Influence of a high-fat diet during adolescence on the reinforcing effects of cocaine and alcohol

Abstract

ABSTRACT Adolescence is a highly vulnerable developmental period in which numerous structural and functional maturational changes occur (Spear, 2000; Chambers et al., 2003). In this early stage of vulnerability, adolescents exhibit eating disorders, substance abuse, novelty-seeking and risk-taking behaviors (Bava and Tapert, 2010). Regarding these environmental hazards, the rise in obesity rates worldwide has encouraged extensive research to improve understanding of this problem, in which the excessive intake of food, especially sugar-rich and high-fat food has become a serious problem for society. As we know, addiction is a chronic and multifactorial relapsing disorder resulting from an interaction of biological and environmental aspects, characterized by a loss of control in the use of the substance and relapse (Koob and Volkow, 2010). Developmental factors are important components of vulnerability, with strong evidence supporting that exposure to drugs of abuse during adolescence leads to a significantly higher likelihood of drug dependence and drug-related problems in adulthood. Feeding is regulated by homeostatic and hedonic mechanisms. Abnormalities in these functions can cause several feeding alterations and produce obesity (Kenny et al., 2011). The reward system, which is essentially constituted by the dopamine mesocorticolimbic system, regulates motivation to seek and take rewarding stimuli, such as drugs or highly palatable food. Therefore, drug abuse or hedonic eating activate the same reward pathways. Our body was initially developed in a context characterized by nutritional deficiencies and getting food was the daily main objective to achieve. It processes foods quickly and we have innate preference for high energy meals, especially those high in fat and sugar, because in a situation of scarcity those would be the energy stores that would help us to survive. This type of food, like drugs of abuse, produces a dopamine release in the brain reward system, which explains its pleasurable effects. Nowadays, there is such abundance and variety of food, that this survival-oriented evolutionary adaptation has lost its sense, since we eat not only for hunger, but also for pleasure (Gold, 2011). Thus, hedonic eating affects neural mechanisms connected with reward and maintains this behavior (For reviews: Avena et al., 2008; Volkow et al., 2013). In summary, both natural reinforcers and drugs stimulate the brain reward circuit, producing pleasure and euphoria. The nutritional status is an important factor in the development of addiction, since some studies indicate psychological and biological similarities between fast food intake and addiction to drugs, sharing common reward mechanisms (Garber and Lustig, 2011; Avena et al., 2012). For example, both drug addiction and obesity can be defined as disorders in which the value of the type of reinforcement (drug or food, respectively) is abnormally increased in relationship to other reinforcements (Avena et al., 2012; Volkow et al., 2013). Drug addiction and binge eating are characterized by a loss of control over consummatory behaviors, exhibiting escalation, dependence and craving when the reward is not available, and both present a high comorbidity (Swanson et al., 2011). Several studies report that drug use during adolescence often predicts an increased likelihood of continued use into adulthood (Arteaga et al., 2010; Merline et al., 2004). Based on these relationships, a Theory of Gateway has also been proposed for eating disorders and substance abuse (Degenhardt et al., 2008), in which it is postulated that eating disorders, such as binge eating, can lead to the development of another desadaptive behavior, such as drug abuse. At the moment, preclinical studies indicate, for example, that intake of certain types of sugar leads to a sensitization to amphetamine (Avena and Hoebel, 2003) and to an increase in alcohol self-administration (Avena et al., 2004). Studies with sugar are abundant, unlike studies with high-fat food and drug vulnerability. For example, there are no studies reporting the effects of bingeing on fat during adolescence and vulnerability to drug abuse, like cocaine or alcohol, nor are there studies examining the effects of interrupting fat consumption on the subsequent vulnerability to drugs like cocaine or alcohol. Thus, the objective of the present work was to evaluate how a high-fat diet exposure during adolescence modulates the reinforcing effects of cocaine and alcohol. We studied two different types of fat diet consumption: continuous access (animals have ad libitum access to high-fat food without a limit) and the intermittent and limited access. The latter has been shown to induce a binge eating pattern (Puhl and cols., 2011; Bocarsly et al., 2011), and our protocol is based on that used by Corwin et al. (1998). Here, mice had access to the high-fat diet only for 2 hours every Monday, Wednesday and Friday, with ad libitum access to the standard diet. The main methodology employed to assess the vulnerability to cocaine and alcohol rewarding effects was the Conditioned Place Preference paradigm and the operant Self-Administration procedure. The conditioned place preference is the most commonly used test to evaluate the