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Reinforcing effects of very low nicotine content cigarettes: A review
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Abstract / Drug and Alcohol Dependence 156 (2015) e183–e245
methods offer a multivariate approach for identification and prediction. Methods: We applied support vector machine (SVM) classification to fMRI data from six individuals who received d-Amphetamine (AMP) and placebo (PLB). BOLD signals were recorded in four 15 min blocks (i.e., Pre, Post1, Post2 and Post3) as subjective experiences were reported. SVM models were constructed for each block with whole-brain and striatal masks in a 6-fold, leave one subject out cross-validation scheme. Significance values were obtained from 100 repetitions of a permutation test. Vector weights were projected in brain space to reveal patterns contributing to classifications. Results: Whole-brain data significantly predicted classes in all blocks (each p < 0.01). Vectors contributing most to AMP were observed throughout the pre- frontal cortex in the Pre block, while vectors contributing most to Post blocks were in movement, visual, cingulate and insular cortices. Striatal data alone failed to distinguish AMP from PLB in the Pre block. However, they significantly predicted class association in all Post blocks (Post1 = 91.7%, Post2 = 75%, and Post3 = 83.3%; all p < 0.04). Conclusions: These data highlight a benefit of multivariate classification, which considers joint and connected features in an attempt to classify brain states. Furthermore, they demonstrate that drug-specific information processed in the striatum is sufficient for discrimination of the presence of a monoaminergic agonist. Financial support: P50 DA005312 and UL1TR000117. http://dx.doi.org/10.1016/j.drugalcdep.2015.07.640 Simultaneous PET/MRI of neurovascular coupling to the -opioid receptor occupancy Hsiao-Ying Wey 1,∗ , Jacob M. Hooker 1 , Michael S. Placzek 1,2 , Bruce R. Rosen 1 , Joseph B. Mandeville 1 1 Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States 2 Brain Imaging Center, McLean Hospital, Harvard Medical School, Belmont, MA, United States
Aims: The interaction between the brain’s opioid and dopamine systems has been highlighted as potentially pivotal in opioid addiction. Simultaneous PET/MRI is a novel imaging technology and could be used to investigate receptor system interactions and to dissect complex fMRI signals into neurochemical constituents. Methods: Simultaneous PET/MRI were acquired on two male macaques on a 3T Siemens PET/MRI. CBV-fMRI data were obtained following iron oxide injection. [11 C]Carfentanil (∼8 mCi) was given as a bolus-infusion. An opioid antagonist, naloxone (0.005, 0.01, 0.03, and 0.05 mg/kg), and a -opioid agonist, remifentanil (10 g/kg), were given i.v. in separate scans. PET data was analyzed for receptor binding potentials (BPND ). A gamma function was used to model the temporal response to a drug challenge. Results: At baseline, PET BPND maps showed a high-level of binding in the thalamus, caudate, putamen, frontal cortex, which corresponded well to known -opioid receptors distribution. Opioid receptor BPND and %CBV were reduced after naloxone challenges in a dose-dependent manner. A dose of 0.05 mg/kg naloxone achieved >90% receptor occupancy. The largest BPND reductions were observed in the thalamus and caudate, while the largest CBV changes were observed in the putamen. Regional analyses of the BPND and CBV data revealed a linear coupling
relationship. Naloxone induced a negative CBV response, which could be due to activating the inhibitory neurotransmitter, GABA, and/or its downstream effects (i.e., GABA depletes basal dopamine in the basal ganglia). A -opioid agonist (remifentanil) evoked robust bi-directional CBV responses in the basal ganglia. Drugevoked dopamine release may be responsible for the initial negative CBV. Conclusions: Future pharmacological studies modulating the GABA and dopamine systems can be used to confirm the opioid direct vs. indirect modulations on the fMRI signals. Financial support: NIDA K99DA037928 (H.Y.W.). http://dx.doi.org/10.1016/j.drugalcdep.2015.07.641 Reinforcing effects of very low nicotine content cigarettes: A review Thomas J. White 1,2,∗ , Ryan Redner 1,2 , Stephen T. Higgins 1,2,3 1
