Brain mGlu5 Is Linked to Cognition and Cigarette Smoking but Does Not Differ From Control in Early Abstinence From Chronic Methamphetamine Use.

BACKGROUND: The group-I metabotropic glutamate receptor subtype 5 (mGlu5) has been implicated in methamphetamine exposure in animals and in human cognition. Because people with methamphetamine use disorder (MUD) exhibit cognitive deficits, we evaluated mGlu5 in people with MUD and controls and tested its association with cognitive performance. METHODS: Positron emission tomography was performed to measure the total VT of [18F]FPEB, a radiotracer for mGlu5, in brains of participants with MUD (abstinent from methamphetamine for at least 2 weeks, N = 14) and a control group (N = 14). Drug use history questionnaires and tests of verbal learning, spatial working memory, and executive function were administered. Associations of VT with methamphetamine use, tobacco use, and cognitive performance were tested. RESULTS: MUD participants did not differ from controls in global or regional VT, and measures of methamphetamine use were not correlated with VT. VT was significantly higher globally in nonsmoking vs smoking participants (main effect, P = .0041). MUD participants showed nonsignificant weakness on the Rey Auditory Verbal Learning Task and the Stroop test vs controls (P = .08 and P = .13, respectively) with moderate to large effect sizes, and significantly underperformed controls on the Spatial Capacity Delayed Response Test (P = .015). Across groups, Rey Auditory Verbal Learning Task performance correlated with VT in the dorsolateral prefrontal cortex and superior frontal gyrus. CONCLUSION: Abstinent MUD patients show no evidence of mGlu5 downregulation in brain, but association of VT in dorsolateral prefrontal cortex with verbal learning suggests that medications that target mGlu5 may improve cognitive performance.

Up-regulation of nicotinic acetylcholine receptors in menthol cigarette smokers.

One-third of smokers primarily use menthol cigarettes and usage of these cigarettes leads to elevated serum nicotine levels and more difficulty quitting in standard treatment programmes. Previous brain imaging studies demonstrate that smoking (without regard to cigarette type) leads to up-regulation of ß(2)*-containing nicotinic acetylcholine receptors (nAChRs). We sought to determine if menthol cigarette usage results in greater nAChR up-regulation than non-menthol cigarette usage. Altogether, 114 participants (22 menthol cigarette smokers, 41 non-menthol cigarette smokers and 51 non-smokers) underwent positron emission tomography scanning using the α(4)ß(2)* nAChR radioligand 2-[(18)F]fluoro-A-85380 (2-FA). In comparing menthol to non-menthol cigarette smokers, an overall test of 2-FA total volume of distribution values revealed a significant between-group difference, resulting from menthol smokers having 9-28% higher α(4)ß(2)* nAChR densities than non-menthol smokers across regions. In comparing the entire group of smokers to non-smokers, an overall test revealed a significant between-group difference, resulting from smokers having higher α(4)ß(2)* nAChR levels in all regions studied (36-42%) other than thalamus (3%). Study results demonstrate that menthol smokers have greater up-regulation of nAChRs than non-menthol smokers. This difference is presumably related to higher nicotine exposure in menthol smokers, although other mechanisms for menthol influencing receptor density are possible. These results provide additional information about the severity of menthol cigarette use and may help explain why these smokers have more trouble quitting in standard treatment programmes.

Sex differences in striatal dopamine D2/D3 receptor availability in smokers and non-smokers.

In previous research, nicotine-dependent men exhibited lower putamen D2/D3 dopamine-receptor availability than non-smokers (Fehr et al. 2008), but parallel assessments were not performed in women. Women and men (19 light smokers, 18 non-smokers) were tested for differences due to sex and smoking in striatal D(2)/D(3) dopamine-receptor availability, using positron emission tomography with [(18)F]fallypride. Receptor availability was determined using a reference region method, in striatal volumes and in whole-brain, voxel-wise analysis. Significant sex × smoking interactions were observed in the caudate nuclei and putamen. Post-hoc t tests showed that male smokers had significantly lower D(2)/D(3) dopamine-receptor availability than female smokers (-17% caudate, -21% putamen) and male non-smokers (-15% caudate, -16% putamen). Female smokers did not differ from non-smokers. Whole-brain analysis demonstrated no statistically significant voxels or clusters. These results suggest that low receptor availability may confer vulnerability to nicotine dependence or that smoking selectively affects D2/D3 receptor down-regulation in men but not women.

