Effects of the Triple Monoamine Uptake Inhibitor DOV 102,677 on Alcohol-Motivated Responding and Antidepressant Activity in Alcohol-Preferring (P) Rats

• Published in: Alcoholism, clinical and experimental research Vol. 36; no. 5; pp. 863 - 873
• Main Authors: Yang, Andrew R. S. T., Yi, Heon S., Warnock, Kaitlin T., Mamczarz, Jacek, June Jr, Harry L., Mallick, Nikhil, Krieter, Philip A., Tonelli, Leonardo, Skolnick, Phil, Basile, Anthony S., June Sr, Harry L.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.05.2012; Wiley; Wiley Subscription Services, Inc
• Subjects: Adult and adolescent clinical studies; Alcohol; Alcohol Responding; Alcoholism; Alcoholism - complications; Alcoholism - drug therapy; Alcoholism and acute alcohol poisoning; Animals; Antidepressants; Biological and medical sciences; Bridged Bicyclo Compounds, Heterocyclic - pharmacokinetics; Bridged Bicyclo Compounds, Heterocyclic - therapeutic use; Central Nervous System Depressants - administration & dosage; Depression; Depression - complications; Depression - drug therapy; Disease Models, Animal; Dopamine; Dose-Response Relationship, Drug; Drug abuse; Drug Evaluation, Preclinical; Drug therapy; Ethanol; Ethanol - administration & dosage; Forced Swim Test; Kinetics; Male; Medical sciences; Metabolites; Monoamine Reuptake Inhibitor; monoamines; Mood disorders; Neurotransmitter Uptake Inhibitors - pharmacokinetics; Neurotransmitter Uptake Inhibitors - therapeutic use; Norepinephrine; P Rats; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Rats; Rats, Sprague-Dawley; Rodents; Serotonin; Sucrose; Sucrose - administration & dosage; Sweetening Agents - administration & dosage; Swimming; Toxicology; Mood disorder; Alcohol Responding; Monoamine Reuptake Inhibitor; Ethanol; Rat; Psychotropic; Rodentia; Forced Swim Test; Depression; Reuptake inhibitor; Biological activity; Uptake; Alcoholic beverage; Vertebrata; Mammalia; P Rats; Motivation; Animal; Antidepressant agent
• ISSN: 0145-6008; 1530-0277
• DOI: 10.1111/j.1530-0277.2011.01671.x

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.