Daniel S. Albrecht

Striatal dopamine transporter availability in unmedicated bipolar disorder

OBJECTIVES Dopamine transmission abnormalities have been implicated in the etiology of bipolar disorder (BPD). However, there is a paucity of receptor imaging studies in BPD, and little information is available about the dopamine system in BPD. Reuptake of synaptic dopamine by the dopamine transporter (DAT) is the principal mechanism regulating dopamine neurotransmission, and is often used as a marker for presynaptic dopamine function. This positron emission tomography (PET) study investigated whether DAT availability differed between BPD and healthy control subjects. METHODS A total of 11 unmedicated BPD patients in either the euthymic or depressed phase and 13 closely matched healthy subjects underwent PET imaging with the DAT-selective radiotracer [(11) C]CFT and a structural magnetic resonance imaging (MRI) scan. Striatal binding potential (BP(ND) ) was estimated using the multilinear reference tissue model. Region of interest and analyses were conducted to test for differences in [(11) C]CFT BP(ND) between groups. RESULTS Unmedicated BPD subjects had significantly lower DAT availability relative to healthy controls in bilateral dorsal caudate. CONCLUSIONS The results of this study support the hypothesis that there are abnormalities in the dopaminergic system in BPD, and suggest that DAT availability may be related to the neuropathology of BPD. Future studies are needed to determine if DAT availability cycles with disease phase.

Beer Flavor Provokes Striatal Dopamine Release in Male Drinkers: Mediation by Family History of Alcoholism

Striatal dopamine (DA) is increased by virtually all drugs of abuse, including alcohol. However, drug-associated cues are also known to provoke striatal DA transmission- a phenomenon linked to the motivated behaviors associated with addiction. To our knowledge, no one has tested if alcohol’s classically conditioned flavor cues, in the absence of a significant pharmacologic effect, are capable of eliciting striatal DA release in humans. Employing positron emission tomography (PET), we hypothesized that beer’s flavor alone can reduce the binding potential (BP) of [11C]raclopride (RAC; a reflection of striatal DA release) in the ventral striatum, relative to an appetitive flavor control. Forty-nine men, ranging from social to heavy drinking, mean age 25, with a varied family history of alcoholism underwent two [11C]RAC PET scans: one while tasting beer, and one while tasting Gatorade. Relative to the control flavor of Gatorade, beer flavor significantly increased self-reported desire to drink, and reduced [11C]RAC BP, indicating that the alcohol-associated flavor cues induced DA release. BP reductions were strongest in subjects with first-degree alcoholic relatives. These results demonstrate that alcohol-conditioned flavor cues can provoke ventral striatal DA release, absent significant pharmacologic effects, and that the response is strongest in subjects with a greater genetic risk for alcoholism. Striatal DA responses to salient alcohol cues may thus be an inherited risk factor for alcoholism.

Striatal D2/D3 receptor availability is inversely correlated with cannabis consumption in chronic marijuana users

BACKGROUND Although the incidence of cannabis abuse/dependence in Americans is rising, the neurobiology of cannabis addiction is not well understood. Imaging studies have demonstrated deficits in striatal D(2)/D(3) receptor availability in several substance-dependent populations. However, this has not been studied in currently using chronic cannabis users. OBJECTIVE The purpose of this study was to compare striatal D(2)/D(3) receptor availability between currently using chronic cannabis users and healthy controls. METHODS Eighteen right-handed males age 18-34 were studied. Ten subjects were chronic cannabis users; eight were demographically matched controls. Subjects underwent a [(11)C]raclopride (RAC) PET scan. Striatal RAC binding potential (BP(ND)) was calculated on a voxel-wise basis. Prior to scanning, urine samples were obtained from cannabis users for quantification of urine Δ-9-tetrahydrocannabinol (THC) and THC metabolites (11-nor-Δ-9-THC-9-carboxylic acid; THC-COOH and 11-hydroxy-THC;OH-THC). RESULTS There were no differences in D(2)/D(3) receptor availability between cannabis users and controls. Voxel-wise analyses revealed that RAC BP(ND) values were negatively associated with both urine levels of cannabis metabolites and self-report of recent cannabis consumption. CONCLUSIONS In this sample, current cannabis use was not associated with deficits in striatal D(2)/D(3) receptor availability. There was an inverse relationship between chronic cannabis use and striatal RAC BP(ND). Additional studies are needed to identify the neurochemical consequences of chronic cannabis use on the dopamine system.

Cortical dopamine release during a behavioral response inhibition task.

Dopamine (DA) dysregulation within fronto‐striatal circuitry may underlie impulsivity in alcohol and other substance use disorders. To date, no one has directly demonstrated DA release during a task requiring the control of impulsive behavior. The current study was conducted to determine whether a response inhibition task (stop signal task; SST) would elicit detectable extrastriatal DA release in healthy controls. We hypothesized that DA release would be detected in regions previously implicated in different aspects of inhibitory control. [18F]Fallypride (FAL) PET imaging was performed in nine healthy males (24.6 ± 4.1 y.o.) to assess changes in cortical DA during a SST relative to a baseline “Go” task. On separate days, subjects received one FAL scan during the SST, and one FAL scan during a “Go” control; task‐order was counter‐balanced across subjects. Parametric BPND images were generated and analyzed with SPM8. Voxel‐wise analysis indicated significant SST‐induced DA release in several cortical regions involved in inhibitory control, including the insula, cingulate cortex, orbitofrontal cortex, precuneus, and supplementary motor area. There was a significant positive correlation between stop signal reaction time and DA release in the left orbitofrontal cortex, right middle frontal gyrus, and right precentral gyrus. These data support the feasibility of using FAL PET to study DA release during response inhibition, enabling investigation of relationships between DA function and impulsive behavior. Synapse 68:266–274, 2014.

