Antipsychotic drugs,dopamine receptors,and schizophrenia

The clinical potencies of antipsychotic drugs are directly related to their affinities for the dopamine D2 receptor. In addition, the concentrations of antipsychotic drugs (given at therapeutic maintenance doses) in the plasma water or in the spinal fluid are almost identical to the antipsychotic dissociation constants at the dopamine D2 receptor. A consistent 70–75% of brain D2 receptors are occupied by antipsychotic drugs, as calculated from the therapeutic concentration and the antipsychotic dissociation constant. The D3 and D4 dopamine receptors, however, are not consistently occupied by antipsychotic drugs, the occupancies being 0–85% for D3, and 0–95% for D4. Human brain imaging also reveals that therapeutic doses of antipsychotic drugs occupy ∼70% of D2 receptors. Between 2 and 4 h after the daily oral dose, clozapine and quetiapine occupy high levels (∼70%) of the dopamine D2 receptors in schizophrenia patients, with lower occupancies at 6 and 12 h. Although clozapine and quetiapine occupy low levels of D2 receptors many hours after the oral dose, the observed fraction of D2 receptors occupied by these drugs, however, depends on the radioligand used, with high occupancy seen when using ¹¹C]raclopride, and low occupancy seen with ¹¹C]methylspiperone (which is tightly bound to D2). This dependence on the radioligand occurs because clozapine and quetiapine are loosely bound to D2. The loose binding of clozapine and quetiapine to D2 permits endogenous dopamine to displace these antipsychotic drugs much more quickly than haloperidol. In addition, the small dose of radioactive raclopride injected (in brain imaging) can displace a little of the D2-bound clozapine. Hence, the observed low level of D2 occupancy by clozapine in patients may arise from a combination of the above three factors – the ligand dependency, the endogenous dopamine, and the displacement by the imaging dose. Parkinsonism and extrapyramidal effects occur with antipsychotics which have a high affinity for D2 and which are, therefore, tightly bound to D2. Clozapine and quetiapine have a low affinity for D2, and, being readily displaced by endogenous dopamine, do not give rise to extrapyramidal effects. Because the loosely bound antipsychotics dissociate from D2 more rapidly, clinical relapse may occur earlier than that found with the tightly bound traditional antipsychotics. The dopamine hypothesis of schizophrenia is supported by the fact that D2 is the main target of antipsychotic action, that monomers of D2 appear elevated in schizophrenia, and that the synaptic levels of dopamine in schizophrenia are at least two-fold higher than in control subjects.