Platelet monoamine oxidase : From genetic regulation to behavior

• Genetic and environmental factors contribute to the development of personality and vulnerability forpsychiatric disorders. The activity of monoamine oxidase in platelets (trbc-MAO), which is mainlygenetically determined, correlates to personality traits such as sensation-seeking and impulsiveness, andlow trbc-MAO activity is more common in patients with type 2 alcoholism. Recent association studies ongenes encoding proteins important for CNS functions have also produced evidence that genetic factorsunderlie personality traits and risk for psychiatric disorders.In this thesis, biochemical and molecular methods, as well as psychological variables, have beenused to study trbc-MAO and variable regions of candidate genes in relation to regulation of trbc-MAO, andto certain behaviors in humans as well as in rhesus macaques.Radiometric measurement of trbc-MAO and PCR based genotyping of variable regions ofcandidate genes showed that there is no significant co-variation between trbc-MAO and genotype ofpolymorphisms investigated in the genes encoding dopamine D4 receptor (D4DR). serotonin transporter (5-HTT), monoamine oxidase type A (MAOA), and tyrosine hydroxylase (TH). Evidence was found for asignificant association between trbc-MAO and intron 13 genotype of the MAOB gene.Trbc-MAO and genotypes of D4DR and 5-HTT, but not MAOA, were significantly associatedwith human fear-conditioning as estimated by the skin conductance response.Gel-shift analyses showed that the transcriptional regulation of MAO-B differs between brain andblood cells, and that the binding pattern of two nuclear proteins from blood cells were highly correlated totrbc-MAO activity.Rhesus macaques with low trbc-MAO drink more alcohol, are less socially competent, and havelower levels of CSF 5-HIAA. It is known that smoking individuals display lower trbc-MAO activities, andthat tobacco smoke possesses MAO inhibiting constituents. However, the present results indicate that lowtrbc-MAO in type 2 alcoholism is not au artifact of concurrent tobacco smoking.The data of this investigation has provided further knowledge about trbc-MAO, its geneticregulation, and relation to behavior such as type 2 alcoholism. The results may be of relevance fordevelopment of new treatment strategies of certain behavioral disorders.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Neurologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Neurology (hsv//eng)

Nyckelord

Neurosciences

monoamine oxidase

platelet

personality

CNS

serotonin

dopamine

Neurovetenskap

Neurology

Neurologi

medicinsk farmakologi

Medical Pharmacology

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