Neurochemical changes underlying cognitive impairment in olfactory bulbectomized rats and the impact of the mGlu₅-positive allosteric modulator CDPPB

The olfactory bulbectomized (OBX) rat model is a well-established model of depression in which antidepressant drugs reverse deficits in the passive avoidance test 14 days after administration. Recently, the olfactory bulbectomized rat model has been proposed to be a model of Alzheimer's disease (AD), and the available data indicate similarities between the changes that typically occur in AD and those observed in OBX animals. In the present study, the occurrence of neurochemical impairments related to AD were investigated 8 months after OB ablation. The expression of the nitric oxide synthases eNOS and nNOS, receptor for advanced glycation endproducts (RAGEs) and dimethylarginine dimethylaminohydrolase (DDAH1) in the prefrontal cortices (PFCs), hippocampi and striata of olfactory bulbectomized and sham-operated rats was evaluated. Subsequently, the impact of the administration of a positive allosteric modulator of the mGlu₅ receptor, CDPPB (14 days, 2.5 or 5 mg/kg), on OBX-related changes was assessed. OB ablation induced typical deficits in passive avoidance. Significant aberrations in the expression of both isoforms of NOS were observed in the hippocampus and striatum, and the expression of DDAH1 was increased in the PFCs of OBX animals. CDPPB at a dose of 5 mg/kg ameliorated cognitive impairment in the passive avoidance test and partially reversed the changes in eNOS and nNOS expression induced by the lesion. The results of this study confirm that some of the neurochemical changes observed in OBX animals may resemble those associated with AD pathology and that activation of the mGlu₅ receptor may partially counteract these pathological alterations.