Functional sites of neuroleptic drug action in the human brain: PET/FDG studies with and without haloperidol.
OBJECTIVE
The functional pathways through which antipsychotic drugs act in the brain to decrease psychosis remain unknown, despite our knowledge that their site of initial action is through blockade of dopamine D2 receptors. The authors sought to define the brain regions that are functionally altered by neuroleptic drugs.


METHODS
Regional cerebral glucose metabolism was studied in 12 subjects with schizophrenia while they were receiving a fixed dose of haloperidol, again 5 days after withdrawal of the drug, and a third time 30 days after withdrawal. Positron emission tomography with an [18F]fluorodeoxyglucose tracer was used in a within-subject design.


RESULTS
The analysis demonstrated a decrease in glucose metabolism in the caudate and putamen 30 days after withdrawal, indicating that haloperidol treatment enhanced glucose utilization in these areas. The thalamus, bilaterally but only in anterior areas, showed the same response to haloperidol. Only in the frontal cortex and in the anterior cingulate had metabolism increased 30 days after withdrawal, indicating that in those two cortical areas haloperidol depressed glucose metabolism. In the 5-day drug free scans, no regions differed significantly from those in the haloperidol condition, despite numerical changes.


CONCLUSIONS
It appears that 5 days of neuroleptic withdrawal are inadequate to escape the effects of neuroleptic drugs on regional cerebral glucose metabolism. The pattern and localization of changes in metabolic activity between the haloperidol condition and the 30-day drug-free condition suggest that haloperidol exerts its primary antidopaminergic action in the basal ganglia. It is proposed that the additional changes in the thalamus and cortex are secondary to this primary site of drug action, mediated through classically described striato-thalamo-cortical pathways.
Holcomb
H H
HH
Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, USA.
Cascella
N G
NG
Thaker
G K
GK
Medoff
D R
DR
Dannals
R F
RF
Tamminga
C A
CA
D000328:Adult; D017668:Age of Onset; D001479:Basal Ganglia / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism*; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D003847:Deoxyglucose / Q000031:analogs & derivatives; D005260:Female; D019788:Fluorodeoxyglucose F18; D005947:Glucose / Q000378:metabolism*; D006220:Haloperidol / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008032:Limbic System / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D011569:Psychiatric Status Rating Scales; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism; D012559:Schizophrenia / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism; D012565:Schizophrenic Psychology; D013788:Thalamus / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D014055:Tomography, Emission-Computed
D011954:Receptors, Dopamine; D019788:Fluorodeoxyglucose F18; D003847:Deoxyglucose; D005947:Glucose; D006220:Haloperidol