title: Effects of the triple monoamine uptake inhibitor DOV 102,677 on alcohol-motivated responding and antidepressant activity in alcohol-preferring (P) rats.
abstract: BACKGROUND
  Concurrent inhibitors of dopamine, norepinephrine, and serotonin uptake have been proposed as novel antidepressants. Given the high comorbidity between alcoholism and depression, we evaluated the activity of DOV 102,677 (DOV) on alcohol-maintained responding and performance in the forced swim test (FST), a model of antidepressant (AD) activity, using alcohol-preferring (P) rats.
  
  
  METHODS
  Following training to lever press for either alcohol (10% v/v) or sucrose (3, 2%, w/v) on a fixed-ratio 4 (FR4) schedule, DOV (1.56 to 50 mg/kg; PO) was given 25 minutes or 24 hours prior to evaluation. The effects of DOV (12.5 to 50 mg/kg; PO) in the FST were evaluated 25 minutes posttreatment.
  
  
  RESULTS
  DOV (6.25 to 50 mg/kg) dose-dependently reduced alcohol-maintained responding by 59 to 88% at 25 minutes posttreatment, without significantly altering sucrose responding. The reduction in alcohol responding (44% at 50 mg/kg) was sustained for up to 120 hours after a single dose. Administration of a single dose of DOV (25, 50 mg/kg) 24 hours before testing suppressed alcohol responding for 48 hours by 59 to 62%. DOV (12.5 to 50 mg/kg) also dose-dependently reduced immobility of P rats in the FST.
  
  
  CONCLUSIONS
  DOV produces both prolonged and selective reductions of alcohol-motivated behaviors in P rats. The elimination kinetics of DOV suggests that its long duration of action may be due to an active metabolite. DOV also produced robust AD-like effects in P rats. We propose that DOV may be useful in treating comorbid alcoholism and depression in humans.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Howard University College of Medicine, Washington, DC, USA.
authors.forename: Andrew R S T
authors.initials: AR
authors.lastname: Yang
authors.forename: Heon S
authors.initials: HS
authors.lastname: Yi
authors.forename: Kaitlin T
authors.initials: KT
authors.lastname: Warnock
authors.forename: Jacek
authors.initials: J
authors.lastname: Mamczarz
authors.forename: Harry L
authors.initials: HL
authors.lastname: June
authors.forename: Nikhil
authors.initials: N
authors.lastname: Mallick
authors.forename: Philip A
authors.initials: PA
authors.lastname: Krieter
authors.forename: Leonardo
authors.initials: L
authors.lastname: Tonelli
authors.forename: Phil
authors.initials: P
authors.lastname: Skolnick
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Basile
authors.forename: Harry L
authors.initials: HL
authors.lastname: June
mesh_terms: D000437:Alcoholism / Q000150:complications* / Q000188:drug therapy; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002492:Central Nervous System Depressants / Q000008:administration & dosage; D003863:Depression / Q000150:complications / Q000188:drug therapy*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D000431:Ethanol / Q000008:administration & dosage; D008297:Male; D014179:Neurotransmitter Uptake Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013395:Sucrose / Q000008:administration & dosage; D013549:Sweetening Agents / Q000008:administration & dosage; D013550:Swimming
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D002492:Central Nervous System Depressants; C519037:DOV 102,677; D014179:Neurotransmitter Uptake Inhibitors; D013549:Sweetening Agents; D000431:Ethanol; D013395:Sucrose