Striatal dopamine d2/d3 receptor availability is reduced in methamphetamine dependence and is linked to impulsivity.

While methamphetamine addiction has been associated with both impulsivity and striatal dopamine D(2)/D(3) receptor deficits, human studies have not directly linked the latter two entities. We therefore compared methamphetamine-dependent and healthy control subjects using the Barratt Impulsiveness Scale (version 11, BIS-11) and positron emission tomography with [(18)F]fallypride to measure striatal dopamine D(2)/D(3) receptor availability. The methamphetamine-dependent subjects reported recent use of the drug 3.3 g per week, and a history of using methamphetamine, on average, for 12.5 years. They had higher scores than healthy control subjects on all BIS-11 impulsiveness subscales (p < 0.001). Volume-of-interest analysis found lower striatal D(2)/D(3) receptor availability in methamphetamine-dependent than in healthy control subjects (p < 0.01) and a negative relationship between impulsiveness and striatal D(2)/D(3) receptor availability in the caudate nucleus and nucleus accumbens that reached statistical significance in methamphetamine-dependent subjects. Combining data from both groups, voxelwise analysis indicated that impulsiveness was related to D(2)/D(3) receptor availability in left caudate nucleus and right lateral putamen/claustrum (p < 0.05, determined by threshold-free cluster enhancement). In separate group analyses, correlations involving the head and body of the caudate and the putamen of methamphetamine-dependent subjects and the lateral putamen/claustrum of control subjects were observed at a weaker threshold (p < 0.12 corrected). The findings suggest that low striatal D(2)/D(3) receptor availability may mediate impulsive temperament and thereby influence addiction.

Smoking-induced change in intrasynaptic dopamine concentration: effect of treatment for Tobacco Dependence.

The aim of this study was to determine whether standard treatments for Tobacco Dependence affect smoking-induced changes in intrasynaptic dopamine (DA) concentration. Forty-three otherwise healthy adult cigarette smokers (10 to 40 cigarettes per day) were treated with either practical group counseling (PGC) psychotherapy (n=14), bupropion HCl (n=14), or matching pill placebo (n=15) (random assignment) for 8 weeks. Before and after treatment, each subject underwent a bolus-plus-continuous-infusion (11)C-raclopride positron emission tomography (PET) scanning session, during which he or she smoked a regular cigarette. The PET scanning outcome measure of interest was percent change in smoking-induced (11)C-raclopride binding potential (BP(ND)) in the ventral caudate/nucleus accumbens (VCD/NAc), as an indirect measure of DA release. Although the entire study sample had a smaller mean smoking-induced reduction in VCD/NAc BP(ND) after treatment (compared to before treatment), this change was highly correlated with smaller total cigarette puff volumes (and not other treatment variables). These data indicate that smoking-induced DA release is dose-dependent, and is not significantly affected by reductions in daily smoking levels or treatment type.

No significant elevation of translocator protein binding in the brains of recently abstinent methamphetamine users.

BACKGROUND: Radioligands for the translocator protein (TSPO) 18 kDa have been used with positron emission tomography (PET) to assess neuroinflammation and microglial activation in psychiatric disorders. One study using this approach showed substantial TSPO elevation throughout the brain in chronic methamphetamine users following long-term abstinence (0.5-4 years), but clients typically present for treatment earlier in abstinence. METHODS: We used PET with [11C]DAA1106 to compare standardized uptake values (SUVs) as an index of TSPO binding in the brains of methamphetamine-dependent participants who were abstinent for < 6 months (n = 11) and healthy controls (n = 12). We also assayed other typical correlates of Methamphetamine Dependence (e.g., striatal D2-type dopamine receptor deficits, depressed mood, anxiety and impaired emotion regulation). RESULTS: Methamphetamine users exhibited depression (p < 0.0001), anxiety (p = 0.002), difficulties in emotional regulation (p = 0.01), and lower striatal dopamine D2-type receptor availability vs. controls (p = 0.02). SUVs for [11C]DAA1106 were larger in all brain regions of methamphetamine-dependent participants vs. controls, but the effect size was small to medium and not statistically significant. CONCLUSIONS: The discrepancy between the lack of significant difference in TSPO binding in early-abstinent methamphetamine users vs. controls in this study and a previous report of elevated binding in longer-abstinent methamphetamine users may reflect methodological differences or limitations of TSPO binding as an index of neuroinflammation. It also seems possible that gliosis increases over time during the first 6 months of abstinence; longitudinal studies could clarify this possibility.

