Under- to Over-Eating: How Do Serotonin Receptors Contribute?
Under- to Over-Eating: How Do Serotonin Receptors Contribute?
Deep-brain stimulation has been highlighted as an effective treatment of depression, proposed as a treatment of addiction and, recently, debated as a possible mode of treatment of anorexia nervosa. Ten decades of studies has, however, demonstrated the implication of specific neural pathways in several brain structures in the regulation of one specific behavior. It remains unclear how invasive procedures targeting one brain area can treat such disorders. Targeting structures of the reward system to treat anorexia nervosa could be conceivable using specific pharmaceuticals of the 5-HTR4 because: stimulating the NAc-5-HTR4 favors a restrictive diet following the activation of an addiction-related signaling pathway (cAMP/PKA); an addiction-related animal model (5-HTR1B KO) continues to fast following partial food restriction, strengthening the molecular rewarding facet of anorexia; and the anorexia of 5-HTR1B KO mice was hyperactivity-dependent because their NAc-5-HTR4/CART pathway is more active than normal. This pathway may represent a 'functional unit' in the brain involved in energy expenditure (elevated motor activity with reduced motor activity), and introduce an additional repartition of functions in brain. Motor and feeding behaviors, and likely other behaviors, could be regulated by common molecular signaling pathways and not only by neural systems acting in parallel. Targeting specific receptors may then be advantageous to treat one syndrome rather than only one symptom.
Accordingly, we have found a new molecular mechanism that may underlie the transition from under- to over-eating. This mechanism is related to changes in the activity of the 5-HTR4 involved in the regulation of feeding behavior. This new mechanism depends on a peculiar property of GPCRs. Like other GPCR, 5-HTR4 displays an active form (G-protein coupled) and inactive (G-protein uncoupled) form in the plasma membrane. Agonists, including 5-HT, stabilize 5-HTR4 in their active form (symbolized by R*). The 5-HTR4 and some other GPCRs (including melanocortin receptors) have a particular property, described so far in vitro. They may exhibit an autonomous capacity to regulate their own intracellular signaling pathways, without agonist stimulation. This autonomous capacity (or agonist-independent activity) defines their constitutive activity. Inhibiting the constitutive activity, in other words, removing the autonomous capacity of 5-HTR4 to regulate their own intracellular signaling pathways stabilizes these receptors in their inactive form (R). An inverse agonist has the property to inhibit the constitutive activity of GPCRs, including the 5-HTR4, and then displaces the significant amount of active R* form towards R, until R* is suppressed, in the absence of stimulation. Inverse agonist stabilizes the inactive form of these receptors. In brief, agonists enrich R* whereas inverse agonists stabilize R and antagonists equilibrate R/R*. However, the physiological consequences of the R*/R transition ('toggling') remains unknown. Since stimulating 5-HTR4 in the NAc favors anorexia, completely inactivating the 5-HTR4 in the NAc of freely moving mice would be expected to provoke overeating. We hypothesized that the two extremes of the 5-HTR*4/5-HTR4 in the NAc correspond to two extremes of feeding patterns: restrictive diet and overeating
Activation of the main signaling pathway (cAMP/PKA) of 5-HTR4 in the NAc (R*) favors a restrictive diet. Completely inactivating 5-HTR4, in other words injecting a specific inverse agonist of 5-HTR4 in freely moving mice, causes overeating. From R* to R, cAMP levels increase then decrease in the NAc. Analyses of downstream molecular changes show that activation of 5-HTR4 in the NAc promotes anorexia because the levels of an anorectic peptide CART increase (Figure 2). Silencing R5-HT4 decreases CART and increases the mRNA levels of NPY, an orexigenic peptide in the NAc (Figure 2). siRNA-mediated NPY knockdown in the NAc suppresses overeating induced by the total inactivation of 5-HTR4. Results further include that the absence of 5-HTR4 'hijacks' cocaine abuse to excessive food intake. Selecting one's addiction may then depend on the activity state of 5-HTR4.
