Note Cite This: J. Nat. Prod. 2017, 80, 2839-2844
pubs.acs.org/jnp
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 § ̀ Area 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.
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The effects of tetrabenazine on effort-related choice are attenuated by adenosine A2A receptor antagonism, the antidepressant bupropion, and several dopamine (DA) transport 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 effortbased 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
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 effects1 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 commonly seen in depression and related disorders.13−18 A bias toward low-effort choices in rodents is induced by manipulations 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 (VMAT2), 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 intake23,24). © 2017 American Chemical Society and American Society of Pharmacognosy
Received: May 15, 2017 Published: September 14, 2017 2839
DOI: 10.1021/acs.jnatprod.7b00425 J. Nat. Prod. 2017, 80, 2839−2844
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curcumin/sucrose pellets, or a mixture of the two, before behavioral testing. To determine if curcumin exerted effects via actions on the brain, an additional experiment studied the effects of intracerebroventricular (ICV) administration of curcumin. It was hypothesized that (a) tetrabenazine would shift choice behavior toward the low-effort option, decreasing lever pressing and increasing chow intake, and (b) these effortrelated effects of tetrabenazine would be attenuated by oral ingestion and central infusion of curcumin. In all experiments, the total number of lever presses and gram quantity of chow intake from the 30 min session were analyzed using repeated measures analysis of variance (ANOVA). A computerized statistical program (SPSS 21.0 for Windows) was used to perform all analyses. When there was a significant ANOVA, nonorthogonal planned comparisons using the overall error term were used to assess the differences between each treatment and the control condition. The number of comparisons was restricted to the number of treatments minus one.35 The effects of the VMAT-2 inhibitor tetrabenazine were not significantly attenuated by curcumin administered 2 h prior to testing. Repeated measures ANOVA showed that there was an overall significant effect of treatment on lever pressing ([F(3,9) = 16.2777; p < 0.01]; Figure 1A). Nonorthogonal planned comparisons revealed that tetrabenazine significantly lowed lever presses relative to vehicle control (p < 0.05). There was no significant overall effect of 80 or 160 mg/kg curcumin on lever pressing compared to tetrabenazine-treated animals (p > 0.05). The overall treatment effect for chow consumption was also statistically significant ([F(3,9) = 13.96; p < 0.01]; Figure 1B). Administration of tetrabenazine increased chow consumption relative to vehicle−vehicle conditions (planned comparisons, p < 0.01). Nonorthogonal planned comparisons revealed that there was not a significant decrease in chow consumption with either 80 or 160 mg/kg curcumin compared to tetrabenazine-treated animals (p > 0.05). In contrast, curcumin ingested 3 h prior to testing produced a partial reversal of the effects of tetrabenazine in animals tested on the FR5/chow feeding choice task (Figure 2A,B). Repeated measures ANOVA revealed that there was an overall significant effect of treatment on lever pressing ([F(3,15) = 7.77; p < 0.002]; Figure 2A). Planned comparisons showed that tetrabenazine produced a significant reduction in lever pressing compared to vehicle control conditions (p < 0.05). Coadministration of 160 mg/kg curcumin 3 h prior to testing significantly increased lever pressing compared to tetrabenazine plus vehicle treated animals (planned comparisons, p < 0.05). There was also a significant overall effect of treatment on chow intake ([F(3,15) = 4.41, p < 0.021]; Figure 2B). Tetrabenazine significantly increased chow consumption compared to vehicletreated control animals (planned comparisons, p < 0.05). Coadministration of 160 mg/kg curcumin plus tetrabenazine significantly decreased chow consumption relative to tetrabenazine plus control pellets (planned comparisons, p < 0.05). Thus, coadministration of 160 mg/kg curcumin with tetrabenazine significantly increased lever pressing and decreased chow consumption compared to the tetrabenazine alone condition. In the third experiment, low doses of curcumin were injected directly into the brain via chronic indwelling cannulae. Repeated measures ANOVA demonstrated that there was an overall significant effect of drug treatment on lever presses [F(4,48) = 34.048, p < 0.001; Figure 3A]. Planned comparisons
Figure 1. Effects of orally ingested curcumin (2 h before testing) on tetrabenazine (TBZ)-induced changes in performance on the concurrent FR5/chow feeding procedure. Rats (n = 9) received i.p. injections of either vehicle or 0.75 mg/kg TBZ 90 min prior to testing, and curcumin pellets were ingested 2 h prior to behavioral testing. All rats received the following treatment conditions: i.p. vehicle plus placebo sucrose pellets (Veh/Veh), i.p. TBZ plus placebo sucrose pellets (TBZ/Veh), TBZ plus 80.0 mg/kg curcumin pellets (TBZ/ 80Cu), and TBZ plus 160 mg/kg curcumin pellets (TBZ/160Cu). (A) Mean (+SEM) number of lever presses (FR5 schedule) during the 30 min session. (B) Mean (+SEM) chow consumption (in grams) during the 30 min session. #p < 0.01 different from vehicle/vehicle, planned comparison; *p < 0.05, different from vehicle plus TBZ, planned comparisons.
