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The VMAT-2 inhibitor tetrabenazine affects effort-related decision making in a progressive ratio/chow feeding choice task: reversal with antidepressant drugs.

Randall PA, Lee CA, Nunes EJ, Yohn SE, Nowak V, Khan B, Shah P, Pandit S, Vemuri VK, Makriyannis A, Baqi Y, Müller CE, Correa M, Salamone JD - PLoS ONE (2014)

Bottom Line: Tasks measuring effort-based decision making can be used as animal models of the motivational symptoms of depression, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT-2) inhibitor tetrabenazine.Previous work has shown that the DA antagonist haloperidol reduced PROG work output on this task, but did not reduce chow intake, effects that differed substantially from those of reinforcer devaluation or appetite suppressant drugs.Similar effects were produced by administration of the subtype selective DA antagonists ecopipam (D1) and eticlopride (D2), but not by the cannabinoid CB1 receptor neutral antagonist and putative appetite suppressant AM 4413, which suppressed both lever pressing and chow intake.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychology, University of Connecticut, Storrs, Connecticut, United States of America.

ABSTRACT
Behavioral activation is a fundamental feature of motivation, and organisms frequently make effort-related decisions based upon evaluations of reinforcement value and response costs. Furthermore, people with major depression and other disorders often show anergia, psychomotor retardation, fatigue, and alterations in effort-related decision making. Tasks measuring effort-based decision making can be used as animal models of the motivational symptoms of depression, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT-2) inhibitor tetrabenazine. Tetrabenazine induces depressive symptoms in humans, and also preferentially depletes dopamine (DA). Rats were assessed using a concurrent progressive ratio (PROG)/chow feeding task, in which they can either lever press on a PROG schedule for preferred high-carbohydrate food, or approach and consume a less-preferred lab chow that is freely available in the chamber. Previous work has shown that the DA antagonist haloperidol reduced PROG work output on this task, but did not reduce chow intake, effects that differed substantially from those of reinforcer devaluation or appetite suppressant drugs. The present work demonstrated that tetrabenazine produced an effort-related shift in responding on the PROG/chow procedure, reducing lever presses, highest ratio achieved and time spent responding, but not reducing chow intake. Similar effects were produced by administration of the subtype selective DA antagonists ecopipam (D1) and eticlopride (D2), but not by the cannabinoid CB1 receptor neutral antagonist and putative appetite suppressant AM 4413, which suppressed both lever pressing and chow intake. The adenosine A2A antagonist MSX-3, the antidepressant and catecholamine uptake inhibitor bupropion, and the MAO-B inhibitor deprenyl, all reversed the impairments induced by tetrabenazine. This work demonstrates the potential utility of the PROG/chow procedure as a rodent model of the effort-related deficits observed in depressed patients.

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The DA uptake inhibitor and common antidepressant bupropion reverses the effects of TBZ on the PROG/Chow procedure.On measures of lever pressing, mean (+SEM) total lever presses (A), highest ratio achieved (B), and active lever time (measured in seconds, C), TBZ produced significant decreases at 0.75 mg/kg. Chow consumption (mean +SEM, in grams) during test sessions was unaffected by TBZ (D). Bupropion reversed the effects on total lever presses, highest ratio achieved and active lever time at 15.0 mg/kg. (# p<0.05, different from vehicle; * p<0.05, different from TBZ alone).
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pone-0099320-g006: The DA uptake inhibitor and common antidepressant bupropion reverses the effects of TBZ on the PROG/Chow procedure.On measures of lever pressing, mean (+SEM) total lever presses (A), highest ratio achieved (B), and active lever time (measured in seconds, C), TBZ produced significant decreases at 0.75 mg/kg. Chow consumption (mean +SEM, in grams) during test sessions was unaffected by TBZ (D). Bupropion reversed the effects on total lever presses, highest ratio achieved and active lever time at 15.0 mg/kg. (# p<0.05, different from vehicle; * p<0.05, different from TBZ alone).

Mentions: Repeated measures ANOVA demonstrated a significant effect of treatment on total lever presses (F[4], [40] = 7.683, p<0.05, Figure 6A). Planned comparisons revealed that total lever presses were significantly decreased by TBZ compared to vehicle (p<0.05), and that total lever presses were significantly increased at 15.0 mg/kg bupropion plus TBZ compared to TBZ alone (p<0.05). There also was a significant effect of treatment on highest ratio achieved (F[4], [40] = 14.364, p<0.05, Figure 6B). Planned comparisons showed that highest ratio achieved was significantly decreased by TBZ compared to vehicle (p<0.05), and that 15.0 mg/kg bupropion plus vehicle significantly differed from TBZ alone (p<0.05). Active lever time also showed a significant overall effect of treatment (F[4], [40] = 5.416, p<0.05, Figure 6C); this measure was significantly decreased by TBZ compared to vehicle (p<0.05), and 15.0 mg/kg bupropion plus TBZ differed from TBZ alone (p<0.05). There was a significant effect of treatment on chow consumption (F[4], [40] = 9.041, p<0.05, Figure 6D), but the only significant planned comparison was that chow intake was significantly decreased by 15.0 mg/kg bupropion compared to TBZ alone (p<0.05).


