Food Dependence in Rats Selectively Bred for Low Versus High Saccharin Intake: Implications for “Food Addiction.” V

Occidental College

From the SelectedWorks of Nancy K Dess

2011

Food dependence in rats selectively bred for low versus high saccharin intake: Implications for “food addiction.” V. Yakovenko E. R. Speidel C. D. Chapman Nancy K Dess, Occidental College

Available at: https://works.bepress.com/nancy_dess/10/ Appetite 57 (2011) 397–400

Contents lists available at ScienceDirect

Appetite

journal homepage: www.elsevier.com/locate/appet

Short communication Food dependence in rats selectively bred for low versus high saccharin intake. Implications for ‘‘food addiction’’§ Veronica Yakovenko, Elizabeth R. Speidel, Clinton D. Chapman, Nancy K. Dess *

Occidental College, United States

ARTICLE INFO ABSTRACT

Article history: The ‘‘food addiction’’ concept implies that proneness to drug dependence and to food dependence should Received 17 February 2011 covary. The latter was studied in low- (LoS) and high- (HiS) saccharin-consuming rats, who differ in drug Received in revised form 23 May 2011 self-administration (HiS > LoS) and withdrawal (LoS > HiS). Sugary food intake in the ﬁrst 1–2 h was Accepted 1 June 2011 higher in HiS than LoS rats. Sugar intake predicted startle during abstinence only among LoS rats. These Available online 12 June 2011 results may suggest bingeing-proneness in HiS rats and withdrawal-proneness among LoS rats. However, intake escalation and somatic withdrawal did not differ between lines. Further study with Keywords: selectively bred rats, with attention to deﬁnitions and measures, is warranted. Sugar ß 2011 Elsevier Ltd. All rights reserved. Startle Dependence Withdrawal Saccharin phenotype

Introduction controversial (e.g. Avena, 2010; Benton, 2010; Corsica and Pelchat, 2010; Epstein & Shaham, 2010; Hughes, 2007; Wilson, 2010). The Criteria for drug dependence, such as bingeing and withdrawal, present study contributes to the discussion by reporting effects of are increasingly being applied to nutritive substances (Blumenthal & periodic sugar and/or fat access in rats selectively bred on an Gold, 2010; Corwin & Grigson, 2009; Gearhardt, Corbin, & Brownell, ingestive phenotype who respond differently to drugs of abuse. 2009). Laboratory rats, long used to study basic biobehavioral Relative to Occidental low-saccharin-consuming rats (LoS), Occi- mechanisms of drug dependence, now are being used to study food dental high-saccharin-consuming rats (HiS) overconsume sapid dependence. Rats display rapid, escalating overconsumption over a solutions (Dess, 2000), acquire and escalate cocaine self-adminis- course of periodic access to calorie-rich foods and, during tration faster, regulate food and cocaine intake less tightly, and are abstinence, behaviors such as chattering and shaking; aspects of more impulsive (Carroll, Morgan, Anker, Perry, & Dess, 2008). these phenomena resemble drug bingeing and withdrawal (Avena, Consistent with other evidence that rat lines more prone to Rada, & Hoebel, 2008; Hoebel, Avena, Bocarsly, & Rada, 2009). Such voluntary ethanol intake are less vulnerable to withdrawal research represents an important bridge between humans and other (Chester, Blose, & Froehlich, 2003), HiS rats show higher voluntary animals: All animals eat, and consuming biochemically complex ethanol intake (Dess, Badia-Elder, Thiele, Kiefer, & Blizard, 1998) food, like using drugs, creates an allostatic load to which reward and and less withdrawal than do LoS rats after 14 days of comparable, other systems respond (Woods, 2002). Moreover, psychoactive forced-choice ethanol intake (Dess, O’Neill, & Chapman, 2005). If drugs ingested by other animals are consumed mostly in food, such food dependence is a form of drug dependence, the lines should as ethanol in fermenting fruit (Dudley, 2002). Eating (dys)regulation differentially overconsume and/or withdraw from foods. has comparative validity, especially for social omnivores such as Three experiments examined LoS and HiS rats’ behavior in two humans and rats, as a tool for studying the use and abuse of diverse leading food-dependence protocols, at the core of which is periodic substances. access to calorie-rich substances. Sugar solution (Experiments 1 How far the parallel between food and drugs of abuse should be and 2; Colantuoni et al., 2002) and high-fat foods high or low in taken – whether there is such a thing as ‘‘food addiction’’ – is sugar (Experiment 3; Corwin, 2006; Corwin & Wojnicki, 2006: Chapter 9) were used, as they may differentially activate addiction- related mechanisms (Avena, Rada, and Hoebel (2009)). Because § The authors are grateful for the support of the Fletcher-Jones Foundation periodic access to putatively addictive food can increase ethanol Science Scholar program and the Dennis A. VanderWeele Student Research Fund intake – a ﬁnding interpretable as drug cross-sensitization (Avena, and for assistance with data collection by Brian Arizmendi, Adam Greenhouse, and Carrillo, Needham, Leibowitz, & Hoebel, 2004) – Experiment 3 Berkeley McNaughton. * Corresponding author. included two ethanol-intake probe tests. The key issue here is not E-mail address: [email protected] (N.K. Dess). the robustness of overall effects. It is whether lines distinguished

