Do you feel it now? Route of administration and Δ9-tetrahydrocannabinol-like discriminative stimulus effects of synthetic cannabinoids in mice

Abstract

A recent push to provide more translationally relevant preclinical models for examination of pharmacological mechanisms underlying inhaled substances of abuse has resulted in the development of equipment and methods that allows exposure of freely moving rodents to aerosolized psychoactive drugs. In the present study, synthetic cannabinoids (CP55,940, ABCHMINACA, and AMB-FUBINACA) were administered intraperitoneally (i.p.) or aerosolized via a modified electronic cigarette device. Subsequently, the compounds were evaluated in adult male and female C57/Bl6 mice trained to discriminate i.p. 5.6 mg/kg Δ 9 -tetrahydrocannabinol (THC) for food reinforcement. When administered i.p., THC and AB-CHMINACA were equally potent at producing THC-like effects in both sexes, but CP55,940 and AMB-FUBINACA were more potent in males. Upon aerosol exposure, all compounds continued to produce THC-like effects in both sexes, with AMB-FUBINACA remaining the most potent. In contrast, aerosolized CP55,940 showed substantial decreases in potency in both sexes. Aerosolized nicotine did not substitute for THC in either sex. In females, aerosolized cumyl-4CN-BINACA produced concentration-dependent increases in responding on the THC-associated nosepoke. In addition, the effects of an active concentration of AMB-FUBINACA were reversed by rimonabant, suggesting CB 1 receptor mediation. These results show that synthetic cannabinoids produce THC-like effects when injected i.p. or after aerosolization. This study adds to a growing literature suggesting that evaluation of abuse liability of substances via aerosol exposure is feasible and may provide a translationally relevant method that allows for investigation of factors important to the abuse of drugs which humans typically smoke or vape.

Sex‐dependent pharmacological profiles of the synthetic cannabinoid MMB‐Fubinaca

“…Accordingly, previous studies also showed sex differences in tetrad behaviors induced by THC 42,43 . In addition, the sex‐biased impact of MMB‐Fubinaca has recently started to be evaluated 36 . Our results show a higher sensitivity for MMB‐Fubinaca in male than in female mice, at both behavioral and synaptic levels.…”

“…MMB‐Fubinaca intoxication in mouse models has been shown to induce cannabinoid‐like behavioral effects such as seizures, hypolocomotion, or hypothermia 3,6,24,28,29,35 . Interestingly, a sex‐dependent effect of MMB‐Fubinaca has been described to be blocked by CB 1 antagonists in a paradigm assessing addictive‐like behavior 36 . However, previous studies only used pharmacological tools and did not address CB 1 dependency by using specific mutant mice lacking CB 1 receptors.…”

Systemic administration with tetrahydrocannabinol causes retinal damage in BALB/c mice

“…26 Evaluation of abuse liability of substances via ip administration is comparable to vapor inhalation. 27 This study was to investigate the effects of systemic administration with THC, the major component in cannabis, on mouse retinas and its underlying mechanisms. For the first time, we explored the effects of dosing and administration duration (up to 2 months) that reflect cannabis abuse situations, complementing studies into the mechanisms underlying retina damage caused by cannabis abuse.…”

Acute Toxic Effects of AB-CHMINACA on Lung, Heart and Liver: An Experimental Pilot Study

“…injection. Wiley et al (2015), Lefever et al (2017), andWiley et al (2019) all used doses ranged between 0.03 mg/kg and 3 mg/kg. All these studies showed full THC substitution by AB-CHMINACA and produced the tetrad effect (decreased motor activity, decreased temperature, catalepsy, and antinociception which means decrease the sensation to painful stimuli).…”