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Nicotine deprivation and craving in smokers are positively related to improved inhibition in smoking-related contexts
The wider shores of addiction extinction trainings as part of smoking cessation programs. The negative correlation between nicotine dependence and attentional bias we observed is in line with previous research [5], suggesting that smoking behaviour may be maintained largely by incentive processes in less nicotine-dependent smokers, and by habit in those with higher dependence. Reference(s) [1] Drummond, D.C., 2001. Theories of drug craving, ancient and modern. Addiction 96, 33–46. [2] Robinson, T.E., Berridge, K.C., 1993. The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Revi 18, 247–291. [3] Yan, X., Jiang, Y., Wang, J., Deng, Y., He, S., Weng, X., 2009. Preconscious attentional bias in cigarette smokers: a probe into awareness modulation on attentional bias. Addict Biol 14, 478–488. [4] Nestor, L., McCabe, E., Jones, J., Clany, L., Garavan, H., 2011. Differences in “bottom-up” and “top-down” neural activity in current and former cigarette smokers: Evidence for neural substrates which may promote nicotine abstinence through increased cognitive control. Neuroimage 15, 2258–2275. [5] Vollstädt-Klein, S., Kobiella, A., Bühler, M., Graf, C., Fehr, C., Mann, K., Smolka, M.N., 2011. Severity of dependence modulates smokers’ neuronal cue reactivity and cigarette craving elicited by tobacco advertisement. Addict Biol 16, 166–175. P.4.007 Nicotine deprivation and craving in smokers are positively related to improved inhibition in smoking-related contexts A. Kräplin1*, G. Bühringer1, T. Goschke1. 1Technische Universität Dresden, Department of Psychology, Dresden, Germany Background and aims: Dysfunctional cognitive control is one core characteristic of Substance Use Disorders [1,2]. However, it remains an open question whether those impairments are generalized or specifically present in substance-related contexts. From models of aberrant learning processes in Substance Use Disorders, it can be hypothesized that the preferential cognitive processing of substance-related context cues interferes with cognitive control performance. In this study, we aimed to find out (1) whether smoking-related cues have an impairing effect on cognitive control performance in Nicotine Dependence and (2) whether these impairments are positively related to craving and nicotine deprivation.
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Methods: We recruited two groups aged 19 to 53: One group of 27 cigarette smokers with Nicotine Dependence according to DSM-IV and a control group of 33 never smokers. Cognitive control was assessed as inhibitory control performance in a go-nogo task [3]. As context manipulation, one of 77 neutral or 77 smokingrelated pictures was selected at random and presented before each trial. The dependent variable of our regression model was the context effect defined as performance differences between trials with smokingrelated pictures and those with neutral pictures. We used group as predictor and additionally the performance in the neutral priming condition to control for general performance differences between the groups. Furthermore, we used Spearman correlation to test the association of the context effect with nicotine deprivation as time since the last cigarette and self-reported craving during the task. Results: There were no general performance differences in inhibitory control between participants with Nicotine Dependence and never smokers. Compared to never-smokers, participants with Nicotine Dependence exhibited increased inhibitory control after smokingrelated pictures compared to neutral pictures (β = −0.05; p = 0.04). In Nicotine Dependence, this context effect was positively related to craving and nicotine deprivation: a longer time since the last cigarette (Spearman’s rho = 0.68, p = 0.001) and higher subjective craving during the task (Spearman’s rho = 0.44, p = 0.03) were related to an increased inhibitory control after smoking-related compared to neutral cues. Conclusions: Cognitive control networks in Nicotine Dependence may specifically be affected by smokingrelated contexts. Surprisingly, and against our hypothesis, we found an improved inhibitory control after smoking-related compared to neutral cues in Nicotine Dependence compared to never smokers. This improvement was greater with increased nicotine deprivation and higher craving. In Nicotine Dependence, nicotine deprivation and craving may coincide with a positive approach-driven motivation towards smoking-related cues. The intensification of the top-down goal-directed attentional focus by this positive approach motivation [4] may account for the unexpectedly increased inhibitory control performance. Theoretical models of Substance Use Disorders and further studies should modify the dual-process perspective to a more complex perspective including interactions between cognitive control, motivation, and valuation networks. Regarding interventions of Substance Use Disorders, our results suggest that substance-related inhibition or approach-avoidance trainings should be favoured over general inhibition trainings [5].
