Increased baseline occupancy of D2 receptors by dopamine in schizophrenia

Abstract

The classical dopamine hypothesis of schizophrenia postulates a hyperactivity of dopaminergic transmission at the D(2) receptor. We measured in vivo occupancy of striatal D(2) receptors by dopamine in 18 untreated patients with schizophrenia and 18 matched controls, by comparing D(2) receptor availability before and during pharmacologically induced acute dopamine depletion. Acute depletion of intrasynaptic dopamine resulted in a larger increase in D(2) receptor availability in patients with schizophrenia (19% +/- 11%) compared with control subjects (9% +/- 7%, P = 0.003). The increased occupancy of D(2) receptors by dopamine occurred both in first-episode neuroleptic-naive patients and in previously treated chronic patients experiencing an episode of illness exacerbation. In addition, elevated synaptic dopamine was predictive of good treatment response of positive symptoms to antipsychotic drugs. This finding provides direct evidence of increased stimulation of D(2) receptors by dopamine in schizophrenia, consistent with increased phasic activity of dopaminergic neurons.

Figures

Figure 1

Schematic presentation of the experiment. The blue rectangles represent the total population of D2 receptors. At baseline, an unknown proportion of these receptors is occupied by dopamine (shaded area), and only a fraction of receptors are unoccupied and available to [123I]IBZM binding. After α-MPT-induced depletion of endogenous dopamine, all receptors are available to [123I]IBZM binding. Thus, comparing the [123I]IBZM binding potential at baseline and after dopamine depletion allows derivation of the proportion of D2 receptors that were masked by dopamine at baseline. The SPECT images display distribution of [123I]IBZM in one subject at baseline and after dopamine depletion (note the increase in specific binding in the striatum).

Figure 2

Increase in [123I]IBZM BP to D2 receptors after acute dopamine depletion in controls and patients with schizophrenia (●, previously treated patients; ○, first-episode neuroleptic-naive patients).

Figure 3

Relationship between baseline dopamine levels, as estimated by the α-MPT effect on [123I]IBZM BP, and the decrease in positive symptoms measured after 6 weeks of antipsychotic treatments.