However, the dopamine hypothesis is far from a complete explanation of all aspects of schizophrenia. Diminished cortical or hippocampal dopaminergic activity has been suggested to underlie the cognitive impairment and negative symptoms of schizophrenia. Postmortem and in vivo imaging studies of cortical, limbic, nigral, and striatal dopaminergic neurotransmission in schizophrenic subjects have reported findings consistent with diminished dopaminergic activity in these regions. Decreased dopaminergic innervation in medial temporal cortex, dorsolateral prefrontal cortex, and hippo-campus, and decreased levels of DOPAC, a metabolite of dopamine, in the anterior cingulate have been reported in postmortem studies. Imaging studies have found increased prefrontal D1-receptor levels that correlated with working memory impairments.
The fact that several of the atypical antipsychotic drugs have much less effect on D2 receptors and yet are effective in schizophrenia has redirected attention to the role of other dopamine receptors and to nondopamine receptors. Serotonin receptors— particularly the 5-HT2A-receptor subtype—may mediate synergistic effects or protect against the extrapyramidal consequences of D2 antagonism. As a result of these considerations, the direction of research has changed to a greater focus on compounds that may act on several transmitter-receptor systems, eg, serotonin and glutamate. The atypical antipsychotic drugs share the property of weak D2-receptor antagonism and more potent 5-HT2A-receptor blockade.
Glutamate is the major excitatory neurotransmitter in the brain (see Chapter 21). Phencyclidine (PCP) and ketamine are noncompetitive inhibitors of the NMDA receptor that exacerbate both cognitive impairment and psychosis in patients with schizophrenia. PCP and a related drug, MK-801, increase locomotor activity and, acutely or chronically, a variety of cognitive impairments in rodents and primates. These effects are widely employed as a means to develop novel antipsychotic and cognitive-enhancing drugs. Selective 5-HT2A antagonists, as well as atypical antipsychotic drugs, are much more potent than D2 antagonists in blocking these effects of PCP and MK-801. This was the starting point for the hypothesis that hypofunction of NMDA receptors, located on GABAergic interneurons, leading to diminished inhibitory influences on neuronal function, contributed to schizophrenia. The diminished GABAergic activity can induce disinhibition of downstream glutamatergic activity, which can lead to hyperstimulation of cortical neurons through non-NMDA receptors. Preliminary evidence suggests that LY2140023, a drug that acts as an agonist of the metabotropic 2/3 glutamate receptor (mGLuR2/3), may be effective in schizophrenia.
The NMDA receptor, an ion channel, requires glycine for full activation. It has been suggested that in patients with schizophre nia, the glycine site of the NMDA receptor is not fully saturated.
There have been several trials of high doses of glycine to promote glutamatergic activity, but the results are far from convincing.
Currently, glycine transport inhibitors are in development as pos sible psychotropic agents.
Ampakines are drugs that potentiate currents mediated by
AMPA-type glutamate receptors. In behavioral tests, ampakines of schizophrenia and depression. They protect neurons against neurotoxic insults, in part by mobilizing growth factors such as brain-derived neurotrophic factor (BDNF, see also Chapter 30).
A number of chemical structures have been associated with antipsychotic properties. The drugs can be classified into several groups as shown in Figures 29–1 and 29–2.
in the nucleus