title: PET imaging of dopamine transporter and drug craving during methadone maintenance treatment and after prolonged abstinence in heroin users. Dopamine transporter and D2-receptor density in late-onset alcoholism Opiate-Induced Dopamine Release Is Modulated by Severity of Alcohol Dependence: An [18F]Fallypride Positron Emission Tomography Study Deficits in Dopamine D2 Receptors and Presynaptic Dopamine in Heroin Dependence: Commonalities and Differences with Other Types of Addiction Dopamine transporter availability in heroin-dependent subjects and controls: longitudinal changes during abstinence and the effects of Jitai tablets treatment Longitudinal changes of dopamine transporters in heroin users during abstinence Effects of alcohol detoxification on dopamine D2 receptors in alcoholics: a preliminary study
abstract: It has been documented that methadone maintenance treatment is effective in reducing drug craving and relevant risk behaviors in heroin users . However , it is not understood whether methadone maintenance treatment impairs the dopamine transporter in the striatum . To establish whether chronic opiate use might impair brain dopamine neurons in humans , we assessed dopamine transporter ( DAT ) uptake function in the striatum ( cau date and putamen ) , and analyzed the correlation between DAT in the striatum and heroin craving and subjective anxiety in former heroin users with prolonged abstinence and in patients receiving methadone maintenance treatment .  Binding of [(11)C]-2beta-carbomethoxy-3beta-aryltropane ( [ (11)C ] CFT ) as a brain dopamine transporter lig and was measured with positron emission tomography ( PET ) in eleven former heroin users with prolonged abstinence , ten patients receiving methadone maintenance treatment and ten healthy control subjects .  Heroin craving and subjective anxiety in prolonged abstinence and methadone maintenance treatment groups were assessed and the correlations between DAT of striatum and heroin craving or subjective anxiety were determined . In comparison with healthy control subjects , methadone maintenance treatment subjects had lower DAT uptake function in the bilateral cau date and putamen and prolonged abstinence subjects showed significantly lower DAT uptake function in the bilateral cau date . Moreover , in comparison to the prolonged abstinence subjects , the methadone maintenance treatment subjects showed significant decreases of DAT uptake in the bilateral putamen . DAT uptake function in bilateral striatum was not associated with heroin craving in prolonged abstinence or in methadone maintenance treatment subjects ; however , DAT uptake function in the bilateral cau date was significantly correlated with subjective anxiety in methadone maintenance treatment subjects . Our findings suggest that chronic opioid use induces long-lasting striatum dopamine neuron impairment , and prolonged withdrawal from opioids can benefit the recovery of impaired dopamine neurons in the brain Abstract Rationale : Late onset type 1 alcoholism has been suggested to be associated with an underlying dopaminergic defect . Therefore , it is relevant to study both postsynaptic D2-receptor and presynaptic dopamine transporter ( DAT ) densities among alcoholics . Objective : We investigated DAT densities , along with striatal and extrastriatal dopamine D2-receptor densities , in nine non-violent late-onset male alcoholics , who had no major mental disorder nor antisocial personality disorder ( ASPD ) , and nine healthy controls . Methods : [123I]PE2I and [123I]epidepride were used in SPECT imaging . Results : DAT occupancy ratios ( striatum/cerebellum ) were significantly lower among alcoholics than in controls . Extrastriatal D2-receptor occupancy ratios ( temporal pole/cerebellum ) were not significantly different between the groups . Conclusions : Striatal presynaptic DAT densities are decreased among type 1 alcoholics , and this finding is not associated with recent alcohol abuse BACKGROUND Pre clinical data implicate the reinforcing effects of alcohol to be mediated by interaction between the opioid and dopamine systems of the brain . Specifically , alcohol-induced release of β-endorphins stimulates μ-opioid receptors ( MORs ) , which is believed to cause dopamine release in the brain reward system . Individual differences in opioid or dopamine neurotransmission have been suggested to be responsible for enhanced liability to abuse alcohol . In the present study , a single dose of the MOR agonist remifentanil was administered in detoxified alcohol-dependent patients and healthy control subjects to mimic the β-endorphin-releasing properties of ethanol and to assess the effects of direct MOR stimulation on dopamine release in the mesolimbic reward system . METHODS Availability of D(2/3 ) receptors was assessed before and after single-dose administration of the MOR agonist remifentanil in 11 detoxified alcohol-dependent patients and 11 healthy control subjects with positron emission tomography with the radiotracer [(18)F]fallypride . Severity of dependence as assessed with the Alcohol Use Disorders Identification Test was compared with remifentanil-induced percentage change in [(18)F]fallypride binding ( Δ%BP(ND ) ) . RESULTS The [(18)F]fallypride binding potentials ( BP(ND)s ) were significantly reduced in the ventral striatum , dorsal putamen , and amygdala after remifentanil application in both patients and control subjects . In the patient group , ventral striatum Δ%BP(ND ) was correlated with the Alcohol Use Disorders Identification Test score . CONCLUSIONS The data provide evidence for a MOR-mediated interaction between the opioid and the dopamine system , supporting the assumption that one way by which alcohol unfolds its rewarding effects is via a MOR-(γ-aminobutyric acid)-dopamine pathway . No difference in dopamine release was found between patients and control subjects , but evidence for a patient-specific association between sensitivity to MOR stimulation and severity of alcohol dependence was found BACKGROUND Positron emission tomography ( PET ) imaging studies have shown that addiction to a number of substances of abuse is associated with a decrease in dopamine D(2/3 ) receptor binding and decreased presynaptic dopamine release in the striatum . Some studies have also shown that these reductions are associated with the severity of addiction . For example , in cocaine dependence , low dopamine release is associated with the choice to self-administer cocaine . The goal of the present study was to investigate these parameters of striatal dopamine transmission in heroin dependence and their association with drug seeking behavior . METHODS Heroin-dependent