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Positron emission tomography imaging of the serotonin transporter and 5-HT(1A) receptor in alcohol dependence.

ABSTRACT: Rodent models as well as studies in humans have suggested alterations in serotonin (5-HT) innervation and transmission in early-onset genetically determined or type II alcoholism. This study examines two indices of serotonergic transmission, 5-HT transporter levels and 5-HT(1A) availability, in vivo, in type II alcoholism. This is the first report of combined tracers for pre- and postsynaptic serotonergic transmission in the same alcoholic subjects and the first study of 5-HT(1A) receptors in alcoholism.Fourteen alcohol-dependent subjects were scanned (11 with both tracers, 1 with [(11)C]DASB only, and two with [(11)C]WAY100635 only). Twelve healthy control subjects (HC) subjects were scanned with [(11)C]DASB, and another 13 were scanned with [(11)C]WAY100635. Binding potential (BP(p), mL/cm(3)) and the specific to nonspecific partition coefficient (BP(ND), unitless) were derived for both tracers using a two-tissue compartment model and compared with control subjects across different brain regions. Relationships to severity of alcoholism were assessed.No significant differences were observed in regional BP(p) or BP(ND) between patients and control subjects in any of the regions examined. No significant relationships were observed between regional 5-HT transporter availability, 5-HT(1A) availability, and disease severity, with the exception of a significant negative correlation between 5-HT transporters and years of dependence in amygdala and insula.This study did not find alterations in measures of 5-HT(1A) or 5-HT transporter levels in patients with type II alcoholism.

SUBMITTER: Martinez D

PROVIDER: S-EPMC2621104 | biostudies-literature | 2009 Jan

REPOSITORIES: biostudies-literature

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Positron emission tomography imaging of the serotonin transporter and 5-HT(1A) receptor in alcohol dependence.

Martinez Diana D Slifstein Mark M Gil Roberto R Hwang Dah-Ren DR Huang Yiyun Y Perez Audrey A Frankle W Gordon WG Laruelle Marc M Krystal John J Abi-Dargham Anissa A

Biological psychiatry 20081029 2

<h4>Background</h4>Rodent models as well as studies in humans have suggested alterations in serotonin (5-HT) innervation and transmission in early-onset genetically determined or type II alcoholism. This study examines two indices of serotonergic transmission, 5-HT transporter levels and 5-HT(1A) availability, in vivo, in type II alcoholism. This is the first report of combined tracers for pre- and postsynaptic serotonergic transmission in the same alcoholic subjects and the first study of 5-HT( ...[more]

PMID: 18962444

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Project description:Animal data indicate that the recreational drug ecstasy (3,4-methylenedioxymethamphetamine) can damage brain serotonin neurons. However, human neuroimaging measurements of serotonin transporter binding, a serotonin neuron marker, remain contradictory, especially regarding brain areas affected; and the possibility that structural brain differences might account for serotonin transporter binding changes has not been explored. We measured brain serotonin transporter binding using [(11)C] N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine in 50 control subjects and in 49 chronic (mean 4 years) ecstasy users (typically one to two tablets bi-monthly) withdrawn from the drug (mean 45 days). A magnetic resonance image for positron emission tomography image co-registration and structural analyses was acquired. Hair toxicology confirmed group allocation but also indicated use of other psychoactive drugs in most users. Serotonin transporter binding in ecstasy users was significantly decreased throughout all cerebral cortices (range -19 to -46%) and hippocampus (-21%) and related to the extent of drug use (years, maximum dose), but was normal in basal ganglia and midbrain. Substantial overlap was observed between control and user values except for insular cortex, in which 51% of ecstasy user values fell below the lower limit of the control range. Voxel-based analyses confirmed a caudorostral gradient of cortical serotonin transporter binding loss with occipital cortex most severely affected. Magnetic resonance image measurement revealed no overall regional volume differences between groups; however, a slight left-hemispheric biased cortical thinning was detected in methamphetamine-using ecstasy users. The serotonin transporter binding loss was not related to structural changes or partial volume effect, use of other stimulant drugs, blood testosterone or oestradiol levels, major serotonin transporter gene promoter polymorphisms, gender, psychiatric status, or self-reported hyperthermia or tolerance. The ecstasy group, although 'grossly behaviourally normal', reported subnormal mood and demonstrated generally modest deficits on some tests of attention, executive function and memory, with the latter associated with serotonin transporter decrease. Our findings suggest that the 'typical'/low dose (one to two tablets/session) chronic ecstasy-polydrug user might display a highly selective mild to marked loss of serotonin transporter in cerebral cortex/hippocampus in the range of that observed in Parkinson's disease, which is not gender-specific or completely accounted for by structural brain changes, recent use of other drugs (as assessed by hair analyses) or other potential confounds that we could address. The striking sparing of serotonin transporter-rich striatum (although possibly affected in 'heavier' users) suggests that serotonergic neurons innervating cerebral cortex are more susceptible, for unknown reasons, to ecstasy than those innervating subcortical regions and that behavioural problems in some ecstasy users during abstinence might be related to serotonin transporter changes limited to cortical regions.

