Negative symptoms 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 10—10. The mesocortical dopamine pathway mediates the negative and cognitive symptoms of psychosis. 

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. 

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). 

The four major dopamine pathways in the brain have been described. The me-solimbic dopamine system, which may mediate the positive symptoms of psychosis the mesocortical system, which may mediate the negative symptoms and cognitive symptoms of psychosis the nigrostriatal system, which mediates extrapyramidal... 

A new, so-called third generation of antipsychotics has recently been introduced, and at this time one drug, aripiprazole, is available and others are in the late stages of development. This new class of medications has a novel mechanism of action that, at least in theory, should deal with several of the limitations of other atypicals. It will be remembered that all antipsychotics preceding this class had the ability to block the dopamine receptor, and they did so in all four dopamine pathways. As discussed, this had both benefits and drawbacks dopamine blockade resulted in the improvement of positive symptoms (mesolimbic pathway) but had a limited benefit in negative symptom reduction (mesocortical... 

By blocking dopamine 2 receptors excessively in the mesocortical and mesolimbic dopamine pathways, especially at high doses, it can cause worsening of negative and cognitive symptoms (neuroleptic-induced deficit syndrome)... 

Decreased inhibition of the mesocortical dopaminergic pathway and a consequent increase in dopamine secretion in cortical regions. This could explain the potential beneficial effects of SCAs in alleviating negative symptoms. 

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