Editors' ChoiceDRUG ADDICTION

Stimulating the Prefrontal Cortex to Undo Stimulant Addiction

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Science Translational Medicine  01 May 2013:
Vol. 5, Issue 183, pp. 183ec74
DOI: 10.1126/scitranslmed.3006371

Compulsive behavior that individuals pursue in the face of serious consequences is a defining feature of addiction. A new study by Chen et al. sheds light on the neural circuits responsible for such behavior and suggests possible therapeutic strategies.

This study examines a model of cocaine addiction in which rats were trained to press a lever to obtain infusions of intravenous cocaine. After 8 weeks of obtaining cocaine in this fashion, rats began to receive noxious electrical foot shocks in addition to cocaine after 30% of their lever presses. At this point, the experimenters divided rats according to whether they continued seeking cocaine: “Shock-sensitive” rats markedly decreased their lever pressing, whereas the remaining ~1/3 of rats were “shock-resistant” and continued to seek the drug. The prefrontal cortex (PFC) plays major roles in behavioral inhibition, so the experimenters hypothesized that cocaine may decrease PFC activity and thereby contribute to the persistence of cocaine-seeking in shock-resistant rats. Indeed, the excitability of PFC neurons was similar in shock-sensitive and naïve rats but decreased in the shock-resistant group. More strikingly, experimentally induced stimulation of prefrontal neurons reduced lever pressing in shock-resistant rats presented with the opportunity to press a lever and receive cocaine. This reduction only occurred when cocaine infusion was accompanied by the chance of a foot shock. Conversely, inhibiting prefrontal neurons increased lever-pressing in shock-resistant rats. These results suggest that in a subset of rats, cocaine reduces the excitability of PFC neurons, and that when faced with a choice about whether to seek cocaine in the face of a possible foot shock, decreased PFC activity tilts behavior toward cocaine seeking.

These observations raise questions about exactly how stimulating or inhibiting PFC neurons ultimately modulates cocaine-seeking. Do specific prefrontal neurons or targets of PFC mediate these effects? Does the nonspecific approach the authors used simply increase or decrease activity across all PFC neurons, or does it elicit more complex patterns of prefrontal activity? Regardless, these results suggest that focusing on PFC may elucidate factors that contribute to addiction in susceptible individuals and identify new ways to help them.

B. T. Chen et al., Rescuing cocaine-induced prefrontal cortex hypoactivity prevents compulsive cocaine seeking. Nature 496, 359–362 (2013). [Full Text]

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