0195-6663/$ – see front matter ß 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.appet.2011.06.002 398 V. Yakovenko et al. / Appetite 57 (2011) 397–400 by an ingestive phenotype with drug-related correlates would (Greenhouse–Geisser for repeated measures, Bonferroni for yield evidence of being differentially impacted in established food- pairwise contrasts) controlled Type I error. dependence regimes. Such results would constitute novel evidence linking food and drug dependence. Sugar consumption

Glucose solution intake in the first hour was greater among HiS Methods and materials than LoS rats (12 g versus 10 g, Experiments 1 and 2) and increased over the course of periodic access (10 g to 12 g, Experiment 1; 7 g Rats to 13 g, Experiment 2). The increase did not differ between lines. A line Â day ANOVA for each experiment yielded, respectively, main Experimentally naı¨ve female LoS and HiS rats from our colony effects of line, F = 4.61 and 6.53, and day, F = 6.82 and 38.75. Total (generations 33–36), approximately 60–90 days old and averaging daily glucose solution intake also increased (34 g to 52 g, 260 g, were used. Post-experimental testing confirmed the Experiment 1, and 31 g to 50 g, Experiment 2; main effect of phenotype (saccharin intake relative to a water baseline and day, respectively, F = 15.97 and 11.16). The lines did not differ on bodyweight: mean Æ SEM for LoS 4 Æ 1D%, HiS 47 Æ 2D%; see Carroll total daily glucose intake (as previously observed with 24% et al., 2008). Group sizes ranged from 8 (Experiments 2 and 3) to 13– glucose, for which caloric feedback limits daily intake; Dess & 15 (Experiment 1). Littermates (10–14 litters/line in Experiments 1 Minor, 1996) or on increase in intake over days. and 2, 3–4 litters/line in Experiment 3) were balanced across experimental groups. Rats were housed individually on a 12:12 Somatic signs light:dark schedule with water freely available. Colantuoni et al. (2002) reported spontaneous withdrawal after Apparatus and foods eight days of periodic glucose access by three measures: forepaw tremor, teeth chatter, and head shake. Those behaviors provided no Somatic signs were videotaped in a test cage. Acoustic startle evidence of withdrawal in the present study. In Experiment 1, all was measured in an apparatus (San Diego Instruments SR-Pilot) three behaviors were rare. In Experiment 2, forepaw tremor that provides a digital amplitude score in arbitrary units occurred slightly more often but head shake and chatter were rare, (maximum: 2000). Glucose solution (Sigma–Aldrich, 25%, w/v) and none varied as a function of glucose access, naloxone, or line. and ethanol (4%, v/v) were presented in glass bottles. Keebler’s Pecan Sandies and Crisco vegetable shortening were presented in Acoustic startle acrylic dishes. Pelleted chow was Purina 5001. In Experiment 1, LoS rats startled more overall than did HiS rats Procedure (marginal means of 415 versus 301), replicating prior findings (Dess et al., 2000; Gonzales, Garrett, Chapman, & Dess, 2008). Mean Colantuoni et al.’s (2002) 12:12 h feeding:abstinence schedule startle did not differ between chow-glucose and chow-only groups, was used in Experiments 1 (8 days) and 2 (14 days). In Colantuoni and startle amplitude habituated over successive two-trial blocks et al.’s experiments, a group periodically fed chow did not differ at a similar rate in all groups. A line Â glucose access Â trial block from control groups freely fed chow and/or glucose; thus, on ANOVA yielded only main effects of line, F(1, 52) = 5.46, and trial ethical and practical grounds, only the period-fed chow control block, F(14, 728) = 8.67. Inspection of within-group variance condition was used. For 12 h daily (feeding), all rats had access to reveals a line difference in impacts of the periodic feeding regime chow; half also had access to glucose solution. For the other 12 h that are not apparent at the group-aggregated level. Early-course (abstinence), only water was available. After the last feeding and late-course glucose intake were distinguished by averaging period, the usual 12-h abstinence period was extended by 12 h to the first three versus the last three access periods, to minimize increase the sensitivity of tests to withdrawal (Colantuoni et al., effects of novelty and/or estrus. Among LoS rats, higher late-course 2002, Exp. 1C), and withdrawal was assessed. Each rat was glucose intake predicted higher mean startle, r(12) = 0.63; this videotaped for 15 min for blind scoring of somatic signs, after relationship remained significant after controlling for bodyweight, which startle was measured (40-ms, 95-dB stimulus, 30 trials at F (1, 11) = 6.84. Early-course glucose intake did not predict startle. 