title: Probing the molecular basis for an inherited sensitivity to the startle-gating disruptive effects of apomorphine in rats.
abstract: BACKGROUND
  Prepulse inhibition of acoustic startle (PPI) is deficient in several heritable brain disorders. In rats, the dopamine agonist, apomorphine (APO), reduces PPI and expression of the early gene, c-fos, within the nucleus accumbens (NAC) core. Both of these effects are greater in Sprague-Dawley (SD) vs. Long Evans (LE) rats, and this PPI strain pattern is inherited. Here, we examined phosphorylation of cyclic-AMP response element-binding protein (CREB), a putative intermediary step between dopamine receptor stimulation and Fos expression, in SD and LE rats.
  
  
  METHODS
  The effects of APO (vehicle vs. 0.5 mg/kg) on PPI were tested in SD and LE rats in a within-subject design. Seven days later, under conditions mimicking PPI testing, half of the rats from each strain received either vehicle or APO (0.5 mg/kg) 20 min before euthanasia. NAC CREB and phospho-CREB levels were quantified from tissue sections reacted immunohistochemically.
  
  
  RESULTS
  APO reduced PPI in both strains, with a significantly greater effect in SD vs. LE rats. APO also significantly reduced NAC core phospho-CREB levels in both strains, with a significantly greater effect in SD vs. LE rats. Among SD rats receiving APO, the reduction in NAC core CREB phosphorylation correlated significantly with the APO-induced reduction in PPI (R = 0.49).
  
  
  CONCLUSIONS
  A dose of APO that disrupts PPI of acoustic startle causes a profound suppression of CREB phosphorylation in the NAC; both dopamine-sensitive behavioral and molecular phenotypes are more robust in SD vs. LE rats, and within SD rats, they are significantly correlated.
authors.affiliation: Department of Psychiatry, School of Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0804, USA. nswerdlow@ucsd.edu
authors.forename: Neal R
authors.initials: NR
authors.lastname: Swerdlow
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Breier
authors.forename: Richard L
authors.initials: RL
authors.lastname: Saint Marie
mesh_terms: D000818:Animals; D001058:Apomorphine / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology*; D007150:Immunohistochemistry; D007266:Inhibition, Psychological; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D019655:Quantitative Trait, Heritable; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D055139:Sensory Gating / Q000187:drug effects* / Q000235:genetics; D013045:Species Specificity
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D018491:Dopamine Agonists; D001058:Apomorphine