Schizophrenia mesolimbic dopamine pathway

In admittedly oversimplified terms, it is believed that hyperactivity of dopamine neurons in the mesolimbic pathway contribute to the positive symptoms of schizophrenia. All the typical antipsychotics are believed to work by reducing the activity of the mesolimbic dopamine pathway. More specifically, they do this by blocking dopamine receptors on the nerve cells. Over a period of 1-3 weeks, the dopamineblocking effect of the typical antipsychotic begins to relieve the positive symptoms of schizophrenia. 

FIGURE 10-8. This diagram shows the mesolimbic dopamine pathway, which is thought to be hyperactive in schizophrenia and to mediate the positive symptoms of psychosis. 

Alan Mackay-Sim, Francois Feron, Darryl Eyles, Thomas Bume, and John McGrath Possible Contributions of Myelin and Oligodendrocyte Dysfunction to Schizophrenia Daniel G. Stewart and Kenneth L. Davis Brain-Derived Neurotrophic Factor and the Plasticity of the Mesolimbic Dopamine Pathway Oliver Guillin, Nathalie Griffon, Jorge Diaz,... 

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 first generation antipsychotics, now known as typical drugs, were all D2 receptor blockers and, as such, very likely to produce Parkinsonian side effects. Because antipsychotic potency was associated with D2 receptor affinity, it was assumed that dopamine overactivity was the essential defect in schizophrenia and that a direct dopamine blockade was the definitive route to treatment. But these drugs affected both the target dopamine pathways of the mesolimbic projection and the uninvolved nigrostriatal projection. Unfortunately, that meant that movement disorders were the price that had to be paid for antipsychosis. 

Schizophrenia appears to be caused by an overactivity of dopamine pathways in certain parts of the brain such as the limbic system.2,23 This idea is based primarily on the fact that most antipsychotics block dopamine receptors, thereby reducing dopaminergic hyperactivity in mesolimbic pathways and other limbic structures (see the next section of this chapter). The increased dopamine influence underlying psychosis could be caused by excessive dopamine synthesis and release by the presynaptic neuron, decreased dopamine breakdown at the synapse, increased postsy-naptic dopamine receptor sensitivity, or a combination of these and other factors. 

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. 

The localisation of a particular peptide to a particular brain area and possibly associated with a particular transmitter (e.g. CCK with dopamine in mesolimbic pathways) has often prompted a prediction of function (e.g. CCK may have a role in schizophrenia). Animal studies in which the peptide has been injected into the appropriate brain area or tested on slices taken from the brain area have sometimes been taken to confirm such hypotheses. These approaches have lined up the peptides for a whole range of potential roles, some of which are listed in Table 12.4. Whether these predictions are realities will depend on the availability of chemical agents and their evaluation, not only in animals but also in humans. 

Fig. 19.3 Sagittal brain section illustrating dopaminergic pathways. I. Mesolimbic pathway (overactive in psychotic illness according to the dopamine hypothesis of schizophrenia).VTA= ventrotegmental area. 2. Nigrostriatal pathway (involved in motor control, underactive in Parkinson s Disease and associated with extrapyramidal motor symptoms). 3. Tuberoinfundibular pathway (inhibits prolactin release from the hypothalamus).

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. 

The dopamine hypothesis of schizophrenia posits diminished dopaminergic activity in the prefrontal cortex and reciprocal dopaminergic hyperactivity in the mesolimbic pathways, associated presumably with the induction of negative and positive symptoms, respectively. The exact mechanisms responsible for such changes in dopaminergic transmissions are not yet fully understood. However, accumulated data suggest that altered (i.e. hypoactive) glutamatergic receptor expression/function may contribute to the observed abnormalities. 

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