ABSTRACT
BACKGROUND: Preclinical and human positron emission tomography studies have produced inconsistent results regarding the effects of opioids on mesolimbic dopamine (DA). Here, we quantify striatal DA release (measured by [11C]raclopride displacement) in response to an intravenous infusion of morphine, and its relationship with morphine-induced subjective effects, in healthy, nondependent opioid-experienced participants. METHODS: Fifteen healthy male participants were initially included. Sessions were on separate days. On session 1, participants received intravenous morphine (10 mg/70 kg) in the clinic to ensure tolerability. Participants without adverse reactions (n = 10) then received intravenous morphine and placebo (saline) sessions, in counterbalanced order, while undergoing [11C]raclopride positron emission tomography scans. Subjective and physiological responses were assessed. Region-of-interest and voxelwise image analyses were used to assess changes in [11C]raclopride nondisplaceable binding potential. RESULTS: Morphine produced marked subjective and physiological effects and induced a significant decrease in [11C]raclopride nondisplaceable binding potential, particularly in the nucleus accumbens and globus pallidus, where the change in [11C]raclopride nondisplaceable binding potential was approximately 9%. However, the subjective effects of morphine did not show a simple pattern of correlation with DA release. CONCLUSIONS: This is, to our knowledge, the first study providing in vivo human evidence that DA transmission in the ventral striatum is affected by morphine. Further studies are required to fully delineate the DA contribution to the reinforcing effects of opioids.
Subject(s)
Dopamine/metabolism , Morphine/administration & dosage , Ventral Striatum/drug effects , Ventral Striatum/metabolism , Adult , Brain Mapping/methods , Carbon Radioisotopes/administration & dosage , Dopamine Antagonists/administration & dosage , Healthy Volunteers , Humans , Infusions, Intravenous , Male , Positron-Emission Tomography , Raclopride/administration & dosage , Ventral Striatum/diagnostic imaging , Young AdultABSTRACT
OBJECTIVE: To investigate GABA-ergic receptor density and associated brain functional and grey matter changes in focal hand dystonia (FHD). METHODS: 18 patients with FHD of the right hand and 18 age and gender matched healthy volunteers (HV) participated in this study. We measured the density of GABA-A receptors using [11C] Flumazenil and perfusion using [15O] H2O. Anatomical images were also used to measure grey matter volume with voxel-based morphometry (VBM). RESULTS: In FHD patients compared to HV, the vermis VI of the right cerebellum and the left sensorimotor cortex had a decrease of Flumazenil binding potential (FMZ-BP), whereas the striatum and the lateral cerebellum did not show significant change. Bilateral inferior prefrontal cortex had increased FMZ-BP and an increase of perfusion, which correlated negatively with disease duration. Only the left sensorimotor cortex showed a decrease of grey matter volume. INTERPRETATION: Impairments of GABAergic neurotransmission in the cerebellum and the sensorimotor cortical areas could explain different aspects of loss of inhibitory control in FHD, the former being involved in maladaptive plasticity, the latter in surround inhibition. Reorganization of the inferior prefrontal cortices, part of the associative network, might be compensatory for the loss of inhibitory control in sensorimotor circuits. These findings suggest that cerebellar and cerebral GABAergic abnormalities could play a role in the functional imbalance of striato-cerebello-cortical loops in dystonia.
Subject(s)
Brain Mapping , Dystonic Disorders/diagnostic imaging , Dystonic Disorders/pathology , Neural Pathways/diagnostic imaging , Prefrontal Cortex/diagnostic imaging , Adult , Aged , Carbon Radioisotopes/pharmacokinetics , Case-Control Studies , Cerebellum/diagnostic imaging , Cerebellum/drug effects , Cerebrovascular Circulation , Female , Flumazenil/pharmacokinetics , GABA Modulators/pharmacokinetics , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Oxygen Isotopes/pharmacokinetics , Oxygen Radioisotopes/pharmacokinetics , Positron-Emission Tomography , Prefrontal Cortex/drug effects , Young AdultABSTRACT
OBJECTIVE: Chronic alcohol dependence has been associated with disturbed behavior, cerebral atrophy and a low plasma concentration of docosahexaenoic acid (DHA, 22â¶6n-3), particularly if liver disease is present. In animal models, excessive alcohol consumption is reported to reduce brain DHA concentration, suggesting disturbed brain DHA metabolism. We hypothesized that brain DHA metabolism also is abnormal in chronic alcoholics. METHODS: We compared 15 non-smoking chronic alcoholics, studied within 7 days of their last drink, with 22 non-smoking healthy controls. Using published neuroimaging methods with positron emission tomography (PET), we measured regional coefficients (K*) and rates (J(in)) of DHA incorporation from plasma into the brain of each group using [1-(11)C]DHA, and regional cerebral blood flow (rCBF) using [(15)O]water. Data were partial volume error corrected for brain atrophy. Plasma unesterified DHA concentration also was quantified. RESULTS: Mean K* for DHA was significantly and widely elevated by 10-20%, and rCBF was elevated by 7%-34%, in alcoholics compared with controls. Unesterified plasma DHA did not differ significantly between groups nor did whole brain J(in), the product of K* and unesterified plasma DHA concentration. DISCUSSION: Significantly higher values of K* for DHA in alcoholics indicate increased brain avidity for DHA, thus a brain DHA metabolic deficit vis-à-vis plasma DHA availability. Higher rCBF in alcoholics suggests increased energy consumption. These changes may reflect a hypermetabolic state related to early alcohol withdrawal, or a general brain metabolic change in chronic alcoholics.
