The effects of naltrexone on neural responses to methamphetamine cues
Drug and Alcohol Dependence
Despite multiple legislative attempts to restrict access, methamphetamine remains a widely used drug in the United States, and a significant number of individuals develop methamphetamine problems following repeated use of the drug. No medications are currently approved by the FDA for the treatment of methamphetamine use disorders; yet, preclinical and clinical evidence advances naltrexone, an opioid receptor antagonist, as a promising candidate. Naltrexone is thought to reduce drug
... via blocking dopamine-release in the mesolimbic dopamine system, primarily driven by the pathway from the ventral tegmental area (VTA) to the nucleus accumbens (NAcc); however, this theory has not been directly tested and other pathways may also be involved. Thus, the present dissertation investigated the effects of naltrexone on functional magnetic resonance imaging (fMRI) measures of functional connectivity during methamphetamine cue processing and subjective craving for methamphetamine. iii Methods: A final sample of 23 non-treatment seeking individuals with methamphetamine use disorders (74% male, mean age = 34.70 [SD = 8.95]) were enrolled within a randomized, placebo controlled, within-subject design and underwent two blood-oxygen-level dependent (BOLD) methamphetamine cue-reactivity paradigms following three days of naltrexone treatment (50mg) and matched time for placebo. fMRI analyses tested naltrexone-induced differences in BOLD activation associated with methamphetamine and control cues, resting-state cerebral blood flow (CBF), and functional connectivity (using psychophysiological interaction [PPI] analysis) during methamphetamine cue processing. Results: Analyses revealed that (1) the novel methamphetamine cues task employed was successful in eliciting cue-induced craving and relevant regional activation, (2) greater subjective methamphetamine craving is related to enhanced recruitment of prefrontal regions, (3) naltrexone moderates methamphetamine cue-reactivity in sensorimotor regions, (4) the BOLD results are not a reflection of global CBF changes induced by naltrexone, (5) reduced activation of sensorimotor regions during methamphetamine cue processing by naltrexone is related to functional connectivity of dorsal striatum, VTA, periaqueductal gray (PAG), and precuneus with visual, sensory, and motor-related regions, (6) naltrexone enhances dorsal striatum, VTA, and sensorimotor region functional connectivity with the frontal cortex during methamphetamine cues processing , and (7) naltrexone weakens the associations between subjective craving and precuneus functional connectivity with sensorimotor regions and strengthens the associations between subjective craving and dorsal striatum and precuneus connectivity with frontal regions during methamphetamine cue processing, as compared to placebo. Conclusions: The results of this study provide the first evidence of naltrexone-induced changes in BOLD measures of methamphetamine cue-induced craving. Functional connectivity with iv NAcc was not found to be modulated by naltrexone, and instead the results suggest that naltrexone may be functioning to reduce the salience of the methamphetamine cues by reducing sensorimotor processing and integration, and by engaging greater frontal regulation of salience attribution via dopaminergic, glutamatergic, and/or GABAergic pathways linking the dorsal striatum, midbrain, and precuneus to frontal, dorsal striatal, and sensorimotor regions during methamphetamine cue processing. The knowledge of these neurobiological pathways may prove to be useful in the prediction of clinical outcomes and aid in the development and application of medications such as naltrexone for the treatment of methamphetamine use disorders. v The dissertation of Kelly Elizabeth Courtney is approved.