GENETICS, NEUROLEPTIC RESPONSE AND THE ORGANIZATION OF CHOLINERGIC NEURONS IN THE MOUSE STRIATUM

Compared with the neuroleptic nonresponsive (NNR) mouse line, the neur oleptic responsive (NR) line has a significantly higher number of stri atal cholinergic neurons (Hitzemann et al., 1993). We now report addit ional information on this genetic association. At the fifth selected g eneration, a new selection of the NR and NNR lines differed 5-fold in their ED(50) values (1 vs. 5 mg/kg) for haloperidol-induced catalepsy and 20% in the number of striatal cholinergic neurons (higher in the N R line). This association was further examined in 10 standard inbred m ouse strains; eight of the strains had been crossed to form the hetero geneous stock from which the new NR and NNR lines were selected. In th is panel, we detected no significant association between number of cho linergic neurons and haloperidol response. To examine the similarities and differences in the modes of inheritance for the two phenotypes, w e formed a full Mendelian cross from the C57BL/6 (B6) and DBA/2 (D2) m ouse strains. The B6 and D2 strains differ 9-fold in their haloperidol ED(50) values (3.9 vs. 0.4 mg/kg) and more than 30% in the number of cholinergic neurons (higher in the D2 strain). Haloperidol-induced cat alepsy was described by a simple additive genetic model; the narrow se nse heritability was 0.60. In contrast, for the number of cholinergic neurons, the B6 genotype was dominant and heterosis was detected in th e F-1 cross. Despite the differences in heritability, among B6D2 F-2 i ndividuals, increasing haloperidol sensitivity was associated with inc reasing numbers of striatal cholinergic neurons, The BXD recombinant i nbred series (25 strains) showed a 16-fold range of variation in the h aloperidol ED(50) and a greater than 50% variation in the number of st riatal cholinergic neurons. However, we detected no significant associ ation between haloperidol response and number of cholinergic neurons. Overall, the data suggest that the genetic association between the phe notypes is modest, complex and detectable only with some genetic strat egies.