SEX STEROID-HORMONES CHANGE THE DIFFERENTIAL DISTRIBUTION OF THE ISOFORMS OF THE D-2 DOPAMINE-RECEPTOR MESSENGER-RNA IN THE RAT-BRAIN

The two isoforms of the rat dopamine D-2 receptor are generated by alt ernative splicing of the pre-messenger RNA and differ in the length of their third cytoplasmic loop involved in coupling to G-proteins. As q uantified by polymerase chain reaction, the long isoform D-2L is predo minant in the pituitary gland, the striatum and to a lesser extend in the olfactory tubercle, whereas the short isoform D-2S is relatively m ore abundant in the hypothalamus and the substantia nigra. Changes in circulating sex hormone levels modulated the splicing without affectin g the total amount of D-2 receptor messenger RNA. Castration of male r ats increased the ratio D-2L/D-2S in the pituitary, hypothalamus and s ubstantia nigra, and decreased it in the olfactory tubercle. Testoster one substitution reversed the effect of castration in the pituitary an d olfactory tubercle but not in the substantia nigra. In castrated rat s, 17 beta-estradiol had a similar effect to that of testosterone in t he olfactory tubercle, indicating that testosterone may act after arom atization to estradiol. In the hypothalamus, 17 beta-estradiol alone r eversed the effect of castration. In the striatum, neither castration nor hormonal treatments modified the splicing of the D-2 receptor mRNA . Treatment of animals with specific androgen and estrogen receptor bl ockers confirmed that steroids were acting through their specific intr acellular receptors. These observations suggest a molecular mechanism, physiologically relevant, by which circulating sex hormones could mod ulate dopamine transmission in areas implicated in reproductive and pa rental behaviours.