Prolonged reversal of the phencyclidine-induced impairment in novel object recognition by a serotonin (5-HT)1A-dependent mechanism.
Many acute treatments transiently reverse the deficit in novel object recognition (NOR) produced by subchronic treatment with the N-methyl-d-aspartate receptor non-competitive antagonist, phencyclidine (PCP), in rodents. Treatments which restore NOR for prolonged periods after subchronic PCP treatment may have greater relevance for treating the cognitive impairment in schizophrenia than those which restore NOR transiently. We examined the ability of post-PCP subchronic lurasidone, an atypical APD with potent serotonin (5-HT)1A partial agonism and subchronic tandospirone, a selective 5-HT1A partial agonist, to enable prolonged reversal of the subchronic PCP-induced NOR deficit. Rats treated with subchronic PCP (2mg/kg, twice daily for 7 days) or vehicle, followed by a 7day washout period were subsequently administered lurasidone or tandospirone twice daily for 7 days (day 15-21), and tested for NOR weekly for up to two additional weeks. Subchronic lurasidone (1, but not 0.1mg/kg) or tandospirone (5, but not 0.6mg/kg) significantly reversed the PCP-induced NOR deficit at 24h and 7days after the last injection, respectively. The effect of lurasidone persisted for one more week (day 36, 14 days after the last lurasidone dose), while tandospirone-treated rats were able to perform NOR at 7, but not 14, days after the last tandospirone dose. Co-administration of WAY100635 (0.6mg/kg), a 5-HT1A antagonist, with lurasidone, blocked the ability of lurasidone to restore NOR, suggesting that 5-HT1A receptor stimulation is necessary for lurasidone to reverse the effects of PCP. The role of dopamine, GABA and the MAPK/ERK signalling pathway in the persistent, but not indefinite, restoration of NOR is discussed.
Division of Psychiatry and Behavioural Sciences, Northwestern University Feinberg School of Medicine, Chicago IL 60611, USA; Division of Psychopharmacology, Vanderbilt University Medical Center, Nashville TN 37212, USA; Sumitomo Dainippon Pharma Co., Ltd., Osaka 564-0053, Japan.
Masakuni
M
Horiguchi
Division of Psychiatry and Behavioural Sciences, Northwestern University Feinberg School of Medicine, Chicago IL 60611, USA; Sumitomo Dainippon Pharma Co., Ltd., Osaka 564-0053, Japan.
Masanori
M
Miyauchi
Division of Psychiatry and Behavioural Sciences, Northwestern University Feinberg School of Medicine, Chicago IL 60611, USA.
Nichole M
NM
Neugebauer
Division of Psychiatry and Behavioural Sciences, Northwestern University Feinberg School of Medicine, Chicago IL 60611, USA; Sumitomo Dainippon Pharma Co., Ltd., Osaka 564-0053, Japan.
Yoshihiro
Y
Oyamada
Division of Psychiatry and Behavioural Sciences, Northwestern University Feinberg School of Medicine, Chicago IL 60611, USA; Division of Psychopharmacology, Vanderbilt University Medical Center, Nashville TN 37212, USA. Electronic address: h-meltzer@northwestern.edu.
Herbert Y
HY
Meltzer
D000818:Animals; D003072:Cognition Disorders / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D054833:Isoindoles / Q000494:pharmacology; D000069056:Lurasidone Hydrochloride / Q000494:pharmacology*; D010622:Phencyclidine; D010879:Piperazines / Q000494:pharmacology; D011619:Psychotropic Drugs / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011897:Random Allocation; D020318:Rats, Long-Evans; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D021641:Recognition, Psychology / Q000187:drug effects* / Q000502:physiology; D012565:Schizophrenic Psychology; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology*; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000494:pharmacology; D013995:Time
D054833:Isoindoles; D010879:Piperazines; D011619:Psychotropic Drugs; D011725:Pyridines; D011743:Pyrimidines; D016194:Receptors, N-Methyl-D-Aspartate; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D044282:Receptor, Serotonin, 5-HT1A; C055267:tandospirone; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D010622:Phencyclidine; D000069056:Lurasidone Hydrochloride
5-HT(1A); Cognitive impairment; Lurasidone; Novel object recognition; Phencyclidine; Schizophrenia; Tandospirone