Altered dopamine D2 receptor function and binding in obese OLETF rat

Hajnal, A.; Margas, Wojciech; Covașă, Mihai

doi:10.1016/j.brainresbull.2007.07.019

Cited by 44 publications

(42 citation statements)

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“…In this respect, there is evidence in both humans and animal models of obesity for reduced D2 receptor binding (13,42,53,57). Recently, we have found significantly lower [ 125 I]iodosulpride binding in the nucleus accumbens of OLETF at 24 wk of age compared with age-matched LETO rats (29). Thus, in addition to, or as part of, the obesity-related D2 receptor alterations, elevated insulin levels also may further augment behavioral consequences of dopamine regulatory deficits.…”

Section: Discussionmentioning

confidence: 80%

Obese OLETF rats exhibit increased operant performance for palatable sucrose solutions and differential sensitivity to D2 receptor antagonism

Hajnal

Acharya

Grigson

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

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Hajnal A, Acharya NK, Grigson PS, Covasa M, Twining RC. Obese OLETF rats exhibit increased operant performance for palatable sucrose solutions and differential sensitivity to D2 receptor antagonism. Am J Physiol Regul Integr Comp Physiol 293: R1846-R1854, 2007. First published September 5, 2007; doi:10.1152/ajpregu.00461.2007.-CCK-1-receptor-deficient Otsuka Long-Evans Tokushima fatty (OLETF) rats are hyperphagic and exhibit a greater preference for sucrose compared with lean controls [Long-Evans Tokushima Otsuka (LETO)]. To directly assess motivation to work for sucrose reward in this model of obesity and type 2 diabetes, we examined the operant performance of OLETF rats at nondiabetic and prediabetic stages (14 and 24 wk of age, respectively) on fixed-ratio (FR) and progressiveratio (PR) schedules of reinforcement. To evaluate the involvement of dopamine systems, the effects of the D1 receptor antagonist SCH23390 (100 and 200 nmol/kg ip) and the D2 receptor antagonist raclopride (200 and 400 nmol/kg ip), were also tested on PR responding for sucrose. Compared with age-matched LETO rats, 14-wk-old OLETF rats emitted more licks on the "active" empty spout operant on the FR-10 schedule of reinforcement to obtain 0.01 M and 0.3 M sucrose and completed higher ratio requirements on the PR schedule to gain access to 0.3 M and 1.0 M sucrose. At 24 wk, this effect was limited to 1.0 M sucrose. Both antagonists were potent in reducing operant responding to 0.3 M sucrose in both strains at both ages, and there was no strain effect to SCH23390 at either age. OLETF rats, on the other hand, showed an increased sensitivity to the higher dose of raclopride, resulting in reduced responding to sucrose reinforcement at 24 wk. Taken together, these findings provide the first direct evidence for an increased motivation for sucrose reward in the OLETF rats and suggest altered D2 receptor regulation with the progression of obesity and prediabetes. dietary obesity; food reward; appetite; palatability; operant lick task THE EPIDEMIC OF OBESITY AND its associated health consequences represent a major cause of preventable morbidity and mortality in the United States and worldwide (31). Although the etiology of obesity is complex, the motivation to respond to palatable food correlates with obesity (3, 52, 60). Despite this relationship, little is known about food reward functions in the obese. The common view is that obese individuals are presumed to show enhanced liking for palatable foods. Several human studies investigating the relationship between preference and obesity support this notion, whereas others debate it (3,19,20,38).Due to the complexity of human eating behavior there has been growing interest in using animal models to decipher basic neural processes underlying the development of obesity. Our laboratory has been investigating the Otsuka Long-Evans Tokushima fatty (OLETF) rats that lack the CCK-1 receptor, are hyperphagic, obese, and gradually develop non-insulin-dependent diabetes mellitus (36). Unlike in other geneticall...

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Section: Discussionmentioning

confidence: 80%

Obese OLETF rats exhibit increased operant performance for palatable sucrose solutions and differential sensitivity to D2 receptor antagonism

Hajnal

Acharya

Grigson

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Densitometry and statistics are shown in Table 2. Previously, our laboratory showed that blood pressure was increased by 20 -30 mmHg with a switch from a 0.4% to a 4% NaCl diet in obese rats (20). This increase was observed in both sexes, although slightly attenuated in obese females.…”

Section: Obese Zucker Rats Have Reduced Renal Protein Levels Of All Dmentioning

confidence: 82%

“…D2R binding in various areas of the brain has been reported to be decreased in morbidly obese male and female humans (41), obese male Zucker rats (12), male Otsuka Long Evans Tokushima Fatty rats (20), and obesity-prone female rats (17). Disruption of D2R or D4R in mice generates mice with normal plasma renin levels, but AT1R-related hypertension (41,42).…”

Section: Discussionmentioning

confidence: 99%

“…This increase was observed in both sexes, although slightly attenuated in obese females. In the lean rats, males showed a small, but still significant, rise in blood pressure (mean approximately ϩ5 mmHg), while lean females showed a slight, nonsignificant dip (mean approximately Ϫ4 mmHg) (20). We determined whether differential dopamine receptor expression might play a role in these sex differences in salt sensitivity of blood pressure.…”

