U Busto’s research while affiliated with Centre for Addiction and Mental Health and other places

Positron emission tomography (PET) has convincingly provided in vivo evidence that psychoactive drugs increase dopamine (DA) levels in human brain, a feature thought critical to their reinforcing properties. Some controversy still exists concerning the role of DA in reinforcing smoking behavior and no study has explored whether smoking increases DA concentrations at the D3 receptor, speculated to have a role in nicotine's addictive potential. Here we used PET and [(11)C]-(+)-PHNO ([(11)C]-(+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol), to test the hypothesis that smoking increases DA release (decreases [(11)C]-(+)-PHNO binding) in D2-rich striatum and D3-rich extra-striatal regions and is related to craving, withdrawal and smoking behaviour. Ten participants underwent [(11)C]-(+)-PHNO scans after overnight abstinence and after smoking a cigarette. Motivation to smoke (smoking topography), mood and craving were recorded. Smoking significantly decreased self-reported craving, withdrawal, and [(11)C]-(+)-PHNO binding in D2 and D3-rich areas (-12.0% and -15.3%, respectively). We found that motivation to smoke (puff rate) predicted magnitude of DA release in limbic striatum, and the latter was correlated with decreased craving and withdrawal symptoms. This is the first report suggesting that, in humans, DA release is increased in D3 rich areas in response to smoking. Results also support the preferential involvement of the limbic striatum in motivation to smoke, anticipation of pleasure from cigarettes and relief of withdrawal symptoms. We propose that due to the robust effect of smoking on [(11)C]-(+)-PHNO binding, this radiotracer represents an ideal translational tool to investigate novel therapeutic strategies targeting DA transmission.Neuropsychopharmacology accepted article preview online, 19 August 2013. doi:10.1038/npp.2013.209.

The presentation of drug-associated cues has been shown to elicit craving and dopamine release in the striatum of drug-dependent individuals. Similarly, exposure to tobacco-associated cues induces craving and increases the propensity to relapse in tobacco- dependent smokers. However, whether exposure to tobacco-associated cues elicits dopamine release in the striatum of smokers remains to be investigated. We hypothesized that presentation of smoking-related cues compared to neutral cues would induce craving and elevation of intrasynaptic dopamine levels in subregions of the striatum and that the magnitude of dopamine release would be correlated with subjective levels of craving in briefly abstinent tobacco smokers. Eighteen participants underwent two [(11)C]-(+)-PHNO positron emission tomography (PET) scans after one-hour abstinence period: one during presentation of smoking-associated images and one during presentation of neutral images. Smoking cues significantly increased craving compared to neutral cues on one, but not all, craving measures; however, this increase in craving was not associated with overall significant differences in [(11)C]-(+)-PHNO binding potential (BPND) (an indirect measure of dopamine release) between the two experimental conditions in any of the brain regions of interest sampled. Our findings suggest that presentation of smoking cues does not elicit detectable (by PET) overall increases in dopamine in humans after one-hour nicotine abstinence. Future research should consider studying smoking cue-induced dopamine release at a longer abstinence period, since recent findings suggest the ability of smoking-related cues to induce craving is associated with a longer duration of smoking abstinence.

The association between cigarette smoking and depression has been well documented; however, little research has been done to elucidate the neurobiological substrates of this highly prevalent comorbidity. We used multiple linear regression analysis to evaluate the relationship between depression severity as assessed by the Hamilton Depression Rating Scale (HAMD) and blood oxygen level-dependent (BOLD) responses to visual smoking cues in drug-free nicotine-dependent smokers (n=18). Two functional magnetic resonance imaging (fMRI) scans were completed over a single study day, following overnight smoking abstinence (pre-smoking scan) and after cigarette reinstatement (post-smoking scan). During the pre-smoking scan positive correlations between BOLD activity and HAMD scores were observed in areas of the mesocorticolimbic dopaminergic system [inferior frontal gyrus, middle frontal gyrus (MFG), hippocampus (HC), anterior cingulate gyrus] and areas of the visuospatial attention circuit (medial occipital lobe, middle cingulate cortex, superior frontal gyrus, angular gyrus). During the post-smoking scan positive correlations were observed in areas of the brain implicated in drug expectancy (MFG), memory (HC), attentional motivation (posterior cingulate cortex), and visual processing and attention (precuneus). These preliminary findings demonstrate that smokers with higher depression severity attribute greater incentive salience to smoking-related cues and this is especially pronounced during periods of acute abstinence. Such enhanced salience of smoking cues, even after smoking a cigarette, may play a critical role both in the maintenance of smoking in depression and in greater levels of nicotine dependence seen in this patient population.

