Selective permeation of the blood-brain barrier as a cause of the anomalous properties of 'atypical'neuroleptics.

Metoclopramide is a widely used anti-emetic drug with potent dopamine-blocking effects on brain structures involved in emesis and prolactin secretion but it is apparently devoid of therapeutic effect in schizophrenia, thus calling into question the supposed role of dopamine blockade in the action of antischizophrenic drugs. This investigation compared the depression of hypothalamic self-stimulation produced by metoclopramide and by a 'typical' neuroleptic, spiroperidol (spiperone), when injected by different routes. Metoclopramide was found to9 be nearly 30 times more potent when administered directly into the brain via the cerebral ventricles than when injected intraperitoneally; on the other hand the potency of spiroperidol was virtually unaffected by the route of administration. The blood-brain barrier is known to be absent from brain sites controlling emesis and prolactin secretion; thus the potency of metoclopramide as an anti-emetic and in releasing prolactin, and its relative ineffectiveness as an antipsychotic can be accounted for by a failure to enter the brain freely except at privileged sites. Thus its anomalous properties are not necessarily inconsistent with the dopamine theory of schizophrenia.