Liam Davenport

September 20, 2016

VIENNA — Impairments in the endocannabinoid system in the brain could play an important role in the development of anorexia nervosa, say Italian researchers, who report findings that point to novel cannabis-based therapeutic strategies for the eating disorder.

In a mouse model of anorexia, the team found not only that the density of cannabinoid receptors was significantly reduced in areas associated with appetite but also that administration of receptor agonists led to increases in body weight and a reduction in interest in exercise.

Roberto Collu, a PhD student in the Division of Neuroscience and Clinical Pharmacology at the University of Calgiari, Italy, told delegates here at the 29th European College of Neuropsychopharmacology (ECNP) Congress that "pharmacological therapies based on drugs that modulate endocannabinoid system signaling might be useful in the treatment of anorexia nervosa."

Collu began his presentation by noting that although the neurobiology of anorexia nervosa is complex and multifactorial, "it's clear that dysregulation of appetite-regulating hormones is associated with an alteration of neurotransmitter activity, like the dopaminergic system, but also that an alteration of reward processes seems to contribute to the onset and to the development of this pathology."

He said that the endocannabinoid system is an "important" neuromodulator system involved in regulating both the homeostatic and hedonic aspects of eating behavior and that the cannabinoid type 1 (CB1) receptor is expressed in particular in the hypothalamus, which is the "key center" for the homeostatic regulation of feeding.

Collu noted that several previous studies have revealed associations between variants in the CB1 receptor gene and anorexia nervosa. The current study investigates a possible alteration of the endocannabinoid system in the activity-based model of anorexia nervosa in mice.

Activity-based anorexia involves a combination of diet restriction and physical activity that induces an alteration of the behavioral condition and the dysregulation of endocrine function that is similar to the human form of anorexia nervosa.

During the 6-day induction phase of activity-based anorexia, the mice were allowed access to food for 90 minutes per day and were given free access to a running wheel. Body weight, food intake, and running wheel activity (RWA) were measured daily, as were leptin, ghrelin, and corticosterone levels.

At the end of the induction phase, there were significant reductions in endocannabinoid levels in various regions of the brain, including the cortex, the prefrontal cortex, the amygdala, and the hippocampus. Moreover, there were significant reductions in CB1 receptor density in the lateral hypothalamus and the dentate gyrus within the hippocampus.

Administration of the natural CB1/CB2 receptor agents delta-9-tetrahydrocannabinol (THC) at a dose of 0.75 mg/kg led to significant increases in body weight after 6 days. There were also early significant increases in food intake and significant reductions in daily RWA. THC administration was also associated with significant increases in leptin levels in comparison with baseline.

The researchers also administered the synthetic CB1 receptor agonist CP 55,940. They found that the 0.06-mg/kg dose had a similar effect on body weight, food intake, and daily RWA. Furthermore, the compound significantly increased leptin levels and significantly reduced ghrelin levels compared with baseline.

Collu concluded that the results showed that "the endocannabinoid system is involved in the anorexic-like behavior displayed in the activity based anorexia model.

"Administration of CB1 agonists improves, at least partially, the anorexic-like behavior and hormonal dysregulation," he added.

Session cochair Olga Kazakova, MD, PhD, head of the psychiatric department at the Psychiatric Clinic of Minsk City, Belarus, described the study as "very interesting." She said that patients with anorexia are hard to treat, adding: "I don't think that we have any proper drug at the moment for this group of patients.

"What has really impressed me is that they decreased the level of interest in physical activity after administration of this cannabinoid." Although there are a number of reasons that could account for this, she speculated that it may that the subjects were "more relaxed and do not want to be as active," she told Medscape Medical News.

Dr Kazakova pointed out that the researchers also found cannabinoid therapy to be effective in the event of relapse.

"So we can say that it improved [outcomes] in the group of mice, but then later, if they had a kind of relapse, it also worked," she said.

"I think that it sounds really promising, and I'm looking forward to further investigations. I think it's far, far from [being used] in humans, but for the beginning, I think it's a very promising start," Dr Kazakova added.

The research was supported in part by Regione Autonoma della Sardegna, the Italian Ministry of University and Scientific Research, and the Fondazione Banco di Sardegna. The investigators have disclosed no relevant financial relationships.

29th European College of Neuropsychopharmacolgy (ECNP) Congress. Abstract S.12.05. Presented September 18, 2016.


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