Abstract
The endocannabinoid system is an important modulator of brain reward signaling. Investigations have focused on cannabinoid (CB1) receptors, because dissection of specific contributions of individual endocannabinoids has been limited by the available toolset. While we recently described an important role for the endocannabinoid anandamide in the regulation of social reward, it remains to be determined whether the other major endocannabinoid, 2-arachidonoyl-sn-glycerol (2-AG), serves a similar or different function. To study the role of 2-AG in natural reward, we used a transgenic mouse model (MGL-Tg mice) in which forebrain 2-AG levels are selectively reduced. We complemented behavioral analysis with measurements of brain 2-AG levels. We tested male MGL-Tg mice in conditioned place preference (CPP) tasks for high-fat food, social contact, and cocaine. We measured 2-AG content in the brain regions of interest by liquid chromatography/mass spectrometry. Male MGL-Tg mice are impaired in developing CPP for high-fat food and social interaction, but do develop CPP for cocaine. Furthermore, compared to isolated mice, levels of 2-AG in socially stimulated wild-type mice are higher in the nucleus accumbens and ventral hippocampus (183 and 140% of controls, respectively), but unchanged in the medial prefrontal cortex. The results suggest that reducing 2-AG-mediated endocannabinoid signaling impairs social and high-fat food reward in male mice, and that social stimulation mobilizes 2-AG in key brain regions implicated in the control of motivated behavior. The time course of this response differentiates 2-AG from anandamide, whose role in mediating social reward was previously documented.
Highlights
The use of marijuana is reinforced through activation of the mesolimbic reward circuit (Gardner 2005)
The endocannabinoid system has three main components: (i) two lipid-derived local messengers—2-arachidonoyl-sn-glycerol (2-AG) and anandamide (AEA), (ii) enzymes and transporters that are responsible for their formation and elimination, and (iii) receptors that are activated by endocannabinoids and regulate neuronal activity (Piomelli 2014; Mechoulam and Parker 2013)
We recently demonstrated that anandamide regulates social reward via cooperative signaling with oxytocin, a neuropeptide that is crucial for social bonding (Wei et al 2015)
Summary
The use of marijuana is reinforced through activation of the mesolimbic reward circuit (Gardner 2005). In a related but distinct modulatory process, the neurotransmitter system mediating the effects of marijuana in the brain—the endocannabinoid system— facilitates the reward of other stimuli, such as food or drugs of abuse (Solinas et al 2008; Maldonado et al 2006). Genetic and pharmacological studies have unveiled key roles of the CB1 cannabinoid receptor in the modulation of reward-based behaviors. An emerging question is whether endocannabinoids might regulate the reward of social interactions. We recently demonstrated that anandamide regulates social reward via cooperative signaling with oxytocin, a neuropeptide that is crucial for social bonding (Wei et al 2015).
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