showed that 0.75 mg/kg tetrabenazine decreased lever pressing compared to vehicle-control-treated animals (p < 0.01). In addition, ICV injection of curcumin (4.0 and 8.0 μg) to tetrabenazine-treated rats significantly increased lever pressing compared to tetrabenazine plus vehicle (planned comparisons, p < 0.05). There was also an overall significant effect of drug treatment on chow consumption [F(4,48) = 8.705, p < 0.001; Figure 3B]. Administration of 0.75 mg/kg tetrabenazine increased consumption of the concurrently available lab chow compared to vehicle-treated animals (planned comparisons, p < 0.05). Similar to the effects seen on lever pressing, coadministration of 4.0 and 8.0 μg of curcumin significantly decreased chow consumption relative to tetrabenazine-treated animals (planned comparisons, p < 0.05). Thus, administration of curcumin directly into the brain significantly attenuated the effects of tetrabenazine on effort-based choice behavior. 2840
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Figure 2. Effects of orally ingested curcumin (3 h before testing) on TBZ-induced changes in performance on the concurrent FR5/chow feeding procedure. Rats (n = 9) received i.p. injections of either vehicle or 0.75 mg/kg TBZ 90 min prior to testing, and curcumin pellets were ingested 3 h prior to behavioral testing. All rats received the following treatment conditions: i.p. vehicle plus placebo sucrose pellets (Veh/ Veh), i.p. TBZ plus placebo sucrose pellets (TBZ/Veh), TBZ plus 80.0 mg/kg curcumin pellets (TBZ/80Cu), and TBZ plus 160 mg/kg curcumin pellets (TBZ/160Cu). (A) Mean (+SEM) number of lever presses (FR5 schedule) during the 30 min session. (B) Mean (+SEM) chow consumption (in grams) during the 30 min session. #p < 0.01 different from vehicle/vehicle, planned comparison; *p < 0.05, different from vehicle plus TBZ, planned comparisons.
Figure 3. Effects of ICV-injected curcumin (Cu) on tetrabenazineinduced changes in performance on the concurrent FR5/chow feeding procedure. Rats (n = 13) received i.p. injections of either vehicle or 0.75 mg/kg TBZ 90 min prior to testing and various doses of curcumin 20 min prior to testing. All rats received the following treatment conditions: vehicle plus vehicle (VEH/VEH), tetrabenazine plus vehicle (TBZ/VEH), tetrabenazine plus 2.0 μg of curcumin (TBZ/2.0Cu), tetrabenazine plus 4.0 μg of curcumin (TBZ/4.0Cu), and tetrabenazine plus 8.0 μg of curcumin (TBZ/8.0Cu). (A) Mean (+SEM) number of lever presses (FR5 schedule) during the 30 min session. (B) Mean (+SEM) chow consumption (in grams) during the 30 min session. #p < 0.01 different from vehicle/vehicle, planned comparison; *p < 0.05, different from vehicle plus TBZ, planned comparisons.
