In an attempt to find an agent active in treating depression and alcoholism, we employed P rats (McBride and Li, 1998
; Murphy et al., 2002
) to model effectiveness of the TUI, DOV 102,677, on alcohol-motivated behaviors and FST performance. DOV produced robust, prolonged suppression of alcohol-maintained responding, with reductions as large as 59 – 88% on the day of treatment, and lasted as long as 6 days after treatment with 50 mg/kg. Subsequently, we observed a prolonged suppression of responding (83 and 62% of control levels at 24 and 48 h post-treatment) by DOV (12.5–50 mg/kg) when given 24 h prior
to evaluation, suggesting that DOV did not interact with alcohol on the day of pre-treatment. Thus, reduction of alcohol drinking by DOV may occur following intermittent treatments.
The exact mechanism by which DOV reduces alcohol-maintained responding is unknown. DOV (20 mg/kg) significantly elevated dialysate levels of all three biogenic amines in the medial prefrontal cortex [mPfc], and dopamine and serotonin levels in the nucleus accumbens, with lower doses (5 mg/kg) preferentially increasing DA and 5-HT levels in the mPfc (Popik et al., 2006
). Radioligand binding assays (Popik et al., 2006
) reported that DOV was a potent and “balanced” (i.e., approximately equipotent) inhibitor of SERT, NET and DAT transporters at a dose (20 mg/kg) which is highly effective in reducing alcohol responding. Thus, DOV may mediate its effect on alcohol responding via activation of 5-HT, NE, and DA pathways in the mPfc, nucleus accumbens, or other putative alcohol reward loci (McBride and Li, 1998
). In addition, DOV may normalize hypodopaminergic and hyposerotonergic tone (McBride and Li, 1998
) in putative alcohol reward loci in P rats, thereby reducing alcohol-motivated behaviors.
DOV-induced reductions in alcohol-mediated responding did not result from a generalized reduction of consummatory behaviors, or reduced propensity to work as a reinforcer; DOV did not reduce sucrose-maintained responding either on the day of pretreatment or several days after (). Even when the sucrose response rates approximated those produced by alcohol (affected by lowering the sucrose concentration), all the DOV doses failed to alter sucrose-motivated behaviors 25 min () to 48 h after administration. Both selective and prolonged suppression of alcohol-motivated behaviors by DOV is consistent with previous observations of suppression of alcohol consumption by DOV in mHEP rats (McMillen et al., 2007
). The ability of DOV to produce sustained reduction in drinking, and its failure to alter non-alcohol rewarded behaviors may facilitate its effectiveness in human alcoholics.
Potential antidepressant properties of DOV in P rats were examined in a modified FST (Cryan et al., 2005
). As previously reported in a “traditional” FST (where only immobility is scored), a negative association was found between immobility and alcohol preference, with decreases in immobility observed in P rats relative to NP rats (Godfrey et al., 1997
; Viglinskaya et al., 1995
). As rat immobility may models depressive symptoms in humans (Cryan et al., 2005
), this suggests an association between depression and alcohol consumption. However, to our knowledge, no evidence exists in the clinical literature for this. Finally, elevations in active behavior measures observed in naïve P versus NP rats may reflect innate alterations in monoaminergic signaling in P rats (McBride and Li, 1998
Immobile time for naïve P rats in the FST was dose-dependently reduced by DOV administration, with the MED (25 mg) being more effective than imipramine. All doses of DOV, compared to imipramine, significantly elevated climbing. Findings for DOV in the present study partially agree with AD-inhibition of activity of more than one monoamine transporter. Regardless of the predominant mechanism of action, DOV significantly reduces immobility of P and outbred rats in the FST, predictive of clinical AD activity. Together, these data suggest that triple monoamine uptake inhibitors may act as novel ADs (Skolnick and Basile, 2007
), even in subjects with comorbid alcoholism.
The long duration of DOV-induced suppression of alcohol-maintained responding following administration may reflect its pharmacokinetic and pharmacodynamic profile as a TUI. This is true particularly when DOV is given 24 h before evaluation [; Study #3]. After oral administration to Sprague-Dawley rats, DOV accumulates in the brain to levels approximately twice that of plasma. Consistent with this, microdialysis studies indicate that extracellular DA, NE, and 5-HT levels in the prefrontal cortex reach maximum 40 min after DOV administration, and are sustained for at least 120 min, after which 5-HT levels decline (Popik et al., 2006
). DA and NE levels remain stable or continue to rise throughout the rest of the 240 min observation period. Continued elevations of DA and NE (but not 5-HT) levels beyond Tmax
of the parent compound suggest that DOV may be converted to an active metabolite, a lactam which is 165- and 66-fold less potent an inhibitor of the 5-HT and NE transporters, respectively. However, this metabolite inhibits [3
H]DA uptake with an IC50
≈ 1.9 µM, so it is possible that brain concentrations may be sufficient to increase synaptic DA levels for at least 24 h after a behaviorally-active dose of DOV (20 mg/kg). Although pharmacokinetic studies were not performed in P rats, elimination t1/2
of the lactam metabolite (2.5 h) would have to be 5 times longer in P rats in order to explain the 6 day duration of action of a single, 50 mg/kg dose of DOV. Not even the long MRT0-∞
of the metabolite can account for this.. Overall, pharmacokinetics of DOV, coupled with the knowledge that alcohol reward is regulated by a number of neurotransmitters (McBride and Li, 1998
), suggests that dopaminergic activities of DOV, or of its primary metabolite, are not solely
responsible for its actions in modulating alcohol-seeking behaviors.
In conclusion, the present study provides compelling evidence that DOV produces both sustained and selective reductions on alcohol-motivated behaviors. The extended MRT0-∞
of DOV suggests that this may be attributable in part to an active metabolite. This hypothesis merits further investigation. In addition, DOV produced robust effects on measures of AD activity in P rats. We hypothesize that DOV functions to “normalize” monoaminergic neurotransmission in DA and 5-HT deficient P rats (Murphy et al., 2002
), thereby reducing alcohol-motivated and depression-like behaviors. Consistent with McMillen et al. (2007)
, we propose that DOV may be useful in treating comorbid alcoholism and depression in humans.