DOPAMINE REQUIRES THE UNOCCUPIED PROGESTERONE-RECEPTOR TO INDUCE SEXUAL-BEHAVIOR IN MICE

Using the recently generated mutant mice strain (PRKO) carrying a null mutation for the progesterone receptor (PR) gene by gene targeting, w e examined the critical role of PR as a coordinator of key regulatory events involved in the steroid hormone and dopamine-facilitated sexual behavior in female mice. In vitro one-point binding analyses of estra diol benzoate (EB)-induced cellular PRs and immunohistochemistry of PR in the mediobasal hypothalamus demonstrated a reduction in binding in the homozygous females, equivalent to background levels seen in EB-un responsive tissue. The biochemical findings correlated well with the b ehavioral observations, with the wild type females exhibiting high lev els of lordosis, while the homozygous females showed minimal lordosis in response to mating by male mice. As a critical validation of our ea rlier studies on ligand-independent activation of PRs by dopamine, we examined the facilitation of sexual behavior by a dopamine agonist in the null mutants. Wild type females having the full complement of PRs exhibited high levels of lordosis, while the homozygous females showed minimal lordosis in response to dopamine. To determine whether this r educed response was due to a general lack of ability to express lordos is, mice were treated with another neurotransmitter, serotonin. No sig nificant difference in the serotonin-facilitated lordosis response was observed between the wild type and the homozygous females. We conclud e that multiple signal transduction pathways coexist in the neuroendoc rine system for reproductive behavior, with PR acting as a transcripti onal mediator for dopamine, as well as progesterone, to achieve integr ation of neural communication in the central nervous system.