Anorexia induced by activation of serotonin 5-HT ₄ receptors is mediated by increases in CART in the nucleus accumbens

Abstract

Anorexia nervosa is a growing concern in mental health, often inducing death. The potential neuronal deficits that may underlie abnormal inhibitions of food intake, however, remain largely unexplored. We hypothesized that anorexia may involve altered signaling events within the nucleus accumbens (NAc), a brain structure involved in reward. We show here that direct stimulation of serotonin (5-hydroxytryptamine, 5-HT) 4 receptors (5-HT4R) in the NAc reduces the physiological drive to eat and increases CART (cocaine-and amphetamine-regulated transcript) mRNA levels in fed and food-deprived mice. It further shows that injecting 5-HT4R antagonist or siRNA-mediated 5-HT4R knockdown into the NAc induced hyperphagia only in fed mice. This hyperphagia was not associated with changes in CART mRNA expression in the NAc in fed and food-deprived mice. Results include that 5-HT4R control CART mRNA expression into the NAc via a cAMP/PKA signaling pathway. Considering that CART may interfere with food-and drug-related rewards, we tested whether the appetite suppressant properties of 3,4-N-methylenedioxymethamphetamine (MDMA, ecstasy) involve the 5-HT4R. Using 5-HT4R knockout mice, we demonstrate that 5-HT4R are required for the anorectic effect of MDMA as well as for the MDMA-induced enhancement of CART mRNA expression in the NAc. Directly injecting CART peptide or CART siRNA into the NAc reduces or increases food consumption, respectively. Finally, stimulating 5-HT4R-and MDMA-induced anorexia were both reduced by injecting CART siRNA into the NAc. Collectively, these results demonstrate that 5-HT4R-mediated upregulation of CART in the NAc triggers the appetite-suppressant effects of ecstasy.A norexia nervosa is one of the mental diseases exhibiting the highest mortality rates in industrialized countries (1, 2). No effective strategies for treating this disorder are available. If one defines anorexia as self-imposed deprivation despite an energy demand, similar behavior can be provoked by treatments that increase serotonin (5-hydroxytryptamine, 5-HT) neuromodulation (3). For instance, fenf luramine, which increases synaptic 5-HT levels, lowers the consumption of food in humans and rodents (4, 5). Similarly, amphetamine and 3,4-N-methylenedioxymethamphetamine (MDMA, ecstasy) diminish food consumption in humans (6) and rats (7) and reduce deprivation-induced eating in mice (8). 5-HTinduced hypophagia is mediated by both 5-HT 1B and 5-HT 2C receptors (5-HT 1B R and 5-HT 2C R) (9 -11). In particular, 5-HT 2C R in the hypothalamus contributes to fenf luramineand MDMA-induced anorexia-like behavior (5, 8, 12). Moreover, 5-HT 1B R and 5-HT 2C R knockout (KO) mice are less sensitive to fenf luramine (4, 5).Stress and anxiety can also induce anorexia (13), and increases in 5-HT neuromodulation are known to participate in the decreased food intake caused by stress (14-16). We have demonstrated that 5-HT 4 R KO displays attenuated responses to stress-induced hypophagia (17). Because MDMA is a rewarding drug that reduces the intake of food...

Role of p11 in Cellular and Behavioral Effects of 5-HT4 Receptor Stimulation

“…Indeed, 5-HTR4 agonists are used in humans for the treatment of gastrointestinal disorders, like irritable-bowel syndrome (Tonini and Pace, 2006). In addition, 5-HTR4 receptors may mediate the appetite-related component of stress disorders (Compan et al, 2004;Jean et al, 2007).…”

How Does the Brain Implement Adaptive Decision Making to Eat?

“…Therefore, the sensitivity to subsequent drug exposures decreases (tolerance) with increased activity of reward pathways (dependence) to the point that drugs removal triggers depressive states . Stimulation of the cAMP/PKA/cocaine-and amphetamine-regulated transcript (CART) pathway in the NAc after local stimulation of the serotonin (5-hydroxytryptamine, 5-HT) 4 receptors (5-HTR 4 ) provokes anorexia (Jean et al, 2007). This pathway is also involved in anorexia induced by the 3,4-N-methylenedioxymethamphetamine, the psychogenic compound of ecstasy (Jean et al, 2007).…”

Distribution and immunohistochemical characteristics of cocaine- and amphetamineregulated transcript-positive nerve elements in the pelvic ganglia of the female pig

“…In peripheral autonomic ganglia, SIF cells are considered as interneurons involved in endocrine secretion including releasing of biologically active substances into intercellular spaces (Matthews 1989). To offer the full per-spective on CART-serotonin interactions, it must be mentioned that anti-CART peptide IgG changes the density of hippocampal 5-HT 2A receptor (Rothman et al 2003) and anorexia-associated activation of 5-HT 4 receptor increases the level of CART in the nucleus accumbens (Jean et al 2007). The presence of SP-IR varicose basket-like formations around CART-IR pelvic ganglia neurons suggests the direct neuromodulatory role of SP in passing signals through CART-ergic neurons.…”