environmental cues conditioned to the rewarding effects of the drug (Aguilar et al., 2013), while the self-administration procedure evaluates directly the animals’ motivation to obtain the substance of abuse. Both models provide a complete scenario to evaluate vulnerability to drug abuse, since they allow us to measure both the external and the individual cues. We have also studied some metabolic effects on circulating leptin, ghrelin and corticosterone levels and examined changes in gene expression with real time polymerase chain reaction (rt-PCR) related to dopaminergic, opioid and endocannabinoid systems, because of their involvement in the rewarding properties of drugs and food. Regarding our results, in the first study we observed no effects on the behavioral response to drugs while fat is available. However, following fat discontinuation, mice exhibited increased anxiety, augmented locomotor response to cocaine, and developed preference for subthreshold doses of cocaine. In addition, there were changes in MOr, CB1 and GHSR gene expression. On the other hand, we observed how high-fat diets act as an alternative reinforcer, as its administration after conditioned place preference reduces the number of sessions required to extinguish the preference and decreased sensitivity to drug priming-induced reinstatement. In the second study, we observed that animals that binged on fat were more sensitive to the reinforcing effects of a subthreshold dose of cocaine in the conditioned place preference and enhanced self-administration. We also observed changes in MOr, CB1 and GHSR gene expression. In the third study, we employed the same procedure as in the former study, but with the aim of evaluating if the increased sensitivity also arises with alcohol. Animals in the high-fat binge group presented more sensitivity to the rewarding effects of subthreshold doses of ethanol and greater ethanol consumption with a higher motivation to obtain the drug. In addition, they presented changes in gene expression after the self-administration procedure which are different from those found with the fat administration alone. In the fourth study, we evaluated if these effects of bingeing on fat and alcohol intake would have a long term consequences, even when fat consumption is interrupted. Our results showed how after 15 days from the last binge session, animals still presented a greater ethanol consumption, but they were not sensitive to subthreshold doses in the conditioned place preference anymore. The fifth study aimed to evaluate the role of chronic stress, such as isolation, on the modulatory effects of fat on the rewarding properties of cocaine. We observed opposite effects as those found in grouped animals, as isolated mice with a standard diet access were more sensitive to subthreshold doses of cocaine than those fed with a fat binge eating pattern. In addition, the groups that developed preference (isolated with standard diet and grouped with high-fat binge) were those who presented increased circulating leptin levels. In the sixth and last study, we drew a behavioral profile with the groups used in the present doctoral thesis, and found a few alterations in animals that binge on fat, such as hyperlocomotion and aggressive behaviors. On the other hand, we observed marked spatial learning deficits in animals eating fat continuously as well as increased attack behaviors with conspecifics. In both diet patterns, discontinuation of fat led to an increase in anxiety levels. Our results show that bingeing on fat is quite different from eating fat continuously. While the former does not produce great metabolic effects, it produces significant changes in the sensitivity to drugs such as alcohol and cocaine. On the other hand, continuously eating fat produces big metabolic changes like hyperleptinemia and increased bodyweight and but has no effect regarding vulnerability to drug use. However, when access to fat is interrupted (withdrawal period), the increased response to the rewarding effects of drugs arises, confirming that the reward system has become sensitized. Both fat consumption patterns produce several changes in gene expression of mu opioid receptor, of cannabinoid receptor CB1 and of ghrelin receptor GHSR, indicating that both patterns of fat consumption changed the reward system function in different manners, having long-lasting effects, even when fat is no longer available. Our work shows that the nutritional habits not only produce metabolic alterations in our organism or modify our body weight, they also modify our CNS and change the way we respond to drug abuse. One of the main contributions of this work is the demonstration that consuming a high-fat diet on a continuous form, which induces several metabolic changes and obesity, as well as behavioral alterations, does not seem to modulate the drug sensitivity until fat consumption is interrupted. At this moment, we observe an increased response to cocaine. However, bingeing on fat does not modify metabolism or bodyweight, but it increases the sensitivity to drugs like cocaine or ethanol, even when fat is no longer available. Therefore, we hope that the studies that constitute this Doctoral Thesis help to increase knowledge and awareness about the relevance of nutritional habits on the intervention in the multifactorial disorder that is drug addiction.