title: Opposite effects of tolcapone on amphetamine-disrupted startle gating in low vs. high COMT-expressing rat strains.
abstract: BACKGROUND
  Differential sensitivity to the prepulse inhibition (PPI)-disruptive effects of dopamine agonists in Sprague-Dawley (SD) vs. Long Evans (LE) rats is heritable, reflects differential activation of DA signaling, and is associated with differences in the brain expression of specific genes, including those of the catecholamine catabolic enzyme, catechol-O-methyltransferase (COMT). In humans, both basal and drug-modified PPI differs significantly between individuals with polymorphisms conferring low- vs. high-activity of COMT. We used the COMT inhibitor, tolcapone, to assess the role of COMT activity in regulating the differential effects of the dopamine releaser, amphetamine (AMPH), on PPI in SD and LE rats.
  
  
  METHODS
  Acoustic startle and PPI were assessed in SD and LE male rats after pretreatment with tolcapone (vehicle vs. 30 mg/kg ip) and treatment with AMPH (vehicle vs. 4.5mg/kg sc), using 10-120 ms prepulse intervals.
  
  
  RESULTS
  After tolcapone, AMPH significantly potentiated PPI in LE rats, and significantly disrupted PPI in SD rats. These patterns could not be explained by drug effects on pulse alone startle magnitude.
  
  
  CONCLUSIONS
  The impact of COMT inhibition on AMPH-modified PPI was categorically different in strains exhibiting low vs. high levels of forebrain Comt expression, consistent with reports in humans that tolcapone has opposite effects on PPI among individuals with polymorphisms conferring low vs. high COMT activity. The present model provides a basis for understanding the mechanisms by which the effects of COMT inhibition on sensorimotor gating - and potentially, related neurocognitive and clinical functions - under hyperdopaminergic states are dependent on an individual's basal levels of COMT activity.
authors.affiliation: Department of Psychiatry, 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: Samantha R
authors.initials: SR
authors.lastname: Hines
authors.forename: Sebastian D
authors.initials: SD
authors.lastname: Herrera
authors.forename: Martin
authors.initials: M
authors.lastname: Weber
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Breier
mesh_terms: D000662:Amphetamines / Q000494:pharmacology*; D000818:Animals; D001577:Benzophenones / Q000494:pharmacology*; D065098:Catechol O-Methyltransferase Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D009596:Nitrophenols / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects*; D013045:Species Specificity; D000077867:Tolcapone
chemical_list: D000662:Amphetamines; D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D004791:Enzyme Inhibitors; D009596:Nitrophenols; D000077867:Tolcapone