Title

CB1 inverse agonists and antagonists as obesity therapies: Effects on food motivation and emotion

Date of Completion

January 2008

Keywords

Health Sciences, Mental Health|Health Sciences, Pharmacology|Health Sciences, Epidemiology

Degree

Ph.D.

Abstract

The CB1 inverse agonist SR141716 has recently been approved in Europe as an anti-obesity pharmacotherapy. However, the FDA has not approved this medication in the United States, in part because of concerns regarding possible correlations with negative emotional states. Potential psychiatric side effects including fear and anxiety, as well as actions such as nausea and malaise, increase the risk of clinical non-compliance, and substantially complicate the clinical profile of a person trying to lose weight. It has recently been demonstrated that a CB1 neutral antagonist also effectively suppresses food intake in rats, but appears to have less propensity to induce certain adverse effects, such as nausea. As issues related to CB1 inverse agonist and antagonist effects on feeding and emotion are important for understanding the clinical utility of these drugs as obesity treatments, the purpose of this work was to compare effects of CB1 inverse agonist AM251 and the neutral antagonist AM4113 on behaviors and neurobiological correlates of food motivation, fear, and anxiety in rats. Experiments 1-6 demonstrated that both AM251 and AM4113 potentiated anxiety-like behaviors on some measures in open field and elevated plus maze tests of anxiety in rats, but that comparable doses of AM4113 may induce weaker anxiogenesis than AM251, at least on some measures. The anxiogenic effects of both drugs were mild compared to those of the anxiogenic benzodiazepine inverse agonist FG-7142. Experiments 7-9 compared AM251 and AM4113 on the acquisition and retention of conditioned fear. Both drugs substantially increased baseline freezing, possibly indicating an increase in general anxiety. Compared to vehicle, AM251 decreased freezing during the initial stages of fear acquisition and during retention testing to a conditioned tone, but decreased freezing to a conditioned context. In experiments 10-14, neither AM251 nor AM4113 had any effect upon FR5 operant responding for food pellets when administered ICV, even though ICV injection of either drug effectively reversed locomotor suppression induced by CB1 agonist AM411 (experiments 15-16). Although it has been proposed that CB1 inverse agonists and antagonists may influence feeding behaviors via modulation of nucleus accumbens dopamine transmission, behavioral effects of AM251 and AM4113 were dissimilar to those of dopamine D1 and D2 antagonists in a paradigm sensitive to systemic or local accumbens dopamine depletion or antagonism. Whereas the dopamine antagonists produced a shift away from lever pressing for a preferred food toward consumption of a freely available but less preferred chow, both AM251 and AM4113 decreased lever pressing but did not increase chow consumption (experiments 17-20). In agreement with these behavioral results, it was found in experiment 21 that changes in extracellular nucleus accumbens DA were not correlated with suppression of palatable food intake induced by AM251. Experiment 22 compared the ability of AM251 and AM4113 to induce c-Fos expression within hypothalamus, amygdala, and striatum, all structures shown to mediate fear, anxiety, and feeding behaviors. It was found that AM4113 induced very little expression in any structure except hypothalamus, but compared to vehicle, AM251 significantly increased c-Fos expression within hypothalamus, central amygdala, dorsal striatum, and both shell and core compartments of nucleus accumbens. Thus, it appears that AM251 induced more extensive neural activation than AM4113 within the structures examined. Lastly, a comparison of the oral bioavailability of two CB1 antagonists, AM4113 and AM6527, found that orally administered AM6527 dose-dependently suppressed FR5 lever pressing for food pellets but AM4113 had no effect (experiments 22-26). To conclude, it appears that CB1 antagonists, as well as drugs that have inverse agonist properties, can affect food-motivated behaviors, and may do so via interactions with peripherally located CB1 receptors. Both drugs also display some potential to evoke fear- or anxiety-related behaviors in rats; however, it appears that the overall pattern of effects on emotional responses and neural activation patterns points to weaker efficacy of AM4113 on these outcomes compared to AM251. This could indicate that CB1 receptor neutral antagonists have a lower potential for inducing psychiatric side-effects compared to inverse agonists, which may, in turn, translate into a greater clinical utility for CB1 antagonists as obesity therapies. ^