Scientists know that pathology in the mesolimbic and mesocortical pathways causes schizophrenia, or simply called psychosis. Are there any other neurotransmitters causing the disease? I will start with the hypothesis that “Dopamine involves with schizophrenia.” Scientists found evidences that support this hypothesis, and it becomes the most fully developed more than several hypotheses. If I were about to test the hypothesis, first, I would think that if I introduce a drug that will enhance DA releasing in the brain to schizophrenics and non-schizophrenics, at a certain level of the drug, I would be able to see aggravation of the symptoms in schizophrenics group and I would expect to see schizophrenia-like symptoms in non-schizophrenics group. Second, if I use DA blocking agents in schizophrenics their symptoms would be alleviated. Third, I am going to do positron emission tomography (PET) to see the difference in DA receptors density in schizophrenics and non-schizophrenics. Actually, scientists have done these experiments and they confirm that DA involves in schizophrenia. They have also investigated postmortem brains and found the increase in DA receptors density in schizophrenics who have not been treated with antipsychotic drugs. Another evidence that support DA theory is changing in the level of homovanillic acid (HVA), a metabolite of DA, in the cerebrospinal fluid, plasma, and urine in the patients who were successfully treated. These experiments confirm that DA involves in schizophrenia, but can we make a conclusion that DA system is the system and the only system that plays an important role in schizophrenia? In greater detail are there any subtypes of DA receptors that play different roles? These questions arose because antipyschotic drugs did not give therapeutic results as good as they were expected. For examples, in a group of patients who have had the psychosis for ten to thirty years, a PET (Positron Emission Topography) scan revealed 90% of D2 receptor binding of antipsychotic drugs but the patients had minimal reduction in psychoses. However, the PET scan in a group of first-episode patients showed 60-70% D2 receptor binding, but the patients responded to low dose antipsychotics. In addition, it is found that typical antipsychotics selectively bind to D2 receptor 50 times more than binding to D1 and D3 receptors. These data support a hypothesis that selective D2 blocking has no significant in increasing antipsychotic activity, and therefore the research trend, in stead of focusing only on improving selectivity and potency of blocking D2 receptor, has been changed to a broader consideration–new drugs with less D2 selectivity.
Below is a nice illustration and explanation of DA receptor subtypes borrowed from www.cnsforum.com. I am going to discuss about this slide and other pathways that involve schizophrenia on Monday. Have a nice weekend.
“There are two types of dopamine receptor, D1-like and D2-like receptors. The D1-like receptors comprise D1- and D5-receptor subtypes that are associated with stimulation of adenylate cyclase. The D2-like receptors comprise D2-, D3- and D4-receptor subtypes and these are associated with inhibition of adenylate cyclase. The known functions of dopamine appear to be mediated mainly by D2-like receptors. All dopamine receptor subtypes are expressed in the brain in distinct but overlapping areas. D1 receptors are the most abundant and widespread in areas receiving dopaminergic innervation (the striatum, limbic system, thalamus and hypothalamus); D2 receptors are widespread in these areas, as well as the pituitary gland. D3 and D4 receptors are present in the limbic system. Schizophrenia is associated with dopaminergic hyperactivity. Dopamine antagonists used as antipsychotic drugs (eg chlorpromazine, haloperidol, risperidone) exert their effects mainly by blocking D2-like receptors. Dopamine agonists, such as apomorphine and bromocriptine, also have greater potency at D2-like receptors. Bromocriptine is used clinically to suppress prolactin secretion arising from tumours of the pituitary gland.”
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