My ultimate goal as an Addiction’s Researcher is to characterize pharmaco-responsive endophenotypes in smokers to aid them in achieving successful smoking cessation. There are two major factors that motivate relapse to smoking: a) craving induced my pharmacological withdrawal from nicotine and b) craving elicited by exposure to smoking reminders (smoking cues). We hypothesize that there is inter-individual variability in the relative contribution of withdrawal- and smoking cue-induced craving to relapse. In our lab we focus on cue-vulnerable subtypes of smokers – and pharmacotherapies that reduce relapse rates in these subtypes. The tools I am using to identify the subtypes are a) appetitive smoking cue videos in a withdrawal vs sated imaging paradigm, b) the quantitative imaging technique of continuous arterial spin labeled (CASL) perfusion fMRI, c) GABA B agonists such as baclofen, d) the partial nicotinic agonist and FDA-approved agent, varenicline, e) behavioral probes that predict relapse, including treatment outcome, f) objective measures of smoking behavior, and g) a candidate gene approach of functional polymorphisms involved in smoking behavior. We have published and replicated our findings showing that genetic variance in the dopamine transporter (DAT) modulates brain and behavioral responses during smoking cue exposure. We are currently exploring the interaction between the DAT and other dopaminergic regulating molecules, which have been shown to be involved in reward and smoking cue responsivity.
Further exploration into the characterization of phenotypes in smokers includes the study of sex and menstrual cycle influences on smoking behavior. Evidence suggests that female smoking behavior is motivated more by the sensory aspects of smoking while the relative contribution to continued smoking in males is influenced more by the maintenance of nicotine levels in the brain (withdrawal). Although preliminary neuroimaging data supported this hypothesis, in a large cohort, we have shown the opposite; males and females both show activation to smoking cues in the medial orbitofrontal cortex but males have stronger and more activation in a priori reward-related structures. We have also shown that menstrual cycle phase influences smoking cue responsivity and treatment outcome: luteal females (females in the premenstrual phase of their cycle) have greater subjective craving elicited by smoking cue exposure compared to follicular females. Further, we demonstrated that premenopausal females who begin treatment in the follicular phase, and are simultaneously protected from withdrawal have at least a 70% chance of success in smoking cessation compared to a 20% success rate in females who begin treatment in the luteal phase.
In addition to studying genetic and male/female/menstrual cycle influences on smoking cue responsivity, we also are examining the brain and behavioral responses to smoking cues in smokers with co-morbidities such as Attention Deficit Hyperactivity Disorder (ADHD), anxiety disorder, and marijuana addiction. For example, varenicline, which has positive effects on cognition may provide dual benefit to ADHD smokers by improving attention and focus, while also aiding in smoking cessation. We also have data evincing that varenicline, which is known to reduce withdrawal and the reinforcement received from smoking, also blocks subjective craving and the reward-related neural ‘signature’ of smoking cue exposure. Our unique perfusion fMRI paradigm allowed us to deduce the mechanisms underlying varenicline’s effectiveness. Further, we have evidence that both marijuana cues and smoking cues activate the same reward-related brain circuitry, suggesting that medications that might aid smokers may also aid marijuana-dependent cigarette smokers. