title: Androgen-induced norepinephrine release mediating guinea pig seminal vesicle smooth muscle proliferation: potential role of pre-synaptic alpha2-adrenoceptors.
abstract: BACKGROUND
  Recent studies from our laboratory have demonstrated that androgen-induced basal norepinephrine (NE) release is responsible for the onset of proliferation in seminal vesicle smooth muscle (SVM) cells during early puberty. With subsequent sexual maturation, SVM was irreversibly differentiated to an androgen-resistant-amitotic state in which basal NE release remained elevated and resistant to androgen withdrawal or repletion. Based on these findings, we hypothesized that this irreversible elevation of basal NE release during pubertal development is caused, at least in part, by the down-regulation of pre-synaptic NE feedback inhibition, secondary to irreversible reduction in the expression of neuronal (pre-synaptic) alpha(2)-adrenoceptors. Functional alpha(2)-adrenoceptors are selectively localized to pre-synaptic sites in SVM.
  
  
  METHODS
  To test this hypothesis, we employed ligand binding techniques with [(3)H]RX821002, an antagonist which labeled all alpha(2)-adrenoceptor sub-types. Initial experiments focused on analysis of competitor specificity to identify the predominant alpha(2)-adrenoceptor sub-type in SVM. Subsequently, we quantified the changes in the receptor concentration (B(max)) for [(3)H]RX821002 at the point of maximal dihydrotestosterone (DHT)-induced change in basal NE release.
  
  
  RESULTS
  Based on competitor specificity for [(3)H]RX821002, the alpha(2D)-adrenoceptor sub-type predominated in SVM. We treated pre-pubertal castrate animals with DHT for 7 days, which was previously demonstrated to maximally induce basal NE release. This treatment reduced the pre-synaptic alpha(2)-adrenoceptor B(max) 4-fold. In animals which had been castrated as adults, the B(max) for [(3)H]RX821002 remained irreversibly suppressed.
  
  
  CONCLUSIONS
  The DHT-dependent reduction in the alpha(2)-adrenoceptor concentration is consistent with the developmental pattern of increased basal NE release. These findings support the hypothesis that the down-regulation of pre-synaptic NE feedback is mechanistically involved in the irreversible elevation of basal NE release. NE mediates proliferation in SVM in early pubertal development. Thus, the androgen-dependent pubertal growth of smooth muscle cells may be indirectly controlled at the level of neurotransmission.
authors.affiliation: Department of Surgery (Division of Urology), West Virginia University, Morgantown, West Virginia 26506, USA.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Kim
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Cole
authors.forename: Grant L
authors.initials: GL
authors.lastname: Franklin
authors.forename: Michael G
authors.initials: MG
authors.lastname: Mawhinney
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D013196:Dihydrotestosterone / Q000494:pharmacology*; D006168:Guinea Pigs; D019329:Idazoxan / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D009130:Muscle, Smooth / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D017661:Receptors, Presynaptic / Q000378:metabolism; D012669:Seminal Vesicles / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D012741:Sexual Maturation / Q000502:physiology; D014316:Tritium
chemical_list: D000317:Adrenergic alpha-Antagonists; D018341:Receptors, Adrenergic, alpha-2; D017661:Receptors, Presynaptic; D013196:Dihydrotestosterone; D014316:Tritium; C058525:2-methoxyidazoxan; D009638:Norepinephrine; D019329:Idazoxan