Section: Obese Zucker Rats Have Reduced Renal Protein Levels Of All Dmentioning

confidence: 97%

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Reduction of renal dopamine receptor expression in obese Zucker rats: role of sex and angiotensin II

Wang

José

et al. 2010

American Journal of Physiology-Renal Physiology

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Ecelbarger CM. Reduction of renal dopamine receptor expression in obese Zucker rats: role of sex and angiotensin II. Am J Physiol Renal Physiol 299: F1164-F1170, 2010. First published September 1, 2010 doi:10.1152/ajprenal.00604.2009.-Dopamine produced by renal proximal tubules increases sodium excretion via a decrease in renal sodium reabsorption. Dopamine natriuresis is impaired in obese Zucker rats; however, the mechanism is not fully understood. To test the hypothesis that renal expression of one or more of the subtypes are altered in these rats, we measured whole kidney protein levels by immunoblotting of D1-like (D1R and D5R) and D2-like (D2R, D3R, and D4R) dopamine receptors in both male and female obese and lean Zucker rats. In obese males on 1% NaCl diet, D1R, D2R, D4R, and D5R were decreased, while D3R was increased, relative to lean rats. Under a 4% NaCl diet, D2R and D3R levels in obese rats were restored to lean levels. 4% NaCl diet reduced D5R in both body types, relative to 1% NaCl diet. Female rats had higher expression of D1R and D3R than did male; however, the sex difference for D1R was markedly blunted in obese rats. In obese rats, dietary candesartan (angiotensin II type 1 receptor blocker) normalized downregulated D1R and D2R, but either decreased (D3R), did not affect (D4R), or further downregulated (D5R) the other subtypes. Candesartan also decreased D4R in lean rats. In summary, reduced renal protein levels of D1R, D2R, D4R, and D5R in obese Zucker rats could induce salt sensitivity and elevate blood pressure. Increased angiotensin II type 1 receptor activity may be mechanistically involved in the decreased expression of D1R and D2R in obese rats. Finally, reduced D1R and D3R in male rats may contribute to sex differences in blood pressure.

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“…OLETF rats show pre-obese characteristics from infancy and sex-differences in patterns of obesity emergence (Schroeder et al, 2009a; Schroeder et al, 2009b). Research has showed that adult OLETF rats demonstrate high avidity for sucrose (De Jonghe et al, 2005; Hajnal et al, 2005), greater dopamine (DA) response to cocaine and amphetamine in the Nucleus accumbens (Nac) region (Feifel et al, 2003) and low D2R function and binding in the Nac shell area (Hajnal et al, 2008). Previous research in our lab revealed that OLETF males developed obesity in a gradual manner until PND 60-70, with specific “turning points” when their body weight diverged dramatically from controls.…”

Section: Introductionmentioning

confidence: 99%

Feeding and reward: Ontogenetic changes in an animal model of obesity

Marco¹,

Schroêder²,

Weller³

2012

Neuropharmacology

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Given that food is a natural reinforcement, deficits in the reward system can lead to disordered eating behavior, inducing or worsening an already existing pre-obese phenotype. In order to evaluate developmental, food-reward-related measures we used the OLETF rat, an animal model of early-onset overeating-induced obesity, and a natural CCK-1 receptor knockout. Dopamine-like-receptor type 1 (D1R) and D2R levels were examined in a reward-related brain area (Nac shell) and sucrose preference was assessed at selected time points from weaning to adulthood (postnatal day [PND]90). In addition, a group of OLETF was pair fed (PF) to the amount of food consumed by same age LETO controls (from weaning to PND90) to examine the contribution of overweight to the alteration in DR expression. In addition, we examined food “craving”-like behavior by analyzing microstructural patterns of licking a palatable liquid diet. OLETF rats expressed significantly lower D2R levels than LETO controls only on PND90. In PF OLETF, weight and D2R levels were normalized. In addition, OLETF presented exaggerated preference for the high sucrose concentration. After 30-day abstinence, OLETF rats presented significant increased initial rate of licking, suggesting food “craving”. Thus, adult OLETF rats demonstrated altered D2R signaling similar to drug-induced sensitization, suggesting a link with their avidity for sucrose and their abnormal craving response. However, the current findings of a late deficit appearance and the novel PF results suggest that deficits in the motivation/regulatory systems of the OLETF rat are a developing process (at least from weaning and on) depending on the overeating and obese phenotype of the rats and not only on the CCK mutation.

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Altered dopamine D2 receptor function and binding in obese OLETF rat

Cited by 44 publications

References 47 publications

Obese OLETF rats exhibit increased operant performance for palatable sucrose solutions and differential sensitivity to D2 receptor antagonism

Obese OLETF rats exhibit increased operant performance for palatable sucrose solutions and differential sensitivity to D2 receptor antagonism

Reduction of renal dopamine receptor expression in obese Zucker rats: role of sex and angiotensin II

Feeding and reward: Ontogenetic changes in an animal model of obesity

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