Pharmaceuticals or Brain Surgery for Anorexia & Bulimia Nervosa?
Deep-brain stimulation has been highlighted as an effective treatment of depression, proposed as a treatment of addiction and, recently, debated as a possible mode of treatment of anorexia nervosa. Ten decades of studies has, however, demonstrated the implication of specific neural pathways in several brain structures in the regulation of one specific behavior. It remains unclear how invasive procedures targeting one brain area can treat such disorders. Targeting structures of the reward system to treat anorexia nervosa could be conceivable using specific pharmaceuticals of the 5-HTR4 because: stimulating the NAc-5-HTR4 favors a restrictive diet following the activation of an addiction-related signaling pathway (cAMP/PKA); an addiction-related animal model (5-HTR1B KO) continues to fast following partial food restriction, strengthening the molecular rewarding facet of anorexia; and the anorexia of 5-HTR1B KO mice was hyperactivity-dependent because their NAc-5-HTR4/CART pathway is more active than normal. This pathway may represent a 'functional unit' in the brain involved in energy expenditure (elevated motor activity with reduced motor activity), and introduce an additional repartition of functions in brain. Motor and feeding behaviors, and likely other behaviors, could be regulated by common molecular signaling pathways and not only by neural systems acting in parallel. Targeting specific receptors may then be advantageous to treat one syndrome rather than only one symptom.
Accordingly, we have found a new molecular mechanism that may underlie the transition from under- to over-eating. This mechanism is related to changes in the activity of the 5-HTR4 involved in the regulation of feeding behavior. This new mechanism depends on a peculiar property of GPCRs. Like other GPCR, 5-HTR4 displays an active form (G-protein coupled) and inactive (G-protein uncoupled) form in the plasma membrane. Agonists, including 5-HT, stabilize 5-HTR4 in their active form (symbolized by R*). The 5-HTR4 and some other GPCRs (including melanocortin receptors) have a particular property, described so far in vitro. They may exhibit an autonomous capacity to regulate their own intracellular signaling pathways, without agonist stimulation. This autonomous capacity (or agonist-independent activity) defines their constitutive activity. Inhibiting the constitutive activity, in other words, removing the autonomous capacity of 5-HTR4 to regulate their own intracellular signaling pathways stabilizes these receptors in their inactive form (R). An inverse agonist has the property to inhibit the constitutive activity of GPCRs, including the 5-HTR4, and then displaces the significant amount of active R* form towards R, until R* is suppressed, in the absence of stimulation. Inverse agonist stabilizes the inactive form of these receptors. In brief, agonists enrich R* whereas inverse agonists stabilize R and antagonists equilibrate R/R*. However, the physiological consequences of the R*/R transition ('toggling') remains unknown. Since stimulating 5-HTR4 in the NAc favors anorexia, completely inactivating the 5-HTR4 in the NAc of freely moving mice would be expected to provoke overeating. We hypothesized that the two extremes of the 5-HTR*4/5-HTR4 in the NAc correspond to two extremes of feeding patterns: restrictive diet and overeating
Activation of the main signaling pathway (cAMP/PKA) of 5-HTR4 in the NAc (R*) favors a restrictive diet. Completely inactivating 5-HTR4, in other words injecting a specific inverse agonist of 5-HTR4 in freely moving mice, causes overeating. From R* to R, cAMP levels increase then decrease in the NAc. Analyses of downstream molecular changes show that activation of 5-HTR4 in the NAc promotes anorexia because the levels of an anorectic peptide CART increase (Figure 2). Silencing R5-HT4 decreases CART and increases the mRNA levels of NPY, an orexigenic peptide in the NAc (Figure 2). siRNA-mediated NPY knockdown in the NAc suppresses overeating induced by the total inactivation of 5-HTR4. Results further include that the absence of 5-HTR4 'hijacks' cocaine abuse to excessive food intake. Selecting one's addiction may then depend on the activity state of 5-HTR4.
Source...