House of Mind

Cue-induced drug motivation in humans

Our evolutionary legacy is an old brain circuit that is exquisitely sensitive to rewards. Form an evolutionary perspective, response to rewards is critical to survival (food-life, sex-passing on gene pool). Rewards and their signals activate the mesocorticolimbic circuitry. Cues for reward acquire the ability to elicit motivation through classical conditioning; an individual pairs a particular cue (smell, sound, place, etc..) with drug use and the reinforcing effects that shortly follow. Thus, brain substrates of cue-induced drug motivation and its modulation serve as go signal (for drug administration). However, limbic (memory, emotion) activation is required for go signal in response to cues. Evidence from cocaine studies have even found an increase in striatal dopamine release in response to cocaine cues, not even the drug itself!

However, craving is not always related to cues. Some patients report a volcanic desire to use and state that their craving seems to come out of nowhere. Is this really possible? An incontrollable, urgent desire to use? Or is it just that these individuals are seemingly unaware of the cues (triggers)? To test this, Childress and others employed the backward-masking: extremely short “unseen” cue paradigm. In this paradigm, patients were instructed to watch a video that contained super short clips (less than 30 millieseconds) of cocaine cues mixed in with normal and pretty boring things (buildings, etc) and other non-drug rewards (sex). The found that even though the patients were unaware of the hidden cues, as indexed by a failure to report having seen them when asked to summarize the video, these unseen cues activate amygdala, ventral striatum, insula, temporal poles and others. Thus, the limbic circuit of these individuals was activated even if patients couldn’t recall the unseen cues! This response was also found to predict the future affective (positive) response to visible cocaine cues, which suggests a continuity between processes outside/inside awareness. Taking all this into consideration, I think it’s fair to say that limbic response to brief unseen cocaine cues predicts future relapse.

The group also looked into individual variability that may help explain susceptibility for use and relapse. They found that dopamine transporter 9 (DAT9) carriers have fewer or less efficient dopamine transporter activity that can lead to a perpetuation of dopamine response to drug cues. Also, they found greater limbic activation to drug cues in DAT9 carriers. History of trauma also interferes with the ability to modulate stress and have much more limbic activation to both aversive and appetitive cues. 

Next, they questioned whether a medication can modulate the brain response during cue-induced limbic ativation and found that baclofen (a GABA receptor agonist that induces inhibition) blunts amygdala connectivity during seen cocaine cues.

Notes taken at SfN in San Diego, CA on Nov. 14, 2010. Notes taken during A.R. Childress symposia: Cue-induced drug motivation in human addiction: new modulators.