Brain nicotinic acetylcholine receptor occupancy: effect of smoking a denicotinized cigarette.

Our group recently reported that smoking a regular cigarette (1.2-1.4 mg nicotine) resulted in 88% occupancy of brain alpha4beta2* nicotinic acetylcholine receptors (nAChRs). However, this study did not determine whether nicotine inhalation or the many other pharmacological and behavioural factors that occur during smoking resulted in this receptor occupancy. If nicotine is solely responsible for alpha4beta2* nAChR occupancy from smoking, then (as estimated from our previous data) smoking a denicotinized (0.05 mg nicotine) or a low-nicotine (0.6 mg nicotine) cigarette (commonly used for research and clinical purposes) would result in substantial 23% and 78% alpha4beta2* nAChR occupancies, respectively, and a plasma nicotine concentration of 0.87 ng/ml would result in 50% alpha4beta2* nAChR occupancy (EC50). Twenty-four positron emission tomography sessions were performed on tobacco-dependent smokers, using 2-[F-18]fluoro-A-85380 (2-FA), a radiotracer that binds to alpha4beta2* nAChRs. 2-FA displacement was determined from before to 3.1 hours after either: no smoking, smoking a denicotinized cigarette, or smoking a low-nicotine cigarette. Analysis of this PET data revealed that smoking a denicotinized and a low-nicotine cigarette resulted in 26% and 79% alpha4beta2* nAChR occupancies, respectively, across three regions of interest. The EC50 determined from this dataset was 0.75 ng/ml. Given the consistency of findings between our previous study with regular cigarettes and the present study, nicotine inhalation during smoking appears to be solely responsible for alpha4beta2* nAChR occupancy, with other factors (if present at all) having either short-lived or very minor effects. Furthermore, smoking a denicotinized cigarette resulted in substantial nAChR occupancy.

Gene variants of brain dopamine pathways and smoking-induced dopamine release in the ventral caudate/nucleus accumbens.

CONTEXT: Preclinical studies demonstrate that nicotine administration leads to dopamine release in the ventral striatum. However, human studies reveal considerable interindividual variability in the extent of smoking-induced dopamine release. OBJECTIVE: To determine whether common gene variants of the brain dopamine pathway explain this observed phenotypic variability in humans. DESIGN: Blood samples were drawn to determine gene variants of dopamine system components, and positron emission tomography scanning with the radiotracer raclopride labeled with radioactive carbon (11C) was performed to measure smoking-induced dopamine release. SETTING: Academic brain imaging center. PARTICIPANTS: Forty-five tobacco-dependent smokers. INTERVENTIONS: Subjects either smoked a cigarette (n = 35) or did not smoke (n = 10) during positron emission tomography scanning. MAIN OUTCOME MEASURES: Gene variants of dopamine system components (the dopamine transporter variable nucleotide tandem repeat, D2 receptor Taq A1/A2, D4 receptor variable nucleotide tandem repeat, and catechol-O-methyltransferase Val158Met polymorphisms) and change in [11C]raclopride binding potential in the ventral caudate/nucleus accumbens on positron emission tomography scans. RESULTS: For subjects who smoked during scanning, those with at least one 9 allele of the dopamine transporter variable nucleotide tandem repeat, fewer than 7 repeats of the D4 variable nucleotide tandem repeat, and the Val/Val catechol-O-methyltransferase genotype had greater decreases in binding potential (an indirect measure of dopamine release) with smoking than those with the alternate genotypes. An overall decrease in ventral caudate/nucleus accumbens binding potential in those who smoked compared with those who did not smoke was also found but was smaller in magnitude than previously reported. CONCLUSIONS: Smokers with genes associated with low resting dopamine tone have greater smoking-induced (phasic) dopamine release than those with alternate genotypes. These findings suggest that dopamine system genotype variabilities explain a significant proportion of the interindividual variability in smoking-induced dopamine release and indicate that smoking-induced dopamine release has a genetic predisposition.