Across all experiments, tetrabenazine induced a low-effort bias. Tetrabenazine is a VMAT-2 inhibitor that blocks storage and depletes levels of monoamines, and at low doses such as the 0.75 mg/kg dose used in the present study this drug is relatively effective at depleting dopamine and reducing postsynaptic dopamine signaling in striatal areas, including nucleus accumbens.13,36,37 Tetrabenazine induces depressive symptoms including fatigue in people,26,27 and previous work has shown that low doses of tetrabenazine alter effort-related choice behavior across multiple paradigms, decreasing selection of the high-effort alternative and increasing selection of the lower valued option that can be obtained through minimal work.13,23−25 These shifts in choice behavior are not due to changes in food consumption, food preference, hedonic taste reactivity, or reference memory.13,23,24,38 Tetrabenazine-treated rats still remain directed toward the acquisition and consumption of food, but select an alternative path to obtain food that requires minimal effort (i.e., approach/consumption
of the freely available chow). Tetrabenazine-induced shifts in behavior can be attenuated through coadministration of a variety of compounds, such as the adenosine A2A antagonist MSX-3, the catecholamine uptake inhibitor and antidepressant bupropion,13,23−25 the dopamine transport inhibitors GBR1290925 and PRX-04040,31 and the stimulant drugs lisdexamfetamine30 and methylphenidate.17 Consistent with these previous findings, the present studies showed that tetrabenazine altered effort-based decision making in rats tested on the FR5/ chow feeding choice task, reducing work output on the lever pressing schedule but increasing selection of the freely available lab chow (Figures 1−3). These behavioral effects thus served as a model for assessing the effort-related motivational effects of curcumin. Evaluation of the potential utility of substances for 2841
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effective at treating motivational dysfunction and fatigue in depressed people.49−52 Furthermore, the positive effect of curcumin in the present model stands in contrast to the ineffectiveness of the serotonin uptake blockers fluoxetine and s-citalopram, which failed to reverse the effort-related effects of tetrabenazine.25,30 This contrast is potentially important in view of human clinical reports indicating that inhibitors of serotonin uptake are relatively ineffective at treating motivational symptoms in depressed people and that anergia, fatigue, and lassitude are often residual symptoms seen after treatment with these commonly used drugs.11,12,53 In summary, coadministration of curcumin attenuates tetrabenazine-induced shifts in effort-related choice behavior. It should be recognized that tests of effort-related choice behavior are not intended to serve as animal models of depression, per se. Rather, they are being studied as potential models of a specific class of symptoms (i.e., effort-related motivational symptoms) that is characteristic of depression, but also spans multiple disorders and conditions. This suggestion is consistent with the recent trend in mental health research that places less emphasis on traditional diagnostic categories and instead focuses on the neural circuits mediating specific pathological symptoms (i.e., the research domain criteria approach54). The mechanism underlying the antidepressant action of curcumin remains uncertain, but it has been suggested that curcumin acts at least in part by inhibiting the activity of monoamine oxidase (MAO2,12). Administration of curcumin or its metabolite tetrahydrocurcumin has been shown to reduce MAO-B activity and reduce the impact of DA depletions,55 which is consistent with recent findings from our laboratory indicating that the MAO-B inhibitor selegiline was able to reverse the effort-related effects of tetabenazine.23 Another possibility is that curcumin is acting by producing antiinflammatory effects.12 Recent papers have shown that administration of the pro-inflammatory cytokines IL-1β and IL-6 can produce a low-effort bias similar to tetrabenazine,21,22 and several reports indicate that curcumin reduces levels of IL1β and IL-6.56−59 Future studies should focus on characterizing the neural mechanism through which curcumin exerts is effortrelated motivational effects and determining the effectiveness of repeated administration.
