Abstract
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 (4-[bis(1,3-benzodioxol-5-yl)hydroxymethyl]-1-piperidinecarboxylic acid 4-nitrophenyl ester) attenuated operant responding for ICSS and food, and also reduced spontaneous locomotor activity. In contrast, the FAAH inhibitor PF-3845 (N-3-pyridinyl-4-[[3-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenyl]methyl]-1-piperidinecarboxamide) 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 (4-[2-(4-chlorophenyl)ethyl]-1-piperidinecarboxylic acid 2-(methylamino)-2-oxoethyl ester) 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), whereas peak effects of SA-57 were associated with increased levels of both N-arachidonoylethanolamine (anandamide) and 2-AG. The cannabinoid receptor type 1 receptor antagonist rimonabant, but not the cannabinoid receptor type 2 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 nonreinforced behaviors.
Footnotes
- Received July 27, 2014.
- Accepted November 13, 2014.
Wiebelhaus JM (2013) Cannabinoid Modulation of Reinforcement Maintained by Stimulation of the Medial Forebrain Bundle in C57Bl/6J Mice. Doctoral dissertation, Virginia Commonwealth University, Richmond, VA.
This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grants T32-DA007027, F31-DA030869, P01-DA009789, P01-DA017259, P30-DA033934, R01-DA026449, R01-DA032933, and R01-DA030404]; and by a Toni Rosenberg fellowship.
Sections of this work were presented at the following scientific meetings: Wiebelhaus JM (2013) THC and endocannabinoid catabolic enzyme inhibitors attenuate ICSS in C57BL/6 mice. Carolina Cannabinoid Collaborative (CCC) Meeting; 2013 Oct 25–27; Richmond, VA; and Wiebelhaus JM, Grim TW, and Lichtman AH (2012) Investigating the effects of monoacylglycerol lipase inhibition using intracranial self-stimulation (ICSS) in mice. National Institute on Drug Abuse Frontiers in Addiction Research, held in conjunction with the Society for Neuroscience (SFN) Annual Meeting; 2012 Oct 12; New Orleans, LA.
↵This article has supplemental material available at jpet.aspetjournals.org.
- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|