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 four (FR4) schedule, DOV (1.56–50 mg/kg; PO) was given 25 min or 24 h prior to evaluation. The effects of DOV (12.5–50 mg/kg; PO) in the FST were evaluated 25 min post-treatment. Results DOV (6.25–50 mg/kg) dose-dependently reduced alcohol-maintained responding by 59–88% at 25 min post-treatment, without significantly altering sucrose responding. The reduction in alcohol responding (44% at 50 mg/kg) was sustained for up to 120 h after a single dose. Administration of a single dose of DOV (25, 50 mg/kg) 24 h before testing suppressed alcohol responding for 48 h by 59 -62%. DOV (12.5–50 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.

A Genetic Animal Model of Alcoholism for Screening Medications to Treat Addiction

“…Additonally, ethanol drinking by P rats was reduced by microinfusion of the D 2 antagonist sulpiride into the VTA (Nowak et al, 2000), NAcb (Levy et al, 1991) and ventral pallidum (Melendez et al, 2005). Finally, systemic administration of the D 3 antagonist SB-277011-A (Thanos et al, 2005) as well as the DAT inhibitors GBR 12909 (McBride et al, 1990) and DOV 102,677 (Yang et al, 2012) reduced ethanol intake by this line of rats.…”

“…However, most work has examined receptor antagonists, including WAY 100,635 (Zhou, McKinzie, Patel, Lumeng, & Li, 1998) which targets the 5HT 1A receptor; amperozide/FG 5606 (Lankford, Bjork, & Myers, 1996; Overstreet, McArthur, Rezvani, & Post, 1997), and FG 5974 (Lankford et al, 1996; Overstreet et al, 1997; Piercy, Bjork, & Myers, 1996) which target 5HT 2 receptors; as well as MDL 72222 (Rodd-Henricks, McKinzie, Edmundson, et al, 2000) and ICS 205-930 (Rodd et al, 2010; Rodd-Henricks, McKinzie, Edmundson, et al, 2000) which target 5HT 3 receptors, all of which reduce ethanol intake or the acquisition of operant ethanol self-administration by P rats. Additionally, the SERT inhibitors fluoxetine (Murphy et al, 1985, 1988; Rezvani et al, 2000; Zhou et al, 1998), fluvoxamine (Murphy et al, 1985) and DOV 102,677 (Yang et al, 2012) all reduced ethanol intake by P rats. The last compound also inhibits the norepinephrine and dopamine transporters.…”

“…Another study found that clonidine, an α2-adrenergic receptor agonist, can also reduce ethanol drinking by P rats (Rasmussen, Alexander, Malone, Federoff, & Froehlich, 2014; Rasmussen, Beckwith, Kincaid, & Froehlich, 2014). In addition, the triple monoamine uptake inhibitor (i.e., DAT, NET and SERT) DOV 102,677 reduced ethanol intake by P rats (Yang et al, 2012). Paralleling the preclinical findings, prazosin also has shown promise in the treatment of AUDs in humans (e.g., Simpson, Saxon, Meredith, et al, 2009).…”

Alcoholism and mental illness: overlapping diseases requiring a renewed focus

“…Moreover, a number of animal models have been developed to try to replicate alcohol addiction and anxiety, depression, stress, or PTSD for the purpose of understanding mechanisms of addiction and mental illness or testing candidate therapeutics (Barr et al, 2009;Becker, Lopez, & Doremus-Fitzwater, 2011;Edwards et al, 2013;Edwards & Koob, 2012;Maynard & Leasure, 2013;Peters, Slattery, Flor, Neumann, & Reber, 2013;Warnock et al, 2012;Yang et al, 2012). These models have major limitations.…”

“…These models have major limitations. Unlike humans, laboratory animals are selectively bred for alcohol preference and are trained to consume high doses of ethanol for predetermined time periods (Edwards et al, 2013;Peters et al, 2013;Warnock et al, 2012;Yang et al, 2012). These methods are employed to encourage animals to consume a specific amount of substance in a particular timeframe, a motivation that is distinct from those that drive human consumption of alcohol.…”