ., ), depressed spontaneous locomotion in ND4 Swiss‐Webster mice and positively substituted for the discriminative stimulus effects of Δ 9 ‐THC in rats (Gatch & Forster, ). Moreover, a recently published study (Kevin et al ., ) reports several acute effects (decreased locomotor activity at high and low doses, increased anxiety‐like behaviors and audible vocalizations, and reduced weight gain) and long‐term effects (object recognition memory deficits) of AB‐FUBINACA in rats.…”