Mapping the genes for haloperidol-induced catalepsy

The strain means for haloperidol-induced catalepsy were determined in the 26 strain BXD recombinant inbred series. The ED₅₀ values ranged from 0.55 mg/kg (strain 30) to 7.9 mg/kg (strain 2). Heritability for the catalepsy response was 0.78 and the number of effective loci was estimated to be four. The strain means were correlated with the strain distribution patterns for 1300 marker loci of known chromosomal location and polymorphic between the C57BL/6J and DBA/2J strains. Six quantitative trait loci (QTLs) were identified at P < .01. Two of the six QTLs were confirmed in a sample of B6XD2 F₂ animals (n = 144), phenotyped for haloperidol response and genotyped for microsatellites closely linked to the QTLs. The confirmed QTL on chromosome 4 is near the b locus. The confirmed QTL on chromosome 9 is closely linked to Drd2, the D₂ dopamine receptor gene. One hundred of the F₂ individuals were phenotyped for D₂ dopamine receptor binding using the ligand [¹²⁵I]epidepride as the ligand. Consistent with previous results, the nonresponsive F₂ individuals showed modestly higher receptor binding in all brain regions examined: the nucleus accumbens core, the nucleus accumbens shell, the lateral caudate putamen, the dorsomedial caudate putamen, the substantia nigra zona compacta and the ventral tegmental area. The DBA/2J allele of the chromosome 9 QTL was associated with higher receptor binding in all brain areas except the ventral tegmental area. Overall, the data illustrate that either near or part of Drd2 is a QTL which has significant effects on both haloperidol response and D₂ dopamine receptor binding. However, the data also illustrate that most of the genetic variance in either haloperidol response or D₂ dopamine receptor binding is not associated with Drd2.