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The wider shores of addiction
Reference(s) [1] Goschke, T., 2014. Dysfunctions of decision-making and cognitive control as transdiagnostic mechanisms of mental disorders: advances, gaps, and needs in current research. Int J Methods Psychiatr Res 23, 41–57. [2] Bühringer, G., Wittchen, H.-U., Gottlebe, K., Kufeld, C., Goschke, T., 2008. Why people change? The role of cognitive control processes in the onset and cessation of substance abuse disorders. Int J Methods Psychiatr Res 17(S1), 4–15. [3] Beck, S.M., Ruge, H., Schindler, C., Burkart, M., Miller, R., Kirschbaum, C., Goschke, T., 2016. Effects of Ginkgo biloba extract EGb 761® on cognitive control functions, mental activity of the prefrontal cortex and stress reactivity in elderly adults with subjective memory impairment – a randomized double-blind placebo-controlled trial. Hum Psychopharmacol Clin Exp 31, 227–242. [4] Harmon-Jones, E., Gable, P., Price, T.F., 2012. The influence of affective states varying in motivational intensity on cognitive scope. Front Integr Neurosci 6, 1–5. [5] Wiers, R.W., Gladwin, T.E., Hofmann, W., Salemink, E., Ridderinkhof, K.R., 2013. Cognitive bias modification and cognitive control training in addiction and related psychopathology: mechanisms, clinical perspectives, and ways forward. Clinical Psychological Science 1, 192–212. P.4.008 Effects of long-term ketamine selfadministration on the glutamate synapse F. Mottarlini1*, L. Caffino1, A. Piva2, G. Giannotti1, M. Di Chio2, M. Venniro2, D.T. Yew3, C. Chiamulera2, F. Fumagalli1. 1University of Milan, Dipartimento di scienze farmacologiche e biomolecolari, Milano, Italy; 2 University of Verona, Neuropsychopharmacology Lab- Section Pharmacology- Dept Diagnostic & Public Health, Verona, Italy; 3The Chinese University of Hong Kong, Brain Research Centre- School of Biomedical Science- Faculty of Medicine, Hong Kong, China Ketamine abuse is becoming a major health problem worldwide and, therefore, it is imperative to understand the effects of repeated consumption. Ketamine is a noncompetitive antagonist of the NMDA glutamate receptors with psychotomimetic and reinforcing properties, although recent data have identified a rapid antidepressant response following a single infusion of the compound in subjects with major depression [1]. Despite various lines
of evidence have shown that repeated exposure to ketamine induces cognitive dysfunction and schizophrenia-like syntomps [2], research addressing the effects of long-term exposure to ketamine remains elusive. Taking into account the crucial importance of unveiling the mechanism(s) through which ketamine mediates its multiple actions, the major aim of our work was to investigate the expression of the major components of the glutamatergic synapse following chronic ketamine selfadministration (S/A), focusing our attention on medial prefrontal cortex (mPFC) and hippocampus (Hip), two brain regions involved in compulsive drug-seeking and drug-related cognitive disorders. To this end, adult male rats self-administered ketamine (0.5 mg/kg/infusion) for 35–43 days and were sacrificed 24 hours after the last drug exposure, immediately before the daily ketamine S/A session. Molecular analyses were performed on the crude synaptosomal fraction of mPFC and Hip tissues by Western-blot analysis. Molecular data were collected in individual animals and were analyzed by an unpaired two-tailed Student’s t test. Rats trained to self-administer ketamine met the acquisition criteria at different session, then animals maintained constant ketamine intake during 35–43 days of S/A (active lever presses, 26.7 ± 4.6, number of reinforcement, 14.4 ± 2.6, mean ± SEM of the last three self-administration sessions). Our findings reveal a general down-regulation of glutamate receptors expression that was brain region-dependent. In fact, in the mPFC, we found reduced expression of different