Savage ST, Oberg J, Pernold K, Mattsson A (2008) Enhanced sensitivity to phencyclidine following cortical cholinergic denervation. Neuroscience 2008 Abstracts 842.7/X2. Society for Neuroscience, Washington, DC.
Summary: Alterations in cholinergic signaling in the brain have been implicated as a contributing factor in the pathogenesis of schizophrenia. We have recently shown that cholinergic denervation of cortex cerebri by stereotaxic infusion of the immunotoxin 192 IgG-saporin in the nucleus basalis magnocellularis in adult rats, leads to an enhanced sensitivity to amphetamine. Thus, saporin lesioned rats show a marked increase in locomotor activity, as well as a potentiated dopamine release in nucleus accumbens when challenged with amphetamine. We hypothesize that the loss of cortical cholinergic input alters the activity of cortical glutamatergic neurons and in turn, their regulation of subcortical dopamine neurons. We have previously shown that this cortical cholinergic denervation leads to an increased locomotor response to the NMDA receptor antagonist phencyclidine (PCP), suggesting that disruption of cortical cholinergic activity can lead to disturbances of glutamatergic transmission. In current studies we are investigating attention and memory functions of rats with cholinergic denervation of neocortex using the novel object recognition task. Preliminary data from these investigations shows impairment in performance under PCP-challenge in saporin lesioned rats as compared to sham lesioned controls. These results indicate that cortical cholinergic deficits, in addition to leading to a dramatic potentiation of the locomotor response to PCP, can also lead to an enhanced sensitivity to PCP-induced cognitive impairments. Using pharmacological magnetic resonance imaging (MRI) we are investigating possible spatiotemporal differences in brain activation in rats with cortical cholinergic deficits following administration of PCP. Preliminary data have provided indications of a greater activation in cortical areas in saporin lesioned rats as compared to sham lesioned controls following PCP-challenge. Evaluations of possible alterations in social behavior following cortical cholinergic denervation are ongoing. Social interaction will be investigated under normal conditions, as well as after PCP-challenge. Preliminary results from these studies together with our previous results indicate that loss of cortical acetylcholine can lead to alterations in glutamatergic signaling. These observations are compatible with a possible role of cholinergic deficits in schizophrenia, and provide a possible link between different hypotheses of the disorder.
Related Products: 192-IgG-SAP (Cat. #IT-01)