PT  - JOURNAL ARTICLE
AU  - Jason M. Wiebelhaus
AU  - Travis W. Grim
AU  - Robert A. Owens
AU  - Matthew F. Lazenka
AU  - Laura J. Sim-Selley
AU  - Rehab A. Abdullah
AU  - Micah J. Niphakis
AU  - Robert E. Vann
AU  - Benjamin F. Cravatt
AU  - Jenny L. Wiley
AU  - S. Stevens Negus
AU  - Aron H. Lichtman
TI  - Delta-9 tetrahydrocannabinol (THC) and endocannabinoid degradative enzyme inhibitors attenuate intracranial self-stimulation (ICSS) in mice
AID  - 10.1124/jpet.114.218677
DP  - 2014 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.114.218677
4099  - http://jpet.aspetjournals.org/content/early/2014/11/14/jpet.114.218677.short
4100  - http://jpet.aspetjournals.org/content/early/2014/11/14/jpet.114.218677.full
AB  - A growing body of evidence implicates endogenous cannabinoids as modulators of the mesolimbic dopamine system and motivated behavior. Paradoxically, the reinforcing effects of Δ9-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis, have been difficult to detect in preclinical rodent models. In this study, we investigated the impact of THC and inhibitors of the endocannabinoid hydrolytic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) on operant responding for electrical stimulation of the medial forebrain bundle (intracranial self-stimulation, ICSS), which is known to activate the mesolimbic dopamine system. These drugs were also tested in assays of operant responding for food reinforcement and spontaneous locomotor activity. THC and the MAGL inhibitor JZL184 attenuated operant responding for ICSS and food, and also reduced spontaneous locomotor activity. In contrast, the FAAH inhibitor PF-3845 was largely without effect in these assays. Consistent with previous studies showing that combined inhibition of FAAH and MAGL produces a substantially greater cannabimimetic profile than single enzyme inhibition, the dual FAAH-MAGL inhibitor SA-57 produced a similar magnitude of ICSS depression as that produced by THC. ICSS attenuation by JZL184 was associated with increased brain levels of 2-arachidonoylglycerol (2-AG), while peak effects of SA-57 were associated with increased levels of both N-arachidonoylethanolamine (anandamide; AEA) and 2-AG. The CB1 receptor antagonist rimonabant, but not the CB2 receptor antagonist SR144528, blocked the attenuating effects of THC, JZL184, and SA-57 on ICSS. Thus, THC, MAGL inhibition, and dual FAAH-MAGL inhibition not only reduce ICSS, but also decrease other reinforced and non-reinforced behaviors.