Vermont Center on Behavior & Health, University of Vermont, Burlington, VT, United States 2 Psychiatry, University of Vermont, Burlington, VT, United States 3 Psychology, University of Vermont, Burlington, VT, United States Aims: The US Food and Drug Administration has the authority to reduce the nicotine content of cigarettes to very low (potentially sub-addictive) levels. Effective implementation of such a plan would benefit from careful analysis of the relative effects of very low-nicotine (VLNC) and high-content (HC) cigarettes. Methods: Experimental laboratory studies comparing VLNC and HC cigarettes were reviewed. Results: VLNC and HC both reduce self-reported craving and withdrawal, both are sensitive to price increases, and both how similar measures of relative reinforcing efficacy when tested alone (e.g., no differences in Progressive Ratio breakpoint). When presented concurrently, HC are preferred over VLNC cigarettes (i.e., they differ in relative reinforcing effects). Conclusions: Laboratory studies indicate that VLNC and HC cigarettes are both effective in suppressing withdrawal and craving, suggesting VLNC cigarettes could be effective substitutes for HC cigarettes on that dimension. However, when concurrently available there is a clear preference for HC cigrettes, suggesting that VLNC cigarettes would not compete effectively with HC cigarettes in the market where both were available unless they were less expensive or supplemented in some manner. Research parametrically comparing concurrently available VLNC and HC cigarettes at varying prices would be helpful in identifying a price differential that can reliably promote preference for VLNC over HC cigarettes. Financial support: This research was supported in part by National Institutes of Health Center of Biomedical Research Excellence award P20GM103644 from the National Institute of General Medical Sciences, Tobacco Centers of Regulatory Science award P50DA036114 from the National Institute on Drug Abuse and U.S. Food and Drug Administration, and an Institutional Training grant T32DA07242 from the National Institute on Drug Abuse. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the Food and Drug Administration. http://dx.doi.org/10.1016/j.drugalcdep.2015.07.642
Abstract / Drug and Alcohol Dependence 156 (2015) e183–e245
methods offer a multivariate approach for identification and prediction. Methods: We applied support vector machine (SVM) classification to fMRI data from six individuals who received d-Amphetamine (AMP) and placebo (PLB). BOLD signals were recorded in four 15 min blocks (i.e., Pre, Post1, Post2 and Post3) as subjective experiences were reported. SVM models were constructed for each block with whole-brain and striatal masks in a 6-fold, leave one subject out cross-validation scheme. Significance values were obtained from 100 repetitions of a permutation test. Vector weights were projected in brain space to reveal patterns contributing to classifications. Results: Whole-brain data significantly predicted classes in all blocks (each p < 0.01). Vectors contributing most to AMP were observed throughout the pre- frontal cortex in the Pre block, while vectors contributing most to Post blocks were in movement, visual, cingulate and insular cortices. Striatal data alone failed to distinguish AMP from PLB in the Pre block. However, they significantly predicted class association in all Post blocks (Post1 = 91.7%, Post2 = 75%, and Post3 = 83.3%; all p < 0.04). Conclusions: These data highlight a benefit of multivariate classification, which considers joint and connected features in an attempt to classify brain states. Furthermore, they demonstrate that drug-specific information processed in the striatum is sufficient for discrimination of the presence of a monoaminergic agonist. Financial support: P50 DA005312 and UL1TR000117. http://dx.doi.org/10.1016/j.drugalcdep.2015.07.640 Simultaneous PET/MRI of neurovascular coupling to the -opioid receptor occupancy Hsiao-Ying Wey 1,∗ , Jacob M. Hooker 1 , Michael S. Placzek 1,2 , Bruce R. Rosen 1 , Joseph B. Mandeville 1 1 Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States 2 Brain Imaging Center, McLean Hospital, Harvard Medical School, Belmont, MA, United States
