Nicole M. Avena

DEFICITS OF MESOLIMBIC DOPAMINE NEUROTRANSMISSION IN RAT DIETARY OBESITY

Increased caloric intake in dietary obesity could be driven by central mechanisms that regulate reward-seeking behavior. The mesolimbic dopamine system, and the nucleus accumbens in particular, underlies both food and drug reward. We investigated whether rat dietary obesity is linked to changes in dopaminergic neurotransmission in that region. Sprague-Dawley rats were placed on a cafeteria-style diet to induce obesity or a laboratory chow diet to maintain normal weight gain. Extracellular dopamine levels were measured by in vivo microdialysis. Electrically evoked dopamine release was measured ex vivo in coronal slices of the nucleus accumbens and the dorsal striatum using real-time carbon fiber amperometry. Over 15 weeks, cafeteria-diet fed rats became obese (>20% increase in body weight) and exhibited lower extracellular accumbens dopamine levels than normal weight rats (0.007+/-0.001 vs. 0.023+/-0.002 pmol/sample; P<0.05). Dopamine release in the nucleus accumbens of obese rats was stimulated by a cafeteria-diet challenge, but it remained unresponsive to a laboratory chow meal. Administration of d-amphetamine (1.5 mg/kg i.p.) also revealed an attenuated dopamine response in obese rats. Experiments measuring electrically evoked dopamine signal ex vivo in nucleus accumbens slices showed a much weaker response in obese animals (12 vs. 25x10(6) dopamine molecules per stimulation, P<0.05). The results demonstrate that deficits in mesolimbic dopamine neurotransmission are linked to dietary obesity. Depressed dopamine release may lead obese animals to compensate by eating palatable comfort food, a stimulus that released dopamine when laboratory chow failed.

A diet promoting sugar dependency causes behavioral cross-sensitization to a low dose of amphetamine

Previous research in this laboratory has shown that a diet of intermittent excessive sugar consumption produces a state with neurochemical and behavioral similarities to drug dependency. The present study examined whether female rats on various regimens of sugar access would show behavioral cross-sensitization to a low dose of amphetamine. After a 30-min baseline measure of locomotor activity (day 0), animals were maintained on a cyclic diet of 12-h deprivation followed by 12-h access to 10% sucrose solution and chow pellets (12 h access starting 4 h after onset of the dark period) for 21 days. Locomotor activity was measured again for 30 min at the beginning of days 1 and 21 of sugar access. Beginning on day 22, all rats were maintained on ad libitum chow. Nine days later locomotor activity was measured in response to a single low dose of amphetamine (0.5 mg/kg). The animals that had experienced cyclic sucrose and chow were hyperactive in response to amphetamine compared with four control groups (ad libitum 10% sucrose and chow followed by amphetamine injection, cyclic chow followed by amphetamine injection, ad libitum chow with amphetamine, or cyclic 10% sucrose and chow with a saline injection). These results suggest that a diet comprised of alternating deprivation and access to a sugar solution and chow produces bingeing on sugar that leads to a long lasting state of increased sensitivity to amphetamine, possibly due to a lasting alteration in the dopamine system.

Hormonal and neural mechanisms of food reward, eating behaviour and obesity

With rising rates of obesity, research continues to explore the contributions of homeostatic and hedonic mechanisms related to eating behaviour. In this Review, we synthesize the existing information on select biological mechanisms associated with reward-related food intake, dealing primarily with consumption of highly palatable foods. In addition to their established functions in normal feeding, three primary peripheral hormones (leptin, ghrelin and insulin) play important parts in food reward. Studies in laboratory animals and humans also show relationships between hyperphagia or obesity and neural pathways involved in reward. These findings have prompted questions regarding the possibility of addictive-like aspects in food consumption. Further exploration of this topic may help to explain aberrant eating patterns, such as binge eating, and provide insight into the current rates of overweight and obesity.

Hyperphagia: Current Concepts and Future Directions Proceedings of the 2nd International Conference on Hyperphagia

Hyperphagia is a central feature of inherited disorders (e.g., Prader–Willi Syndrome) in which obesity is a primary phenotypic component. Hyperphagia may also contribute to obesity as observed in the general population, thus raising the potential importance of common underlying mechanisms and treatments. Substantial gaps in understanding the molecular basis of inherited hyperphagia syndromes are present as are a lack of mechanistic of mechanistic targets that can serve as a basis for pharmacologic and behavioral treatments.