Test–retest variability of [11C]raclopride-binding potential in nontreatment-seeking alcoholics

Knowledge of the reproducibility of striatal [11C]raclopride (RAC) binding is important for studies that use RAC PET paradigms to estimate changes in striatal dopamine (DA) during pharmacological and cognitive challenges. To our knowledge, no baseline test–retest data exist for nontreatment‐seeking alcoholics (NTS). We determined the test–retest reproducibility of baseline RAC binding potential (BPND) in 12 male NTS subjects. Subjects were scanned twice with single‐bolus RAC PET on separate days. Striatal RAC BP (BPND) for left and right dorsal caudate, dorsal putamen, and ventral striatum was estimated using the Multilinear Reference Tissue Method (MRTM) and Logan Graphical Analysis (LGA) with a reference region. Test–retest variability (TRV), % change in BPND between scan days, and the intraclass correlation coefficient (ICC) were used as metrics of reproducibility. For MRTM, TRV for striatal RAC binding in NTS subjects was ±6.5% and ±7.1% for LGA. Average striatal ICCs were 0.94 for both methods (P < 0.0001). Striatal BPND values were similar to those reported previously for detoxified alcoholics. The results demonstrate that baseline striatal RAC binding is highly reproducible in NTS subjects, with a low variance similar to that reported for healthy control subjects. Synapse, 2011.

Monetary discounting and ventral striatal dopamine receptor availability in nontreatment-seeking alcoholics and social drinkers

RationaleDopamine (DA) in the ventral striatum (VST) has long been implicated in addiction pathologies, yet its role in temporal decision-making is not well-understood.ObjectivesTo determine if VST DA D2 receptor availability corresponds with greater impulsive choice in both nontreatment-seeking alcoholics (NTS) and social drinkers (SD).MethodsNTS subjects (n = 10) and SD (n = 13) received PET scans at baseline with the D2/D3 radioligand [11C]raclopride (RAC). Outside the scanner, subjects performed a delay discounting procedure with monetary rewards. RAC binding potential (BPND) was estimated voxelwise, and correlations were performed to test for relationships between VST BPND and delay discounting performance. Self-reported impulsivity was also tested for correlations with BPND.ResultsAcross all subjects, greater impulsive choice for

Effects of smoking on D2/D3 striatal receptor availability in alcoholics and social drinkers

20 correlated with lower BPND in the right VST. NTS showed greater impulsive choice than SD and were more impulsive by self-report. Across all subjects, the capacity of larger rewards to reduce impulsive choice (the magnitude effect) correlated negatively (p = 0.028) with problematic alcohol use (AUDIT) scores. Self-reported impulsivity did not correlate with BPND in VST.ConclusionsPreference for immediate reinforcement may reflect greater endogenous striatal DA or lower D2 number, or both. Alcoholic status did not mediate significant effects on VST BPND, suggesting minimal effects from alcohol exposure. The apparent lack of BPND correlation with self-reported impulsivity highlights the need for objective behavioral assays in the study of the neurochemical substrates of behavior. Finally, our results suggest that the magnitude effect may be more sensitive to alcohol-induced problems than single discounting measures.

Reliability of striatal [11C]raclopride binding in smokers wearing transdermal nicotine patches

Studies have reported lower striatal D2/D3 receptor availability in both alcoholics and cigarette smokers relative to healthy controls. These substances are commonly co-abused, yet the relationship between comorbid alcohol/tobacco abuse and striatal D2/D3 receptor availability has not been examined. We sought to determine the degree to which dual abuse of alcohol and tobacco is associated with lower D2/D3 receptor availability. Eighty-one subjects (34 nontreatment-seeking alcoholic smokers [NTS-S], 21 social-drinking smokers [SD-S], and 26 social-drinking non-smokers [SD-NS]) received baseline [11C]raclopride scans. D2/D3 binding potential (BPND ≡ Bavail/KD) was estimated for ten anatomically defined striatal regions of interest (ROIs). Significant group effects were detected in bilateral pre-commissural dorsal putamen, bilateral pre-commissural dorsal caudate; and bilateral post-commissural dorsal putamen. Post-hoc testing revealed that, regardless of drinking status, smokers had lower D2/D3 receptor availability than non-smoking controls. Chronic tobacco smokers have lower striatal D2/D3 receptor availability than non-smokers, independent of alcohol use. Additional studies are needed to identify the mechanisms by which chronic tobacco smoking is associated with striatal dopamine receptor availability.

Differences in IV alcohol-induced dopamine release in the ventral striatum of social drinkers and nontreatment-seeking alcoholics

PurposeIn studies where [11C]raclopride (RAC) positron emission tomography (PET) is used to assess changes in striatal dopamine, it is important to control for cognitive states, such as drug craving, that could alter dopamine levels. In cigarette smokers, transdermal nicotine patches (TNP) can control nicotine craving, but the effects of nicotine patches on RAC binding are unknown. Thus, we sought to determine the test-retest reliability of RAC binding in the presence of nicotine patches.MethodsEleven male smokers were scanned twice with RAC on separate days while wearing TNP.ResultsAcross the striatum, test-retest variability was 7.63 ± 5.88; percent change in binding potential was 1.11 ± 9.83; and the intraclass correlation coefficient was 0.91 (p < 0.0001).ConclusionBaseline RAC binding is highly reproducible in smokers wearing nicotine patches. This suggests that TNP are an acceptable method for controlling cigarette craving during studies that utilize RAC to examine changes in dopamine.