TY - JOUR
T1 - Atypical but not typical antipsychotic drugs ameliorate phencyclidine-induced emotional memory impairments in mice
AU - Adem, Abdu
AU - Madjid, Nather
AU - Stiedl, Oliver
AU - Bonito-Oliva, Alessandra
AU - Konradsson-Geuken, Åsa
AU - Holst, Sarah
AU - Fisone, Gilberto
AU - Ögren, Sven Ove
N1 - Funding Information:
SOÖ was supported by two grants: (1) The Swedish Brain Foundation , Hjärnfonden (2016). (2) The Swedish Alzheimer Foundation ( AF-555891 ). AA was supported by two grants: (1) Interdisciplinary grant ( 31R142 ) from the United Arab Emirates University . (2) Faculty grant ( NP14-42 ) from the College of Medicine and Health Sciences .
Funding Information:
SOÖ was supported by two grants: (1) The Swedish Brain Foundation, Hjärnfonden (2016). (2) The Swedish Alzheimer Foundation (AF-555891). AA was supported by two grants: (1) Interdisciplinary grant (31R142) from the United Arab Emirates University. (2) Faculty grant (NP14-42) from the College of Medicine and Health Sciences. We wish to thank Sophia Wadenberg, Department of Neuroscience, Karolinska Institutet, for her secretarial work.
Funding Information:
SO? was supported by two grants: (1)The Swedish Brain Foundation, Hj?rnfonden (2016). (2)The Swedish Alzheimer Foundation (AF-555891). AA was supported by two grants: (1)Interdisciplinary grant (31R142)from the United Arab Emirates University. (2)Faculty grant (NP14-42)from the College of Medicine and Health Sciences. We wish to thank Sophia Wadenberg, Department of Neuroscience, Karolinska Institutet, for her secretarial work.
Publisher Copyright:
© 2019
PY - 2019/5
Y1 - 2019/5
N2 - Schizophrenia is associated with cognitive impairments related to hypofunction in glutamatergic N-methyl-D-aspartate receptor (NMDAR)transmission. Phencyclidine (PCP), a non-competitive NMDAR antagonist, models schizophrenia-like behavioral symptoms including cognitive deficits in rodents. This study examined the effects of PCP on emotional memory function examined in the passive avoidance (PA)task in mice and the ability of typical and atypical antipsychotic drugs (APDs)to rectify the PCP-mediated impairment. Pre-training administration of PCP (0.5, 1, 2 or 3 mg/kg)dose-dependently interfered with memory consolidation in the PA task. In contrast, PCP was ineffective when administered after training, and immediately before the retention test indicating that NMDAR blockade interferes with memory encoding mechanisms. The typical APD haloperidol and the dopamine D 2/3 receptor antagonist raclopride failed to block the PCP-induced PA impairment suggesting a negligible role of D 2 receptors in the PCP impairment. In contrast, the memory impairment was blocked by the atypical APDs clozapine and olanzapine in a dose-dependent manner while risperidone was effective only at the highest dose tested (1 mg/kg). The PCP-induced impairment involves 5-HT 1A receptor mechanisms since the antagonist NAD-299 blocked the memory impairment caused by PCP and the ability of clozapine to attenuate the impairment by PCP. These results indicate that atypical but not typical APDs can ameliorate NMDAR-mediated memory impairments and support the view that atypical APDs such as clozapine can modulate glutamatergic memory dysfunctions through 5-HT 1A receptor mechanisms. These findings suggest that atypical APDs may improve cognitive impairments related to glutamatergic dysfunction relevant for emotional memories in schizophrenia.
AB - Schizophrenia is associated with cognitive impairments related to hypofunction in glutamatergic N-methyl-D-aspartate receptor (NMDAR)transmission. Phencyclidine (PCP), a non-competitive NMDAR antagonist, models schizophrenia-like behavioral symptoms including cognitive deficits in rodents. This study examined the effects of PCP on emotional memory function examined in the passive avoidance (PA)task in mice and the ability of typical and atypical antipsychotic drugs (APDs)to rectify the PCP-mediated impairment. Pre-training administration of PCP (0.5, 1, 2 or 3 mg/kg)dose-dependently interfered with memory consolidation in the PA task. In contrast, PCP was ineffective when administered after training, and immediately before the retention test indicating that NMDAR blockade interferes with memory encoding mechanisms. The typical APD haloperidol and the dopamine D 2/3 receptor antagonist raclopride failed to block the PCP-induced PA impairment suggesting a negligible role of D 2 receptors in the PCP impairment. In contrast, the memory impairment was blocked by the atypical APDs clozapine and olanzapine in a dose-dependent manner while risperidone was effective only at the highest dose tested (1 mg/kg). The PCP-induced impairment involves 5-HT 1A receptor mechanisms since the antagonist NAD-299 blocked the memory impairment caused by PCP and the ability of clozapine to attenuate the impairment by PCP. These results indicate that atypical but not typical APDs can ameliorate NMDAR-mediated memory impairments and support the view that atypical APDs such as clozapine can modulate glutamatergic memory dysfunctions through 5-HT 1A receptor mechanisms. These findings suggest that atypical APDs may improve cognitive impairments related to glutamatergic dysfunction relevant for emotional memories in schizophrenia.
KW - 5-HT receptor
KW - Atypical antipsychotic drugs
KW - Clozapine
KW - Emotional memory
KW - Passive avoidance
KW - Phencyclidine
UR - http://www.scopus.com/inward/record.url?scp=85063191776&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85063191776&partnerID=8YFLogxK
U2 - 10.1016/j.euroneuro.2019.03.007
DO - 10.1016/j.euroneuro.2019.03.007
M3 - Article
C2 - 30910381
AN - SCOPUS:85063191776
SN - 0924-977X
VL - 29
SP - 616
EP - 628
JO - European Neuropsychopharmacology
JF - European Neuropsychopharmacology
IS - 5
ER -