Pituitary Lactotroph Hyperplasia and Chronic Hyperprolactinemia in Dopamine D2 Receptor-Deficient Mice

Abstract

Dopamine secreted from hypophysial hypothalamic neurons is a principal inhibitory regulator of pituitary hormone secretion. Mice with a disrupted D2 dopamine receptor gene had chronic hyperprolactinemia and developed anterior lobe lactotroph hyperplasia without evidence of adenomatous transformation. Unexpectedly, the mutant mice had no hyperplasia of the intermediate lobe melanotrophs. Aged female D2 receptor -/- mice developed uterine adenomyosis in response to prolonged prolactin exposure. These data reveal a critical role of hypothalamic dopamine in controlling pituitary growth and support a multistep mechanism for the induction and perpetuation of lactotroph hyperplasia, involving the lack of dopamine signaling, a low androgen/estrogen ratio, and a final autocrine or paracrine "feed-forward" stimulation of mitogenesis, probably by prolactin itself.

Dopaminergic Signaling Mediates the Motivational Response Underlying the Opponent Process to Chronic but Not Acute Nicotine

“…Male wild-type mice were C57BL/6 (n ¼ 329; Charles River, Montreal, Canada) weighing 25-35 g. Heterozygous fifthgeneration D 2 breeder mice were received as a gift (Kelly et al, 1997) and crosses were bred at the University of Toronto to obtain homozygous male D 2 receptor knockout (KO) mice (n ¼ 26) and their controls (n ¼ 20). Mice were housed individually in plastic cages in a sound-attenuated room at a temperature of 22 1C with lights on from 0700 to 1900 hours.…”

Contributions of Dopamine D1, D2, and D3 Receptor Subtypes to the Disruptive Effects of Cocaine on Prepulse Inhibition in Mice

“…The D2R mutant mice (Kelly et al, 1997(Kelly et al, , 1998, official strain designation B6.129S2-Drd2 tm1Low , were originally generated at OHSU and backcrossed for 14 generations (N14) onto the inbred C57BL/6J line. N14 C57BL/6J D2R HET breeding pairs were used to generate fully congenic mice used in behavioral studies.…”

Comparative, Topographically-Based Evaluation of Behavioural Phenotype and Specification of D1-Like:D2 Interactions in a Line of Incipient Congenic Mice with D2 Dopamine Receptor 'Knockout'

“…The original F2 hybrid strain (129S2/SvPas ϫ C57BL/ 6J) containing the mutated D 2 receptor allele was generated as reported previously (Kelly et al 1997 ) littermates were bred and genotyped by PCR among the progeny of heterozygous intermatings. They were housed in groups of 3-5 with food and water available ad libitum , and were maintained at 21 Ϯ 1 Њ C on a 12 h/12 h (0700 on; 1900 off) light/dark schedule.…”

“…Over recent years, several groups have applied recombinant DNA technology to construct mice with targeted gene deletion ['knockout'] of individual dopamine receptor subtypes (Sibley 1999;Waddington et al 2001), and three of these have concerned the D 2 subtype (Baik et al 1995;Kelly et al 1997Kelly et al , 1998Jung et al 1999). Although different genetic strategies were utilised, all three groups demonstrated comparable neurochemical evidence that functional D 2 receptors had been ablated.…”