ADDICTION AND OBESITY-BRAIN SYSTEM COMMONALITIES
What Marijuana Is Teaching Us About Food Intake and Body Weight Regulation
Daniele Piomelli, Ph.D.
[Slides not available]
Although it is well established that marijuana smokers eat more marshmallows than they should, exactly why this occurs is still largely a mystery. A few facts appear to be clear, however. Cannabinoid agonists stimulate food intake in animals, an effect that is likely due to the activation of CB1 receptors and is accompanied by enhanced food palatability. Moreover, CB1 antagonists, such as rimonabant, reduce food intake and body weight. Lastly, feeding status and feeding-regulating hormones, such as leptin, affect endocannabinoid synthesis in the hypothalamus and intestinal tissue. The neural substrates of these actions have not been fully elucidated yet, but their therapeutic potential is now being actively explored. Synthetic THC (Marinol®, dronabinol) is approved by the Food and Drug Administration to treat anorexia associated with AIDS, while rimonabant is in advanced clinical development for the treatment of obesity. In a recently completed Phase III trial, rimonabant produced a marked reduction of body weight in obese patients. Importantly, the drug is also under consideration as a treatment for tobacco abuse, a reminder of the common neural substrates that underlie drug and food rewards. Oleoylethanolamide, a natural endocannabinoid-like compound produced by cells in the upper intestine, inhibits feeding in rodents by binding with nanomolar affinity to the nuclear receptor PPAR-alpha; (peroxisome proliferator-activated receptor type-alpha;) which suggests that endocannabinoid and endocannabinoid-like lipid mediators play an important role in the regulation of feeding and energy balance.
Neural Systems Recruited by Drugs and Food: Focus on Corticostriatal-Hypothalamic Integration
Ann E. Kelley, Ph.D.
[Slides not available]
Two of the greatest threats to public health in the United States in the 21st century are obesity and drug addiction including nicotine. Although these two health issues obviously are not related in terms of etiology or phenomenology, they share important commonalities and can be conceptualized as disorders of appetitive motivation. There is a growing realization that the neural pathways underlying the motivation for food and those affected by drugs of abuse share many commonalities. Both highly palatable food and rewarding drugs stimulate specific neurotransmitter systems in corticostriatal-hypothalamic circuits. Dr. Kelley has been particularly interested in how corticostriatal systems, involved with motivation, decisionmaking, and learning, interact with hypothalamic systems in both an upstream and downstream manner. Dr. Kelley’s work has shown that these neurochemical systems play specific and dissociable roles in different aspects of food seeking, food intake, and reward learning. This study proposes that the striatum integrates information related to cognitive and emotional processing, with hypothalamic mechanisms mediating energy balance. The system as a whole enables complex hierarchical control of adaptive ingestive behavior, but its dysregulation underlies many compulsive aspects of both addiction and overeating.
Brain Processing of Food-Related Stimuli With Relevance to the Control of Appetite: Taste, Olfactory, Texture, and Visual Representations of Food in the Brain
Edmund T. Rolls, D.Sc., D.Phil.
[Slides not available]
The orbitofrontal cortex (OFC) contains the secondary taste and olfactory cortices, in which the reward value of taste and smell and the texture and temperature of food in the mouth is represented, as shown by neuronal recordings in macaques. Human functional neuroimaging studies have shown that activation of the OFC and adjoining anterior cingulate cortex (ACC) by odors and liquid food is hunger-dependent, and that the pleasantness of the food is correlated with the degree of activation found. Also, it has been shown that the modulation is sensory-specific so that sensory-specific satiety is implemented in the OFC. The viscosity of food is represented in the human taste and nontaste insula and in the OFC. Fat in the mouth is detected by its texture, and this is represented in the ACC and OFC. The pleasantness of odors is represented in the OFC and flavor representations are formed by combining taste and olfactory inputs in the OFC. Cognitive influences, such as a word label, can influence activations produced by olfactory stimuli in the OFC. This neurophysiological and human functional neuroimaging evidence thus shows that the OFC is involved in decoding some primary reinforcers, such as taste, odor, texture, touch, and temperature; learning and reversing associations of visual and other stimuli to these primary reinforcers; and representing the subjective pleasantness of food in a way that correlates directly with whether food is eaten. The OFC and connected areas play key roles in representing the sensory qualities and affective value of oral sensory stimuli and, thus, in controlling intake. Moreover, the OFC is involved with other types of reward, including reward produced by amphetamine, and damage to the OFC impairs affective responses and can produce impulsive behavior.
Common Brain Mechanisms in Addiction and Obesity
Nora D. Volkow, M.D.
The reinforcing effects of food are mediated in part by its ability to increase dopamine (DA) in brain reward and motivation circuits. Brain imaging studies in humans have shown that increases in dopamine induced by a display of food are associated with the desire and the motivation to consume the food. Since the reinforcing effects of drugs of abuse are also mediated by their ability to increase DA in the same circuits as food, why does food not produce addiction? This is likely to reflect the fact that, when compared with the increases in DA induced by drugs of abuse, those induced by food are smaller, of shorter duration, and habituate with repeated administration. Despite these differences, in some obese individuals the loss of control and compulsive food-taking behavior shares characteristics with the compulsive drug intake observed in drug-addicted subjects. We have used brain imaging in obese individuals to investigate both the brain DA system as well as regional brain metabolism, and to compare these with the changes seen in drug-addicted individuals. These studies have shown that morbidly obese subjects have significant reductions in striatal DA D2 receptor availability, which are equivalent to those we have previously reported in drug-addicted subjects. However, obese subjects showed enhanced activity of somatosensory cortical regions involved with processing palatability, which is a variable that contributes to the hedonic properties of food. Decreased levels of D2 receptors may make addicted subjects less sensitive to natural reinforcers at the expense of more powerful reinforcers; in the case of obese individuals, the enhanced sensitivity to palatability would make food a stronger reinforcer, driving its preference over that of other reinforcers.