Parabrachial endocannabinoid mechanisms and food intake

Nicholas Vincent DiPatrizio

doi:10.17918/00000658

The investigations in this dissertation aimed to identify roles for parabrachial endocannabinoid mechanisms in modulating food intake. The parabrachial nucleus (PBN) gates neurotransmission from multiple sensory systems, including gustatory information associated with the taste properties of food and viscerally-derived satiety signals. Multiple receptor systems in the PBN have been implicated in modulating feeding. For example, our laboratory demonstrated that the local activation of serotonergic and opioidergic signaling pathways decreased and increased food intake, respectively, in rats. In addition, irreversibly inhibiting parabrachial mu-opioid receptor (MOPR) function chronically decreased the intake of a standard chow. Cannabinoid 1 receptors (CB1Rs) and their messenger RNA have been identified in the PBN; however, their functional characteristics and behavioral roles in feeding have not been evaluated. In this dissertation, immunofluorescence identified a wide distribution of CB1Rs throughout the PBN, and in vitro GTP[gamma]S autoradiography revealed their functional capacity to couple to their G-proteins following stimulation with the endocannabinoid, 2-AG. Importantly, in parallel with behavioral effects, coupling induced by 2-AG was mediated by CB1Rs, as co-incubation with the selective CB1R antagonist, AM251, completely blocked the actions of the cannabinoid agonist. Feeding responses to parabrachial CB1R stimulation were evaluated systematically to identify roles for the system in modulating food intake. Direct activation of parabrachial CB1Rs with 2-AG increased the consumption of palatable foods containing high concentrations of fat and/or sugar by 30min following infusion, but failed to affect the intake of standard chow. Hyperphagic responses to 2-AG were blocked by AM251, again indicating CB1R mediation of 2-AG actions. Responses were regionally specific, as 2-AG failed to alter intake when infused into sites ~500[mu]m caudal to infusions that successfully stimulated feeding. In addition, indirect activation of parabrachial CB1Rs by pharmacologically inhibiting the enzymatic degradation of native endocannabinoid ligands selectively increased the feeding of the palatable diet versus standard chow. These actions were also mediated by CB1Rs, as co-administration of the inhibitor with AM251 blocked the hyperphagic responses. Furthermore, the amount of time the animals had access to the diets influenced total calorie consumption and the time until regulation of overall calorie intake was re-established. Taken together, these studies indicate that direct or indirect activation of parabrachial CB1Rs selectively stimulates the intake of foods with hedonically-postive sensory properties. Cannabinoid and opioid mechanisms have been reported to interact in a variety of cellular and behavioral functions. We report the presence of MOPRs throughout the PBN in a similar distribution to CB1Rs. Response characteristics to endocannabinoids of CB1Rs differed from those for opioid ligands at parabrachial MOPRs. Stimulating MOPRs indiscriminately increased feeding of all test diets, irrespective of their sensory properties. Unlike 2-AG, orexigenic responses to DAMGO were confined to later timepoints, highlighting a very different temporal component to MOPR actions on feeding when compared to those for CB1Rs. It has been proposed that parabrachial MOPRs may be involved in the general maintenance of feeding behaviors through a dampening of satiety signaling transmitted by second order vagal afferents to the PBN, as evidenced by the delayed onset of response and non-selectivity for test diets. Furthermore, pharmacological blockade of parabrachial MOPRs failed to affect the actions on feeding of stimulating CB1Rs. These results argue against functional interactions between the two receptor systems specifically within the PBN to modulate feeding of a palatable diet. The work in this dissertation provides, for the first time, systematic evidence for a specialized role in the brainstem where CB1Rs may integrate eating with reward. In addition, this work extends previous studies from our laboratory and provides the foundation to Rather evaluate the specific physiological roles for the system in the complex neural network controlling feeding, energy balance and behavioral responses for reward.

Parabrachial endocannabinoid mechanisms and food intake

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Parabrachial endocannabinoid mechanisms and food intake

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