Imaging of the brain opioid system in amphetamine dependence

Sammanfattning: Amphetamine dependence is a global health problem, often giving rise to severe medical and social complications in affected individuals. Unfortunately, there is still limited evidence for any specific treatment that would help amphetamine dependent patients to avoid relapse. One of the most promising treatments is the opioid antagonist naltrexone, which has been shown to attenuate the subjective effects of amphetamine and in some randomized clinical trials also reduce the risk of relapse. The aim of this thesis work was to investigate the mechanism of action of naltrexone for amphetamine dependence, in order to better understand the neurobiology involved and facilitate further treatment development. We used the neuroimaging techniques positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) to study these processes in the human brain. In Study I, we tested the hypothesis that an amphetamine injection causes a release of endogenous opioids in the brain, which might explain why an opioid antagonist such as naltrexone attenuates the subjective effects of amphetamine. However, using PET and the µ opioid radioligand 11C-carfentanil, we found no evidence of such an amphetamine-induced opioid release in healthy human subjects without any previous experience of amphetamine. Study II investigated whether naltrexone pre-treatment affects the dopamine release that occurs in the brain after amphetamine intake, an effect that some previous studies have found to correlate with the subjective effects of amphetamine. If naltrexone were to attenuate this dopamine release, it might help to explain why it affects the subjective effects of amphetamine. In a first experiment, we used PET and the radioligand 11C-raclopride, but found no evidence that naltrexone affected amphetamine-induced dopamine release in healthy, previously amphetamine-naïve human subjects. We proceeded with experiments using in vivo microdialysis in rats, where similar results were found: pre-treatment with naltrexone did not affect the dopamine release caused by an acute amphetamine dose in rats without previous exposure to amphetamine. However, in rats that had been treated with amphetamine for a longer time period, naltrexone did attenuate the dopamine release when amphetamine was reinstated, suggesting that the brain opioid system might be involved in the adaptations to chronic amphetamine exposure. In Study III, we investigated the effects of naltrexone on cue reactivity, i.e. the reaction of substance dependent patients to environmental stimuli reminding them of drug use. This process is interesting as it can be an important trigger of relapse. For this study, we included 40 men with severe, intravenous amphetamine dependence, who received one oral dose of naltrexone or placebo and then underwent an fMRI examination including exposure to drugrelated and neutral film clips. The hypothesis was that the drug-related films would cause a subjective craving reaction and increase the activity of a number of motivationally relevant brain regions, and that naltrexone would attenuate this reactivity. We found that the films did cause strong craving and wide-spread fMRI activations, but there was no evidence of any effect of naltrexone on these measures. Study IV investigated the proposed phenomenon of subliminal cue reactivity, where the brains of substance dependent patients have been reported to react specifically to drug-related pictures, even when the pictures are presented very fast and with a backward mask, so that they never reach conscious awareness. In our study, which used the same patient sample as Study III and 30 healthy controls, we found no evidence of any subliminal drug cue reactivity. Upon closer examination of the earlier studies, we found that the reliability of their statistical inferences could be questioned, which together with our negative results suggest that there is no strong evidence for subliminal cue reactivity in addiction. In summary, the studies of this thesis have not corroborated the hypotheses we started out with regarding the mechanisms behind naltrexone’s effects in amphetamine dependence. Instead, the results have inspired new hypotheses, for example regarding how the interplay between the brain dopamine and opioid systems may change with long-term amphetamine use. These studies have also highlighted methodological challenges that may help to improve future neuroimaging studies of addiction.