Cigarette smoking saturates brain alpha 4 beta 2 nicotinic acetylcholine receptors.

CONTEXT: 2-[18F]fluoro-3-(2(S)-azetidinylmethoxy) pyridine (2-F-A-85380, abbreviated as 2-FA) is a recently developed radioligand that allows for visualization of brain alpha 4 beta 2* nicotinic acetylcholine receptors (nAChRs) with positron emission tomography (PET) scanning in humans. OBJECTIVE: To determine the effect of cigarette smoking on alpha 4 beta 2* nAChR occupancy in tobacco-dependent smokers. DESIGN: Fourteen 2-FA PET scanning sessions were performed. During the PET scanning sessions, subjects smoked 1 of 5 amounts (none, 1 puff, 3 puffs, 1 full cigarette, or to satiety [2(1/2) to 3 cigarettes]). SETTING: Academic brain imaging center. PARTICIPANTS: Eleven tobacco-dependent smokers (paid volunteers). Main Outcome Measure Dose-dependent effect of smoking on occupancy of alpha 4 beta 2* nAChRs, as measured with 2-FA and PET in nAChR-rich brain regions. RESULTS: Smoking 0.13 (1 to 2 puffs) of a cigarette resulted in 50% occupancy of alpha 4 beta 2* nAChRs for 3.1 hours after smoking. Smoking a full cigarette (or more) resulted in more than 88% receptor occupancy and was accompanied by a reduction in cigarette craving. A venous plasma nicotine concentration of 0.87 ng/mL (roughly 1/25th of the level achieved in typical daily smokers) was associated with 50% occupancy of alpha 4 beta 2* nAChRs. CONCLUSIONS: Cigarette smoking in amounts used by typical daily smokers leads to nearly complete occupancy of alpha 4 beta 2* nAChRs, indicating that tobacco-dependent smokers maintain alpha 4 beta 2* nAChR saturation throughout the day. Because prolonged binding of nicotine to alpha 4 beta 2* nAChRs is associated with desensitization of these receptors, the extent of receptor occupancy found herein suggests that smoking may lead to withdrawal alleviation by maintaining nAChRs in the desensitized state.

Smoking-induced ventral striatum dopamine release.

OBJECTIVE: Substantial evidence from animal models demonstrates that dopamine release in the ventral striatum underlies the reinforcing properties of nicotine. The authors used [(11)C]raclopride bolus-plus-continuous-infusion positron emission tomography (PET) to determine smoking-induced ventral striatum dopamine release in humans. METHOD: Twenty nicotine-dependent smokers (who smoked > or =15 cigarettes/day) underwent a [(11)C]raclopride bolus-plus-continuous-infusion PET session. During the session, subjects had a 10-minute break outside the PET apparatus during which 10 subjects smoked a cigarette and 10 did not smoke (as a control condition). RESULTS: The group that smoked had greater reductions in [(11)C]raclopride binding potential in ventral striatum regions of interest than the group that did not smoke, particularly in the left ventral caudate/nucleus accumbens and left ventral putamen (range for smoking group=-25.9% to -36.6% reduction). Significant correlations were found between change from before to after the smoking break in craving ratings and change from before to after the break in binding potential for these two regions. CONCLUSIONS: Nicotine-dependent subjects who smoked during a break in PET scanning had greater reductions in [(11)C]raclopride binding potential (an indirect measure of dopamine release) than nicotine-dependent subjects who did not smoke. The magnitude of binding potential changes was comparable to that found in studies that used similar methods to examine the effects of other addictive drugs.

Radiation dosimetry and biodistribution of the translocator protein radiotracer [(11)C]DAA1106 determined with PET/CT in healthy human volunteers.

