Pituitary Adenylate Cyclase-Activating Peptide in the Central Amygdala Causes Anorexia and Body Weight Loss via the Melanocortin and the TrkB Systems

Abstract

Growing evidence suggests that the pituitary adenylate cyclase-activating polypeptide (PACAP)/PAC1 receptor system represents one of the main regulators of the behavioral, endocrine, and autonomic responses to stress. Although induction of anorexia is a well-documented effect of PACAP, the central sites underlying this phenomenon are poorly understood. The present studies addressed this question by examining the neuroanatomical, behavioral, and pharmacological mechanisms mediating the anorexia produced by PACAP in the central nucleus of the amygdala (CeA), a limbic structure implicated in the emotional components of ingestive behavior. Male rats were microinfused with PACAP (0-1 μg per rat) into the CeA and home-cage food intake, body weight change, microstructural analysis of food intake, and locomotor activity were assessed. Intra-CeA (but not intra-basolateral amygdala) PACAP dose-dependently induced anorexia and body weight loss without affecting locomotor activity. PACAP-treated rats ate smaller meals of normal duration, revealing that PACAP slowed feeding within meals by decreasing the regularity and maintenance of feeding from pellet-to-pellet; postprandial satiety was unaffected. Intra-CeA PACAP-induced anorexia was blocked by coinfusion of either the melanocortin receptor 3/4 antagonist SHU 9119 or the tyrosine kinase B (TrKB) inhibitor k-252a, but not the CRF receptor antagonist D-Phe-CRF(12-41). These results indicate that the CeA is one of the brain areas through which the PACAP system promotes anorexia and that PACAP preferentially lessens the maintenance of feeding in rats, effects opposite to those of palatable food. We also demonstrate that PACAP in the CeA exerts its anorectic effects via local melanocortin and the TrKB systems, and independently from CRF.

Pituitary adenylate cyclase-activating polypeptide (PACAP) in the central nucleus of the amygdala induces anxiety via melanocortin receptors

“…This mechanism is in line with previous observations showing that central administration of PACAP (but not VIP) activates melanocortinergic neurons, and that the effects of PACAP, both in the hypothalamus and in the CeA, on food intake are mediated by MC 4 R (Iemolo et al 2015; Mounien et al 2006; Mounien et al 2009). PACAP administered into the CeA has indeed been shown to reduce food intake (Iemolo et al 2015).…”

“…Interestingly, the 0.3 μg/rat dose was the most effective one in inducing anxiety-like behavior (44% reduction), which suggests that PACAP at higher doses may lose selectivity. The number of entries in the closed arms, commonly inferred as a measure of motor activity (Cruz et al 1994), was unaffected by PACAP treatment; this observation confirms that the anxiety-like behavior following PACAP administration into the CeA was not due to a general suppression of motor activity, as we have already shown previously analyzing the number of beam breaks (Iemolo et al 2015). Importantly, intra-CeA PACAP was able to induce anxiety-like behavior also using a different behavioral task, the defensive withdrawal test.…”

“…SHU9119 has been described to be a potent melanocortin MC3/4 receptor antagonist and MC5 receptor agonist (IC50 = 0.23 ± 0.02 nM at the hMC3R and IC50 = 0.06 ± 0.01 nM at the hMC4R with no cAMP activity at the receptor at 10–5 M concentration of ligand; IC50 = 0.09 ± 0.02 nM and EC50 = 0.12 ± 0.01 nM with 97% of activity at the hMC5R) (Grieco et al 2007; Hruby et al 1995). PACAP doses were chosen based on previous reports from our laboratory using intracranial administration (Dore et al 2013a; Iemolo et al 2015). For SHU9119 a sub-threshold dose of SHU9119 was chosen based on previous reports using intracranial administration of the drug in the range of 10–100 pmol (Boghossian et al 2010; Hagan et al 1999; Iemolo et al 2015; Liu et al 2007; Roseberry 2013).…”

“…PACAP doses were chosen based on previous reports from our laboratory using intracranial administration (Dore et al 2013a; Iemolo et al 2015). For SHU9119 a sub-threshold dose of SHU9119 was chosen based on previous reports using intracranial administration of the drug in the range of 10–100 pmol (Boghossian et al 2010; Hagan et al 1999; Iemolo et al 2015; Liu et al 2007; Roseberry 2013). A subthreshold of SHU9119 was chosen to ensure no per se activity at any of the melanocortin receptors bound.…”

Pituitary adenylate cyclase-activating polypeptide induces a depressive-like phenotype in rats

“…This finding excludes potential locomotor suppressive effects of the peptides, in line with a lack of increased immobility in the FST as well as previous reports showing no locomotor impairment following administration of PACAP in rodents (Dore et al 2013; Iemolo et al 2015; Kocho-Schellenberg et al 2014; Mounien et al 2009; Resch et al 2011). We believe that the demonstration of the attenuation in the brain reward system function following administration of PACAP is a very significant one, as ICSS can be considered a direct read-out of intact reward functioning in the brain.…”