Antidepressant-like activity of the neuropeptide Y Y5 receptor antagonist Lu AA33810: behavioral, molecular, and immunohistochemical evidence

• Published in: Psychopharmacology Vol. 234; no. 4; pp. 631 - 645
• Main Authors: Domin, Helena, Szewczyk, Bernadeta, Pochwat, Bartłomiej, Woźniak, Monika, Śmiałowska, Maria
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.02.2017; Springer; Springer Nature B.V
• Subjects: Analysis; Animals; Antagonists (Biochemistry); Antidepressants; Antidepressive Agents - pharmacology; Antidepressive Agents - therapeutic use; Behavior, Animal - drug effects; Benzothiepins - pharmacology; Benzothiepins - therapeutic use; Biomedical and Life Sciences; Biomedicine; Brain; Brain-Derived Neurotrophic Factor - metabolism; Chromones - pharmacology; Depression - drug therapy; Depression - metabolism; Disease Models, Animal; Drug therapy; Enzyme Inhibitors - pharmacology; Health aspects; Immunohistochemistry; Major depressive disorder; Male; Morpholines - pharmacology; Neuropeptide Y; Neuropeptide Y - metabolism; Neuropeptides; Neurosciences; Neurotransmitter receptors; Original Investigation; Pharmacological research; Pharmacology/Toxicology; Phosphoinositide-3 Kinase Inhibitors; Physiological aspects; Prefrontal Cortex - drug effects; Prefrontal Cortex - metabolism; Psychiatry; Psychopharmacology; Rats; Signal Transduction - drug effects; Studies; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; Swimming; Antidepressant; Lu AA33810; Neuropeptide Y; Forced swim test; BDNF; Astrocyte; Prefrontal cortex; GFAP; Gliotoxin
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-016-4495-3

Rationale It has recently been found that chronic treatment with the highly selective, brain-penetrating Y5 receptor antagonist, Lu AA33810 [N-[[trans-4-[(4,5-dihydro [1] benzothiepino[5,4-d] thiazol-2-yl) amino] cyclohexyl]methyl]-methanesulfonamide], produces antidepressant-like effects in the rat chronic mild stress model. Objective In the present study, we investigated the possible antidepressant-like activity of Lu AA33810 in rats subjected to glial ablation in the prefrontal cortex (PFC) by the gliotoxin L-AAA, which is an astroglial degeneration model of depression. Results We observed that Lu AA33810 administered intraperitoneally at a single dose of 10 mg/kg both reversed depressive-like behavioral changes in the forced swim test (FST) and prevented degeneration of astrocytes in the mPFC. The mechanism of antidepressant and glioprotective effects of Lu AA33810 has not been studied, so far. We demonstrated the contribution of the noradrenergic rather than the serotonergic pathway to the antidepressant-like action of Lu AA33810 in the FST. Moreover, we found that antidepressant-like effect of Lu AA33810 was connected with the influence on brain-derived neurotrophic factor (BDNF) protein expression. We also demonstrated the antidepressant-like effect of Lu AA33810 in the FST in rats which did not receive the gliotoxin. We found that intracerebroventricular injection of the selective MAPK/ERK inhibitor U0126 (5 μg/2 μl) and the selective PI3K inhibitor LY294002 (10 nmol/2 μl) significantly inhibited the anti-immobility effect of Lu AA33810 in the FST in rats, suggesting that MAPK/ERK and PI3K signaling pathways could be involved in the antidepressant-like effect of Lu AA33810. Conclusion Our results indicate that Lu AA33810 exerts an antidepressant-like effect and suggest the Y5 receptors as a promising target for antidepressant therapy.