Increased Baseline Occupancy of D₂ receptors by Dopamine in Schizophrenia

A. Abi-Dargham, J. Rodenhiser, D. Printz, Y. Zea-Ponce, R. Gil, L. S. Kegeles, R. Weiss, T. B. Cooper, J. J. Mann, R. L. Van Heertum, J. M. Gorman, and M. Laruelle

 
Proc. Natl Acad. Sci. USA
 97(15): 8104-8109, July 2000

This paper looked at the baseline occupancy of D₂ receptors (a specific type of dopamine receptor, where the chemical binds and leads to an effect) by dopamine in patients with schizophrenia.  Eighteen untreated patients were matched with 18 controls and the D₂ receptor availability was measured before and during pharmacologically induced dopamine depletion.  Similarly to the LaRuelle et al. (1996) paper, SPECT was used and the dopamine antagonist (a chemical that binds to a receptor and blocks the normal effect)  [¹²³I] IBZM was injected and used for quantification.  The drug that depleted dopamine was alpha-MPT, a chemical that inhibits tyrosine hydroxylase, a precursor to dopamine. 

        
After treatment with alpha-MPT, patients with schizophrenia had more available dopamine D₂ receptors compared to controls (19%+ 11% in patients with schizophrenia compared to 9%+ 7% in controls).  Baseline availability levels did not differ between groups, but after dopamine depletion D₂ receptor availability was significantly higher in patients with schizophrenia.  Some of the patients had received previous neuroleptic treatment (n=10), which can lead to alterations in receptor numbers as well as endogenous dopamine levels.  The other 8 patients were drug naïve.  The effect of dopamine depletion on receptor availability was not statistically different between the two patient groups, while each group was different from participants without schizophrenia.  However, there was found to be a higher D₂ receptor density in drug treated patients, possibly a side effect of neuroleptic treatment.  Severity of baseline positive or negative symptoms was not a good predictor of the effectiveness of alpha-MPT.  The dopamine depletion did result in a decrease in positive symptoms relative to the increased receptor binding potential.  This increase in receptor binding potential also slightly increased negative symptoms, although this was not statistically significant. 

          
 Fourteen of the patients completed a 6-week period of neuroleptic treatment.  A decrease in positive symptoms, compared to baseline, was noted after alpha-MPT treatment, 1-week after neuroleptic treatment began and at the end of the 6-week treatment period.  Additionally, a higher baseline dopamine level, which was measured by the affect of alpha-MPT, was associated with greater improvement of positive symptoms after the neuroleptic treatment.  Both of these results suggest a connection between increased dopamine levels in patients with schizophrenia and severity of positive symptoms. 

The larger D₂ occupancy in patients could be due to increased free dopamine near the receptors, a higher affinity for the receptors, or a combination of both factors.  Understanding the role that these factors play in the manifestations of schizophrenic symptoms may lead to better treatments for the disease.  Some patients experienced a decline in symptoms after treatment, while others showed no correlation of receptor occupancy with positive symptomology.  This may be due to limitations in the equipment used or to non-dopaminergic imbalances leading to the observed symptoms.  These results give reason to pursue alternate pharmacological treatments for psychotic symptoms.  With this in mind, this study was able to show in vivo evidence of schizophrenia being associated with excessive stimulation of D­­₂ receptors by dopamine, and this disregulation of receptors being a good predictor of a positive response to neuroleptic treatment.  This and other imaging studies have been able to show alterations in dopamine leading to psychotic symptoms, which directly support the dopamine hypothesis of schizophrenia.  However, these studies all are unable to produce results across the board, leading to the belief that a subsection of patients have different disregulations of dopamine systems, or a disregulation of an alternate metabolic system.