Different pharmaceutical preparations of Δ9‐tetrahydrocannabinol differentially affect its behavioral effects in rats. (2nd April 2019)

• Record Type: Journal Article
• Authors: Rohleder, Cathrin; Pahlisch, Franziska; Graf, Rudolf; Endepols, Heike; Leweke, F. Markus
• Is Part Of: Addiction biology. Volume 25:Number 3(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-04-02
• Subjects: animal model -- cannabinoids -- delta‐9‐THC -- open field -- rodents -- sensorimotor gating; Substance abuse -- Periodicals; Substance abuse -- Physiological aspects -- Periodicals; Substance-Related Disorders -- periodicals; 616.86
• DOI: 10.1111/adb.12745
• Languages: English
• ISSNs: 1355-6215

Abstract

Abstract: Based on the contribution of the endocannabinoid system to the pathophysiology of schizophrenia, the primary pro‐psychotic ingredient of Cannabis sativa, Δ‐9‐tetrahydrocannabinol (Δ‐9‐THC), is used in preclinical as well as clinical research to mimic schizophrenia‐like symptoms. While it is common to administer lipid‐based formulations of Δ‐9‐THC in human studies orally, intraperitoneal injections of water‐based solutions are used in animal models. Because of the poor water solubility of Δ‐9‐THC, solubilizers such as ethanol and/or emulsifiers are needed for these preparations. In order to test whether a lipid‐based solvent would be superior over a water‐based vehicle in rats, we compared the effects on locomotor activity and prepulse inhibition (PPI) of the acoustic startle reaction, as well as pharmacokinetic data obtained from rats' serum and brain tissue samples. Up to 50 mg/kg Δ‐9‐THC in the lipid‐based formulation was not able to induce any behavioral alterations, while already 5 mg/kg of the water‐based Δ‐9‐THC preparation significantly reduced locomotor activity. This also induced a small but significant PPI reduction, which was prepulse intensity dependent. Interestingly, the reflexive motor response to the startle stimulus was not affected by the water‐based Δ‐9‐THC solution. Analysis of serum and brain Δ‐9‐THC levels by high‐performance liquid chromatography/mass spectrometry revealed that although the final concentration reached in the brain was comparable for both pharmaceutical preparations, the water‐based formulation achieved a faster kinetic. We, therefore, conclude that the slope of the Δ‐9‐THC concentration‐time curve and the resulting cannabinoid receptor type 1 activation per time unit are responsible for the induction of behavioral alterations. Abstract : Δ 9 ‐tetrahydrocannabinol (Δ 9 ‐THC) is used in preclinical and clinical research to induce schizophrenia‐like symptoms. In this study, we demonstrate that the delivery mechanism of the Δ 9 ‐THC compound is important for these effects, as only the water‐based preparation induced behavioral changes, while no effects were seen from the administration of the lipid‐based preparation. The final brain Δ 9 ‐THC levels were comparable; however, we observed a faster kinetic for the water‐based preparation, indicating that the rate of receptor activation per time is the key.