and healthy control subjects were scanned with [(11)C]raclopride before and after stimulant administration ( methylpheni date ) to measure striatal D(2/3 ) receptor binding and presynaptic dopamine release . After the PET scans , the heroin-dependent subjects performed heroin self-administration sessions . RESULTS Both striatal D(2/3 ) receptor binding and dopamine release were reduced in the heroin-dependent subjects compared with healthy control subjects . However , neither PET measure of dopamine transmission predicted the choice to self-administer heroin . CONCLUSIONS These findings show that heroin addiction , like addiction to other drugs of abuse , is associated with low D(2/3 ) receptor binding and low presynaptic dopamine . However , neither of these outcome measures was associated with the choice to self-administer heroin Rationale Previous imaging studies have indicated that the levels of the dopamine transporter ( DAT ) are reduced in the brains of heroin users . However , whether these changes can be reversed by abstinence and /or treatment remains unclear . Objectives This study aims to investigate DAT availability in heroin users and changes in DAT availability after abstinence and treatment with the Jitai tablets , a traditional Chinese medicinal product that is approved for the treatment of opioid addiction . Methods Single-photon emission computed tomography ( SPECT ) with [ 99mTc ] TRODAT-1 was performed on heroin-dependent patients ( n = 64 ) and healthy controls ( n = 15 ) . The patients were r and omly assigned to treatment with either placebo or the Jitai . All patients underwent SPECT imaging both at baseline and after 6 months of treatment . DAT availability was assessed in the cau date and putamen . Depression and anxiety were evaluated at baseline . Results DAT availability remained at low levels during a 6-month period in the placebo-treated group but was increased ( 14–17 % ) in the Jitai-treated group . The ratio of DAT availability at month 6 to that at baseline in the Jitai-treated group was significantly higher than that in the placebo-treated group in both the bilateral cau date and putamen . DAT uptake in the striatum was significantly correlated with daily heroin dose , years of heroin use , and depression . Conclusions These findings suggest that chronic heroin use induces long-lasting striatal DAT reductions . DAT availability remained unchanged during a 6-month period of abstinence . Treatment with Jitai appears to be effective at increasing striatal DAT availability Rationale Chronic exposure to heroin results in decreased dopamine transporter levels . Jitai tablets , a traditional Chinese medicine , have been effective at increasing striatal dopamine transporter availability after 6 months of treatment . However , it remains unknown how long the heroin-induced impairment persists and whether dopamine transporter can be normalized following long-term abstinence or treatment . Objectives This study was to evaluate the time course of dopamine transporter changes in heroin users undergoing long-term abstinence and treatment with Jitai tablets for 1 year . Methods Single-photon emission computed tomography using [99mTc]TRODAT-1 was performed on 64 heroin users and 20 healthy subjects to assess striatal dopamine transporter availability at baseline , 3 , 6 , and 12 months . Heroin users were r and omly assigned to treatment with either placebo or Jitai tablets  . Depression and anxiety scores were measured before each imaging session . Results Compared with healthy controls , significant reduction in dopamine transporter availability was found in heroin users at baseline in both the right ( by ∼31.6 % ) and left striatum ( by ∼33.2 % ) . At 6 months , dopamine transporter availability was significantly higher in Jitai tablet-treated group than placebo group in the bilateral striatum ( p < 0.01 ) . At 12 months , dopamine transporter levels in both groups were upregulated substantially from baseline but still not recovered to normal levels in the left striatum ( p < 0.05 ) . Depression and anxiety scores significantly decreased at 3 , 6 , and 12 months ( p < 0.05 ) . Conclusions Our results confirmed that heroin abuse induces pronounced , long-term reduction in dopamine transporter . Treatment with Jitai tablets appears to stimulate recovery Imaging studies in patients with Type II alcohol dependence have revealed significant reductions in dopamine ( DA ) D2 receptor availability . Here we assessed the effects of alcohol detoxification in DA D2 receptors in alcoholic subjects . We evaluated 14 patients with Type II alcohol dependence tested within 6 weeks of detoxification and then re-tested 1 - 4 months later while alcohol free . The comparison group comprised 11 healthy controls .  PET was used with [11C]raclopride to measure DA D2 receptors . Eight alcoholics and all control subjects were tested with a CTI 931 PET scanner and six alcoholics with a  Siemens HR+ PET scanner .  Data were analyzed separately for the studies done in the different scanners . Comparisons between early and late alcohol detoxification showed no significant changes in DA D2 receptor availability ( B(max)/K(d ) ) for the studies done with the CTI and the HR+ scanners . Comparison with controls showed lower DA D2 receptor levels in cau date and putamen in alcoholics tested during early detoxification and in cau date during late detoxification . These studies replicate previous findings of lower striatal DA D2 receptors in alcoholics than in controls and absence of significant recovery during alcohol detoxification . These findings suggest that low DA D2 receptor availability in alcoholics is not due to alcohol withdrawal and may reflect a predisposing factor
target: Our analysis indicated that changes of dopamine receptors and transporters are moderated by the duration of abstinence .
  Our analysis provides strong evidence for a central role of the striatal dopamine system in use of alcohol or opioids .
background: Use of alcohol , cannabis and opioids is highly prevalent and is associated with global disease burden and high economic costs .
  The exact pathophysiology of abuse or addiction associated with these sedative substances is not completely understood , but previous research implicates the important role of the striatal dopamine system in the addiction process .
  Multiple studies investigated changes in the striatal dopamine systems of users of sedative substances , but currently these results are very heterogeneous .
  Therefore , we conducted a meta- analysis of in vivo neuroimaging studies investigating dopaminergic alterations in the striatum of users of alcohol , opioids or cannabis .