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Orbitofrontal activation restores insight lost after cocaine use.

ABSTRACT: Addiction is characterized by a lack of insight into the likely outcomes of one's behavior. Insight, or the ability to imagine outcomes, is evident when outcomes have not been directly experienced. Using this concept, work in both rats and humans has recently identified neural correlates of insight in the medial and orbital prefrontal cortices. We found that these correlates were selectively abolished in rats by cocaine self-administration. Their abolition was associated with behavioral deficits and reduced synaptic efficacy in orbitofrontal cortex, the reversal of which by optogenetic activation restored normal behavior. These results provide a link between cocaine use and problems with insight. Deficits in these functions are likely to be particularly important for problems such as drug relapse, in which behavior fails to account for likely adverse outcomes. As such, our data provide a neural target for therapeutic approaches to address these defining long-term effects of drug use.

SUBMITTER: Lucantonio F

PROVIDER: S-EPMC4120653 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Orbitofrontal activation restores insight lost after cocaine use.

Lucantonio Federica F Takahashi Yuji K YK Hoffman Alexander F AF Chang Chun Yun CY Bali-Chaudhary Sheena S Shaham Yavin Y Lupica Carl R CR Schoenbaum Geoffrey G

Nature neuroscience 20140720 8

Addiction is characterized by a lack of insight into the likely outcomes of one's behavior. Insight, or the ability to imagine outcomes, is evident when outcomes have not been directly experienced. Using this concept, work in both rats and humans has recently identified neural correlates of insight in the medial and orbital prefrontal cortices. We found that these correlates were selectively abolished in rats by cocaine self-administration. Their abolition was associated with behavioral deficits ...[more]

PMID: 25042581

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Project description:Cocaine use during adolescence decreases the likelihood that individuals will seek treatment for recurrent drug use. In rodents, developmental cocaine exposure weakens action-consequence decision-making, causing a deferral to familiar, habit-like behavioral response strategies. Here, we aimed to improve action-outcome decision-making. We found that acute pharmacological stimulation of the tyrosine/tropomyosin receptor kinase B (trkB) via 7,8-dihydroxyflavone (7,8-DHF) or 3,4-methylenedioxymethamphetamine (MDMA) blocked cocaine-induced habit biases by strengthening memory for action-outcome associations. We believe that MDMA acts by stimulating neurotrophin/trkB systems in the orbitofrontal cortex (OFC), a region involved in prospectively evaluating the consequences of one's action, because 1) MDMA also increased brain-derived neurotrophic factor (BDNF) in the OFC, 2) MDMA corrected habit biases due to Bdnf loss in the OFC, and 3) overexpression of a truncated isoform of trkB occluded the memory-enhancing effects of MDMA. Thus, selecting actions based on their consequences requires BDNF-trkB in the OFC, the stimulation of which may improve goal attainment in both drug-naïve and cocaine-exposed individuals. SIGNIFICANCE STATEMENT: Cocaine use during adolescence decreases the likelihood that individuals will seek treatment for recurrent drug use, even as adults. Understanding how early-life cocaine exposure impacts goal-oriented action and prospective decision-making in adulthood is thus important. One key aspect of goal-directed decision-making is anticipating the consequences of one's actions, a process that likely involves the orbitofrontal cortex (OFC). In rodents, developmental cocaine exposure weakens action-consequence decision-making, causing a deferral to familiar, habit-like behavioral response strategies. Here, we report that we can improve memory for action-consequence relationships by stimulating neurotrophic factors, which support cell survival, development, and plasticity in the brain. With strengthened action-consequence associations, cocaine-exposed mice regain the ability to optimally select actions based on their likely outcomes. Brain region-selective manipulations reveal that neurotrophin systems in the OFC are necessary for stable memory of action-consequence relationships.

Dataset Information

Orbitofrontal activation restores insight lost after cocaine use.

Publications

Orbitofrontal activation restores insight lost after cocaine use.

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