Blockade of uptake for dopamine, but not norepinephrine or 5-HT, increases selection of high effort instrumental activity: Implications for treatment of effort-related motivational symptoms in psychopathology
Introduction
Motivational symptoms such as psychomotor retardation, fatigue, lassitude, lack of energy and reduced exertion of effort are critical and debilitating features of major depressive disorder (Stahl, 2002, Demyttenaere et al., 2005, Salamone et al., 2006, Treadway and Zald, 2011, Fava et al., 2014). Factor analysis studies have reported that a lack of energy factor is a critical component of depressive symptoms (Gullion and Rush, 1998). The severity of effort-related motivational symptoms in depression is highly correlated with problems in social function, employment, and treatment outcomes (Tylee et al., 1999, Stahl, 2002). These motivational symptoms are very resistant to treatment (Stahl, 2002, Nutt et al., 2007, Fava et al., 2014), and the treatment of motivational dysfunction in depressed people appears to be more problematic than treatment of mood or anxiety symptoms. Many common antidepressants, including serotonin transport (SERT) inhibitors such as fluoxetine and citalopram, are relatively ineffective for treating motivational dysfunction, and in fact have been reported to induce or exacerbate these symptoms in some patients (Katz et al., 2004, Nutt et al., 2007, Daly et al., 2011, Targum and Fava, 2011, Padala et al., 2012, Stenman and Lilja, 2013, Nierenberg, 2013, Rothschild et al., 2014, Fava et al., 2014). There is some evidence suggesting that SERT inhibitors may be better at treating anxiety-related symptoms as opposed to motivational symptoms (Papakostas et al., 2008, Papakostas et al., 2012). Bell et al. (2013) reported that individual differences in behavioral traits can differentiate between depressed patients that are more responsive to fluoxetine (people with mood problems, irritability, and rumination) vs. the catecholamine uptake blocker bupropion (i.e., motivated, achievement-oriented, active, exercise-oriented people). This observation is consistent with several previous studies indicating that catecholamine uptake inhibitors such as bupropion can somewhat improve fatigue or anergic symptoms (Rampello et al., 1991, Papakostas et al., 2006, Pae et al., 2007, Cooper et al., 2014).
Because of the clinical significance of motivational dysfunctions, and the growing emphasis on identifying neural circuits related to specific psychiatric symptoms (i.e., the NIMH Research Domain Criterion approach), it is critical to develop animal models of these symptoms. Recent studies have focused upon tasks involving effort-based decision making. These procedures offer animals a choice between a preferred reward that can only be obtained with a high degree of effort vs. a low reward/low effort option. Conditions associated with depression, including stress (Shafiei et al., 2012, Bryce and Floresco, 2016), inflammatory challenge (Nunes et al., 2014), and administration of the vesicular monoamine transport (VMAT-2) inhibitor tetrabenazine (Nunes et al., 2013, Randall et al., 2014, Yohn et al., 2015a), which blocks monoamine storage and selectively depletes striatal dopamine (DA) at low doses, all can affect effort-related decision making and bias rodents towards the low effort option. These results are validated by studies showing that people with major depression show a bias towards the low effort option in human tasks of effort-based decision making (Treadway et al., 2012, Yang et al., 2014, Yang et al., 2016). Several recent studies have focused upon a recently developed rodent model that uses tetrabenazine to induce effort-related motivational impairments (Nunes et al., 2014, Yohn et al., 2015a, Yohn et al., 2015b, Yohn et al., 2016a, Yohn et al., 2016b). Tetrabenazine induces depressive symptoms in people (Frank, 2010, Guay, 2010), and consistent with the clinical pharmacology data reviewed above, Yohn et al., 2016a, Yohn et al., 2016b observed that the ability of monoamine uptake inhibitors to reverse the effects of tetrabenazine on rats performing on a concurrent fixed ratio 5 (FR5)/chow feeding choice task depended upon the specific mechanism of action. Administration of the catecholamine uptake inhibitor bupropion and the selective DAT inhibitor GBR12909 significantly attenuated the tetrabenazine-induced shifts in effortful responding, while administration of SERT or norepinephrine transport (NET) inhibitors failed to reverse the effects of tetrabenazine, and in fact produced further behavioral impairments (Yohn et al., 2016a, Yohn et al., 2016b).
