Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation
449—Cocaine: Neural Mechanisms of Addiction III
Monday, November 11, 2013, 1:00 pm - 5:00 pm
449.20: Cocaine and cocaine expectancy depress inhibition of the dopamine system and cocaine reward by leptin signaling
Location: Halls B-H
*Z.-B. YOU, B. WANG, Q.-R. LIU, Y. WU, R. A. WISE; Behavioral Neurosci, NIDA-IRP/NIH/DHHS, BALTIMORE, MD
Abstract Body: Plasma levels of leptin, an endogenous antagonist for food reward, are depressed during and in anticipation of regular cocaine self-administration sessions in rats. To assess whether these plasma leptin depressions are accompanied by decreases in central leptin signalling, we measured ventral tegmental intracellular signalling markers (STAT3, Akt and ERK) in the pathways normally regulated by leptin receptor activation. While Akt and ERK levels were normal at the two time points, phosphorylated STAT3 (p-STAT3) levels were significantly decreased in cocaine-trained rats just prior to the normal time of cocaine self-administration (a time when leptin levels are significantly depressed) but returned to normal by several hours after the session (after the self-administered cocaine had been metabolized and the animals had eaten a meal). The levels of total proteins measured were not changed significantly. VTA infusions of leptin blocked cocaine conditioned place preference, increased p-STAT3 levels in the VTA, and reduced the elevations of dopamine in the nucleus accumbens by cocaine. Thus, the present findings reveal a close relationship between plasma leptin levels and leptin signaling in brain reward circuitry that mediates the rewarding effects of cocaine. Leptin replacement therapy may be a useful adjunct to the initial treatment of compulsive cocaine self-administration.
Lay Language Summary: We have found that cocaine interacts with leptin, a hormone released by fat cells that contributes to the control of food intake by acting on the brain reward system. The interaction is a complex one: leptin attenuates the rewarding effect of cocaine but cocaine suppresses leptin levels and does so in two interesting ways: leptin is depressed when cocaine is given, and leptin is depressed when cocaine is expected. These findings help us understand one of the multiple influences that cocaine has on the reward system, and they suggest the possibility that leptin deficiency contributes to the hold that cocaine gains over those who take the drug repeatedly. Inasmuch as leptin deficiency appears to result from cocaine use, these findings raise the possibility that leptin replacement therapy may prove to be useful in cocaine detoxification. While it has been known for some time that leptin inhibits the rewarding effects of food and the rewarding effects of electrical stimulation of hunger-related sites in the lateral hypothalamus, this is the first evidence suggesting that leptin can attenuate cocaine reward. We first measured leptin levels in the blood to see if they are affected by 4-hour binges of cocaine self-administration. We found that self-administered injections of intravenous cocaine depressed leptin levels by about 40%. In addition, we found that leptin levels prior to testing became progressively lower over the course of two weeks of testing. In animals that were tested at the same time each day, leptin levels started decreasing 1-2 hours in advance of the time when cocaine availability was expected. Leptin is a peripheral horomone that does not cross the blood-brain barrier easily, so to determine whether the fluctuations in blood level were having effects in the brain, we measured fluctuations in the central neurochemical effects that leptin has when it gets into the brain and activates its receptors there; the anticipation of cocaine was decreasing leptin effects in the brain as found in leptin levels in the blood. The leptin effect we measured in the brain was an inhibition of brain reward circuitry. Cocaine and even the anticipation of cocaine was reducing one of the factors that contributes not only to food satiation, but also to cocaine satiation. To determine if this effect was sufficient to influence cocaine-taking or cocaine-seeking, we made microinjections of leptin into the brain of rats trained to lever-press for intravenous cocaine. The injections did not affect cocaine intake within a binge, but they attenuated cocaine-seeking in the drug-free state between binges. They also attenuated the ability of cocaine to activate the reward system. These experiments establish that leptin is an endogenous inhibitor of the central effects of cocaine, but also that cocaine is an inhibitor of endogenous leptin. Several questions remain for future investigation. First, does leptin deficiency develop in human users? This is an important question because we are learning that there are some subtle and some not-so-subtle differences in the reward systems of different species. Second, does leptin deficiency develop with other addictions? The dependence syndromes associated with different drugs are sometimes similar but sometimes very different. Third, does leptin replacement therapy help during the early phases of cocaine detoxification, when environmental stimuli and emotional events are powerful forces for relapse? Finally these findings encourage the study of other feeding-related hormones like insulin and ghrelin, each of which has an on feeding and each of which may be fluctuating and influencing drug self-administration as well as food intake.
Neuroscience 2013 (43rd annual meeting of the Society for Neuroscience)Exit