In schizophrenia there is an increase in dopamine transmission between the substantia nigra to the caudate nucleus-putamen (neostriatum) compared with normal. While in the other major dopaminergic pathways — to the mesolimbic forebrain and the tubero-infundibular system — dopamine transmission is reduced. The dopamine hypothesis of schizophrenia proposes that increased levels of dopamine or dopamine receptors in the dorsal and or ventral striatum underlie the disorder.
In the normal brain the prominent glutamatergic pathways are: the cortico-cocortical pathways; the pathways between the thalamus and the cortex; and the extrapyramidal pathway (the projections between the cortex and striatum). Other glutamate projections exist between the cortex, substantia nigra, subthalmic nucleus and pallidum. The glutamatergic pathways are hypoactive in the brains people diagnosed with schizophrenia and this is thought to cause the confusion and psychosis associated with the disorder.
The two key serotonergic pathways in schizophrenia are the projections from the dorsal raphe nuclei into the substantia nigra and the projections from the rostral raphe nuclei ascending into the cerebral cortex, limbic regions and basal ganglia. The up-regulation of these pathways leads to hypofunction of the dopaminergic system, and this effect may be responsible for the negative symptoms of schizophrenia. The serotonergic nuclei in the brainstem that give rise to descending serotonergic axons remain unaffected in schizophrenia.