The central cholinergic system as a therapeutic target for the cognitive dysfunction of schizophrenia
Herman, Elizabeth Joan
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Schizophrenia is characterized by three core symptoms: positive, negative and cognitive dysfunction, the latter symptom is best correlated with long term functional outcome. While most studies related to schizophrenia (including those related to cognitive function) have focused on abnormalities in the neurotransmitters, dopamine, serotonin and glutamate, there is also evidence that acetylcholine neurotransmission (i.e., central cholinergic function) is altered in the illness. Thus, the central cholinergic system could serve as a therapeutic target for improving cognition in schizophrenia. In the evaluation of two commonly used AChEIs for effects on sensorimotor gating in an experimental animal model, galantamine (depending on dose) improved PPI deficits in three pharmacologic models of PPI impairment, whereas donepezil ameliorated PPI deficits induced by scopolamine and apomorphine, but was not effective in the MK801 model. In radial arm maze experiments neither haloperidol nor risperidone affected win-shift acquisition although DNMTP performance was modestly impaired at the longer delays by risperidone. Haloperidol, but not risperidone, impaired water maze hidden platform acquisition as well as probe trial performance possibly due to psychomotor impairments and elevated levels of anxiety. In 5CSRTT experiments haloperidol and, to a lesser degree, risperidone, impaired task acquisition as indicated by the failure (or increase in the number of trials) to meet specific performance criteria. Results from these behavior experiments indicate task dependent and temporal effects of exposure to therapeutic doses of haloperidol and risperidone and risperidone may impair spatial working and short-term memory as the demands of the task increase. Haloperidol and risperidone were without significant effect in the ELISA experiments which were conducted to detect potential (antipsychotic-related) alterations in the levels of VAChT and α7 nAChR in medial prefrontal cortex of rats treated for 320 days.