subunits of the NMDA receptor: the obligatory subunit GluN1 was reduced (−14%, t(17) = 2.228, p = 0.04) and so were the accessory subunits GluN2A (−28%, t(17) = 2.174, p = 0.044) and GluN2B (−19%, t(15) = 2.435, p = 0.028), whereas AMPA receptor protein levels were reduced in Hip: GluA1 (−30%, t(15) = 2.295, p = 0.037) and GluA2 (−36%, t(16) = 2.664, p = 0.017). Of note, specific scaffolding proteins of NMDA and AMPA receptors were also reduced in mPFC, PSD-95 (−23%, t(17) = 3.273, p = 0.0045), SAP102 (−24%, t(17) = 2.417, p = 0.027) and in Hip SAP97 (−32%, t(16) = 2.587, p = 0.02), respectively, giving a different picture. Moreover, the metabotropic mGluR5 receptor was similarly downregulated in both areas (mPFC: −25%, t(16) = 3.258, p = 0.0049, Hip: −27%, t(17) = 2.350, p = 0.031. To summarize, our results show that ketamine-treated rats acquire and maintain the self-administration behavior and long-term ketamine S/A animals display an overall reduction of the post-synaptic glutamate receptors in a brain region-dependent fashion. The reduction of expression of NMDA and AMPA subunits, as well as of scaffolding proteins, contribute to delineate an overall
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Methods: We recruited two groups aged 19 to 53: One group of 27 cigarette smokers with Nicotine Dependence according to DSM-IV and a control group of 33 never smokers. Cognitive control was assessed as inhibitory control performance in a go-nogo task [3]. As context manipulation, one of 77 neutral or 77 smokingrelated pictures was selected at random and presented before each trial. The dependent variable of our regression model was the context effect defined as performance differences between trials with smokingrelated pictures and those with neutral pictures. We used group as predictor and additionally the performance in the neutral priming condition to control for general performance differences between the groups. Furthermore, we used Spearman correlation to test the association of the context effect with nicotine deprivation as time since the last cigarette and self-reported craving during the task. Results: There were no general performance differences in inhibitory control between participants with Nicotine Dependence and never smokers. Compared to never-smokers, participants with Nicotine Dependence exhibited increased inhibitory control after smokingrelated pictures compared to neutral pictures (β = −0.05; p = 0.04). In Nicotine Dependence, this context effect was positively related to craving and nicotine deprivation: a longer time since the last cigarette (Spearman’s rho = 0.68, p = 0.001) and higher subjective craving during the task (Spearman’s rho = 0.44, p = 0.03) were related to an increased inhibitory control after smoking-related compared to neutral cues. Conclusions: Cognitive control networks in Nicotine Dependence may specifically be affected by smokingrelated contexts. Surprisingly, and against our hypothesis, we found an improved inhibitory control after smoking-related compared to neutral cues in Nicotine Dependence compared to never smokers. This improvement was greater with increased nicotine deprivation and higher craving. In Nicotine Dependence, nicotine deprivation and craving may coincide with a positive approach-driven motivation towards smoking-related cues. The intensification of the top-down goal-directed attentional focus by this positive approach motivation [4] may account for the unexpectedly increased inhibitory control performance. Theoretical models of Substance Use Disorders and further studies should modify the dual-process perspective to a more complex perspective including interactions between cognitive control, motivation, and valuation networks. Regarding interventions of Substance Use Disorders, our results suggest that substance-related inhibition or approach-avoidance trainings should be favoured over general inhibition trainings [5].
