Schizophrenia mesocortical dopamine pathway

In contrast, it is often hypothesized that the negative symptoms of schizophrenia are a result of decreased activity of the mesocortical dopamine pathway. Unfortunately, dopamine blocking by typical antipsychotics in the mesocortical pathway does not improve the negative symptoms, and may even worsen them. 

FIGURE 11—27. The mesocortical dopamine pathway may mediate deficits in cognitive functioning and negative symptoms in schizophrenia because of a relative deficiency in dopamine, due either to a primary deficiency or to various secondary causes, such as serotonin excess. In either case, blockade of 5HT2A receptors with an atypical antipsychotic should lead to dopamine release, which could compensate for the dopamine deficiency and improve negative and cognitive symptoms. 

Schizophrenia is the most common psychotic disorder. It may be due to an abnormality of dopamine receptors or increased release of dopamine in particular regions of the brain, the mesolimbic and mesocortical pathways. In addition, there may be an abnormality of serotonin pathways that interact with dopamine. Most drugs effective in the treatment of schizophrenia block dopamine receptors and some of the newer ones block serotonin receptors. Adverse effects of antipsychotics can be severe and are largely due to the blocking of dopamine receptors in other parts of the brain. For example Parkinsonism and tardive dyskinesia are the result of dopamine receptor blocking in the basal nuclei. 

Underactivity of dopamine in mesocortical pathways, specifically those projecting to the frontal lobes, may account for the negative symptoms of schizophrenia (e.g., anergia, apathy, lack of spontaneity) (Davis et al. 1991 Goff and Evins 1998). In addition, this underactivity in the frontal lobes may serve to disinhibit mesolimbic dopamine activity via a corticolimbic feedback loop. Overactivity of mesolimbic dopamine is the result, which manifests as the positive symptoms of schizophrenia (e.g., hallucinations, delusions). 

It is thought that there is an abnormality of dopamine receptors or increased release of dopamine in the mesolimbic and mesocortical pathways in schizophrenics. However, no reproducible changes in dopaminergic systems have been found in schizophrenia and the abnormality may be in another system that is somehow linked to dopaminergic neurones. More recently, it has been suggested that schizophrenia may be a developmental disorder of the prefrontal cortex where there is actually a deficiency of dopamine, which leaves dopamine activity in the mesolimbic pathway unbalanced. 

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