Post-natal deficiency of omega-3 fatty acids: its role on cocaine-seeking behaviors and drug withdrawal severity.

Abstract

Adolescence is a transitional stage characterized by unique neurobiological changes in the brain. The brain's maturation during this stage, particularly in the frontal cortex and the limbic system, is responsible for cognitive control and reward-seeking behaviors. Adolescence is also characterized by an enhanced vulnerability to external factors: Nutritional deficiencies, for example, can lead to long-lasting neurochemical changes that may persist into adulthood. Research studies have highlighted the adverse effects of omega-3 (ω-3) on brain function, which result in cognitive impairments and modified reward processing.<br /> <br /> It has been noted that deficiencies in ω-3 play an essential role during adolescence, predisposing individuals to behavioral and cognitive deficits. Molecular studies in rodents have indicated that deprivation of ω-3 can dysregulate neurotransmitters, such as the dopaminergic, serotoninergic, glutamatergic and endocannabinoids, involved in the pathophysiology of addiction. While several mechanisms underlying the effects of dietary ω-3 deficiency have been described, those specifically linked to adolescence are limited and poorly understood. The modulatory effect triggered by such a deficiency may influence addictive drug behaviors and neurotransmitters associated with motivation and reward.<br /> <br /> Research studies have demonstrated that low levels of omega-3 (ω-3) in the brain can alter the dopaminergic system of the brain and, as a result, increase the risk of developing addictive disorders as well as the severity of the disorder. Studies have additionally shown the detrimental effects of ω-3 deficiency in the treatment of cocaine abuse: ω-3 deficiency can aggravate withdrawal symptoms such as anxiety, anger, cravings, and depression. Conversely, it has been demonstrated that dietary supplementation reverse these symptoms. Together, this evidence suggests that insufficient levels of ω-3 may influence addictive behaviors. The precise mechanisms by which ω-3 modulate addiction, however, remain uncertain. To the best of our knowledge, evidence linking ω-3 deficiencies and cocaine use disorder within the brain's reward regions was non-existent.<br /> <br /> Thus, the aim of this dissertation was to examine whether adolescence may represent a critical period during which ω-3 deprivation may contribute to a higher vulnerability of future cocaine abuse in adulthood. Moreover, we analyzed subsequent predisposition to depression and anxiety at several timepoints. We hypothesized that deficiency on the intake of ω-3 starting in adolescence would have a direct effect on cocaine consumption, intensifying cue-induced and cocaine-seeking behaviors in adulthood.<br /> <br /> Based on the preceding, Chapter 1 addresses general biochemical concepts about fatty acids and reviews the literature regarding the harmful consequences of ω-3 deficiency and its impact on neurodevelopment, rewardrelated neurocircuitry, and the likelihood of its influence on addictive behaviors. Chapter 2 evaluates how ω-3 deficiency alters the development of cocaineseeking behaviors using the cocaine self-administration paradigm with a fixed-ratio schedule. Furthermore, Chapter 2 includes evidence about the etiology of anxietylike behaviors after a short abstinence period. Our results show that prolonged dietary deprivation of ω-3 did not exert any significant effect in lever-pressing activity through the acquisition and extinction phases of the cocaine seeking behavior paradigm. However, DEF group demonstrated a substantial decrease in lever pressing during cue-induced reinstatement. Moreover, n-3 PUFA-deficient animals showed enhanced anxiety-like behaviors after 14 days of cocaine abstinence. Furthermore, we discover that protein levels of the dopaminergic receptor-1 (DR1) were increased within the PFC. Chapter 3 considers how ω-3 deprivation and chronic cocaine consumption disturb cue-induced reinstatement behaviors using the incubation of cue reactivity between ID1 (Incubation Day 1) and ID40 after forced abstinence. In addition, anxiety-like and depression-like behaviors were evaluated after 10 weeks using the elevated plus maze test (EPM) and the Forced Swimming Test (FST). On ID40, the DEF group showed lower cue-induced cocaine-seeking behavior compared to the CON group. In the EPM, the DEF group showed an enhanced anxiety based on a gradual reduction in the time spent on the open-arm and an increased time in the closed-arms. During the FST test, the DEF group demonstrated greater immobility time compared to the CON group which is interpreted as an enhanced depressive-like behavior. Finally, Chapter 4 summarizes results, evaluates limitations, and recommends future experiments.<br /> <br /> We concluded that dietary absence of ω-3 could intensify the symptoms of anxiety and depression during withdrawal periods after extended access of cocaine self-administration. Furthermore, we suggested that this deficiency could modify sensitivity to the rewarding effects of cocaine. We can speculate that these dietary-induced perturbations in PUFA homeostasis can deregulate the dopaminergic systems, leading to behavioral mood changes and impaired responsiveness to positive events. Future studies will further address this statement, evaluate other neurotransmitter systems and brain areas that might also be involved to achieve a more definite conclusion.