10 s intervals). Naloxone can enhance withdrawal if it is opioid D Among HiS rats, neither early- nor late-course glucose intake mediated. Therefore, in Experiment 2, rats received either saline or predicted startle. naloxone (20 mg/kg i.p.; Colantuoni et al., 2002, Exp. 1B) before In Experiment 2, with one exception explained below, all testing. In summary, group treatments yielded a 2 Â 2 (line - findings were replicated. A line Â glucose access Â naloxone/ Â glucose access) design in Experiment 1 and a 2 Â 2 Â 2 (line - saline Â trial block ANOVA indicated that startle habituated at a Â glucose access Â naloxone/saline) design in Experiment 2. similar rate in all groups [trial block main effect only, F(14, In Experiment 3, half of the rats received cookies for 2 weeks 784) = 6.49], and marginal group means did not differ as a function and then shortening for 4 weeks, in a 2 h/session 3 days/week of glucose access. Among LoS rats, higher late-course glucose protocol used to model binge eating (Corwin, 2006; Corwin & intake predicted higher startle, r(14) = 0.50, to a similar degree Wojnicki, 2006: Chapter 9). Chow was available except when high- among naloxone- and saline-treated rats [r(6) = 0.56 and 0.54]. The fat food was available. Controls had only continuous access to correlation remained significant after controlling for bodyweight chow. All rats received a 24-h two-bottle ethanol test at the and naloxone treatment, F (1, 12) = 4.81. Early-course glucose midpoint and end of the periodic access regime. D intake did not predict startle. Among HiS rats, neither early- nor late-course glucose intake predicted startle. In both experiments, Results and discussion all nonsignificant rs 0.20. The presence or absence of correlations is not an artifact of more or less variance in glucose intake, as Analyses of variance, Pearson’s r, and hierarchical regression within-group variance was relatively homogenous over the course were conducted. Significant test statistics (p .05) and the of periodic access and between lines in both experiments. descriptive statistics to which they correspond are reported in The finding in Experiment 1 that was not observed in the text; all nonsignificant results had p > .10. Adjusted p values Experiment 2 was the main effect of line on startle. In prior V. Yakovenko et al. / Appetite[(Fig._1)TD$IG] 57 (2011) 397–400 399 studies yielding a line difference (Experiment 1; Dess et al., 2000; Gonzales et al., 2008), rats were freely fed. A followup experiment was conducted in which naı¨ve rats were fed chow freely or periodically for 14 days: the usual line difference was obtained for freely fed groups [LoS 527 versus HiS 290; t(58) = 3.16]; periodic feeding reduced LoS rats’ startle such that the lines did not differ (LoS 371 versus HiS 275, n.s.). This result comports with findings in several paradigms of greater sensitivity to feeding status in LoS rats, including modulation of methylphenidate effects (McLaugh- lin, Dess, & Chapman, 2011). One other finding in Experiment 2 is noteworthy. The lines were differentially affected by naloxone [line Â naloxone interaction, F(1, 56) = 4.07]; contrasts showed that naloxone reduced startle in HiS rats (from a marginal mean of 395 to 270) but had no significant effect on LoS rats (respectively, 326 versus 381). This line difference was independent of glucose access. Little is known Fig. 1. Mean intake (g/kg bodyweight) of high-fat foods and ethanol in Experiment about neurochemical mediation of behavioral HiS/LoS line 3. Arrows indicate when ethanol tests occurred. differences, and endogenous opioids merit further attention. Glucose effects were not as robust as reported by others using the same parameters. Whereas Colantuoni et al. (2002) observed gross HiS rats drank more ethanol than LoS rats (right panel, Fig. 1), motor signs of withdrawal, we obtained evidence of subtler effects replicating earlier results (Dess et al., 1998). In contrast to Avena within the LoS line using elevated startle as a measure. Hyperstar- et al.’s (2004) finding that periodic access to one putatively tling is reasonably interpreted as a withdrawal symptom here, as in addictive food (sugar) increased ethanol intake, period-fed rats previous studies with ethanol (Dess et al., 2005), morphine drank less ethanol than controls. All groups drank more