Obesity-resistant S5B rats showed greater cocaine conditioned place preference than the obesity-prone OM rats
Research Highlights
►Obesity-resistant S5B rats showed greater cocaine CPP than obesity-prone OM rats. ►Vulnerability for reinforcer preferences (food and cocaine) are not the same. ►Bromocriptine (BC) reduced cocaine CPP in both OM and S5B rats ►BC efficacy on cocaine CPP was influenced by strain (genetic differences). ►Data suggest a partial regulatory role of D2R in conditioned responses to drugs.
Introduction
Obesity is one of the fastest growing public health problems worldwide. Nearly 30% of the adult US population is obese; an alarming statistic considering the increased morbidity and mortality linked with obesity, including an estimate of as many as 300,000 deaths per year in the US [1].
Similarly, drug addiction continues to be a pervasive problem worldwide. In the US alone it is estimated that 21.6 million people aged 12 or older (9.1% of the US population) need treatment for illicit drug or alcohol abuse [2]. Dopamine (DA) and more specifically DA D2 receptors (D2R) have been previously implicated in obesity as well as drug addiction and are specifically involved in the rewarding and conditioned responses to natural (food) and drug rewards [3], [4], [5], [6], [7].
In addition, the DA transporter (DAT) has also been implicated in both cocaine abuse and obesity. Cocaine has been known to block the action of DAT, therefore increasing levels of extra synaptic DA [8]. Clinical studies have shown that an intravenous dose of (0.3–0.6 mg/kg) cocaine produces a “high” and leads to a 60–77% blockade of DAT [8]. In obese individuals, age and body mass index were negatively correlated with DAT levels [9]. Similarly, lower levels of DAT were found in C57 mice that were fed a high-fat (40%) diet [10].
Therefore, both obesity and addiction have been linked with impaired brain DA function. Specifically for both conditions, clinical and preclinical studies have shown lower than normal levels of D2R in the striatum [11], [12], [13], [14], [15], [16], [17], [2], [18]. Similarly, when fed a high-fat diet, rats exhibited decreased DA turnover in the mesolimbic pathways and show reduced preference for amphetamines in the CPP paradigm [19]. It follows from these observations that this shared mechanism may result in enhanced responses to natural rewards as well as drugs of abuse. We assessed this hypothesis by examining cocaine preference in two inbred rat strains with differing susceptibilities to diet-induced obesity. For this, we first examined cocaine conditioned place preference (CPP) in Osborne–Mendel (OM) rats, which favor high-fat diets over carbohydrates or proteins [20], [21], [22], [23] and S5B/P (S5B) rats, which favor low-fat diets [20], [21]. Because of these preferences, OM rats are considered susceptible to dietary obesity while S5B rats are considered obesity-resistant [20], [21], [23]. Furthermore, to be able to assess the role of D2R in cocaine CPP, we also assessed the effects of bromocriptine (BC), a D2R agonist drug that reduces food intake in leptin receptor deficient obese Zucker (fa/fa) and in diet-induced obese rats [24], on cocaine's reinforcing effects. We hypothesized that OM and S5B rats will show differences in CPP to cocaine and in their response to BC.
Section snippets
Animals
This study used 13 OM and 13 S5B male 3–4 month old rats which were obtained from a colony at Pennington Biomedical Research Center. Rats were individually housed in clear plexi-glass cages with wire covers under standard laboratory conditions (22 ± 2 °C, 50 ± 10% relative humidity) and a reverse12 h/12 h light/dark cycle with lights on at 2000 h and off at 0800 h. All experimental sessions occurred during the rat's dark cycle. Rat chow (Lab Diet, St. Louis, MO; laboratory rodent diet 5001: 13.496% fat,
Cocaine conditioned place preference
A two-way RM ANOVA with test session (pretest vs. test) and group set as factors showed no significant difference between groups [F (3, 51) = 0.594, p > .05]; but a significant difference between test sessions [F (1, 51) = 20.855, p < .001; Fig. 2]. A pair-wise comparison of test sessions within each group showed significant increases in time spent in the cocaine-paired chamber on test day compared to the pretest in the S5B rats both for the 5 mg/kg (t = 3.273, p < .05; Fig. 2) and the 10 mg/kg cocaine doses
Discussion
The present study examined whether differential sensitivity to diet-induced obesity in non-obese rats would be mirrored by a similar differential sensitivity to the reinforcing motor simulating effects of cocaine. The specific rat strains used express either genetic susceptibility or resistance to obesity and thus may serve as an appropriate model to make generalizations on drug abuse susceptibility in genetically susceptible and resistant obese populations.
Here we show that cocaine only
Acknowledgements
Support contributed by the NIAAA (Intramural Research Program, LNI) is duly acknowledged.
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