Exposure to Elevated Levels of Dietary Fat Attenuates Psychostimulant Reward and Mesolimbic Dopamine Turnover in the Rat

Department of Psychiatry, Genome Research Institute, University of Cincinnati, Cincinnati, OH 45237, USA.
Behavioral Neuroscience (Impact Factor: 2.73). 01/2009; 122(6):1257-63. DOI: 10.1037/a0013111
Source: PubMed


Recent studies indicate that decreased central dopamine is associated with diet-induced obesity in humans and in animal models. In the current study, the authors assessed the hypothesis that diet-induced obesity reduces mesolimbic dopamine function. Specifically, the authors compared dopamine turnover in this region between rats fed a high-fat diet and those consuming a standard low-fat diet. The authors also assessed behavioral consequences of diet-induced obesity by testing the response of these animals in a conditioned place paradigm using amphetamine as a reinforcer and in an operant conditioning paradigm using sucrose reinforcement. Results demonstrate that animals consuming a high-fat diet, independent of the development of obesity, exhibit decreased dopamine turnover in the mesolimbic system, reduced preference for an amphetamine cue, and attenuated operant responding for sucrose. The authors also observed that diet-induced obesity with a high-fat diet attenuated mesolimbic dopamine turnover in the nucleus accumbens. These data are consistent with recent hypotheses that the hormonal signals derived from adipose tissue regulate the activity of central nervous system structures involved in reward and motivation, which may have implications for the treatment of obesity and/or addiction.

