Different pharmaceutical preparations of Δ9-tetrahydrocannabinol differentially affect its behavioral effects in rats

Based on the contribution of the endocannabinoid system to the pathophysiology of schizophrenia, the primary pro-psychotic ingredient of Cannabis sativa, Delta-9-tetrahydrocannabinol (Delta-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 Delta-9-THC in human studies orally, intraperitoneal injections of water-based solutions are used in animal models. Because of the poor water solubility of Delta-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 Delta-9-THC in the lipid-based formulation was not able to induce any behavioral alterations, while already 5 mg/kg of the water-based Delta-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 Delta-9-THC solution. Analysis of serum and brain Delta-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 Delta-9-THC concentration-time curve and the resulting cannabinoid receptor type 1 activation per time unit are responsible for the induction of behavioral alterations.