Comparing the effects of food restriction and overeating on brain reward systems

Both caloric restriction and overeating have been shown to affect neural processes associated with reinforcement. Both preclinical and some clinical studies have provided evidence that food restriction may increase reward sensitivity, and while there are mixed findings regarding the effects of overeating on reward sensitivity, there is strong evidence linking this behavior with changes in reward-related brain regions. Evidence of these changes comes in part from findings that show that such eating patterns are associated with increased drug use. The data discussed here regarding the differential effects of various eating patterns on reward systems may be particularly relevant to the aging population, as this population has been shown to exhibit altered reward sensitivity and decreased caloric consumption. Moreover, members of this population appear to be increasingly affected by the current obesity epidemic. Food, like alcohol or drugs, can stimulate its own consumption and produce similar neurochemical changes in the brain. Age-related loss of appetite, decreased eating, and caloric restriction are hypothesized to be associated with changes in the prevalence of substance misuse, abuse, and dependence seen in this cohort.

Effects of baclofen and naltrexone, alone and in combination, on the consumption of palatable food in male rats

Excess consumption of palatable food has been shown to affect reward-related brain regions, and pharmaceutical treatments for drug addiction may also be effective in treating overeating of such foods. The GABA-B agonist baclofen and opioid antagonist naltrexone have both been used to treat addiction, and have been shown to suppress intake of certain foods. The combination of these drugs has shown to be more effective in reducing alcohol consumption than either drug alone. The present study assessed the effects of naltrexone and baclofen, alone and in combination, on intake of foods comprised of various macronutrients. Male Sprague-Dawley rats were given 12-hr daily access to chow and a fat emulsion, sugar-fat emulsion, or a sugar solution for 21 days. Rats were then administered (intraperitoneal) baclofen-naltrexone combinations (0.1 mg/kg naltrexone and 1.0 mg/kg baclofen, 1.0 mg/kg naltrexone and 1.8 mg/kg baclofen), and naltrexone (0.1, 1.0 mg/kg) and baclofen (1.0, 1.8 mg/kg) alone. The high dose of the baclofen-naltrexone combination reduced palatable food intake in both the fat and sugar-fat groups compared with vehicle, without affecting chow consumption in these groups. Naltrexone showed little significant effects on intake of either palatable food or chow. Baclofen also reduced palatable food intake in the fat and fat-sugar groups, but differences were only noted between the low and high dose. The combination of baclofen and naltrexone may be a useful tool in selectively targeting the consumption of high-fat and sugar- and fat-rich foods.

The next generation of obesity treatments: beyond suppressing appetite

Obesity remains a prominent public health concern in the United States as well as many other countries, with 33% of adults worldwide overweight or obese in 2005 and an estimated 60% by 2030 (Kelly et al., 2008). This data highlights the need for effective prevention and intervention strategies. Obesity can be viewed as an endpoint with many possible contributing factors, including genetic propensity, sedentary lifestyles, and the relative ease with which one can obtain food, particularly in modern industrialized societies. Such factors may result in an imbalance between the number of calories consumed vs. expended. The majority of pharmaceutical compounds that have been developed to combat obesity aim to correct or improve this last factor by suppressing appetite (See Table u200bTable1).1). However, the number of people with obesity in the United States does not appear to be decreasing (Flegal et al., 2012). Here we present some possible reasons why these drugs have failed to fully address the problem of obesity.

GS 455534 selectively suppresses binge eating of palatable food and attenuates dopamine release in the accumbens of sugar-bingeing rats.

Binge eating palatable foods has been shown to have behavioral and neurochemical similarities to drug addiction. GS 455534 is a highly selective reversible aldehyde dehydrogenase 2 inhibitor that has been shown to reduce alcohol and cocaine intake in rats. Given the overlaps between binge eating and drug abuse, we examined the effects of GS 455534 on binge eating and subsequent dopamine release. Sprague–Dawley rats were maintained on a sugar (experiment 1) or fat (experiment 2) binge eating diet. After 25 days, GS 455534 was administered at 7.5 and 15 mg/kg by an intraperitoneal injection, and food intake was monitored. In experiment 3, rats with cannulae aimed at the nucleus accumbens shell were maintained on the binge sugar diet for 25 days. Microdialysis was performed, during which GS 455534 15 mg/kg was administered, and sugar was available. Dialysate samples were analyzed to determine extracellular levels of dopamine. In experiment 1, GS 455534 selectively decreased sugar intake food was made available in the Binge Sugar group but not the Ad libitum Sugar group, with no effect on chow intake. In experiment 2, GS 455534 decreased fat intake in the Binge Fat group, but not the Ad libitum Fat group, however, it also reduced chow intake. In experiment 3, GS 455534 attenuated accumbens dopamine release by almost 50% in binge eating rats compared with the vehicle injection. The findings suggest that selective reversible aldehyde dehydrogenase 2 inhibitors may have the therapeutic potential to reduce binge eating of palatable foods in clinical populations.

