Increased caudate dopamine D2 receptor availability as a genetic marker for schizophrenia.
BACKGROUND
Schizophrenia has a heritability of about 80%, but the detailed molecular genetic basis of the disorder has remained elusive. Relative hyperfunction of the subcortical dopamine system has been previously suggested to be one of the key pathophysiologic mechanisms in schizophrenic psychosis.


OBJECTIVE
To examine the contributions of genetic vulnerability for schizophrenia to the dopamine system in the human brain.


METHODS
Population-based twin cohort study.


METHODS
Finland.


METHODS
Six monozygotic and 5 dizygotic unaffected co-twins of patients with schizophrenia were ascertained, along with 4 monozygotic and 3 dizygotic healthy control twins with no family history of psychotic disorders.


METHODS
Striatal dopamine D(2) receptor availability estimated with positron emission tomographic imaging and carbon 11 ((11)C)-labeled raclopride, and performance on neuropsychological tests sensitive to frontal lobe functioning and to schizophrenia vulnerability.


RESULTS
Unaffected monozygotic co-twins had increased caudate D(2) density compared with unaffected dizygotic co-twins and healthy control twins. Higher D(2) receptor binding in caudate was associated with a poor performance on cognitive tasks related to schizophrenia vulnerability in the whole sample.


CONCLUSIONS
The caudate dopamine D(2) receptor up-regulation is related to genetic risk for schizophrenia. Higher dopamine D(2) receptor density in caudate is also associated with poorer performance on cognitive tasks involving corticostriatal pathways. This finding suggests that caudate dopamine dysregulation is also a trait phenomenon related to psychosis vulnerability. This pattern of results provides a theoretical rationale for early pharmacologic intervention approaches using dopamine D(2) receptor blocking drugs.
Hirvonen
Jussi
J
Department of Pharmacology and Clinical Pharmacology, and Turku PET Centre, University of Turku, Kiinamyllynkatu, Turku 20520, Finland.
van Erp
Theo G M
TG
Huttunen
Jukka
J
Aalto
Sargo
S
Någren
Kjell
K
Huttunen
Matti
M
Lönnqvist
Jouko
J
Kaprio
Jaakko
J
Hietala
Jarmo
J
Cannon
Tyrone D
TD
D002250:Carbon Radioisotopes; D002421:Caudate Nucleus / Q000000981:diagnostic imaging / Q000378:metabolism*; D003072:Cognition Disorders / Q000175:diagnosis / Q000378:metabolism; D015331:Cohort Studies; D004200:Diseases in Twins / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism; D004298:Dopamine / Q000235:genetics / Q000378:metabolism; D005260:Female; D005387:Finland; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D049268:Positron-Emission Tomography; D020891:Raclopride; D017448:Receptors, Dopamine D2 / Q000235:genetics* / Q000378:metabolism*; D012559:Schizophrenia / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism; D014429:Twins, Dizygotic / Q000235:genetics; D014430:Twins, Monozygotic
D002250:Carbon Radioisotopes; D005819:Genetic Markers; D017448:Receptors, Dopamine D2; D020891:Raclopride; D004298:Dopamine