Following the introduction of mandatory Canadian folic acid flour fortification in mid-1997, the incidence of selected childhood cancers that declined in Ontario prior to and subsequent to this public policy initiative was examined. A population-based cohort study of all incident cases of childhood malignancy in Ontario between the years 1985 and 2006 was conducted. Participants were identified from a database provided by the Pediatric Oncology Group of Ontario and included children 0 to 4 years of age and 5 to 9 years of age who were diagnosed with cancer. Among children aged 0 to 4 years, the incidence rate of Wilms' tumor declined from 1.94 to 1.43 per 100,000 (incidence rate ratio 0.74, 95% confidence interval, 0.57-0.95). No significant change was seen in the prefortification vs postfortification time periods for acute lymphoblastic leukemia, brain cancers, or embryonal cancers among the 0- to 4-year or 5- to 9-year age groups. There was an approximately 30% reduction in risk of Wilms' tumor following introduction of the initiative. This corroborates a recent case-control study from Germany. These data may also provide some reassurance that universal flour fortification does not heighten the risk of pediatric cancer.

Variation in the activity of cytochrome P450 2D6 (CYP2D6) affects the pharmacokinetics and effectiveness of dextromethorphan (DM), because it controls the production of dextrorphan, an active metabolite, with higher affinity for the NMDA receptor than the parent compound. This study examined whether pharmacological inhibition of CYP2D6 activity with quinidine would mimic the genetic mutation and thus also alter the psychoactive effects of DM. In a single-blind, within-subjects study, eight healthy volunteers (all homozygous for the wild type allele for CYP2D6) received placebo and varying doses of DM, both with and without quinidine pre-treatment. Pharmacokinetic and pharmacodynamic measures were assessed at baseline and every hour post-drug for 6 h. Compared to the no quinidine condition, quinidine pre-treatment decreased the area under the dose-response curve on subjective measures of positively reinforcing effects (e.g., euphoria, p < 0.04; drug liking, p < 0.05), and was significantly greater for measures of dysphoria (e.g., unpleasantness, p < 0.02). These changes corresponded to increased DM and decreased dextrorphan plasma concentrations. Compared to DM alone, quinidine pre-treatment inhibited DM metabolism and changed its subjective effects, demonstrating that the psychoactive properties of DM are a function of drug metabolism. These results demonstrate the relationship between CYP2D6 activity, plasma drug levels, and psychoactive drug effects, and have implications for both the abuse liability and therapeutic utility of DM.

Bupropion is an efficacious non-nicotine medication for smoking cessation; however, its cessation-mediating mechanism is unclear. This randomized, placebo-controlled trial examined the effect of bupropion SR (300 mg/day for 6 weeks) on plasma cotinine and on the subjective effects of smoking in 24 current daily smokers who were not trying to quit or reduce smoking. Subjective effects of smoking, as well as cue-elicited responses were assessed at bi-weekly experimental sessions using validated scales. Several indices of cigarette consumption were measured. Plasma cotinine decreased from 280 (+/-133) microg/l at baseline to 205 (+/-108) microg/l at end of treatment in the bupropion group (p=0.036), but no significant change was found in the placebo group. Daily cigarette count and puff topography did not significantly change in either group. In contrast to placebo, bupropion increased post-smoking satiety (p=0.045). Both groups reported higher craving (p=0.025) and withdrawal (p=0.014) after exposure to smoking-related pictures, compared to neutral pictures. This biased reactivity was not significantly affected by treatment condition (p>0.1). Therefore, bupropion does not appear to impact the smokers' response to conditioned smoking-related cues but influences the unconditioned subjective effects of smoking in unmotivated smokers. This study is among the first to systematically investigate the effect of chronic bupropion administration, free from the confounding effect of the smoker's motivation to quit smoking.

The extent of concurrent use and abuse of benzodiazepines and alcohol in chronic alcoholics is not known. Prospective data collected on 216 consecutive outpatient referrals between 1 June and 31 July 1981 (age range, 16 to 70 years, 75 per cent men) showed that benzodiazepines were detected in the urine of 33 per cent of patients undergoing medical assessment. Other drugs identified in urine were ethanol (5.0 %), codeine (1.99 %) and barbiturates (1.5 %). According to patient histories, the predictive value of benzodiazepine allegation was high for positive and negative allegation (0.87 and 0.83, respectively), indicating that patients reliably report benzodiazepine use if questioned. However, only one patient considered himself to be a benzodiazepine abuser. The proportion of women with a positive test for benzodiazepines (48%) was significantly higher than that of men (28%: X – 7.7; p <0.005). Among patients alleging use of benzodiazepines (n = 61), 54 per cent obtained the drug directly by prescription while 46 per cent obtained it indirectly (e.g. a relative, illicit source). Benzodiazepines were taken most frequently for anxiety (53%) and occasionally for alcohol withdrawal (10%). Forty-seven (54%) of the patients could be considered abusers of benzodiazepines (i.e. indirect source and/or cumulative drug exposure of >2700 mg of diazepam or equivalent and a positive urine test). These results · indicate that benzodiazepines are very commonly used and abused by alcoholics. Treatment programmes for alcoholics should identify such patients, consider directing treatment toward control of benzodiazepine use, and monitor changes in benzodiazepine use during and after treatment.