Phosphodiesterase-7 inhibition affects accumbal and hypothalamic thyrotropin-releasing hormone expression, feeding and anxiety behavior of rats

• Published in: Behavioural brain research 2017-02, Vol.319, p.165-173
• Main Authors: Valdés-Moreno, M.I., Alcántara-Alonso, V., Estrada-Camarena, E., Mengod, G., Amaya, M.I., Matamoros-Trejo, G., de Gortari, P.
• Format: Article
• Language: English
• Subjects: Animals; Anxiety; Anxiety - chemically induced; Anxiety - drug therapy; Cyclic AMP - metabolism; Cyclic Nucleotide Phosphodiesterases, Type 7 - antagonists & inhibitors; DNA, Antisense - pharmacology; Dose-Response Relationship, Drug; Eating - drug effects; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Feeding; Feeding Behavior - drug effects; Gene Expression Regulation - drug effects; Hypothalamus; Iodide Peroxidase - genetics; Iodide Peroxidase - metabolism; Iodothyronine Deiodinase Type II; Male; Maze Learning - drug effects; N. accumbens; Nitro Compounds - pharmacology; Nitro Compounds - therapeutic use; Nucleus Accumbens - drug effects; Paraventricular Hypothalamic Nucleus - drug effects; Phosphodiesterase; Rats; Rats, Wistar; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; Thyrotropin-Releasing Hormone - genetics; Thyrotropin-Releasing Hormone - metabolism; Time Factors; TRH
• ISSN: 0166-4328; 1872-7549
• DOI: 10.1016/j.bbr.2016.11.027

•Accumbal administration of a PDE7 inhibitor induces anxiolysis in rats.•Peripheral administration of PDE7 inhibitor is anxiolytic or anorexigenic.•Behavioral effects of PDE7 inhibition could be mediated by NAcc and PVN TRH. Thyrotropin-releasing hormone (TRH) has anorexigenic and anxiolytic functions when injected intraventricularly. Nucleus accumbens (NAcc) is a possible brain region involved, since it expresses proTRH. TRH from hypothalamic paraventricular nucleus (PVN) has a food intake-regulating role. TRHergic pathways of NAcc and PVN are implicated in anxiety and feeding. Both behaviors depend on cAMP and phosphorylated-cAMP response element binding protein (pCREB) intracellular levels. Intracellular levels of cAMP are controlled by the degrading activity of phosphodiesterases (PDEs). Since TRH transcription is activated by pCREB, a specific inhibitor of PDE7B may regulate TRH-induced effects on anxiety and feeding. We evaluated the effectiveness of an intra-accumbal and intraperitoneal (i.p.) administration of a PDE7 inhibitor (BRL-50481) on rats’ anxiety-like behavior and food intake; also on TRH mRNA and protein expression in NAcc and PVN to define its mediating role on the PDE7 inhibitor-induced behavioral changes. Accumbal injection of 4μg/0.3μL of PDE7 inhibitor decreased rats’ anxiety. The i.p. injection of 0.2mg/kg of the inhibitor was able to increase the PVN TRH mRNA expression and to decrease feeding but did not change animals’ anxiety levels; in contrast, 2mg/kg b.w inhibitor enhanced accumbal TRH mRNA, induced anxiolysis with no change in food intake. PDE7 inhibitor induced anxiolytic and anorexigenic like behavior depending on the dose used. Results supported hypothalamic TRH mediated feeding-reduction effects, and accumbal TRH mediation of inhibitor-induced anxiolysis. Thus, an i.p dose of this inhibitor might be reducing anxiety with no change in feeding, which could be useful for obese patients.