Project description:IntroductionA sufficient dietary intake of the vitamin niacin is essential for normal cellular function. Niacin is transported into the cells by the monocarboxylate transporters: sodium-dependent monocarboxylate transporter (SMCT1 and SMCT2) and monocarboxylate transporter (MCT1). Despite the importance of niacin in biological systems, surprisingly, its in vivo biodistribution and trafficking in living organisms has not been reported. The availability of niacin radiolabelled with the short-lived positron emitting radionuclide carbon-11 ([11C]niacin) would enable the quantitative in vivo study of this endogenous micronutrient trafficking using in vivo PET molecular imaging.Methods[11C]Niacin was synthesised via a simple one-step, one-pot reaction in a fully automated system using cyclotron-produced carbon dioxide ([11C]CO2) and 3-pyridineboronic acid ester via a copper-mediated reaction. [11C]Niacin was administered intravenously in healthy anaesthetised mice placed in a high-resolution nanoScan PET/CT scanner. To further characterize in vivo [11C]niacin distribution in vivo, mice were challenged with either niacin or AZD3965, a potent and selective MCT1 inhibitor. To examine niacin gastrointestinal absorption and body distribution in vivo, no-carrier-added (NCA) and carrier-added (CA) [11C]niacin formulations were administered orally.ResultsTotal synthesis time including HPLC purification was 25 ± 1 min from end of [11C]CO2 delivery. [11C]Niacin was obtained with a decay corrected radiochemical yield of 17 ± 2%. We report a rapid radioactivity accumulation in the kidney, heart, eyes and liver of intravenously administered [11C]niacin which is consistent with the known in vivo SMCTs and MCT1 transporter tissue expression. Pre-administration of non-radioactive niacin decreased kidney-, heart-, ocular- and liver-uptake and increased urinary excretion of [11C]niacin. Pre-administration of AZD3965 selectively decreased [11C]niacin uptake in MCT1-expressing organs such as heart and retina. Following oral administration of NCA [11C]niacin, a high level of radioactivity accumulated in the intestines. CA abolished the intestinal accumulation of [11C]niacin resulting in a preferential distribution to all tissues expressing niacin transporters and the excretory organs.ConclusionsHere, we describe the efficient preparation of [11C]niacin as PET imaging agent for probing the trafficking of nutrient demand in healthy rodents by intravenous and oral administration, providing a translatable technique to enable the future exploration of niacin trafficking in humans and to assess its application as a research tool for metabolic disorders (dyslipidaemia) and cancer.

Dataset Information

Positron emission tomography imaging of the serotonin transporter and 5-HT(1A) receptor in alcohol dependence.

Publications

Positron emission tomography imaging of the serotonin transporter and 5-HT(1A) receptor in alcohol dependence.

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