In rodents, a task that has been used to assess effort-related choice behavior is the progressive ratio (PROG)/chow feeding concurrent choice task (Randall et al., 2012, Randall et al., 2014, Randall et al., 2015, Beeler et al., 2012, Sommer et al., 2014). With this task, rats can lever press on a PROG schedule reinforced by preferred high-carbohydrate food pellets, or alternatively approach and consume the less-preferred laboratory chow that is concurrently available. Interference with DA transmission by administration of DA D1 or D2 family antagonists, as well as DA depletions induced by tetrabenazine, selectively reduce PROG lever pressing and tend to increase chow intake (Randall et al., 2012, Randall et al., 2014). These effects of DA antagonism or depletion do not resemble those produced by appetite suppressant drugs or reinforcer devaluation (Randall et al., 2012, Randall et al., 2014). Furthermore, Randall et al. (2012) found that rats with higher work output on the PROG lever pressing component showed greater expression of a key marker of DA-related signal transduction (accumbens core DARPP-32 phosphorylated at the threonine 34 site) compared to low performers. The incrementing lever press requirements of the PROG task present a work-related challenge, and at some point all animals shift their choice to chow intake (Randall et al., 2012, Randall et al., 2014, Randall et al., 2015). Thus, the PROG/chow feeding choice task is well suited for determining if a drug can increase lever pressing work output, because the baseline levels of lever pressing are relatively low for most animals. Increases in selection of PROG lever pressing and concomitant decreases in chow consumption can be produced by acute administration of the adenosine A2A antagonist MSX-3 (Randall et al., 2012), and by several catecholamine uptake inhibitors (Randall et al., 2015, Sommer et al., 2014, Salamone et al., 2016a, Yohn et al., 2016b, Yohn et al.,). However, selective SERT and NET inhibitors have not yet been assessed using PROG/chow feeding choice procedures.
It is very important to evaluate monoamine uptake inhibitors on tests of effort-related function, in part because this is a common strategy for the treatment of depression, and also because of evidence indicating that DAT and SERT inhibitors may have differential effects on motivational symptoms in humans (Rampello et al., 1991, Stahl, 2002, Demyttenaere et al., 2005, Papakostas et al., 2006, Pae et al., 2007, Fava et al., 2014, Cooper et al., 2014). Furthermore, in order to develop a complete picture of the effort-related actions of monoamine uptake inhibitors, it is important to administer them alone, in the absence of a drug like tetrabenazine, because it would allow for the assessment of both increases and decreases in performance, in the absence of a drug condition that induces an impairment. Thus, the present studies investigated the effort-related effects of acute and repeated administration of several monoamine uptake inhibitors, including the DAT inhibitor GBR12909, the NET inhibitors desipramine and atomoxetine, and the SERT inhibitor fluoxetine, to enhance effortful responding (i.e., PROG lever pressing) when administered alone (i.e., without tetrabenazine). It was hypothesized that effortful PROG lever pressing would be enhanced after administration of GBR12909, but not by fluoxetine, desipramine or atomoxetine. Because of the literature implicating accumbens DA in effort-related process (Nunes et al., 2013, Salamone et al., 2003, Salamone et al., 2007, Salamone et al., 2016c, Salamone and Correa, 2012, Yohn et al., 2016a), additional experiments investigated the effects of these drugs on extracellular levels of DA as measured by microdialysis.
Section snippets
Subjects
Adult male, drug-naïve, Sprague Dawley rats (Harlan-Sprague Dawley, Indianapolis, IN, USA) were housed in a colony maintained at 23 °C with 12-h light/dark cycles (lights on at 7:00 h). Rats (n = 32) weighed 275–299 g at the beginning of the study, and were initially food restricted to 85% of their free-feeding body weight for operant training. Rats were fed supplemental chow to maintain weight throughout the study (approximately 15 g per rat on days when there was no testing), with water
Results
Experiment 1 Acute Administration of GBR12909 on PROG/Chow Performance
Repeated measures ANOVA revealed that there was a significant treatment effect on lever pressing [F(4,68) = 6.257, p < 0.001; Fig. 1A], highest ratio achieved [F(4,68) = 7.799, p < 0.001; Fig. 1B], active lever time [F(4,68) = 11.546, p < 0.001; Fig. 1C], and chow consumption [F(4,68) = 16.377, p < 0.001; Fig. 1D]. Planned comparisons revealed that 5.0 and 10.0 mg/kg GBR significantly increased total number of lever presses (p < 0.01),
Discussion
These experiments evaluated the ability of acute and repeated administration of monoamine uptake inhibitors with varying mechanisms of action to increase effortful responding in animals tested on the PROG/chow feeding choice task. This work was undertaken to identify the specific monoamine transporter site at which a pharmacological blockade would shift effort-based choice and increase selection of the high effort alternative (PROG lever pressing). Previous results from Randall et al. (2015)
Conclusions
In conclusion, the present studies indicate that monoamine uptake inhibitors with distinct mechanisms of action have differential effects on effort-related choice behavior. Acute or repeated administration of the DAT inhibitor GBR12909 significantly increased selection of high-effort PROG responding (i.e., lever pressing measures). A dose of GBR12909 that increased effortful responding also elevated levels of extracellular DA in the accumbens. In contrast, neither the NET inhibitors DES or ATO
Funding and disclosure
This research was supported by grants to JS from NIH/NIMH (MH094966) and the UCONN Research Foundation, and to Merce Correa from Fundació Bancaixa/U. Jaume I. (P1.1B2010-43). It also was supported by the Psychology Department Undergraduate Research Grant program. JS has received grants from, and done consulting work for, Pfizer, Roche, Shire and Prexa. The authors have nothing to disclose in terms of competing interests.
Acknowledgments
We wish to thank Gail Harmata, Bridget Wilson and Giuseppe Tripodi for their assistance.
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