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Available from: Jennifer D Schurdak, Jan 13, 2014
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    • "Although it was not directly investigated in the present study (i.e., lean rats, were not included because bariatric surgery is not performed in lean individuals), it is possible that change in diet may contribute to increased substance use. In fact, rats with free access to HFD display impaired acquisition of cocaine self-administration (Wellman et al., 2007) and amphetamine-conditioned place preference (Davis et al., 2008). Thus, one may suppose that the reduced consumption of fatty foods following the surgery (Behary and Miras, 2015) may reverse blunted reward and drug seeking. "
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    ABSTRACT: Roux-en-Y gastric bypass (RYGB) surgery is a commonly performed and very effective method to achieve significant, long-term weight loss. Opioid analgesics are primarily used to manage postoperative pain as fewer alternative medication options are available for bariatric surgery patients than for the general population. Recent clinical studies support a greater risk for substance use following bariatric surgery, including an increased use of opioid medications. The present study is the first to study morphine self-administration in a rat model of RYGB. High fat diet-induced obese (HFD-DIO) rats underwent RYGB (n=14) or sham-surgery with ad libitum HFD (SHAM, n=14) or a restricted amount that resulted in weight matched to the RYGB cohort (SHAM-WM, n=8). An additional normal-diet (ND, n=7), intact (no surgery) group of rats was included. Two months after the surgeries, rats were fitted with jugular catheters and trained on a fixed ratio-2 lick task to obtain morphine intravenously. Both morphine-seeking (number of licks on an empty spout to obtain morphine infusion) and consumption (number of infusion) were significantly greater in RYGB than any control group beginning on Day 3 and reached a two-fold increase over a period of two weeks. These findings demonstrate that RYGB increases motivation for taking morphine and that this effect is independent of weight loss. Further research is warranted to reveal the underlying mechanisms and to determine whether increased morphine use represents a risk for opioid addiction following RYGB. Identifying risk factors preoperatively could help with personalized postoperative care to prevent opioid abuse and addiction. Copyright © 2015. Published by Elsevier Inc.
    Brain research bulletin 08/2015; DOI:10.1016/j.brainresbull.2015.08.003 · 2.72 Impact Factor
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    • "Overdiun et al. showed that ghrelin strongly promotes motivated behaviour but does not seem to affect the " pleasantness " of taste stimuli (Overduin et al., 2012). However, a number of previous studies show ghrelin increases cocaine effectiveness (Davis et al., 2007; Wellman et al., 2008), and that mice lacking ghrelin signalling show deficits in their responses to nicotine or alcohol (Jerlhag et al., 2009, 2011). Collectively, our saccharin and sucrose data together with the results above suggest ghrelin acts an amplifier of other pleasurable stimuli rather than being intrinsically rewarding itself. "
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    ABSTRACT: Diet-induced obesity (DIO) causes ghrelin resistance in hypothalamic Agouti-related peptide (AgRP) neurons. However, ghrelin promotes feeding through actions at both the hypothalamus and mesolimbic dopamine reward pathways. Therefore, we hypothesized that DIO would also establish ghrelin resistance in the ventral tegmental area (VTA), a major site of dopaminergic cell bodies important in reward processing. We observed reduced sucrose and saccharin consumption in Ghrelin KO vs Ghrelin WT mice. Moreover, DIO reduced saccharin consumption relative to chow-fed controls. These data suggest that the deletion of ghrelin and high fat diet both cause anhedonia. To assess if these are causally related, we tested whether DIO caused ghrelin resistance in a classic model of drug reward, conditioned place preference (CPP). Chow or high fat diet (HFD) mice were conditioned with ghrelin (1mg/kg in 10ml/kg ip) in the presence or absence of food in the conditioning chamber. We observed a CPP to ghrelin in chow-fed mice but not in HFD-fed mice. HFD-fed mice still showed a CPP for cocaine (20mg/kg), indicating that they maintained the ability to develop conditioned behaviour. The absence of food availability during ghrelin conditioning sessions induced a conditioned place aversion, an effect that was still present in both chow and HFD mice. Bilateral intra-VTA ghrelin injection (0.33μg/μl in 0.5μl) robustly increased feeding in both chow-fed and high fat diet (HFD)-fed mice; however, this was correlated with body weight only in the chow-fed mice. Our results suggest that DIO causes ghrelin resistance albeit not directly in the VTA. We suggest there is impaired ghrelin sensitivity in upstream pathways regulating reward pathways, highlighting a functional role for ghrelin linking appropriate metabolic sensing with reward processing. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
    Psychoneuroendocrinology 08/2015; 62:114-120. DOI:10.1016/j.psyneuen.2015.08.004 · 4.94 Impact Factor
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    • "Timed daily administration of bromocriptine to reestablish the daily peak in SCN dopaminergic activity also reverses the VMH and PVN abnormalities described above [30] [37] [46] and improves postprandial insulin resistance (even via its intracerebroventricular administration) [26] [30] [45]. Additionally, a large and growing body of evidence implicates functional roles for decreased mesolimbic dopamine activity in the onset of insulin resistance [47] [48] [49] [50] [51] [52] and this neural center is also under the influence of the SCN (reviewed in [53]). Restoration of the circadian peak in central nervous system (hypothalamic) dopaminergic neuronal activity may represent a potential therapeutic target to improve glycemic control in T2DM patients requiring high-dose basal-bolus insulin therapy. "
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    ABSTRACT: Background: The concurrent use of a postprandial insulin sensitizing agent, such as bromocriptine-QR, a quick release formulation of bromocriptine, a dopamine D2 receptor agonist, may offer a strategy to improve glycemic control and limit/reduce insulin requirement in type 2 diabetes (T2DM) patients on high-dose insulin. This open label pilot study evaluated this potential utility of bromocriptine-QR. Methods: Ten T2DM subjects on metformin (1-2 gm/day) and high-dose (TDID ≥ 65 U/day) basal-bolus insulin were enrolled to receive once daily (morning) bromocriptine-QR (1.6-4.8 mg/day) for 24 weeks. Subjects with at least one postbaseline HbA1c measurement (N = 8) were analyzed for change from baseline HbA(1c), TDID, and postprandial glucose area under the curve of a four-hour mixed meal tolerance test (MMTT). Results: Compared to the baseline, average HbA1c decreased 1.76% (9.74 ± 0.56 to 7.98 ± 0.36, P = 0.01), average TDID decreased 27% (199 ± 33 to 147 ± 31, P = 0.009), and MMTT AUC(60-240) decreased 32% (P = 0.04) over the treatment period. The decline in HbA(1c) and TDID was observed at 8 weeks and sustained over the remaining 16-week study duration. Conclusion: In this study, bromocriptine-QR therapy improved glycemic control and meal tolerance while reducing insulin requirement in T2DM subjects poorly controlled on high-dose insulin therapy.
    Journal of Diabetes Research 06/2015; 2015:1-7. DOI:10.1155/2015/834903 · 2.16 Impact Factor
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