Acute induction of anxiety in humans by delta-9-tetrahydrocannabinol related to amygdalar cannabinoid-1 (CB1) receptors

Journal article

CB1 receptor allosteric modulators are an area of growing interest for their potential novel therapeutic actions. In the present study, we examined LDK1258 in a series of pharmacological in vivo tests sensitive to CB1 receptor stimulation. In the tetrad assay, LDK1258 produced significant decreases in locomotor activity and body temperature measures but did not produce either antinociception as measured in the tail-withdrawal assay or catalepsy as assessed in the bar test. These same effects were observed in both CB1 (-/-) and (+/+) mice. Moreover, LDK1258 failed to shift the dose-response curves of two orthosteric CB1 receptor agonists in the triad assay. In the mouse drug discrimination assay, LDK1258 failed to substitute or shift the dose-response curve for either CP55,940 or anandamide, but dose-dependently suppressed response rates. In addition, LDK1258 reduced food consumption in both CB1 (-/-) and (+/+) mice. Unexpectedly, LDK1258 elicited a delayed antinociceptive effect in the CCI model, an effect not blocked by the CB1 receptor antagonist rimonabant. LCMS-MS analysis detected significant levels of the drug in blood and brain tissue 30 min post-administration and remained stable up to 4 hours in the brain. The results of the present study demonstrate that LDK1258 produces a variety of pharmacological effects, including antinociception, but these effects do not require CB1 receptor activation. These findings underscore the need for translational studies to examine newly developed CB1 receptor allosteric modulators that are characterized in in vitro assays to the whole animal, as has been done with other CB1 receptor allosteric modulators

Authors: Bhattacharyya, S; Egerton, A; Kim, E; Rosso, L; Riano Barros, D

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Scientific Reports
• Volume: 7
• Issue: 1
• Pages: 15025-15025
• Publication date: 2017-10-30
• DOI: 10.1038/s41598-017-14203-4
• EISSN: 2045-2322
• ISSN: 2045-2322
• Language: English
• Keywords: Receptor; Anxiety; Neuroscience; Psychology; Cannabinoid receptor; Agonist; Delta-9-tetrahydrocannabinol; Psychiatry; Internal medicine; Tetrahydrocannabinol; Medicine; Amygdala; Cannabis; Endocannabinoid system; Anxiogenic; Anxiolytic; Cannabinoid; Dronabinol; Pharmacology