Particular focus has been placed upon the function of dopamine in the mesolimbic pathway of the brain. This focus largely resulted from the accidental finding that a drug group which blocks dopamine function, known as the phenothiazines, could reduce psychotic symptoms. An influential theory, known as the
“dopamine hypothesis of schizophrenia“
proposes that a malfunction involving dopamine pathways is, therefore, the cause of (the positive symptoms of) schizophrenia.
Evidence for this theory includes findings that the potency of many antipsychotics is correlated with their affinity to dopamine D2 receptors, and the exacerbatory effects of a dopamine agonist (amphetamine) and a dopamine beta hydroxylase inhibitor (disulfiram) on schizophrenia; and post-mortem studies initially suggested an increased density of dopamine D2 receptors in the striatum. Such high levels of D2 receptors intensify brain signals and can exacerbate positive symptoms (i.e. hallucinations and paranoia) in schizophrenia. Impaired glutamate (a neurotransmitter which directs neuron to pass along an impulse) activity appears to be another source of schizophrenia symptoms.
However, there was controversy and conflicting findings over whether postmortem findings resulted from drug tolerance to chronic antipsychotic treatment. Compared to the success of postmortem studies in finding profound changes of dopamine receptors, imaging studies using SPET and PET methods in drug-naive patients have generally failed to find any difference in dopamine D2 receptor density compared to controls. Comparable findings in longitudinal studies show: ” Particular emphasis is given to methodological limitations in the existing literature, including lack of reliability data, clinical heterogeneity among studies, and inadequate study designs and statistic,” suggestions are made for improving future longitudinal neuroimaging studies of treatment effects in schizophrenia. A recent review of imaging studies in schizophrenia shows confidence in the techniques while discussing such operator error. In 2007 one report said, “During the last decade, results of brain imaging studies by use of PET and SPET in schizophrenic patients showed a clear dysregulation of the dopaminergic system.”
Recent findings from meta-analyses suggest that there may be a small elevation in dopamine D2 receptors in drug-free patients with schizophrenia, but the degree of overlap between patients and controls makes it unlikely that this is clinically meaningful. While the review by Laruelle acknowledged more sites were found using methyl-spiperone, it discussed the theoretical reasons behind such an increase (including the monomer-dimer equilibrium) and called for more work to be done to ‘characterize’ the differences. In addition, newer antipsychotic medication (called atypical antipsychotic medication) can be as potent as older medication (called typical antipsychotic medication) while also affecting serotonin function and having somewhat less of a dopamine blocking effect. In addition, dopamine pathway dysfunction has not been reliably shown to correlate with symptom onset or severity. HVA levels correlate trend-wise to symptoms severity. During the application of debrisoquin, this correlation becomes significant.
Giving a more precise explanation of this discrepancy in D2 receptor has been attempted by a significant minority. Radioligand imaging measurements involve the monomer and dimer ratio, and the ‘cooperativity’ model. Cooperativity is a chemical function in the study of enzymes. Dopamine receptors interact with their own kind, or other receptors to form higher order receptors such as dimers, via the mechanism of cooperativity. Philip Seeman has said: “In schizophrenia, therefore, the density of methyl-spiperone sites rises, reflecting an increase in monomers, while the density of raclopride sites remains the same, indicating that the total population of D2 monomers and dimers does not change.” (In another place Seeman has said methyl-spiperone possibly binds with dimers) With this difference in measurement technique in mind, the above-mentioned meta-analysis uses results from 10 different ligands. Exaggerated ligand binding results such as SDZ GLC 756 (as used in the figure) were explained by reference to this monomer-dimer equilibrium.
According to Seeman, “Numerous postmortem studies have consistently revealed D2 receptors to be elevated in the striata of patients with schizophrenia”.However, the authors have concerned the effect of medication may not have been fully accounted for. The study introduced an experiment by Abi-Dargham et al. in which it was shown medication-free live schizophrenics had more D2 receptors involved in the schizophrenic process and more dopamine. Since then another study has shown such elevated percentages in D2 receptors is brain-wide (using a different ligand, which did not need dopamine depletion). In a 2009 study, Annisa Abi-Dagham et al. confirmed the findings of her previous study regarding increased baseline D2 receptors in schizophrenics and showing a correlation between this magnitude and the result of amphetamine stimulation experiments.
Some animal models of psychosis are similar to those for addiction – displaying increased locomotor activity. For those female animals with previous sexual experience, amphetamine stimulation happens faster than for virgins. There is no study on male equivalent because the studies are meant to explain why females experience addiction earlier than males.
Even in 1986, the effect of antipsychotics on receptor measurement was controversial. An article in Science sought to clarify whether the increase was solely due to medication by using drug-naive schizophrenics: “The finding that D2 dopamine receptors are substantially increased in schizophrenic patients who have never been treated with neuroleptic drugs raises the possibility that dopamine receptors are involved in the schizophrenic disease process itself. Alternatively, the increased D2 receptor number may reflect presynaptic factors such as increased endogenous dopamine levels. In either case, our findings support the hypothesis that dopamine receptor abnormalities are present in untreated schizophrenic patients.” (The experiment used 3-N-[11C]methylspiperone – the same as mentioned by Seeman detects D2 monomers and binding was double that of controls.)
It is still thought that dopamine mesolimbic pathways may be hyperactive, resulting in hyperstimulation of D2 receptors and positive symptoms. There is also growing evidence that, conversely, mesocortical pathway dopamine projections to the prefrontal cortex might be hypoactive (underactive), resulting in hypo-stimulation of D1 receptors, which may be related to negative symptoms and cognitive impairment. The overactivity and under-activity in these different regions may be linked, and may not be due to a primary dysfunction of dopamine systems but to more general neurodevelopmental issues that precede them. Increased dopamine sensitivity may be a common final pathway.
Another finding is a six-fold excess of binding sites insensitive to the testing agent, raclopride; Seeman said this increase was probably due to the increase in D2 monomers. Such an increase in monomers may occur via the cooperativity mechanism which is responsible for D2High and D2Low, the supersensitive and low-sensitivity states of the D2 dopamine receptor. More specifically, “an increase in monomers, may be one basis for dopamine supersensitivity”.
Another one of Seeman’s findings was that the dopamine D2 receptor protein looked abnormal in schizophrenia. Proteins change states by flexing. The activating of the protein by folding could be permanent or be fluctuating, just like the course of patients’ illnesses waxes and wanes. Increased folding of a protein leads to increased risk of ‘additional fragments’ forming. The schizophrenic D2 receptor has a unique additional fragment when digested by papain in the test-tube, but none of the controls exhibited the same fragment. The D2 receptors in schizophrenia are thus in a highly active state as found by Seeman et al.