2. The density of dopamine D1 receptors is down by 10%in schizophrenia patients (L. Farde). Because D1 reduces the functional high-affinity state of D2, the low D1 permits an overactive D2.
3. The therapeutic concentrations of antipsychotic drugs in the spinal fluid are identical to their concentrations which block D2 receptors. This also applies to clozapine.
4. Hallucinations and delusions are blocked when any antipsychotic drug, including clozapine, occupies more than 70%of D2 receptors in the human brain.
5. The D2 density is elevated in schizophrenia, using [11C]methylspiperone in patients (D. Wong; A.L. Nordström) or by [3H]nemonapride in postmortem tissues, but not when measured by radioaclopride. The elevated D2 may reflect an increase in D2 monomers (detected by spiperone or nemonapride), but no elevation may occur in D2 dimers (which raclopride may prefer).
6. In all post-mortem schizophrenia tissue samples tested, the binding of [3H]raclopride is insensitive to the addition of guanine nucleotide, unlike control tissues.
7. Using a [3H]benzo[g]quinoline (Sandoz GLC 756) to detect new dopamine-like receptors (while occluding D1, D2, D3 and D5), a D2-like receptor is found in schizophrenia tissues, but is absent or low in Huntington's, Parkinson's or Alzheimer's diseases or in control brain tissues.
8. Because neuroleptics also block D2 receptors in the motor-controlling regions of the brain, Parkinsonism typically occurs with such drugs. Clozapine or olanzapine are “atypical” by eliciting low or negligible levels of Parkinsonism.
9. To develop antipsychotic drugs with low risk for Parkinsonism, it is essential to determine which other receptors are blocked (in addition to D2) by atypical antipsychotic drugs.
10. We have found that the receptor-blocking potency of a neuroleptic depends on the radioactive label used to label the receptor. Our method corrects for this dependence.
11. Thus, accurate blocking potencies of antipsychotic drugs were obtained for cloned D2 and D4 dopamine receptors, and for cloned serotonin-2A receptors.
12. These new results reveal that the traditional typical antipsychotic drugs (chlorpromazine or haloperidol) all readily block D2 receptors at the low concentrations of 0.3 to 5 nM.
13. The atypical antipsychotic drugs, however, fall into two groups: One group (remoxipride, clozapine, perlapine, seroquel and melperone) have a low affinity for D2, requiring concentrations of 30 to 90 nM for D2 block. Such low affinity values make these latter five drugs readily displaceable by high levels of endogenous dopamine in the motor-controlling regions of the brain. Such displacement by dopamine of the loosely attached antipsychotic drug reduces the risk of Parkinsonism. This displacement does not occur for the typical antipsychotic drugs which are tightly attached to D2.
The second atypical group of antipsychotic drugs are those such as olanzapine. These drugs bind tightly to D2, but at the same time they also bind even more tightly (i.e., more selectively) to the D4 dopamine receptor. Clozapine is also selective for D4 with a dissociation constant of 1.6 nM.
14. Using these new blocking potencies, it is possible to relate the receptor-blocking potencies of the neuroleptics with their ability to elicit catalepsy. One theory states that antipsychotic-induced Parkinsonism can be obviated by blocking serotonin-2A receptors. The present data, however, do not support this hypothesis, because there is only a weak relation between the selectivity of the drug for the serotonin-2A receptor (compared to D2) and the ability of the drug to avoid catalepsy in rats. There is, however, a good correlation between the selectivity of the drug for D4 (compared to D2) and the ability of the drug to avoid producing catalepsy.
Thus, atypical neuroleptics fall into two groups, those which have a low affinity for D2 and those which prefer D4 over D2. Clozapine and olanzapine are in the latter group.
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doi:10.1016/j.pnpbp.2008.03.008 
Increased hexosaminidase activity in antipsychotic-induced extrapyramidal side effects: Possible association with higher occurrence in bipolar disorder patients