treating effort-related symptoms is important because alterations in effort-related processes are seen in people with depression and other disorders32,39−42 and because motivational dysfunctions are a debilitating component of major depression that is very difficult to treat with commonly used drugs such as serotonin uptake inhibitors.11,15−18,43,44 Curcumin and other curcuminoids have been widely used as an herbal medicine in many Asian countries for thousands of years.45 Curcumin is a hydrophobic polyphenol, and several studies have revealed it has extremely low water solubility, poor stability, rapid metabolism, and poor absorption, which severely reduces its oral bioavailability.45 Yet despite these characteristics, curcumin has shown positive effects in animal studies with classical tests for depression-like effects, such as immobility in the forced swim test,2,3,5,6,34,46,47 and also shows antidepressant effects in clinical studies.7−10,47 Moreover, recent studies reported that curcumin attenuated fatigue in people with occupational stress and anxiety symptoms.48 However, this substance has not been evaluated for its potential effort-related motivational effects in rodent models. The present experiments assessed the effort-related motivational effects of curcumin, in terms of its ability to attenuate tetrabenazine-induced shifts in behavior. In experiments 1 and 2, curcumin was administered as an easily ingestible oral pellet so that human administration through oral ingestion could be mimicked. While oral ingestion of curcumin 2 h prior to the behavioral test was ineffective, curcumin ingested 3 h prior to testing significantly attenuated tetrabenazine-induced shifts in effort-based choice behavior. At this point, it is not clear if this time difference is due to the temporal characteristics of the bioavailability of oral curcumin or to downstream effects of curcumin on inflammatory processes affecting neurochemical mechanisms such as DA transmission. Nevertheless, these findings demonstrate that orally ingested curcumin can exert effort-related effects, which suggests that curcumin may be effective at treating motivational/psychomotor symptoms in people. Although most clinical antidepressant studies with curcumin have not focused on specific symptoms, there is evidence that curcumin is effective at reducing fatigue in people.48 Experiment 3 studied the effects of injections of low doses of curcumin directly into the lateral ventricle. This method was used in order to bypass factors related to gastric absorption and peripheral metabolism and to determine if the effort-related effects of curcumin were indeed due to actions on the brain. Local administration of curcumin into the lateral ventricle attenuated tetrabenazine-induced shifts in choice behavior, increasing lever pressing and decreasing chow consumption compared to tetrabenazine-vehicle-treated animals. Curcumin administered through ICV injection was extremely potent (more than 1000-fold compared to oral ingestion) and also produced a very robust reversal of tetrabenazine-induced shifts in behavior. Thus, it can be concluded that ICV administration overcomes the limited bioavailability seen with curcumin by oral ingestion and provides proof of principle that curcumin is an effective compound in terms of its ability to reverse effortrelated behavioral impairments. The efficacy of ICV curcumin in attenuating tetrabenazine-induced shifts in behavior was comparable to that seen with systemic administration of the adenosine A2A antagonists13 and several drugs that block dopamine transport, including lisdexamfetamine, PRX-14040, methylphenidate, and modafinil.13,17,25,25,30,31 This observation is important in view of clinical studies indicating that bupropion, modafinil, and psychomotor stimulants can be
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EXPERIMENTAL SECTION
Animals. Adult male Sprague−Dawley rats (Harlan Sprague− Dawley, Indianapolis, IN, USA; starting weights 275−299 g) were pair housed in a colony maintained at 23 °C, with a 12 h light/dark cycle (lights on 07:00). With the exception of postsurgical animals, which were singly housed, all rats were caged in pairs. Rats subject to operant testing were food deprived to 85% of their free-feeding body weight for initial operant training and then allowed modest weight growth (i.e., an additional 5−10%) during the experiment. Water was available ad libitum in the home cages. Animal protocols were approved by the University of Connecticut Institutional Animal Care and Use Committee, and the studies were conducted according to National Institutes of Health (NIH) guidelines. Behavioral Procedures. Behavioral sessions were conducted in operant conditioning chambers (28 × 23 × 23 cm, Med Associates, Georgia, VT, USA) during the light period. Rats were initially trained to lever press on a continuous reinforcement schedule (30 min sessions, during 5 days) to obtain 45 mg pellets, (Bioserve, Frenchtown, NJ, USA) and then were shifted to the FR5 schedule (30 min sessions, 5 days/week) and trained for several additional weeks until reaching baseline targets for number of lever presses (i.e., consistent responding ≥1200 lever presses). Animals needed to consistently reach baseline criteria for at least 1 week before being 2842