ethanol in (Mansbach, Gold, & Harris, 1992), and intermittent access to sugar the first test than in the second. Thus, this protocol yielded no solution (De Jonghe, Di Martino, Hajnal, & Covasa, 2005). The direct evidence of cross-sensitization between high-fat food and ethanol. effect on startle of concurrent access to sugar solution (Martin- A line Â feeding condition Â test ANOVA yielded only main effects Iverson & Stevenson, 2005) or of conditioned signals for sugar of line, feeding condition, and test, F(1, 27) = 15.47, 18.20, and (Schmid, Koch, & Schnitzler, 1995) is exactly the opposite – i.e., 11.84, respectively. attenuation – as is typical of hedonically positive stimuli. Finally, there is no a priori reason other than dose-dependent withdrawal to Conclusion expect a positive correlation between glucose intake and startle. In fact, if one were to presume that glucose intake is causally unrelated These results provide two parallels with line differences to startle, serving at most as a marker for startle-modulating observed for drugs of abuse. First, evidence of vulnerability to processes, the best guess would be of a negative, not a positive, sugar withdrawal was obtained only in LoS rats. Similarly, LoS rats, correlation (Chester et al., 2003; Dess et al., 2005). but not HiS rats, show withdrawal by the same measure – elevated The consistent pattern of correlations reported here therefore startle – after 14 days of ethanol intake (Dess et al., 2005). Whereas points to a line difference in mechanisms sensitive to glucose the ethanol regime produced a significant overall difference access that also modulate startle. Higher startle was associated between LoS ethanol and control groups, glucose access did not. uniquely with late-course glucose intake, only among LoS rats. This Rather, LoS rats’ startle varied systematically with prior glucose temporally dynamic relationship implies an impact of the glucose intake – a result resembling classic drug dose dependency. access regime, with more responsive individuals ultimately Whether the difference between findings with glucose and ethanol consuming more glucose and startling more during abstinence. is attributable to the substances per se or to procedural differences Identification of opioid or non-opioid mechanisms responsible for is unclear. LoS rats’ sugar withdrawal may have been mitigated, for the relationship between glucose intake and startle requires instance, by the line-specific attenuation of startle by periodic further experimental work, ideally with parameters that produce chow access demonstrated in the followup study. In any case, more robust effects without homogenizing groups. Any viable results for both sugar and ethanol point to LoS rats being more explanation, however, must include dispositional differences in vulnerable to withdrawal. the startle-enhancing potential of the periodic glucose regime. The Second, HiS rats consumed more sugar in the first hour of access present results motivate such work by providing prima facie (Experiments 1 and 2) and more cookie in 2 h (Experiment 3) than evidence of dose-dependent withdrawal unique to rats vulnerable LoS rats. The latter finding complements Gosnell et al.’s (2010) to it by virtue of breeding background. report of differential responding for palatable solid reinforcers in LoS and HiS rats and shows that the difference obtains in homecage High-fat food and ethanol intake. HiS rats overconsume palatable substances and drugs with human abuse potential, including ethanol and cocaine (Carroll HiS rats ate more cookie than did LoS rats (left panel, Fig. 1). A et al., 2008). However, overconsumption is not synonymous with line Â session ANOVA yielded only a main effect of line, F(1, dynamic recruitment of increasingly excessive, rapid consumption. 14) = 6.57. Shortening intake (middle panel, Fig. 1) increased over If such recruitment is regarded as a hallmark of bingeing on drugs weeks, stabilizing by the end of testing. A line Â session ANOVA or food – and to the extent that it is appropriate to operationally yielded a main effect of session, F(11, 154) = 3.68. Despite define a consummatory pattern in rats as bingeing – HiS rats do not numerically higher intake among HiS rats by the last week, neither differ from LoS rats in proneness to binge eating. The evidence is the line main effect nor the line Â session interaction approached stronger that HiS rats binge more on cocaine (faster acquisition, significance. 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