Abstract
The antipsychotic effect of neuroleptics cannot be attributed entirely to acute blockade of postsynaptic D2-like dopamine (DA) receptors, but may arise in conjunction with the delayed depolarization block of the presynaptic neurons and reduced DA synthesiscapacity. Whereas the phenomenon of depolarization block is wellestablished in animals, it is unknown if a similar phenomenon occurs inhumans treated with neuroleptics. We hypothesized that haloperidoltreatment should result in decreased DA synthesis capacity. Weused 6-[18F]fluoro-L-dopa (FDOPA) and positron emission tomography (PET) in conjunction with compartmentalmodeling to measurethe relative activity of DOPA decarboxylase (DDC) (kD3min-1) in the brain of nine unmedicated patients with schizophrenia, first in theuntreated condition and again after treatment with haloperidol. Patients were administered psychometric rating scales at baseline andafter treatment. Consistent with our hypothesis, there was a 25% decrease in the magnitude ofk^in both caudate and putamenfollowing 5 weeks of haloperidoltherapy. In addition, the magnitudes of kD3 in cerebralcortex and thalamus were also decreased.Psychopathology as measured with standard rating scales improved significantly in allpatients. The decrease of kD3 in the thalamus washighly significantly correlated with the improvement of negative symptoms. Subchronic treatment with haloperidoldecreased the activityof DDC in the brain of patients with schizophrenia. This observation is consistent with the hypothesis that the antipsychotic effect ofchronic neuroleptic treatment is associated with a decrease in DA synthesis, reflecting a depolarization block of presynaptic DA neurons.We link an alteration in cerebralcatecholamine metabolism in human brain with the therapeutic action of neuroleptic medication.
Original language | English |
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Pages (from-to) | 787-794 |
Number of pages | 8 |
Journal | Neuropsychopharmacology |
Volume | 28 |
Issue number | 4 |
DOIs | |
State | Published - Apr 2003 |
Keywords
- Depolarization block
- Dopamine synthesis
- Fluoro-DOPA
- Haloperidol
- Positron emission tomography
- Schizophrenia