title: Depressive-like behavior is paired to monoaminergic alteration in a murine model of Alzheimer's disease.
abstract: BACKGROUND
  Neuropsychiatric signs are critical in primary caregiving of Alzheimer patients and have not yet been fully investigated in murine models.
  
  
  METHODS
  18-month-old 3×Tg-AD male mice and their wild-type male littermates (non-Tg) were used. The open field test and the elevated plus maze test were used to evaluate anxiety-like behaviors, whereas the Porsolt forced swim test, the tail suspension test, and the sucrose preference test for antidepressant/depression-coping behaviors. Neurochemical study was conducted by microdialysis in freely-moving mice, analyzing the basal and K(+)-stimulated monoamine output in the frontal cortex and ventral hippocampus. Moreover by immunohistochemistry, we analysed the expression of Tyrosin hydroxylase and Tryptophan hydroxylase, which play a key role in the synthesis of monoamines.
  
  
  RESULTS
  Aged 3×Tg-AD mice exhibited a higher duration of immobility in the forced swim and tail suspension tests (predictors of depression-like behavior) which was not attenuated by a noradrenaline reuptake inhibitor, desipramine. In the sucrose preference test, 3×Tg-AD mice showed a significantly lower sucrose preference compared to the non-Tg group, without any difference in total fluid intake. In contrast, the motor functions and anxiety-related emotional responses of 3×Tg-AD mice were normal, as detected by the open-field and elevated plus-maze tests. To strengthen these results, we then evaluated the monoaminergic neurotransmissions by in vivo microdialysis and immunohistochemistry. In particular, with the exception of the basal hippocampal dopamine levels, 3×Tg-AD mice exhibited a lower basal extracellular output of amines in the frontal cortex and ventral hippocampus and also a decreased extracellular response to K(+) stimulation. Such alterations occur with obvious local amyloid-β and tau pathologies and without gross alterations in the expression of Tyrosin and Tryptophan hydroxylase.
  
