Neural responses to cues paired with methamphetamine in healthy volunteers

Abstract

Drug cues, or conditioned responses to stimuli paired with drugs, are widely believed to promote drug use. The acquisition of these conditioned responses has been well characterized in laboratory animals: neutral stimuli paired with drugs elicit conditioned responses resembling the motivational and incentive properties of the drug itself. However, few studies have examined acquisition of conditioning, or the nature of the conditioned response, in humans. In this study, we used fMRI to examine neural responses to stimuli that had been paired with methamphetamine or placebo in healthy young adults. Participants first underwent four conditioning sessions in which visual-auditory stimuli were paired with either methamphetamine (20 mg, oral) or placebo. Then on a drug-free test day, the stimuli were presented during an fMRI scan to assess neural responses to the stimuli. We hypothesized that the stimuli would elicit drug-like brain activity, especially in regions related to reward. Instead, we found that the methamphetamine-paired stimuli, compared to placebo-paired stimuli, produced greater activation in regions related to visual and auditory processing, consistent with the drug's unconditioned effects on sensory processing. This is the first study to demonstrate conditioned neural responses to drug-paired stimuli after just two pairings of methamphetamine in healthy adults. The study also illustrates that conditioned responses may develop to unexpected components of the drug's effects.

Fig. 1

Reaction times on a modified dot-probe task with the methamphetamine-paired and placebo-paired cues (attentional bias) before and after conditioning. Participants responded significantly faster to the probe when it appeared in the same location as the methamphetamine-paired cue following conditioning. **p = .01

Fig. 2

Images in neurological convention (left is right). Methamphetamine-paired images evoked significantly greater activation than placebo-paired images in clusters in bilateral primary/secondary visual cortex (green), left auditory cortex and insula (yellow), and right auditory cortex (orange, red) and insula (red)