Anandamide Hits the “Hedonic Hot Spot.”

Marijuana and the munchies.

It’s no secret that marijuana very reliably increases appetite. Recently, research published in Nature has teased out an apparent mechanism by which internal cannabinoids are involved with gut microbiota. This affects inflammation, the metabolism of adipose tissue, and other factors implicated in obesity.

In addition, research published in the Proceedings of the National Academy of Sciences, and blogged about by Neuroskeptic, showed that CB1 cannabinoid receptors on the tongue selectively boost our pleasurable responses to sweet-tasting food. Conversely, drugs that block cannabinoid receptors have been actively pursued as appetite suppressants. One such drug, trade name rimonabant, was disallowed by the FDA on the grounds that it worked so well in the guise of anandamide’s opposite number that it frequently caused debilitating depression in users. But it did appear to reduce appetites.

Neuroskeptic suggests that a CB1 antagonist that only affects specific sites, like taste buds, might be able to lessen the sweet-tooth effect with fewer complications. “Who knows,” he writes, “in a few years you might even be able to buy CB1 antagonist chewing gum to help you stick to your diet.”

We know that cannabinoids make rats and humans eat more. But how, exactly, does that happen? One reasonable hypothesis is that anandamide, other endocannabinoids, and cannabinoid drugs—anything that tickles the CB1 receptors--must increase sensations of palatability, if eaters are to eat more. A group of University of Michigan researchers chose to investigate the theory that “endogenous cannabinoid neurotransmission in limbic structures such as nucleus accumbens mediates the hedonic impact of natural rewards like sweetness.” They went looking for the precise brain location—the “hedonic hotspot for sensory pleasure”—where endocannabinoids do their work. 

 Writing in Neuropsychopharmacology in 2007, the investigators sought to discover “if anandamide microinjection into medial nucleus accumbens shell enhances these affective reactions to sweet and bitter tastes in rats.” And it did. Anandamide “doubled the number of positive ‘liking’ reactions elicited by intraoral sucrose, without altering negative ‘disliking’ reactions to bitter quinine.” Anandamide reliably increased the number of “positive hedonic reactions” the rats showed to sucrose, and never caused any aversive reactions, or increases in water drinking or other behaviors. In addition, the process worked in reverse: “Food-related manipulations, such as deprivation and satiety, or access to a palatable diet produce changes in CB1 receptor density,” leading to higher levels of endogenous anandamide. 

One location in particular, when dosed with endocannabinoids, increased “liking” responses in the rats threefold. A tiny spot, 1.6 millimeters cubed, but the hottest spot of all: the dorsal half of the medial shell of the nucleus accumbens. At that site, cannabinoid receptors and opioid receptors appear to coexist and interact. If this form of colocalization occurs regularly in rats and humans, it would constitute strong support for the idea that “endocannabinoid and opioid neurochemical signals in the nucleus accumbens might interact to enhance ‘liking’ reactions to the sensory pleasure of sucrose.”

As the authors sum it up, “magnifying the pleasurable impact of food reward” appears to be the baseline effect of endocannabinoids on “appetite or incentive motivation.” Because all of this takes place along the brain’s primary reward pathways in the limbic system, the authors conclude that it would be of interest to know “whether other types of sensory pleasure besides sweetness can be enhanced by the endocannabinoid hedonic hotspot described here.”

Mahler, S., Smith, K., & Berridge, K. (2007). Endocannabinoid Hedonic Hotspot for Sensory Pleasure: Anandamide in Nucleus Accumbens Shell Enhances ‘Liking’ of a Sweet Reward Neuropsychopharmacology, 32 (11), 2267-2278 DOI: 10.1038/sj.npp.1301376

Graphics Credit: NIDA