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introduced to the concurrent FR5/chow feeding choice procedure. With this task, weighed amounts of laboratory chow (Laboratory Diet, 5P00 Prolab RHM 3000, Purina Mills, St. Louis, MO, USA; typically 20−25 g, 4 or 5 large pieces) were concurrently available in the chamber during the 30 min FR5 session. At the end of the session, rats were immediately removed from the chambers, lever pressing totals were recorded, and amount of chow consumed was determined by weighing the remaining food and spillage. Following a postsurgical recovery period of 1 week, rats resumed training until stable baseline was re-established (approximately 2 weeks) before beginning testing. Rats were trained for one month to ingest curcumin pellets, in sessions that were conducted after the daily operant behavior tests. These training sessions were conducted in order to ensure that rats would ingest the curcumin pellets during the drug studies. The first 2 days was the habituation period, in which rodents were allowed free access to sucrose control pellets. Next, rodents were trained for one additional week to consume two curcumin pellets. After consumption of the two curcumin pellets, rodents were slowly introduced to additional pellets (increment increasing by two, until 10 crystalline pellets were readily consumed). Surgery for Implantation of ICV Cannulae. Trained rats were anesthetized at 1.0 mL/kg, i.p. with a solution containing 93.0 mg/mL ketamine and 1.4 mg/mL xylazine (both from Phoenix Scientific, Inc., St. Joseph, MO, USA). For ICV implantations, rats received unilateral implantations of guide cannulae made with 25-gauge extra-thin-wall stainless steel tubing (Small Parts, Inc., Miami Lakes, FL, USA). Guide cannulae were inserted into the lateral ventricle (AP, −0.5 mm from bregma; ML, ±1.0 mm from midline; DV, −3.0 mm from the skull surface; incisor bar set at the same level as the interaural line). The guide cannulae were secured to the skull with stainless steel screws and cranioplastic cement. Stainless steel stylets were inserted into the guide cannulae to maintain patency of the cannulae until injection. All animals were housed in separate cages following surgery and allowed at least 7 days of recovery. Following behavioral testing, each animal was anesthetized with CO2 and perfused intracardially with physiological saline followed by 3.7% formalin solution. The brains were stored in formalin for 3 days before being cut with a vibratome in 60 μm slices and mounted on glass microscope slides. Mounted tissue was stained with cresyl violet and examined by an observer blind to the experimental condition. Any animal with improper cannula placement or significant damage around the injection site was excluded from the behavioral analyses. General Experimental Procedures. The VMAT-2 inhibitor tetrabenazine (9,10-dimethoxy-3-(2-methylpropyl)-1,3,4,6,7,11bhexahydrobenzo[a]quinolizin-2-one) was purchased from Tocris Bioscience (Bristol, UK). Tetrabenazine was dissolved in a vehicle solution of 0.9% saline (80%) and dimethyl sulfoxide (20%). A 1 N HCl/mL volume was then added to adjust the pH and get the drug completely into solution. The saline/20% dimethyl sulfoxide vehicle solution was administered as the vehicle control. The 0.75 mg/kg dose of tetrabenazine that was used for the FR5/chow choice task was based on previous studies conducted by our laboratory.13,24,25 For intraventricular injections, curcumin was purchased from Pflatz & Bauer (Curcumin C.I. 75300 95%; C21H20O6) and was dissolved in dimethyl sulfoxide. For oral ingestion, edible curcumin pellets were manufactured by the Bogner laboratory (School of Pharmacy, University of Connecticut). Curcumin pellets consisted of 7.0 mg of curcumin (PCCA, 95%; Houston, TX, USA), 28.0 mg of Neusilin US2 (Fuji Chemical, Toyama, Japan), 4.0 mg of sodium starch glycolate (JRS Pharma, Patterson, NY, USA), 0.4 mg of stearate (Fisher Scientific, Agawam, MA, USA), and 15.0 mg of sucrose (granulated sugar, American Sugar Refining, West Palm Beach, FL, USA). The doses of curcumin (80.0, 160.0 mg/kg) were selected based upon extensive pilot studies done in our laboratory and were adjusted based on the weight of the animal. Placebo pellets that served as the vehicle-control consisted of 28.0 mg of Neusilin US2, 15.0 mg of sucrose, 4.0 mg of sodium starch glycolate, and 0.4 mg of magnesium stearate. Pellets were pressed weekly by the University of Connecticut, School of Pharmacy (Storrs, CT, USA).
