Abstract
Dopamine (phasic release) is implicated in conditioned responses. Imaging studies in cocaine abusers show decreases in striatal dopamine levels, which we hypothesize may enhance conditioned responses since tonic dopamine levels modulate phasic dopamine release. To test this we assessed the effects of increasing tonic dopamine levels (using oral methylphenidate) on brain activation induced by cocaine-cues in cocaine abusers. Brain metabolism (marker of brain function) was measured with PET and 18FDG in 24 active cocaine abusers tested four times; twice watching a Neutral video (nature scenes) and twice watching a Cocaine-cues video; each video was preceded once by placebo and once by methylphenidate (20 mg). The Cocaine-cues video increased craving to the same extent with placebo (68%) and with methylphenidate (64%). In contrast, SPM analysis of metabolic images revealed that differences between Neutral versus Cocaine-cues conditions were greater with placebo than methylphenidate; whereas with placebo the Cocaine-cues decreased metabolism (p<0.005) in left limbic regions (insula, orbitofrontal, accumbens) and right parahippocampus, with methylphenidate it only decreased in auditory and visual regions, which also occurred with placebo. Decreases in metabolism in these regions were not associated with craving; in contrast the voxel-wise SPM analysis identified significant correlations with craving in anterior orbitofrontal cortex (p<0.005), amygdala, striatum and middle insula (p<0.05). This suggests that methylphenidate's attenuation of brain reactivity to Cocaine-cues is distinct from that involved in craving. Cocaine-cues decreased metabolism in limbic regions (reflects activity over 30 minutes), which contrasts with activations reported by fMRI studies (reflects activity over 2–5 minutes) that may reflect long-lasting limbic inhibition following activation. Studies to evaluate the clinical significance of methylphenidate's blunting of cue-induced limbic inhibition may help identify potential benefits of this medication in cocaine addiction.
Highlights
Dopamine (DA), a neurotransmitter that processes reward and prediction of reward [1,2] is involved with the reinforcing effects of drugs of abuse [3,4] and with responses to drug conditioned cues [5,6,7]
Imaging studies have shown that the fast DA increases achieved with intravenous administration of methylphenidate are associated with its reinforcing effects [12] whereas similar but slower DA increases after oral administration of methylphenidate (MP) are not perceived as reinforcing [13]
The fast DA increases as triggered by conditioned cues [10,11] are linked with craving responses in cocaine abusers [14,15] whereas a similar magnitude of DA increases but achieved slowly do not elicit craving [16]
Summary
Dopamine (DA), a neurotransmitter that processes reward and prediction of reward [1,2] is involved with the reinforcing effects of drugs of abuse [3,4] and with responses to drug conditioned cues [5,6,7]. Fast and large DA increases, as those achieved with phasic DA cell firing (15–30 Hz), are implicated in both drug reward [8,9] and conditioned cues [10,11]. Imaging studies have shown that the fast DA increases achieved with intravenous administration of methylphenidate (stimulant drug that increases DA by blocking DA transporters) are associated with its reinforcing effects [12] whereas similar but slower DA increases after oral administration of methylphenidate (MP) are not perceived as reinforcing [13]. It has been hypothesized that repeated drug use results in increases in tonic DA levels that dampen phasic DA responses driving compulsive drug administration as an attempt to overcome the attenuated phasic DA signaling [18]. Since low tonic DA levels would enhance phasic DA cell firing in response to conditioned-cues [21] we reasoned that increasing tonic DA levels in cocaine abusers would attenuate phasic DA responses to conditioned-cues and blunt the downstream activation of regions and circuits associated with these responses
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