PMID- 27007604 OWN - NLM STAT- MEDLINE DCOM- 20170214 LR - 20181202 IS - 1432-2072 (Electronic) IS - 0033-3158 (Linking) VI - 233 IP - 12 DP - 2016 Jun TI - Piromelatine ameliorates memory deficits associated with chronic mild stress-induced anhedonia in rats. PG - 2229-39 LID - 10.1007/s00213-016-4272-3 [doi] AB - RATIONALE: Previous studies have demonstrated that piromelatine (a melatonin and serotonin 5-HT1A and 5-HT1D agonist) exerts an antidepressant activity in rodent models of acute stress and improves cognitive impairments in a rat model of Alzheimer's disease (AD). However, the role of piromelatine in chronic stress-induced memory dysfunction remains unclear. OBJECTIVE: The aim of this study was to determine whether piromelatine ameliorates chronic mild stress (CMS)-induced memory deficits and explore the underlying mechanisms. METHODS: Rats were exposed randomly to chronic mild stressors for 7 weeks to induce anhedonia (reflected by a significant decrease in sucrose intake), which was used to select rats vulnerable (CMS-anhedonic, CMSA) or resistant (CMS-resistant, CMSR) to stress. Piromelatine (50 mg/kg) was administered daily during the last 2 weeks of CMS. The tail suspension and forced swimming tests were adopted to further characterize vulnerable and resilient rats. The Y-maze and novel object recognition (NOR) tests were used to evaluate memory performance. Brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), phosphorylated CREB (pCREB), and cytogenesis were measured in the hippocampus. RESULTS: We found that only CMSA rats displayed significant increases in immobility time in the tail suspension and forced swimming tests; memory deficits in the Y-maze and NOR tests; significant decreases in hippocampal BDNF, CREB, and pCREB expression; and cytogenesis. All these anhedonia-associated effects were reversed by piromelatine. CONCLUSIONS: Piromelatine ameliorates memory deficits associated with CMS-induced anhedonia in rats and this effect may be mediated by restoring hippocampal BDNF, CREB, and cytogenesis deficits. FAU - Fu, Wan AU - Fu W AD - Department of Neurology, First Affiliated Hospital, University of South China, Hengyang, Hunan, 421001, People's Republic of China. FAU - Xie, Heng AU - Xie H AD - Department of Neurology, First Affiliated Hospital, University of South China, Hengyang, Hunan, 421001, People's Republic of China. FAU - Laudon, Moshe AU - Laudon M AD - Neurim Pharmaceuticals Ltd., Tel-Aviv, Israel. FAU - Zhou, Shouhong AU - Zhou S AD - Department of Physiology, Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China. AD - Institute of Neuroscience, College of Medicine, University of South China, Hengyang, Hunan, 421001, People's Republic of China. FAU - Tian, Shaowen AU - Tian S AD - Department of Physiology, Medical School, University of South China, Hengyang, 421001, Hunan, People's Republic of China. tsw.neuro@126.com. AD - Institute of Neuroscience, College of Medicine, University of South China, Hengyang, Hunan, 421001, People's Republic of China. tsw.neuro@126.com. FAU - You, Yong AU - You Y AD - Department of Neurology, First Affiliated Hospital, University of South China, Hengyang, Hunan, 421001, People's Republic of China. youyong2000@126.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160323 PL - Germany TA - Psychopharmacology (Berl) JT - Psychopharmacology JID - 7608025 RN - 0 (Antidepressive Agents) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Cyclic AMP Response Element-Binding Protein) RN - 0 (Indoles) RN - 0 (Pyrans) RN - 0 (Serotonin 5-HT1 Receptor Agonists) RN - S3UN2146K9 (N-(2-(5-methoxy-indol-3-yl)-ethyl)-4-oxo-4H-pyran-2-carboxamide) SB - IM MH - Anhedonia/*drug effects/physiology MH - Animals MH - Antidepressive Agents/pharmacology/*therapeutic use MH - Brain-Derived Neurotrophic Factor/metabolism MH - Cyclic AMP Response Element-Binding Protein/metabolism MH - Hippocampus/drug effects/metabolism MH - Indoles/pharmacology/*therapeutic use MH - Male MH - Memory Disorders/*drug therapy/etiology/metabolism MH - Pyrans/pharmacology/*therapeutic use MH - Random Allocation MH - Rats MH - Rats, Wistar MH - Serotonin 5-HT1 Receptor Agonists/pharmacology/therapeutic use MH - Stress, Psychological/complications/*drug therapy/metabolism OTO - NOTNLM OT - BDNF OT - CREB OT - Chronic mild stress OT - Memory deficits OT - Neurogenesis OT - Piromelatine EDAT- 2016/03/24 06:00 MHDA- 2017/02/15 06:00 CRDT- 2016/03/24 06:00 PHST- 2015/10/25 00:00 [received] PHST- 2016/03/08 00:00 [accepted] PHST- 2016/03/24 06:00 [entrez] PHST- 2016/03/24 06:00 [pubmed] PHST- 2017/02/15 06:00 [medline] AID - 10.1007/s00213-016-4272-3 [pii] AID - 10.1007/s00213-016-4272-3 [doi] PST - ppublish SO - Psychopharmacology (Berl). 2016 Jun;233(12):2229-39. doi: 10.1007/s00213-016-4272-3. Epub 2016 Mar 23.