Oral Ingestion and Intraventricular Injection of Curcumin Attenuates the Effort-Related Effects of the VMAT‑2 Inhibitor Tetrabenazine: Implications for Motivational Symptoms of Depression Samantha E. Yohn, †,‡ Dea Gorka, † Anisha Mistry, † Samantha Collins, † Emily Qian, † Merce Correa, †,§ Arushi Manchanda, ⊥ Robin H. Bogner, ⊥ and John D. Salamone* ,† † Department of Psychological Sciences and ⊥ Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut 06269-1020, United States § A ̀ rea de Psicobiologia, Universitat Jaume I, Campus de Riu Sec, 12071 Castelló , Spain ABSTRACT: Effort-related choice tasks are used for studying depressive motivational symptoms such as anergia/fatigue. These studies investigated the ability of the dietary supplement curcumin to reverse the low-effort bias induced by the monoamine storage blocker tetrabenazine. Tetrabenazine shifted effort-related choice in rats, decreasing high-effort lever pressing but increasing chow intake. The effects of tetrabenazine were reversed by oral ingestion of curcumin (80.0-160.0 mg/kg) and infusions of curcumin into the cerebral ventricles (2.0-8.0 μg). Curcumin attenuates the effort-related effects of tetrabenazine in this model via actions on the brain, suggesting that curcumin may be useful for treating human motivational symptoms. C urcumin, a dietary alkaloid from the Curcma longa (turmeric) plant, has been used for centuries as a natural remedy. Curcumin has anti-inflammatory and antioxidant effects 1 and also has antidepressant-like actions in classical rodent models. 2-7 Recent placebo-controlled studies indicate that curcumin can induce antidepressant effects in humans. 8-10 Yet despite these positive findings, curcumin is not widely used, in part because of poor oral bioavailability. Motivational symptoms such as anergia and fatigue are particularly debilitating in people with depression. 11, 12 Recently, tasks measuring effort-based decision-making have been developed for modeling motivational symptoms com- monly seen in depression and related disorders. 13-18 A bias toward low-effort choices in rodents is induced by manipu- lations associated with depression, including stress, 19, 20 administration of the pro-inflammatory cytokine interleukins 1-β and IL-6, 21,22 and tetrabenazine. 23-25 Tetrabenazine inhibits the vesicular monoamine transporter-type 2 (VMAT- 2), produces depressive symptoms in people, 26,27 and is active in classical animal depression tests such as forced swim and tail suspension. 28,29 In rodents tested on effort-based choice tasks, tetrabenazine shifted response choice from the high-effort lever pressing toward the low-effort alternative (chow intake 23,24 ). The effects of tetrabenazine on effort-related choice are attenuated by adenosine A 2A receptor antagonism, the antidepressant bupropion, and several dopamine (DA) trans- port blockers. 16,23,30,31 Rodent models of effort-based choice may be useful for developing medications to treat motivational dysfunctions, 15-18 an approach validated by clinical studies reporting that people with depression show alterations in effort- based decision making (i.e., low-effort bias. 32,33 The present study focused on the ability of curcumin to attenuate tetrabenazine-induced shifts in effort-related choice behavior as measured by the fixed ratio 5 (FR5)/chow feeding choice task. The first two experiments evaluated the ability of orally ingested curcumin to reverse the effort-related effects of tetrabenazine in rats tested on the concurrent FR5/chow feeding choice task. Previous curcumin studies have employed gavage feeding for oral administration, 5,6,34 but in the first two experiments below, we investigated an ingestion procedure for oral curcumin administration, which employed edible curcumin pellets, in order to mimic oral ingestion typically done by humans. Rats consumed small amounts of sucrose pellets or Received: May 15, 2017 Note pubs.acs.org/jnp © XXXX American Chemical Society and American Society of Pharmacognosy A DOI: 10.1021/acs.jnatprod.7b00425 J. Nat. Prod. XXXX, XXX, XXX-XXX