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 ED(50) 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 e stimated to be four. The strain means were correlated with the strain distribution patterns for 1300 marker loci of known chromosomal locati on and polymorphic between the C57BL/6J and DBA/2J strains. Six quanti tative trait loci (QTLs) were identified at P < .01. Two of the six QT Ls were confirmed in a sample of B6XD2 F-2 animals (n = 144), phenotyp ed for haloperidol response and genotyped for microsatellites closely linked to the QTLs. The confirmed QTL on chromosome 4 is near the b lo cus. The confirmed QTL on chromosome 9 is closely linked to Drd2, the D-2 dopamine receptor gene. One hundred of the F-2 individuals were ph enotyped for D-2 dopamine receptor binding using the ligand [I-125]epi depride as the ligand. Consistent with previous results, the nonrespon sive F-2 individuals showed modestly higher receptor binding in all br ain regions examined: the nucleus accumbens core, the nucleus accumben s shell, the lateral caudate putamen, the dorsomedial caudate putamen, the substantia nigra zona compacta and the ventral tegmental area. Th e DBA/2J allele of the chromosome 9 QTL was associated with higher rec eptor binding in all brain areas except the ventral tegmental area. Ov erall, the data illustrate that either near or part of Drd2 is a QTL w hich has significant effects on both haloperidol response and D-2 dopa mine receptor binding. However, the data also illustrate that most of the genetic variance in either haloperidol response or D-2 dopamine re ceptor binding is not associated with Drd2.