S88
The wider shores of addiction
Reference(s) [1] Goschke, T., 2014. Dysfunctions of decision-making and cognitive control as transdiagnostic mechanisms of mental disorders: advances, gaps, and needs in current research. Int J Methods Psychiatr Res 23, 41–57. [2] Bühringer, G., Wittchen, H.-U., Gottlebe, K., Kufeld, C., Goschke, T., 2008. Why people change? The role of cognitive control processes in the onset and cessation of substance abuse disorders. Int J Methods Psychiatr Res 17(S1), 4–15. [3] Beck, S.M., Ruge, H., Schindler, C., Burkart, M., Miller, R., Kirschbaum, C., Goschke, T., 2016. Effects of Ginkgo biloba extract EGb 761® on cognitive control functions, mental activity of the prefrontal cortex and stress reactivity in elderly adults with subjective memory impairment – a randomized double-blind placebo-controlled trial. Hum Psychopharmacol Clin Exp 31, 227–242. [4] Harmon-Jones, E., Gable, P., Price, T.F., 2012. The influence of affective states varying in motivational intensity on cognitive scope. Front Integr Neurosci 6, 1–5. [5] Wiers, R.W., Gladwin, T.E., Hofmann, W., Salemink, E., Ridderinkhof, K.R., 2013. Cognitive bias modification and cognitive control training in addiction and related psychopathology: mechanisms, clinical perspectives, and ways forward. Clinical Psychological Science 1, 192–212. P.4.008 Effects of long-term ketamine selfadministration on the glutamate synapse F. Mottarlini1*, L. Caffino1, A. Piva2, G. Giannotti1, M. Di Chio2, M. Venniro2, D.T. Yew3, C. Chiamulera2, F. Fumagalli1. 1University of Milan, Dipartimento di scienze farmacologiche e biomolecolari, Milano, Italy; 2 University of Verona, Neuropsychopharmacology Lab- Section Pharmacology- Dept Diagnostic & Public Health, Verona, Italy; 3The Chinese University of Hong Kong, Brain Research Centre- School of Biomedical Science- Faculty of Medicine, Hong Kong, China Ketamine abuse is becoming a major health problem worldwide and, therefore, it is imperative to understand the effects of repeated consumption. Ketamine is a noncompetitive antagonist of the NMDA glutamate receptors with psychotomimetic and reinforcing properties, although recent data have identified a rapid antidepressant response following a single infusion of the compound in subjects with major depression [1]. Despite various lines
of evidence have shown that repeated exposure to ketamine induces cognitive dysfunction and schizophrenia-like syntomps [2], research addressing the effects of long-term exposure to ketamine remains elusive. Taking into account the crucial importance of unveiling the mechanism(s) through which ketamine mediates its multiple actions, the major aim of our work was to investigate the expression of the major components of the glutamatergic synapse following chronic ketamine selfadministration (S/A), focusing our attention on medial prefrontal cortex (mPFC) and hippocampus (Hip), two brain regions involved in compulsive drug-seeking and drug-related cognitive disorders. To this end, adult male rats self-administered ketamine (0.5 mg/kg/infusion) for 35–43 days and were sacrificed 24 hours after the last drug exposure, immediately before the daily ketamine S/A session. Molecular analyses were performed on the crude synaptosomal fraction of mPFC and Hip tissues by Western-blot analysis. Molecular data were collected in individual animals and were analyzed by an unpaired two-tailed Student’s t test. Rats trained to self-administer ketamine met the acquisition criteria at different session, then animals maintained constant ketamine intake during 35–43 days of S/A (active lever presses, 26.7 ± 4.6, number of reinforcement, 14.4 ± 2.6, mean ± SEM of the last three self-administration sessions). Our findings reveal a general down-regulation of glutamate receptors expression that was brain region-dependent. In fact, in the mPFC, we found reduced expression of different subunits of the NMDA receptor: the obligatory subunit GluN1 was reduced (−14%, t(17) = 2.228, p = 0.04) and so were the accessory subunits GluN2A (−28%, t(17) = 2.174, p = 0.044) and GluN2B (−19%, t(15) = 2.435, p = 0.028), whereas AMPA receptor protein levels were reduced in Hip: GluA1 (−30%, t(15) = 2.295, p = 0.037) and GluA2 (−36%, t(16) = 2.664, p = 0.017). Of note, specific scaffolding proteins of NMDA and AMPA receptors were also reduced in mPFC, PSD-95 (−23%, t(17) = 3.273, p = 0.0045), SAP102 (−24%, t(17) = 2.417, p = 0.027) and in Hip SAP97 (−32%, t(16) = 2.587, p = 0.02), respectively, giving a different picture. Moreover, the metabotropic mGluR5 receptor was similarly downregulated in both areas (mPFC: −25%, t(16) = 3.258, p = 0.0049, Hip: −27%, t(17) = 2.350, p = 0.031. To summarize, our results show that ketamine-treated rats acquire and maintain the self-administration behavior and long-term ketamine S/A animals display an overall reduction of the post-synaptic glutamate receptors in a brain region-dependent fashion. The reduction of expression of NMDA and AMPA subunits, as well as of scaffolding proteins, contribute to delineate an overall