All experiments used a within-groups design in which each rat received all doses of drug or vehicle treatments in their particular experiment in a randomly varied order. Baseline sessions (i.e., nondrug) were conducted 4 days per week. The same group of 9 rats was used for experiments 1 and 2 (4 started with experiment 1 first and 5 started with experiment 2 first). A separate group of animals was used for experiment 3. Experiment 1: Ability of Curcumin To Reverse the Effects of Tetrabenazine on the Concurrent FR5/Chow Choice Procedure: Two-Hour Lead Time. Trained rats (n = 9) received the following treatments: TBZ vehicle plus 10 placebo control pellets (VEH/VEH), 0.75 mg/kg tetrabenazine plus 10 placebo control pellets (TBZ/VEH), tetrabenazine plus 5 control pellets and 5 curcumin pellets (adjusted for an average body weight of 437.5, it comes to approximately 80.0 mg/kg curcumin; TBZ/80), and TBZ plus 10 curcumin pellets (adjusted for body weight, approximately 160.0 mg/kg curcumin; TBZ/160). All animals were trained to selfingest curcumin pellets prior to inclusion in the study as described above. For experiment 1, pellets were administered 2 h prior to testing. Rats were allowed to ingest for 15 min (in individual plastic cages); due to their prior exposure to the pellets, all animals ate all pellets during this time. Rats received i.p. injections of vehicle or 0.75 mg/kg tetrabenazine 90 min prior to testing. Experiment 2: Ability of Curcumin To Reverse the Effects of Tetrabenazine on the Concurrent FR5/Chow Choice Procedure: Three-Hour Lead Time. Trained rats (n = 9) received the following treatments: tetrabenazine vehicle plus 10 placebo control pellets (VEH/VEH), 0.75 mg/kg tetrabenazine plus 10 placebo control pellets (TBZ/VEH), tetrabenazine plus 5 control pellets and 5 curcumin pellets (adjusted for an average body weight of 437.5, it comes to approximately 80.0 mg/kg curcumin; TBZ/80), and tetrabenazine plus 10 curcumin pellets (adjusted for body weight, 160.0 mg/kg curcumin; TBZ/160). All animals had pellets administered 3 h prior to testing and were allowed to eat for 15 min (in individual plastic cages); as with experiment 1, all animals ate all pellets during this time. Rats received i.p. injections of either vehicle or 0.75 mg/kg tetrabenazine 90 min prior to testing. Experiment 3: Effects of Lateral Ventricle Administration of Curcumin on Tetrabenazine-Treated Rats Tested on the FR5/ Chow Choice Procedure. Prior to surgery, rats (n = 13) were trained on the FR5/chow choice procedure. Following 7 days of postsurgical recovery, rats resumed FR5 operant sessions until stable rates of responding were achieved. After maintaining consistently high levels of lever pressing (1500 or more per 30 min session), choice food was reintroduced into the operant chamber. Testing began 3 weeks after postsurgical operant training resumed. Rats were i.p. injected 90 min prior to the operant session with either vehicle or 0.75 mg/kg tetrabenazine. Twenty minutes prior to behavioral testing, rats were injected ICV with DMSO vehicle, or 2.0, 4.0, or 8.0 μg of curcumin. After injection, rats were placed back into their home cages for an additional 20 min.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
John D. Salamone: 0000-0001-6435-9635 Present Address ‡
Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center, 1205 Light Hall, Nashville, Tennessee 37232-0697, United States. Notes
The authors declare the following competing financial interest(s): J. Salamone has received grants from MerckSerrono, Pfizer, Roche, Shire, Lundbeck, Chronos, and Prexa. 2843
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ACKNOWLEDGMENTS This work was supported by a grant to R.B. from the Connecticut Diet and Health Initiative, a grant to S.C. from the University of Connecticut Department of Psychological Sciences, and a grant to J.S. from the University of Connecticut Research Foundation. Much thanks to E. Errante, G. Tripodi, T. Lopardo, and H. Khandaker for their help on this project.
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DOI: 10.1021/acs.jnatprod.7b00425 J. Nat. Prod. 2017, 80, 2839−2844
