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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    816—Cocaine Reinforcement, Seeking, and Reinstatement II

    Wednesday, November 13, 2013, 1:00 pm - 5:00 pm

    816.19: Individual differences in dopamine, cocaine taking, and seeking in female rats as a result of chronic social defeat stress

    Location: Halls B-H

    Tufts Univ., MEDFORD, MA

    Abstract Body: Background: Experiences with chronic stress can engender depressive-like symptoms in some individuals, while others exhibit resilience to such a prolonged stressor. This individual difference in stress response may associate with altered dopamine system that potentially leads to individual differences in subsequent cocaine taking and seeking.
    Objectives: Drug effects are often more profound in females compared to males in every phase of the addiction cycle, which can be further aggravated when experiencing stress. The current study characterized the effects of chronic social defeat stress on females with the focus of cocaine taking and seeking. In parallel, we characterized dopamine response to cocaine challenge in these two subtypes measured in the nucleus accumbens (NAc), a brain area important for reward processing.
    Methods: Female Long-Evans rats were exposed to 21 days of chronic social defeat stress. Weight gain, preference for saccharin, and estrous cycles were assessed during the course of social defeat stress for 21 days. Ten days after the last social defeat, rats were subjected to cocaine self-administration, and tested for reinstatement following 14 days of abstinence. In a subset of animals, the levels of DA in the NAc were measured using in vivo microdialysis as a result of 10 mg/kg of cocaine challenge.
    Results: A strong correlation was observed between the number of cocaine infusions taken by rats during a 24-h binge-like cocaine self-administration and their preceding anhedonia-like responses as a result of chronic social defeat stress (r=0.499, n=26). Compared to the non-stressed control group, the rats that took less cocaine exhibited an anhedonia-like behavioral phenotype, a reduced number of estrous days during social defeat stress period, reduced locomotor activity and DA levels in the NAc as a result of cocaine challenge, and reduced self-administration under fixed ratio 5 and progressive ratio schedules of cocaine reinforcement. By contrast, the rats that took more cocaine did not exhibit depressive-like symptoms as a result of chronic social defeat stress. Both stress-vulnerable and stress-resilience exhibited an increased seeking response in comparison to non-stressed control group, as a result of their preceding abstinence period.
    Conclusion: Cocaine taking and seeking is influenced by its preceding stress reactivity in females that is possibly associated with the alteration in DA system.

    Lay Language Summary: Although excessive stress has been linked to both depression and drug abuse, we have found that female rats that begin to show depressive-like behavior after chronic stress actually take less cocaine. Prolonged stress can alter brain mechanisms, including the neurons associated with reward. This may result in both a key feature of depression, the inability to feel pleasure in previously enjoyable activities, as well as reduction in the reinforcing properties of cocaine.
    It is well known in Psychology and Psychiatry that individuals differ in their vulnerability to stress. Those that can cope better with stress are often referred to as resilient while others are more vulnerable to stress effect. People that are overly vulnerable to stress may be at risk of using psychostimulants such as cocaine or methamphetamine to replace their negative emotions with feelings of euphoria. Women use drugs as much as men do when they suffer from stress-related disorders, but not everyone succumbs to the vicious cycle of addiction as a result. We have been studying this in laboratory rats to determine the neurobiological bases of such individual differences. We have demonstrated that female rats that are exposed to prolonged stress fall into two different subtypes: stress-resilient and stress-vulnerable. Interestingly, the stress-resilient subtype takes much more cocaine than the stress-vulnerable subtype. In other words, the extent of cocaine self-administration in female rats can be determined by their behavioral reaction to an equivalent level of stress.
    Perhaps exposure to prolonged stress alters brain mechanisms, particularly the neurons that contribute to reward, which can increase the likelihood of behaviors. This appears to be largely regulated by dopaminergic neurons, and cocaine helps to increase amounts of dopamine in corresponding brain areas. Therefore, it is likely that prolonged stress changes normal functioning of dopaminergic neurons in some females that results in changes in the propensity for cocaine taking.
    To test our hypothesis, we expose experimental female rats to a prolonged stress -- a daily confrontation with lactating dams over 21 consecutive days. Lactating dams are used because they are highly aggressive to unfamiliar females while they are protecting their young, and this maternal aggression produces significant stress-related symptoms to the experimental females. After the stress exposure is completed, the females are trained to take cocaine by themselves. The amounts of cocaine taken by females with or without experiencing a prolonged stress are subsequently compared. In a subset of animals, we measure the concentration of dopamine molecules released by neurons.
    Rats that are under stress-free conditions take a decent amount of cocaine after being trained for self-administration. However, the rats that are subjected to a prolonged stress but did not show signs of stress-induced symptoms self-administered far more cocaine compared to the stress-free controls. By contrast, the rats that showed signs of stress-related symptoms, such as changes in pleasurable measurements, consumed much less cocaine compared with both the stress-resilient subtype and stress-free controls. Surprisingly, the dopamine released in the brain was identical in quantity between the stress-resilient and stress-vulnerable subtypes, and these results suggest that stress resiliency may be changing other neurons to control cocaine taking.
    The percentages of women who actively contribute to our labor force or who are currently serving as an active-duty soldier in the military are increasing. As a result, more women are experiencing increasing levels of life stress now more than ever. A continuous exposure to such stress can develop into stress-related disorders, such as posttraumatic stress disorder (PTSD), depression, or a regression into drug taking and substance abuse. This study enhances our understanding of female-specific mechanisms that exacerbate stress-related disorders and the consequence of drug taking.