Dopamine mesocortical pathway

Mesocortical A neural pathway that connects the ventral tegmentum to the cortex, particularly the frontal lobes. It is one of the major dopamine pathways in the brain. 

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. 

The Four Dopamine Pathways. There are four major dopamine circuits in the mammalian brain. They are known as the mesolimbic, mesocortical, tuberoinfun-dibnlar, and nigroneostriatal pathways. The mesolimbic pathway arises in the midbrain and projects to the so-called limbic structures. The mesocortical pathway arises in the midbrain and projects to frontal and temporal areas of the brain s cerebral cortex. 

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). 

Four well-defined dopamine pathways in the brain are shown in Figure 10—7. They include the mesolimbic dopamine pathway, the mesocortical dopamine pathway, the nigrostriatal dopamine pathway, and the tuberoinfundibular dopamine pathway. 

A pathway related to the mesolimbic dopamine pathway is the mesocortical dopamine pathway (Fig. 10—10). Its cell bodies arise in the ventral tegmental area of the brainstem, near the cell bodies for the dopamine neurons of the mesolimbic dopa-... 

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

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... 

Serotonin 2A antagonism not only reverses dopamine 2 antagonism but causes a net increase in dopamine activity in the mesocortical dopamine pathway, where the balance between serotonin and dopamine is different from that in the nigrostriatal dopamine pathway. That is, unlike the nigrostriatal dopamine pathway, in which dopamine 2 receptors predominate, there is a preponderance of serotonin 2A receptors over dopamine 2 receptors in many parts of the cerebral cortex. Thus, in the mesocortical dopamine pathway, atypical antipsychotics with SDA properties have a more profound effect in blocking densely populated cortical serotonin 2A receptors, thereby increasing DA release, than in blocking thinly populated cortical D2 recep-... 

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. 

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)... 

As with many neurons (e.g. NA) there are presynaptic autoreceptors on the terminals of dopamine neurons whose activation attenuate DA release. Although most of these receptors appear to be of the D2 type, as found postsynaptically, D3 receptors are also found. It is possible that in addition to the short-term control of transmitter release they may also be linked directly to the control of the synthesising enzyme tyrosine hydroxylase. It seems that autoreceptors are more common on the terminals of nerves in the nigrostriatal (and possibly mesolimbic) than mesocortical pathway. 

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