Time-dependent role of prefrontal cortex and hippocampus on cognitive improvement by aripiprazole in olfactory bulbectomized mice

• Published in: European neuropsychopharmacology Vol. 27; no. 10; pp. 1000 - 1010
• Main Authors: Takahashi, Kohei, Nakagawasai, Osamu, Nemoto, Wataru, Odaira, Takayo, Arai, Yuichiro, Hisamitsu, Tadashi, Tan-No, Koichi
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.10.2017
• Subjects: Animals; Aripiprazole; Aripiprazole - pharmacology; Avoidance Learning - drug effects; Avoidance Learning - physiology; Cell proliferation; Cell Proliferation - drug effects; Cell Proliferation - physiology; Cognitive Dysfunction - drug therapy; Cognitive Dysfunction - pathology; Cognitive Dysfunction - physiopathology; Cognitive function; Cyclic AMP Response Element-Binding Protein - metabolism; Depressive Disorder - drug therapy; Depressive Disorder - pathology; Depressive Disorder - physiopathology; Disease Models, Animal; Dopamine; Extracellular Signal-Regulated MAP Kinases - metabolism; Hippocampus - drug effects; Hippocampus - pathology; Hippocampus - physiopathology; Male; Mice; Motor Activity - drug effects; Motor Activity - physiology; Nerve growth factor; Nerve Growth Factor - metabolism; Nootropic Agents - pharmacology; Olfactory Bulb - physiopathology; Olfactory bulbectomy; Phosphorylation - drug effects; Prefrontal Cortex - drug effects; Prefrontal Cortex - pathology; Prefrontal Cortex - physiopathology; Proto-Oncogene Proteins c-fos - metabolism; Time Factors; Cell proliferation; Dopamine; DG; OBX; Nerve growth factor; Aripiprazole; NGF; PFC; CREB; ANOVA; ARI; SEM; Cognitive function; Olfactory bulbectomy; PCP; DA; BrdU; ERK
• ISSN: 0924-977X; 1873-7862
• DOI: 10.1016/j.euroneuro.2017.08.071

Dopamine (DA) modulates cognitive functions in the prefrontal cortex (PFC) and hippocampus. Olfactory bulbectomy (OBX) in mice induces cognitive dysfunctions. Recently, we reported that aripiprazole (ARI) normalizes the behavioral hyper-responsivity to DA agonists in OBX mice. However, it remains unclear whether ARI affects OBX-induced cognitive dysfunctions. To address this question we evaluated ARI-treated and untreated OBX mice in a passive avoidance test. Then, we investigated the effects of ARI on cell proliferation in the hippocampal dentate gyrus by immunohistochemistry, and on c-fos levels in the PFC and hippocampus, as well as nerve growth factor (NGF) levels in the hippocampus by western blotting. On the 14th day after surgery OBX mice showed an alteration in passive avoidance and decreases in both cell proliferation and levels of p-ERK, p-CREB and NGF in the hippocampus. The cognitive dysfunctions in OBX mice improved 30min to 24h after the administration of ARI (0.01mg/kg). C-fos levels in the PFC but not in the hippocampus was increased 30min after the administration (early response). This early response was inhibited by the selective D1 receptor antagonist SCH23390. Cell proliferation and NGF levels in the hippocampus increased 24h after ARI administration (late response), and these effects were also inhibited by SCH23390. The MEK1/2 inhibitor U0126 prevented ARI from improving the behavioral impairment as well as enhancing NGF levels in OBX mice. These findings revealed the potential of ARI to improve cognitive dysfunctions via D1 receptors with the PFC and hippocampus being affected sequentially.