Further studies on the relationship between dopamine cell density and haloperidol-induced catalepsy

Previous data have suggested that the genetic variability in the sensitivity to haloperidol-induced catalepsy is associated with the number of dopamine neurons in the substantia nigra zona compacta (SNZc). To further investigate this relationship, neuroleptic responsive (NR) and neuroleptic nonresponsive (NNR) lines were selected from the new heterogeneous stock/Northport (Np). At the fourth selected generation (S₄), the NR/Np and NNR/Np lines differed more than 5-fold in their haloperidol ED₅₀, but showed no difference in their ED₅₀ to SCH 23390. Confirming the previous results, tyrosine hydroxylase (TH)-positive cell number in the SNZc was significantly higher in the NNR/Np as compared to the NR/Np line. The difference was most pronounced in the rostral SNZc, where TH cell number was increased 23%. Cell number also was increased significantly (38%) in the caudal ventral tegmental area (VTA). Fifty-two C57BL/6J:DBA/2J (B6D2) F₂ hybrids were phenotyped for haloperidol response before determination of TH cell number. Paralleling the results in the selected lines, TH cell number in the SNZc was significantly (range, 10-28%) higher in the most nonresponsive F₂ hybrids. TH cell number was determined in the SNZc and VTA of 10 standard inbred mouse strains for which the ED₅₀ for haloperidol-induced catalepsy was known. TH cell number showed significant differences among inbred strains, with the largest difference (88%) noted between the 129/J and P/J strains in the rostral SNZc. In the VTA, differences as large as 95% were noted (AKR/crl vs. P/J). Among the inbred strains, there was no significant relationship between cell number and response except in the medial SNZc, where the most responsive strains had the highest cell number. No significant correlations were found in the VTA. As no correlation between response and cell number in the inbred lines was found, this brings into question the validity of using genetic correlations obtained from inbred strains to understand genetic relationships among outbred or hybrid populations.