Presynaptic dopamine function in striatum of neuroleptic-naive schizophrenic patients

Subchronic Haloperidol Downregulates Dopamine Synthesis Capacity in the Brain of Schizophrenic Patients In Vivo

“…Thus, although we cannot totally exclude the possibility that the documented changes in k D 3 are influenced by brain perfusion or tracer distribution, our study has the advantage that it actually measures these effects. Owing to numerous methodological factors, our present baseline estimates of k D 3 (Reith et al, 1994), which represents the rate constant for the decarboxylation of FDOPA, cannot be compared directly with previously reported normative values obtained by other laboratories, and cannot readily be compared with estimates of the net clearance of FDOPA (Hietala et al, 1995) or [b-11 C]DOPA (Lindström et al, 1999) to striatum K i D (ml g À1 min À1 ), which reflect the composite of perfusion, diffusion back to blood, and decarboxylation in nigrostriatal terminals. Consequently, estimates of the magnitude of K i are weighted by the unknown equilibrium volume (V e D ) of FDOPA in the brain tissue.…”

“…Consequently, estimates of the magnitude of K i are weighted by the unknown equilibrium volume (V e D ) of FDOPA in the brain tissue. Therefore, the effects of treatment or condition on the magnitude of K i in the human brain cannot be unambiguously attributed to the altered rate of trapping of FDOPA in the brain (Hietala et al, 1995;Meyer-Lindenberg et al, 2002;Yatham et al, 2002). The present compartmental model explicitly evaluates the magnitude of V e D , and therefore isolates the parameter of interest, the activity of DDC, from the effects of perfusion and distribution.…”

“…This discrepancy led to the suggestion that the antipsychotic effect of neuroleptics may arise in conjunction with the delayed depolarization block of the presynaptic neuron and reduced DA synthesis capacity, a phenomenon which occurs in experimental animals treated chronically with neuroleptics (Grace and Bunney, 1986). Several positron emission tomography (PET) studies with radiolabeled L-DOPA analogues have reported elevated activity of the enzyme DOPA decarboxylase (DDC) in the striatum of untreated patients with schizophrenia (Hietala et al, 1995;Lindström et al, 1999;Reith et al, 1994), indicating the presence of elevated capacity for DA synthesis within the terminals of DA neurons . However, the transition of DA neurons to a partially inactivated state of depolarization block has not been demonstrated in schizophrenic patients under treatment with neuroleptics.…”

Constitutive Hyperdopaminergia is Functionally Associated with Reduced Behavioral Lateralization

“…Recent studies in schizophrenia support a decreased cerebral asymmetry rather than altered directional asymmetry as the potential candidate phenotype of abnormal lateralization that could contribute to individual susceptibility to schizophrenia (Sommer et al, 2001). In vivo imaging studies also pointed to the loss of asymmetry as a candidate marker to better characterize schizophrenia-associated deficits (Hietala et al, 1999(Hietala et al, , 1995Hsiao et al, 2003;Laakso et al, 2000). Our data, showing that hyperdopaminergia directly impairs the degree of lateralization without affecting the direction, further support the magnitude of lateralization as the relevant and informative variable for the study of asymmetry.…”

“…Similarly, in the meta-analysis of three prospective followup studies, pre-schizophrenic subjects were significantly more often non-right-handed than the general population (Sommer et al, 2001). Furthermore, in vivo imaging studies of schizophrenia have provided evidence that the right-left asymmetry of the dopamine (DA) synthesis capacity and of the dopamine transporter (DAT) binding in the caudate are both lost in antipsychotic-naive patients (Hietala et al, 1999(Hietala et al, , 1995Hsiao et al, 2003;Laakso et al, 2000). In addition, neuroleptics are able to change the balance of hemispheric activity, thus improving left-hemispheric attentional processes (for a review, see Gruzelier, 1999), and a recent study demonstrated that haloperidol-induced downregulation of DA synthesis was significantly greater in the left than in the right striatum (Grunder et al, 2003).…”