250. Anergia and Effort-Related Aspects of Motivational Dysfunction in Animal Models of Depressive Symptoms: The Role of Mesolimbic Dopamine and Related Circuitry

Abstract

Background: Motivational symptoms such as anergia, psychomotor retardation, or apathy are common in depression and other disorders. Many depressed people lack behavioral activation, and show reduced selection of high-effort activities. Effort-based choice tasks have been developed as animal models of motivational symptoms. In rodents, these tasks allow animals to choose between a more valued reinforcer obtained by high-effort actions versus a low-effort/low-reward option. Dopamine (DA) antagonism and mesolimbic DA depletions shift decision-making, decreasing selection of the high-effort option and increasing choice of the low effort alternative, under conditions that do not affect reward preference, appetite, or hedonic reactivity. Method(s): A low-effort bias in rodents is induced by conditions associated with depressive symptoms, including injections of tetrabenazine (TBZ), which blocks monoamine storage, and pro-inflammatory cytokines (IL-1B, IL-6). Result(s): Several DA uptake inhibitors can reverse the effortrelated effects of TBZ or cytokines (bupropion, GBR12909, methylphenidate, modafinil, lisdexamfetamine, and others; ANOVA, n>8; p<0.05). The norepinephrine (NE) uptake blocker desipramine does not reverse the effects of TBZ, nor do serotonin uptake blockers (fluoxetine, S-citalopram). The lack of effect of SSRIs is consistent with reports showing that SSRIs are relatively ineffective for treating fatigue and anergia. Furthermore, injections of DA uptake blockers increased progressive ratio work output, while fluoxetine, desipramine, and atomoxetine did not. Bupropion and GBR12909 at behaviorally active doses elevated extracellular DA in accumbens as measured by microdialysis, while fluoxetine, desipramine and atomoxetine did not. Conclusion(s): Effort-related motivational symptoms can be modeled in rodents, and these studies illustrate a key role for DA in regulating these functions.