INTRODUCTION: When microglia become activated (an integral part of neuroinflammation), cellular morphology changes and expression of translocator protein (TSPO) 18 kDa is increased. Over the past several years, [(11)C]DAA1106 has emerged as a reliable radiotracer for labeling TSPO with high affinity during positron emission tomography (PET) scanning. While [(11)C]DAA1106 PET scanning has been used in several research studies, a radiation dosimetry study of this radiotracer in humans has not yet been published. METHODS: Twelve healthy participants underwent full body dynamic [(11)C]DAA1106 PET scanning, with 8 sequential whole body scans (approximately 12 bed positions each), following a single injection. Regions of interest were drawn manually, and time activity curves (TACs) were obtained for 15 organs. OLINDA/EXM 1.1 was used to compute radiation absorbed doses to the target organs, as well as effective dose (ED) and effective dose equivalent (EDE). RESULTS: The ED and EDE were 4.06 ± 0.58 µSv/MBq and 5.89 ± 0.83 µSv/MBq, respectively. The highest absorbed doses were to the heart wall, kidney, liver, pancreas, and spleen. TACs revealed that peak dose rates are during the first scan (at 6 min) for all organs other than the urinary bladder wall, which had its peak dose rate during the fourth scan (at 30 min). CONCLUSIONS: The recently developed radiotracer [(11)C]DAA1106 has its EDE and target-organ absorbed dose such that, for a single administration, its radiation dosimetry is well within the U.S. FDA guidelines for basic research studies in adults. This dose level implies that the dosimetry for multiple [(11)C]DAA1106 scans within a given year also falls within FDA guidelines, and this favorable property makes this radiotracer suitable for examining microglial activation repeatedly over time, which may in the future be useful for longitudinal tracking of disease progression and monitoring of therapy response in conditions marked by neuroinflammation (e.g., head trauma and multiple sclerosis).

Effect of a history of major depressive disorder on smoking-induced dopamine release.

BACKGROUND: Dopamine (DA) system dysfunction is implicated in the pathophysiology of major depressive disorder (MDD). We sought to determine if cigarette smokers with a history of MDD and current mild depressive symptoms have abnormal smoking-induced DA release (measured indirectly as change in (11)C-raclopride binding potential [BP(ND)]). METHODS: Fifty-six cigarette smokers either with (n = 10) or without (n = 46) a history of MDD (MDD+ and MDD-, respectively) underwent bolus-plus-continuous-infusion (11)C-raclopride positron emission tomography, during which they smoked a regular cigarette. Presmoking to postsmoking changes in (11)C-raclopride BP(ND) were compared between groups. Also, correlations were determined between change in BP(ND) and depression, anxiety, and withdrawal rating scale scores for the MDD+ group. RESULTS: The MDD+ group had a significantly greater reduction in (11)C-raclopride BP(ND) (-16.3%) than the MDD- group (-8.4%) (analysis of covariance [ANCOVA], p = .03). Significant negative correlations were found between depression/anxiety and change in (11)C-raclopride BP(ND) (r = -.77, p < .01 and r = -.74, p = .01, respectively). CONCLUSIONS: MDD+ smokers have greater smoking-induced DA release than MDD- smokers, and higher depression/anxiety levels are associated with greater smoking-induced DA release. These findings support the theory that MDD+ smokers have DA system dysfunction, including heightened smoking-induced DA release.

Ventral striatal dopamine release in response to smoking a regular vs a denicotinized cigarette.

Prior studies have demonstrated that both nicotine administration and cigarette smoking lead to dopamine (DA) release in the ventral striatum/nucleus accumbens. In tobacco-dependent individuals, smoking denicotinized cigarettes leads to reduced craving, but less pleasure, than smoking regular cigarettes. Using denicotinized cigarettes and (11)C-raclopride positron emission tomography (PET) scanning, we sought to determine if nicotine is necessary for smoking-induced DA release. Sixty-two tobacco-dependent smokers underwent (11)C-raclopride PET scanning, during which they smoked either a regular or denicotinized cigarette (double-blind). Change in (11)C-raclopride binding potential (BP) in the ventral striatum from before to after smoking was determined as an indirect measure of DA release. Cigarette craving, anxiety, and mood were monitored during scanning. Smoking a regular cigarette resulted in a significantly greater mean reduction in ventral striatal (11)C-raclopride BP than smoking a denicotinized cigarette. Although both groups had reductions in craving and anxiety with smoking, the regular cigarette group had a greater improvement in mood. For the total group, change in BP correlated inversely with change in mood, indicating that greater smoking-induced DA release was associated with more smoking-related mood improvement. Thus, nicotine delivered through cigarette smoking appears to be important for ventral striatal DA release. Study findings also suggest that mood improvement from smoking is specifically related to ventral striatal DA release.