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The Journal of Neuroscience, February 18, 2004, 24(7):1604-1611; doi:10.1523/JNEUROSCI.5124-03.2004

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Behavioral/Systems/Cognitive
A Single Infusion of Brain-Derived Neurotrophic Factor into the Ventral Tegmental Area Induces Long-Lasting Potentiation of Cocaine Seeking after Withdrawal

Lin Lu, Jack Dempsey, Shirley Y. Liu, Jennifer M. Bossert, and Yavin Shaham

Behavioral Neuroscience Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224

Cocaine addiction in humans is associated with long-term propensity to relapse. Using a rat relapse model, we found that cocaine seeking induced by exposure to cocaine-associated cues progressively increases after withdrawal. This progressive increase is associated with increases in brain-derived nerve growth factor (BDNF) levels within the mesolimbic dopamine system. Based on these findings, we studied whether BDNF infusions into the ventral tegmental area (VTA), the cell body region of mesolimbic dopamine neurons, would potentiate cocaine seeking after withdrawal. Rats were trained to self-administer cocaine for 10 d, and cocaine seeking was measured in extinction tests 3, 10, or 30 d after withdrawal. During testing, rats were exposed to contextual cues that had predicted cocaine availability during training, and lever presses resulted in contingent presentations of a discrete tone-light cue that was previously temporally paired with cocaine infusions. BDNF (0-0.75 µg/site) or nerve growth factor (NGF; 0-0.75 µg/site) was infused into the VTA 1-2 hr after the last self-administration session. To examine the role of the mitogen-activated protein kinase (MAPK) pathway in BDNF effects, U0126 (1 µg/site), an MEK inhibitor, was used. A single intra-VTA infusion of BDNF, but not NGF, induced long-lasting enhancement of cocaine seeking for up to 30 d, an effect reversed by U0126. In contrast, neither BDNF infusions into the substantia nigra, nor acute intra-VTA BDNF infusions 2 hr before testing on day 3 of withdrawal, were effective. These data suggest that BDNF-mediated neuroadaptations in mesolimbic areas are involved in the persistent cocaine seeking induced by exposure to drug cues after withdrawal.

Key words: brain-derived nerve growth factor; drug self-administration; extinction; growth factors; MAP kinase; reinstatement; relapse; substantia nigra

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Received Oct 28, 2003; revised December 18, 2003; accepted December 22, 2003.

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