  
  CONCLUSIONS
  These results suggest that 3×Tg-AD mice exhibit changes in depression-related behavior involving aminergic neurotrasmitters and provide an animal model for investigating AD with depression.
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University of Rome, Italy (Drs Romano, Tempesta, Lavecchia, Bedse, and Gaetani); Department of Clinical and Experimental Medicine, University of Foggia, Italy (Drs Pace, Macheda, and Cassano); Puglia and Basilicata Experimental Zooprophylactic Institute, Foggia, Italy (Dr Petrella); School of Pharmacy, Pharmacology Unit, University of Camerino, Italy (Dr Cifani); Department of Medical and Surgical Sciences, University of Foggia, Italy (Drs Serviddio and Vendemiale).
authors.forename: Adele
authors.initials: A
authors.lastname: Romano
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University of Rome, Italy (Drs Romano, Tempesta, Lavecchia, Bedse, and Gaetani); Department of Clinical and Experimental Medicine, University of Foggia, Italy (Drs Pace, Macheda, and Cassano); Puglia and Basilicata Experimental Zooprophylactic Institute, Foggia, Italy (Dr Petrella); School of Pharmacy, Pharmacology Unit, University of Camerino, Italy (Dr Cifani); Department of Medical and Surgical Sciences, University of Foggia, Italy (Drs Serviddio and Vendemiale).
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Pace
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University of Rome, Italy (Drs Romano, Tempesta, Lavecchia, Bedse, and Gaetani); Department of Clinical and Experimental Medicine, University of Foggia, Italy (Drs Pace, Macheda, and Cassano); Puglia and Basilicata Experimental Zooprophylactic Institute, Foggia, Italy (Dr Petrella); School of Pharmacy, Pharmacology Unit, University of Camerino, Italy (Dr Cifani); Department of Medical and Surgical Sciences, University of Foggia, Italy (Drs Serviddio and Vendemiale).
authors.forename: Bianca
authors.initials: B
authors.lastname: Tempesta
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University of Rome, Italy (Drs Romano, Tempesta, Lavecchia, Bedse, and Gaetani); Department of Clinical and Experimental Medicine, University of Foggia, Italy (Drs Pace, Macheda, and Cassano); Puglia and Basilicata Experimental Zooprophylactic Institute, Foggia, Italy (Dr Petrella); School of Pharmacy, Pharmacology Unit, University of Camerino, Italy (Dr Cifani); Department of Medical and Surgical Sciences, University of Foggia, Italy (Drs Serviddio and Vendemiale).
authors.forename: Angelo Michele
authors.initials: AM
authors.lastname: Lavecchia
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University of Rome, Italy (Drs Romano, Tempesta, Lavecchia, Bedse, and Gaetani); Department of Clinical and Experimental Medicine, University of Foggia, Italy (Drs Pace, Macheda, and Cassano); Puglia and Basilicata Experimental Zooprophylactic Institute, Foggia, Italy (Dr Petrella); School of Pharmacy, Pharmacology Unit, University of Camerino, Italy (Dr Cifani); Department of Medical and Surgical Sciences, University of Foggia, Italy (Drs Serviddio and Vendemiale).
authors.forename: Teresa
authors.initials: T
authors.lastname: Macheda
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University of Rome, Italy (Drs Romano, Tempesta, Lavecchia, Bedse, and Gaetani); Department of Clinical and Experimental Medicine, University of Foggia, Italy (Drs Pace, Macheda, and Cassano); Puglia and Basilicata Experimental Zooprophylactic Institute, Foggia, Italy (Dr Petrella); School of Pharmacy, Pharmacology Unit, University of Camerino, Italy (Dr Cifani); Department of Medical and Surgical Sciences, University of Foggia, Italy (Drs Serviddio and Vendemiale).
authors.forename: Gaurav
authors.initials: G
authors.lastname: Bedse
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University of Rome, Italy (Drs Romano, Tempesta, Lavecchia, Bedse, and Gaetani); Department of Clinical and Experimental Medicine, University of Foggia, Italy (Drs Pace, Macheda, and Cassano); Puglia and Basilicata Experimental Zooprophylactic Institute, Foggia, Italy (Dr Petrella); School of Pharmacy, Pharmacology Unit, University of Camerino, Italy (Dr Cifani); Department of Medical and Surgical Sciences, University of Foggia, Italy (Drs Serviddio and Vendemiale).
authors.forename: Antonio
authors.initials: A
authors.lastname: Petrella
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University of Rome, Italy (Drs Romano, Tempesta, Lavecchia, Bedse, and Gaetani); Department of Clinical and Experimental Medicine, University of Foggia, Italy (Drs Pace, Macheda, and Cassano); Puglia and Basilicata Experimental Zooprophylactic Institute, Foggia, Italy (Dr Petrella); School of Pharmacy, Pharmacology Unit, University of Camerino, Italy (Dr Cifani); Department of Medical and Surgical Sciences, University of Foggia, Italy (Drs Serviddio and Vendemiale).
authors.forename: Carlo
authors.initials: C
authors.lastname: Cifani
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University of Rome, Italy (Drs Romano, Tempesta, Lavecchia, Bedse, and Gaetani); Department of Clinical and Experimental Medicine, University of Foggia, Italy (Drs Pace, Macheda, and Cassano); Puglia and Basilicata Experimental Zooprophylactic Institute, Foggia, Italy (Dr Petrella); School of Pharmacy, Pharmacology Unit, University of Camerino, Italy (Dr Cifani); Department of Medical and Surgical Sciences, University of Foggia, Italy (Drs Serviddio and Vendemiale).
authors.forename: Gaetano
authors.initials: G
authors.lastname: Serviddio
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University of Rome, Italy (Drs Romano, Tempesta, Lavecchia, Bedse, and Gaetani); Department of Clinical and Experimental Medicine, University of Foggia, Italy (Drs Pace, Macheda, and Cassano); Puglia and Basilicata Experimental Zooprophylactic Institute, Foggia, Italy (Dr Petrella); School of Pharmacy, Pharmacology Unit, University of Camerino, Italy (Dr Cifani); Department of Medical and Surgical Sciences, University of Foggia, Italy (Drs Serviddio and Vendemiale).
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Vendemiale
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University of Rome, Italy (Drs Romano, Tempesta, Lavecchia, Bedse, and Gaetani); Department of Clinical and Experimental Medicine, University of Foggia, Italy (Drs Pace, Macheda, and Cassano); Puglia and Basilicata Experimental Zooprophylactic Institute, Foggia, Italy (Dr Petrella); School of Pharmacy, Pharmacology Unit, University of Camerino, Italy (Dr Cifani); Department of Medical and Surgical Sciences, University of Foggia, Italy (Drs Serviddio and Vendemiale).
authors.forename: Silvana
authors.initials: S
authors.lastname: Gaetani
authors.affiliation: Department of Physiology and Pharmacology, Sapienza University of Rome, Italy (Drs Romano, Tempesta, Lavecchia, Bedse, and Gaetani); Department of Clinical and Experimental Medicine, University of Foggia, Italy (Drs Pace, Macheda, and Cassano); Puglia and Basilicata Experimental Zooprophylactic Institute, Foggia, Italy (Dr Petrella); School of Pharmacy, Pharmacology Unit, University of Camerino, Italy (Dr Cifani); Department of Medical and Surgical Sciences, University of Foggia, Italy (Drs Serviddio and Vendemiale). tommaso.cassano@unifg.it.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Cassano
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001007:Anxiety / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015306:Biogenic Monoamines / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002491:Central Nervous System Agents / Q000494:pharmacology; D003863:Depression / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D011188:Potassium / Q000494:pharmacology; D014365:Tryptophan Hydroxylase / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D015306:Biogenic Monoamines; D002491:Central Nervous System Agents; C558298:Mapt protein, mouse; D016875:tau Proteins; D014446:Tyrosine 3-Monooxygenase; D014365:Tryptophan Hydroxylase; D011188:Potassium
keywords: anxiety; depression; frontal cortex; hippocampus; monoaminergic neurotransmission; triple transgenic model of AD