Complex genetic determinants of susceptibility to methylxanthine-induced locomotor activity changes

Abstract

The intent of this study was to investigate the role of inheritance in the determination of susceptibility to methylxanthine-induced behavioral changes. Two strains of inbred mice, SWR and CBA, which differ significantly in their response to caffaine- and theophylline-induced stimulation of locomotor activity, were used in classical genetic crosses to produce reciprocal F 1 hybrids, reciprocal backcross progeny and F 2 progeny. Theophylline dose reponse curves in the reciprocal F 1 hybrid strains were identical to each other and to their methylxanthine-responsive (CBA) parent. These results indicated that theophylline responsiveness behaved as a simple autosomal dominant trait. Behavioral responses of these F 1 hybrid strains to caffeine showed the same maximal enhancement of locomotor activity as their CBA progenitor at a dose 10 mg/kg IP, but locomotor activity stimulation also occurred at 32 mg/kg IP, a dose which inhibited their CBA parent. These data suggest that the genes specifying caffeine responsiveness differ from those encoding theophylline responsiveness. For both caffeine and theophylline, behavioral phenotypes and their expected frequencies of occurrence among backcross and F 2 progeny differed significantly from the segregation ratios expected for a trait determined by a single gene. These non-Mendelian segregation ratios suggest that locomotor activity stimulation by both of these methylxanthines is polygenically determined. It was anticipated that the same genetically encoded neurochemical mechanism would underlie the difference in behavioral response to the two methylxanthines. However, no significant correlation between caffeine-induced and theophylline-induced stimulation of locomotor activity was observed among progeny derived from backcrosses of F 1 self-crosses. These data establish that the behavioral effects of methylxanthines on locomotor activity levels are inherited in a complex manner and that, at least in these two strains of inbred mice, different genetic or genetically encoded neurochemical mechanisms underlie the behavioral effects of caffeine and theophylline.