Selective breeding for increased cholinergic function: biometrical genetic analysis of muscarinic responses

Biometric genetic analyses of behavioral and physiologic responses known to be related to muscarinic cholinergic receptors (hypothermia, hypoactivity, inhibited avoidance, and reduced responding for water) were studied in genetic crosses and backcrosses of the Flinders sensitive line (FSL) and Flinders resistant line (FRL) of rats. The FSL rats were more sensitive to the direct muscarinic agonists, arecoline and oxotremorine, and to the indirect agonist, physostigmine, than any other group. The next most sensitive group was the F1 x FSL backcross, followed by the F2, F1, F1 x FRL backcross, and the FRL, in that order. These differences between the genetic groups could be accounted for completely by either solely additive or additive plus dominance genetic factors. When dominance genetic factors contributed to the differences among groups (6 out of 15), the F1 responded like the FRL rats. The variance of the responses measured made it impossible to obtain reliable estimates of the number of genes involved in many instances; when such estimates were possible, several genes (greater than or equal to 3) appeared to be involved. We conclude that muscarinic sensitivity in rats is under genetic control, with the greatest contribution coming from additive genetic factors. Because the FSL rat appears to be a genetic animal model of depression, the finding of several genes influencing muscarinic responses may help account for the difficulties investigators have had in locating a single major gene or biological marker for human depressive disorders.