Enhancement of the behavioral effects of endogenous and exogenous cannabinoid agonists by phenylmethyl sulfonyl fluoride

Marijuana’s effects in humans are most often reported as intoxicating or therapeutic; yet, some humans report dysphoria or other negative affect. To evaluate whether differences in endocannabinoid levels might account for this variability, the present study examined whether sensitivity to cannabinoids changed when anandamide (AEA) metabolism was inhibited through administration of phenylmethyl sulfonyl fluoride (PMSF) a non-specific irreversible amidase inhibitor. Male Long Evans rats were trained to discriminate 3 mg/kg Δ9-tetrahydrocannabinol (THC) versus vehicle in 2-lever drug discrimination procedure. ED50s for THC and CP 55,940 were lower when administered with PMSF than alone. PMSF administration also potentiated characteristic cannabimimetic effects of THC in ICR mice. Potentiation of AEA’s in vivo effects by PMSF were also observed, primarily as a consequence of PMSF inhibition of the enzyme fatty acid amide hydrolase. Enhancement of the effects of THC and CP 55,940 through this mechanism is unlikely, as these cannabinoids are predominantly metabolized through the P450 system. Mass spectrometry revealed that, in the presence of THC, endogenous AEA levels in the brain decreased and that this decrease was prevented by PMSF, suggesting that increased AEA levels may have acted additively with exogenously administered cannabinoids to increase cannabimimetic effects. These findings may account for the varying affect in response to marijuana in humans or cannabinoids in animals while also suggesting that metabolic inhibitors of AEA may potentiate marijuana’s intoxicating effects in humans.This article is part of a Special Issue entitled ‘Post-Traumatic Stress Disorder’.

► Phenylmethyl sulfonyl fluoride (PMSF), a serine protease inhibitor, elevates anandamide brain levels.
► PMSF administration potentiates effects of anandamide and THC in a battery of in vivo tests in mice.
► When given concomitantly with PMSF, anandamide produces THC-like discriminative stimulus effects.
► PMSF-induced leftward shifts in generalization curves for THC and CP55, 940 in THC discrimination.