Requirement for DARPP-32 in progesterone-facilitated sexual receptivity infemale rats and mice

DARPP-32, a dopamine- and adenosine 3',5'-monophosphate (cAMP)-regulated ph osphoprotein (32 kilodaltons in size), is an obligate intermediate in proge sterone (P)-facilitated sexual receptivity in female rats and mice. The fac ilitative effect of P on sexual receptivity in female rats was blocked by a ntisense oligonucleotides to DARPP-32. Homozygous mice carrying a null muta tion for the DARPP-32 gene exhibited minimal levels of P-facilitated sexual receptivity when compared to their wild-type Littermates. P significantly increased hypothalamic cAMP levels and cAMP-dependent protein kinase activi ty. These increases were not inhibited by a D-1 subclass dopamine receptor antagonist. P also enhanced phosphorylation of DARPP-32 on threonine 34 in the hypothalamus of mice. DARPP-32 activation is thus an obligatory step in progestin receptor regulation of sexual receptivity in rats and mice.