Aims: The interaction between the brain’s opioid and dopamine systems has been highlighted as potentially pivotal in opioid addiction. Simultaneous PET/MRI is a novel imaging technology and could be used to investigate receptor system interactions and to dissect complex fMRI signals into neurochemical constituents. Methods: Simultaneous PET/MRI were acquired on two male macaques on a 3T Siemens PET/MRI. CBV-fMRI data were obtained following iron oxide injection. [11 C]Carfentanil (∼8 mCi) was given as a bolus-infusion. An opioid antagonist, naloxone (0.005, 0.01, 0.03, and 0.05 mg/kg), and a -opioid agonist, remifentanil (10 g/kg), were given i.v. in separate scans. PET data was analyzed for receptor binding potentials (BPND ). A gamma function was used to model the temporal response to a drug challenge. Results: At baseline, PET BPND maps showed a high-level of binding in the thalamus, caudate, putamen, frontal cortex, which corresponded well to known -opioid receptors distribution. Opioid receptor BPND and %CBV were reduced after naloxone challenges in a dose-dependent manner. A dose of 0.05 mg/kg naloxone achieved >90% receptor occupancy. The largest BPND reductions were observed in the thalamus and caudate, while the largest CBV changes were observed in the putamen. Regional analyses of the BPND and CBV data revealed a linear coupling
relationship. Naloxone induced a negative CBV response, which could be due to activating the inhibitory neurotransmitter, GABA, and/or its downstream effects (i.e., GABA depletes basal dopamine in the basal ganglia). A -opioid agonist (remifentanil) evoked robust bi-directional CBV responses in the basal ganglia. Drugevoked dopamine release may be responsible for the initial negative CBV. Conclusions: Future pharmacological studies modulating the GABA and dopamine systems can be used to confirm the opioid direct vs. indirect modulations on the fMRI signals. Financial support: NIDA K99DA037928 (H.Y.W.). http://dx.doi.org/10.1016/j.drugalcdep.2015.07.641 Reinforcing effects of very low nicotine content cigarettes: A review Thomas J. White 1,2,∗ , Ryan Redner 1,2 , Stephen T. Higgins 1,2,3 1
Vermont Center on Behavior & Health, University of Vermont, Burlington, VT, United States 2 Psychiatry, University of Vermont, Burlington, VT, United States 3 Psychology, University of Vermont, Burlington, VT, United States Aims: The US Food and Drug Administration has the authority to reduce the nicotine content of cigarettes to very low (potentially sub-addictive) levels. Effective implementation of such a plan would benefit from careful analysis of the relative effects of very low-nicotine (VLNC) and high-content (HC) cigarettes. Methods: Experimental laboratory studies comparing VLNC and HC cigarettes were reviewed. Results: VLNC and HC both reduce self-reported craving and withdrawal, both are sensitive to price increases, and both how similar measures of relative reinforcing efficacy when tested alone (e.g., no differences in Progressive Ratio breakpoint). When presented concurrently, HC are preferred over VLNC cigarettes (i.e., they differ in relative reinforcing effects). Conclusions: Laboratory studies indicate that VLNC and HC cigarettes are both effective in suppressing withdrawal and craving, suggesting VLNC cigarettes could be effective substitutes for HC cigarettes on that dimension. However, when concurrently available there is a clear preference for HC cigrettes, suggesting that VLNC cigarettes would not compete effectively with HC cigarettes in the market where both were available unless they were less expensive or supplemented in some manner. Research parametrically comparing concurrently available VLNC and HC cigarettes at varying prices would be helpful in identifying a price differential that can reliably promote preference for VLNC over HC cigarettes. Financial support: This research was supported in part by National Institutes of Health Center of Biomedical Research Excellence award P20GM103644 from the National Institute of General Medical Sciences, Tobacco Centers of Regulatory Science award P50DA036114 from the National Institute on Drug Abuse and U.S. Food and Drug Administration, and an Institutional Training grant T32DA07242 from the National Institute on Drug Abuse. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the Food and Drug Administration. http://dx.doi.org/10.1016/j.drugalcdep.2015.07.642