Anorexia induced by activation of serotonin 5-HT4 receptors is mediated by increases in CART in the nucleus accumbens.
Alexandra Jean, Grégory Conductier, Christine Manrique, Constantin Bouras, Philippe Berta, René Hen, Yves Charnay, Joël Bockaert, Valérie Compan
Proceedings of the National Academy of Sciences October 9, 2007 DOI: 10.1073/pnas.0701471104 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental animal study Peer reviewed |
|---|---|
| Population | Mice (including 5-HT4 receptor knockout mice) |
| Interventions | CART peptide CART siRNA MDMA |
| Topics | Serotonin |
| Key findings | Stimulating 5-HT4 receptors in the NAc reduces food intake and increases CART mRNA, while blockade or knockdown induces hyperphagia in fed mice. MDMA's anorectic effect requires 5-HT4 receptors and CART upregulation in the NAc. The authors propose that 5-HT4 receptor-mediated CART upregulation in the NAc triggers ecstasy's appetite-suppressant effects. |
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-HT(4)R) 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-HT(4)R antagonist or siRNA-mediated 5-HT(4)R 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-HT(4)R 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-HT(4)R. Using 5-HT(4)R knockout mice, we demonstrate that 5-HT(4)R 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-HT(4)R- and MDMA-induced anorexia were both reduced by injecting CART siRNA into the NAc. Collectively, these results demonstrate that 5-HT(4)R-mediated up-regulation of CART in the NAc triggers the appetite-suppressant effects of ecstasy.
Comparable studies
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| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 6
- Adolescent MDMA exposure diminishes the physiological and neurotoxic consequences of an MDMA binge in female rats Developmental Psychobiology July 1, 2014
- Opioid gene expression changes and post-translational histone modifications at promoter regions in the rat nucleus accumbens after acute and repeated 3,4-methylenedioxy-methamphetamine (MDMA) exposure. Pharmacological Research December 2016
- MDMA (ecstasy) enhances loud noise-induced morphofunctional alterations in heart and adrenal gland. Microscopy research and technique September 2011
- Serotonin 5-HT4 receptors in the nucleus accumbens are specifically involved in the appetite suppressant and not locomotor stimulant effects of MDMA ('ecstasy'). Psychopharmacology February 2011
- Residual social, memory and oxytocin-related changes in rats following repeated exposure to γ-hydroxybutyrate (GHB), 3,4-methylenedioxymethamphetamine (MDMA) or their combination. Psychopharmacology August 21, 2010
and 1 more in the library
Cites 2
- 3,4-N-methlenedioxymethamphetamine-induced hypophagia is maintained in 5-HT1B receptor knockout mice, but suppressed by the 5-HT2C receptor antagonist RS102221. Neuropsychopharmacology June 2005
- Toxicity of methylenedioxymethamphetamine (MDMA) in the dog and the rat. Fundamental and applied toxicology : official journal of the Society of Toxicology July 1, 1987