Animal models lead the way to further understanding food addiction as well as providing evidence that drugs used successfully in addictions can be successful in treating overeating.

To the Editor: We read with great interest the papers relating food and addiction in Biological Psychiatry, Volume 73, Number 9. We agree with the Commentary written by Gearhardt & Brownell (pp. 802-3) that the food addiction model can be a game changer and have summarized this evidence previously(1, 2). Reviews of the neurobiology by Smith and Robbins emphasizing opioid systems in drug and food addiction (pp. 804-10) and Newman et al. suggesting the importance of Gamma Aminobutyric Acid (pp 843-50), along with Volkow & colleagues suggesting that neurobiological advances can help us develop new prevention and treatment for overeating based on addiction models (pp. 811-18) resonate with us. n nOne of us had reported naltrexone effects in binge eating in humans in the 1980s (3). Binge eating affects reward-related brain regions, and pharmaceutical treatments for drug addiction can also be effective in treating overeating(4). The GABA-B agonist baclofen can reduce intake of dietary fat, and the opioid antagonist naltrexone can suppress intake of some foods. The study we reported at ACNP (5) tested the effects of naltrexone-baclofen combinations on binge intake of diets consisting of palatable nutrients. Male Sprague-Dawley rats were given binge access to standard chow and a sugar solution, fat emulsion, or sugar-fat emulsion for 21 days. Rats were then administered (i.p.) naltrexone (0.1 or 1.0 mg/kg), baclofen (1.0 or 1.8 mg/kg) and naltrexone-baclofen (0.1 mg/kg naltrexone and 1.0 mg/kg baclofen, or 1.0 mg/kg naltrexone and 1.8 mg/kg baclofen) and food intake was monitored. Naltrexone-baclofen (1.0 and 1.8 mg/kg, respectively) significantly suppressed binge eating of sugar-fat emulsion. This combination was also superior to either drug alone at reducing binge consumption of the fat emulsion or sugar solution. Baclofen (1.8 mg/kg) significantly reduced binge eating of the fat and sugar-fat emulsions, but naltrexone (1.0 mg/kg) did not show a significant effect on binge consumption in either of these groups. These findings suggest that the combination of baclofen and naltrexone is superior to either drug alone in suppressing binge intake of palatable foods rich in fat and/or sugar. This drug combination may be useful as a therapeutic tool for patients who binge eat, and it also provides a novel pharmacological support for the food addiction hypothesis as both of these medications are used in alcohol dependence and other addictions. Research led by Bart Hoebel, which has been continued by his junior colleague Nicole Avena since his death, has used animal models to show that rats will readily self-administer sugar in ways that resemble drugs of abuse, with loss of control, cross tolerance, failed attempts to quit, and withdrawal signs and symptoms produced spontaneously by opiate antagonist administration(6). This laboratory model might yield new treatments as Volkow has suggested, and it provides a unique way to assess the effects of the act of overeating of palatable foods, like sugars, independent of obesity. Successful treatments for hedonic overeating would not only provide support for the food addiction hypothesis, but also suggest a common mechanism through which addictive behaviors may occur.

A high-fat diet or galanin in the PVN decreases phosphorylation of CREB in the nucleus accumbens

A high-fat diet (HFD) can increase hypothalamic galanin (GAL). GAL has recently been shown to inhibit opiate reward, which in turn, decreases cAMP response element-binding protein (CREB) in the nucleus accumbens (NAc). We hypothesized that injection of GAL into the paraventricular nucleus (PVN), or consumption of a HFD, would be associated with a decrease in NAc CREB. In Exp. 1, GAL in the PVN of naïve rats decreased phosphorylated-CREB (pCREB) which is the activated form of CREB, in the NAc compared to saline-injected controls. In Exp. 2, rats fed ad libitum HFD for 4 weeks had reduced NAc pCREB levels compared to rats with sporadic tastes of the HFD. Body weight, serum triglyceride and leptin levels were also raised in the chronic HFD-fed rats. These data suggest that PVN GAL or chronic intake of a HFD can decrease NAc pCREB. The implications of these findings may help to explain the lack of opiate-like withdrawal that has been reported in response to overeating a HFD, thereby providing a potential mechanism underlying behavioral differences seen with addiction-like overconsumption of different types of palatable foods.