Neuronal mechanisms of the attentional dysfunctions in senile dementia and schizophrenia: two sides of the same coin?

Deficits in early stages of information processing, specifically the inability to "disattend" irrelevant stimuli and to selectively allocate processing resources (i.e., hyperattention), have been associated with the development of psychotic symptoms. Opposite deficits, i.e., the failure to attend and select stimuli, and to divide attention (i.e., hypoattention), represent a major variable in the development of dementia. The hypothesis that hyperattention and hypoattention are mediated via cortical cholinergic hyperactivity and hypoactivity, respectively, is discussed. Several lines of evidence support the role of cholinergic hyperactivity in the development of psychotic symptoms, including the therapeutic effects of anticholinergic drugs in schizophrenic patients, the psychotic effects of chronic exposure to irreversible cholinesterase inhibitors, and the worsening of psychotic symptoms as a result of the treatment with cholinomimetic compounds. The potent impairments of attentional abilities as a result of the administration of muscarinic antagonists in intact subjects, and the attentional effects of cholinomimetic compounds in demented patients are two examples of the evidence that supports the role of cholinergic hypofunction in the cognitive impairments of dementia. A neuronal model of dopamine-GABAergic modulation of cortical acetylcholine is proposed on the basis of evidence indicating that nucleus accumbens dopamine, via a GABAergic pathway to the substantia innominata of the basal forebrain, modulates cortical acetylcholine release. The available evidence confirms several predictions derived from this model, including the dopaminergic regulation of cortical acetylcholine (ACh) release, the bidirectional modulation of this release by benzodiazepine receptor (BZR) agonists and inverse agonists, and the antipsychotic effects of BZR agonists. Bidirectional deviations in the activity of cortical cholinergic inputs are hypothesized to represent a major neuronal substrate of the attentional dysfunctions associated with, or even underlying, the development of psychotic symptoms and dementia.