Dopamine Receptors in Drug - Naïve Schizophrenics

large statistical (radioactivity counting) errors and that the signal from the unbound or nonspecifically bound NMSP in the brain may interfere with the signal from the complex. The 1/k3 value derived in the presence of haloperidol is the primary determinant of the slope [figure 4 of (3)] used to quantify Bmx.. Values for l1/k3 determined in the absence of haloperidol may be inaccurate because, for high levels of available receptor, the kinetics of ["C]NMSP accumulation in the caudate nucleus primarily reflect blood-brain transport and are relatively insensitive to the second-order binding step k.n, so there may be significant errors associated with the numerical extraction of k3 from the observed data. Values for 1/k3 derived in the absence of haloperidol would be the primary determinant of the y-intercept [figure 4 of (3)]. In the absence of additional information about the analysis of the original experimental data or a sensitivity analysis based on computer simulation studies, it is not clear what the magnitude of these errors might be. 5. The y-intercept and 1/k3 before haloperidol treatment will be identical, since 1/k3 before haloperidol treatment is one of the two points used in the 1/k3 versus haloperidol plot. 6. Since K'1, equal to k'0ff/k'.n and determined from the x-intercept of the 1/k3 versus haloperidol plot, is different for normal individuals and for schizophrenics (1), k'0ff or k'on, or both, must be different for normal individuals and for schizophrenics. If k'0ff differs, then in the implementation of the slope method a single assumed constant value cannot be used for both normal individuals and for schizophrenics. If k'0n differs, one would need to assume that kon also differs in such a way that kon (normal)/ kon (schizophrenic) is identical to k'.n normal/k'on (schizophrenic). 7. D. F. Wong et al., Scienac 232, 1270 (1986). 8. D. F. Wong et al., J. Nud. Med. 27, 1074 (1986). 9. P. Seeman, Pharmacol. Rep. 32, 229 (1981); A. A. Hancock and C. L. Marsh, Mol. Phannaco. 26, 439 (1984). 10. In addition to the direct result of haloperidol and dopamine competition in ["C]NMSP binding to the D2 receptor, an analysis of the effects of endogenous dopamine and added haloperidol must take into account the indirect result of the influence of haloperidol on the turnover of dopamine, on occupancy, functioning, and regulation of the presynaptic dopamine autoreceptor and the postsynaptic D,, D2, and D3 dopamine sites, and on the levels of ["C]NMSP and dopamine in the synaptic deft. For example, D. C. Chugani etal. [J. Nud. Med. 28, 612 (1987)] have shown that endogenous dopamine can increase in vivo 3H-spiperone binding by stimulation of endocytotic trapping.