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

    350—Cocaine: Neural Mechanisms of Addiction II

    Monday, November 11, 2013, 8:00 am - 12:00 noon

    350.01: BDNF over-expression in the ventral tegmental area potentiates intermittent social defeat stress-induced escalation of cocaine self-administration

    Location: Halls B-H

    1Arizona State Univ., Tempe, AZ; 2SUNY Univ. at Buffalo, Buffalo, NY; 3Basic Med. Sci., Univ. Arizona, PHOENIX, AZ

    Abstract Body: Brain-derived neurotrophic factor (BDNF) is a neural growth factor which can enhance the survival and activity of dopaminergic neurons and is involved in synaptic plasticity. BDNF is elevated in several portions of the mesocorticolimbic circuit after exposure to psychostimulants, and mediates sensitivity to cocaine. Intermittent exposure to social defeat stress increases BDNF in the ventral tegmental area (VTA) and escalates drug intake in rats. We hypothesized that BDNF over-expression in the VTA will further potentiate stress-induced escalation of cocaine intake. Adult male Sprague-Dawley rats were implanted with intravenous jugular catheters and received bilateral infusion of an adeno-associated viral vector (AAV) containing cDNA of green fluorescent protein (AAV-GFP) or bdnf (AAV-BDNF) into the VTA. Rats were exposed to either intermittent social defeat stress (4 defeats over 10 days) or handling. One week after the last defeat, all rats (GFP-handled, GFP-stressed, BDNF-handled, BDNF-stressed) were trained to self-administer cocaine (0.75 mg/kg/0.1ml, i.v.) under fixed ratio (FR) schedules of reinforcement. After self-administration (SA) stabilized on an FR5 schedule, rats were subjected to three progressive ratio (PR) sessions (0.375 mg/kg) on alternating days with maintenance sessions (0.75 mg/kg) on an FR5 schedule. The day after the last maintenance session, rats were given 12-h access to cocaine (0.375 mg/kg) on an FR5 schedule (12-h binge). Brains were removed ten days later and processed for immunohistochemistry. Both GFP-stressed and BDNF-handled groups exhibited facilitated acquisition of cocaine SA. The BDNF-stressed group showed the highest level of drug intake during the 12-h binge and the greatest BDNF expression in the VTA. We also found a positive correlation between VTA BDNF level and drug intake during the 12-h binge. VTA BDNF over-expression significantly reduced BDNF in the prelimbic cortex (PrL) and prevented stress-induced BDNF increase in PrL. Also VTA BDNF over-expression resulted in greater deltaFosB accumulation in both the shell and core of the NAc than did AAV-GFP after cocaine SA. Our results suggest that the level of BDNF in the VTA may titrate compulsive drug-taking behavior, and that higher VTA BDNF is a risk factor engendering greater vulnerability to cocaine abuse. Elevated BDNF expression in the VTA could induce persistent functional activation of the NAc, resulting in the accumulation of deltaFosB. The reduction of BDNF expression in PrL might also contribute to escalating drug-taking behavior, possibly through decreased inhibitory output to areas involved in drug reinforcement and motivation.

    Lay Language Summary: Our research has uncovered a brain mechanism that may play a critical role in the increase in vulnerability to addiction in people who have a history of social stress. Using a rodent model of cocaine self-administration, we found that heightened brain-derived neurotrophic factor (BDNF) in the ventral tegmental area (VTA) is a risk factor conferring higher vulnerability to cocaine. The more BDNF in this brain region, the faster rats escalate their intake of cocaine when given voluntary access by pressing a lever. Our results also confirm that social stress enhances the reinforcing effect of cocaine, and that this effect is heightened by BDNF in the VTA.
    Addiction has an estimated economic impact of $524 billion annually in the U.S, due to addiction-related health care, loss of productivity, accidents and crime. Its impact stretches beyond the addicted individual to family members and society. There are individual differences and environmental factors that contribute to vulnerability to addiction. One such factor is social stress, which is experienced by some people on a daily basis, for instance from domestic abuse or bullying.
    The vulnerability to drugs of abuse in individuals who experience repeated social stress may have a genetic component, including possible differences in expression of BDNF. BDNF is a modulator of signaling strength between neurons, and therefore, may facilitate adaptations in the nervous system to stress and drugs of abuse. Repeated social defeat stress induces significant elevation of BDNF in the VTA, which is associated with augmented locomotor response to amphetamine. Thus, we hypothesized that heightened BDNF levels in the VTA may interact with stress to facilitate compulsive cocaine intake. Such an effect would be evident as a faster escalation from low to high levels of drug intake in individuals with a history of social stress and high levels of BDNF in the VTA.
    To test our hypothesis, we used an adeno-associated viral vector to increase expression of BDNF in the VTA of male rats. We then exposed rats to intermittent social defeat stress consisting of a brief physical attack/defeat (~3 min) from a larger, territorial rat, and continued psychological stress from the threatening behavior of the intruder (15 min). We then trained rats to press a lever for intravenous cocaine infusions and measured aspects of drug self-administration. The speed of learning to self-administer cocaine was used as an indicator of sensitivity to drug reinforcement. A progressive ratio schedule of reinforcement, in which the number of lever presses needed to obtain a cocaine infusion increases with each successive reinforcer, was subsequently used to quantify the effort the rats were willing exert to attain a drug infusion. The binge procedure, during which the rats had 12 hours of unlimited access to drug, was used to measure of the persistence and escalation of drug intake.
    We found that social defeat stress facilitates the acquisition of cocaine self-administration, increases cocaine intake on a progressive ratio schedule, and potentiates cocaine intake during a binge session, similar to previous findings. Moreover, we showed that BDNF overexpression in the VTA facilitates the acquisition of cocaine self-administration, and potentiates stress-induced escalation of drug taking during the binge session. After measuring levels of BDNF in the VTA of all the animals, we found a significant positive correlation between BDNF expression in the VTA and cocaine intake during the binge session, suggesting the higher BDNF levels in the VTA the higher the level of drug-taking behavior.
    Developing treatments that reduce BDNF in the VTA may provide a new therapeutic strategy to prevent and treat cocaine addiction, particularly in individuals that have a history of repeated social stress.