Pharmacological enhancement of the endocannabinoid system in the nucleus accumbens shell stimulates food intake and increases c‐Fos expression in the hypothalamus

Abstract

Background and purpose: Evidence indicates that the endocannabinoid, 2-arachidonoylglycerol (2-AG), increases food intake when injected into the nucleus accumbens shell (NAcS), thereby potentially activating hypothalamic nuclei involved in food intake regulation. We aimed to evaluate potential orexigenic effects of the endocannabinoid anandamide and of AA5HT, a fatty acid amide hydrolase (FAAH) inhibitor, and OMDM-1, an inhibitor of anandamide uptake, injected in the NAcS, as well as the effect of these treatments on activation of hypothalamic nuclei. Experimental approach: Drugs were given into the NAcS of rats and food intake quantified during the next 4 h. In other groups, after the same treatments the brains were processed for c-Fos immunohistochemistry with focus on hypothalamic nuclei. Additional groups were used to quantify endocannabinoid levels in the nucleus accumbens and the hypothalamus after AA5HT and OMDM-1 intra-NAcS injections. Key results. Our results indicate that the above treatments stimulate food intake during 4 h post-injection. They also increase c-Fos immunoreactivity in hypothalamic nuclei. The CB 1 antagonist, AM251, blocked these effects. Finally, we found elevated levels of 2-AG, but not anandamide, after intra-NAcS injections of AA5HT. Conclusions and implications: These data support the involvement of the endocannabinoid system in feeding behavior at the level of the NAcS and hypothalamus. In addition, this is the first experimental demonstration that the pharmacological inhibition of endocannabinoid inactivation in the NAcS stimulates food intake, suggesting that the endocannabinoid degrading proteins can be a target for treating eating disorders.

Effects of CB1 cannabinoid receptor activation in the nucleos accumbens shell on feeding behavior.

“…Furthermore, behavioral experiments have shown that rimonabant bilaterally microinjected into the NAcS selectively decreased highly palatable food intake in an operant task (Guegan, et al, 2013). Our results confirm and extend the previous evidence that intra-accumbens administration of anandamide or 2-AG increase standard chow consumption (Soria-Gómez, et al, 2007;Kirkham, et al, 2002) by a behavioral-specific mechanism. Taking together these findings, it seems possible that cannabinoid receptors modulate feeding behavior simultaneously by two independent processes; the first one, homeostatic, characterized by affecting energy balance and motivational processes (hunger, appetite, satiety) (Cota, et al, 2003;Escartín-Pérez, et al, 2009); and the second one, hedonic, increasing the rewarding properties of food and its hedonically positive sensory properties (Di Patrizio & Simansky, 2008).…”

“…The endocannabinoid system has been implicated in reward-driven feeding (Matias, Cristino & Di Marzo, 2008), and interestingly cannabinoid receptor 1 (CB1R) KO mice are resistant to diet-induced obesity, indicating that energy dense foods require endocannabinoid signaling to generate obesity (Quarta, et al, 2010). The experimental evidence indicates that the acute activation of CB1R in the NAcS by administration of anandamide (Soria-Gómez, et al, 2007) or 2-AG (Kirkham, Williams, Fezza & Di Marzo, 2002) consistently stimulates chow intake.…”

Orexin in Rostral Hotspot of Nucleus Accumbens Enhances Sucrose ‘Liking’ and Intake but Scopolamine in Caudal Shell Shifts ‘Liking’ Toward ‘Disgust’ and ‘Fear’

“…Other neurotransmitter systems in NAc also modulate food consumption, motivation, and hedonic impact of food rewards including, endocannabinoids, and amino acids (Maldonado-Irizarry et al, 1995;Shinohara et al, 2009;Soria-Gomez et al, 2007), some of which might interact with opioid signals in NAc shell (Faure et al, 2010;Mahler et al, 2007). Here we extended our analyses to orexin and acetylcholine (ACh) systems in NAc that modulate intake and food-motivated behaviors (Pratt and Kelley, 2004;Pratt et al, 2007;Thorpe and Kotz, 2005).…”

The endocannabinoid system as a link between homoeostatic and hedonic pathways involved in energy balance regulation

“…Apart from the aforementioned effects of CB 1 activation in the PBN, an important role is likely to be played by ECS in MCH-expressing neurons of the LH that also regulate the activity of the nucleus accumbens while receiving inhibitory control from this area through GABAergic neurons that are also controlled by CB 1 receptors. 9 Further evidence of the role of ECS in the neuronal circuits integrating the activity of the hypothalamus and NAcS came from a recent study by Soria-Gomez et al 44 The orexigenic effects of (1) anandamide, (2) a FAAH inhibitor and (3) an inhibitor of anandamide cellular uptake, injected into NAcS, were evaluated parallel to their activation of cFos in various hypothalamic nuclei, including the LH. The results indicated that all the treatments stimulate food intake during 4 h post-injection, whereas also increasing cFos immunoreactivity in all hypothalamic nuclei analysed, in a way sensitive to CB 1 antagonism.…”