Nipping cue reactivity in the bud: baclofen prevents limbic activation elicited by subliminal drug cues

Abstract

Relapse is a widely recognized and difficult to treat feature of the addictions. Substantial evidence implicates cue-triggered activation of the mesolimbic dopamine system as an important contributing factor. Even drug cues presented outside of conscious awareness (i.e., subliminally) produce robust activation within this circuitry, indicating the sensitivity and vulnerability of the brain to potentially problematic reward signals. Because pharmacological agents that prevent these early cue-induced responses could play an important role in relapse prevention, we examined whether baclofen-a GABAB receptor agonist that reduces mesolimbic dopamine release and conditioned drug responses in laboratory animals-could inhibit mesolimbic activation elicited by subliminal cocaine cues in cocaine-dependent individuals. Twenty cocaine-dependent participants were randomized to receive baclofen (60 mg/d; 20 mg t.i.d.) or placebo. Event-related BOLD fMRI and a backward-masking paradigm were used to examine the effects of baclofen on subliminal cocaine (vs neutral) cues. Sexual and aversive cues were included to examine specificity. We observed that baclofen-treated participants displayed significantly less activation in response to subliminal cocaine (vs neutral) cues, but not sexual or aversive (vs neutral) cues, than placebo-treated participants in a large interconnected bilateral cluster spanning the ventral striatum, ventral pallidum, amygdala, midbrain, and orbitofrontal cortex (voxel threshold p < 0.005; cluster corrected at p < 0.05). These results suggest that baclofen may inhibit the earliest type of drug cue-induced motivational processing-that which occurs outside of awareness-before it evolves into a less manageable state.

Keywords: addiction; baclofen; cocaine; cues; fMRI; subliminal.

Figure 1.

Representative trial from the backward-masked cue task. In each trial, participants were presented with the following visual stimuli in immediate succession: crosshair (500 ms); target stimulus (33 ms); masking stimulus (467 ms); crosshair (1000 ms). Target images were presented from one of four categories [i.e., cocaine (shown), neutral, sexual, and aversive].

Figure 2.

Neural activation to backward-masked cocaine (vs neutral) cues in baclofen- and placebo-treated cocaine-dependent men. A, Baclofen-treated compared with placebo-treated participants demonstrated significantly less neural activation in a large interconnected cluster bilaterally spanning the ventral striatum, ventral pallidum, amygdala, midbrain, and orbitofrontal cortex (voxel threshold p < 0.005; cluster corrected at p < 0.05). The image on the left shows the significant cluster of reduced activation rendered in 3D (crosshairs are centered on the left ventral striatum. S, Superior; I, inferior; A, anterior; R, right; L, left). Cross-sectional coronal and axial images of ventral striatum, amygdala, and midbrain are displayed on the right. B, Placebo-treated participants demonstrated increased neural activation in response to cocaine (vs neutral) cues in the ventral striatum, ventral pallidum, amygdala, and orbitofrontal cortex (left); neural activation to cocaine cues was absent in baclofen-treated participants (right; data displayed at p < 0.01, k > 10, uncorrected). For cross-sectional images, data are displayed neurologically (left is left) and the color bars represent T values.