The VMAT-2 inhibitor tetrabenazine affects effort-related decision making in a progressive ratio/chow feeding choice task: reversal with antidepressant drugs.

Randall PA, Lee CA, Nunes EJ, Yohn SE, Nowak V, Khan B, Shah P, Pandit S, Vemuri VK, Makriyannis A, Baqi Y, Müller CE, Correa M, Salamone JD - PLoS ONE (2014)

The DA uptake inhibitor and common antidepressant bupropion reverses the effects of TBZ on the PROG/Chow procedure.On measures of lever pressing, mean (+SEM) total lever presses (A), highest ratio achieved (B), and active lever time (measured in seconds, C), TBZ produced significant decreases at 0.75 mg/kg. Chow consumption (mean +SEM, in grams) during test sessions was unaffected by TBZ (D). Bupropion reversed the effects on total lever presses, highest ratio achieved and active lever time at 15.0 mg/kg. (# p<0.05, different from vehicle; * p<0.05, different from TBZ alone).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4061002&req=5

pone-0099320-g006: The DA uptake inhibitor and common antidepressant bupropion reverses the effects of TBZ on the PROG/Chow procedure.On measures of lever pressing, mean (+SEM) total lever presses (A), highest ratio achieved (B), and active lever time (measured in seconds, C), TBZ produced significant decreases at 0.75 mg/kg. Chow consumption (mean +SEM, in grams) during test sessions was unaffected by TBZ (D). Bupropion reversed the effects on total lever presses, highest ratio achieved and active lever time at 15.0 mg/kg. (# p<0.05, different from vehicle; * p<0.05, different from TBZ alone).
Mentions: Repeated measures ANOVA demonstrated a significant effect of treatment on total lever presses (F[4], [40] = 7.683, p<0.05, Figure 6A). Planned comparisons revealed that total lever presses were significantly decreased by TBZ compared to vehicle (p<0.05), and that total lever presses were significantly increased at 15.0 mg/kg bupropion plus TBZ compared to TBZ alone (p<0.05). There also was a significant effect of treatment on highest ratio achieved (F[4], [40] = 14.364, p<0.05, Figure 6B). Planned comparisons showed that highest ratio achieved was significantly decreased by TBZ compared to vehicle (p<0.05), and that 15.0 mg/kg bupropion plus vehicle significantly differed from TBZ alone (p<0.05). Active lever time also showed a significant overall effect of treatment (F[4], [40] = 5.416, p<0.05, Figure 6C); this measure was significantly decreased by TBZ compared to vehicle (p<0.05), and 15.0 mg/kg bupropion plus TBZ differed from TBZ alone (p<0.05). There was a significant effect of treatment on chow consumption (F[4], [40] = 9.041, p<0.05, Figure 6D), but the only significant planned comparison was that chow intake was significantly decreased by 15.0 mg/kg bupropion compared to TBZ alone (p<0.05).

Bottom Line: Tasks measuring effort-based decision making can be used as animal models of the motivational symptoms of depression, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT-2) inhibitor tetrabenazine.Previous work has shown that the DA antagonist haloperidol reduced PROG work output on this task, but did not reduce chow intake, effects that differed substantially from those of reinforcer devaluation or appetite suppressant drugs.Similar effects were produced by administration of the subtype selective DA antagonists ecopipam (D1) and eticlopride (D2), but not by the cannabinoid CB1 receptor neutral antagonist and putative appetite suppressant AM 4413, which suppressed both lever pressing and chow intake.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychology, University of Connecticut, Storrs, Connecticut, United States of America.

ABSTRACT
Behavioral activation is a fundamental feature of motivation, and organisms frequently make effort-related decisions based upon evaluations of reinforcement value and response costs. Furthermore, people with major depression and other disorders often show anergia, psychomotor retardation, fatigue, and alterations in effort-related decision making. Tasks measuring effort-based decision making can be used as animal models of the motivational symptoms of depression, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT-2) inhibitor tetrabenazine. Tetrabenazine induces depressive symptoms in humans, and also preferentially depletes dopamine (DA). Rats were assessed using a concurrent progressive ratio (PROG)/chow feeding task, in which they can either lever press on a PROG schedule for preferred high-carbohydrate food, or approach and consume a less-preferred lab chow that is freely available in the chamber. Previous work has shown that the DA antagonist haloperidol reduced PROG work output on this task, but did not reduce chow intake, effects that differed substantially from those of reinforcer devaluation or appetite suppressant drugs. The present work demonstrated that tetrabenazine produced an effort-related shift in responding on the PROG/chow procedure, reducing lever presses, highest ratio achieved and time spent responding, but not reducing chow intake. Similar effects were produced by administration of the subtype selective DA antagonists ecopipam (D1) and eticlopride (D2), but not by the cannabinoid CB1 receptor neutral antagonist and putative appetite suppressant AM 4413, which suppressed both lever pressing and chow intake. The adenosine A2A antagonist MSX-3, the antidepressant and catecholamine uptake inhibitor bupropion, and the MAO-B inhibitor deprenyl, all reversed the impairments induced by tetrabenazine. This work demonstrates the potential utility of the PROG/chow procedure as a rodent model of the effort-related deficits observed in depressed patients.

Show MeSH
Related in: MedlinePlus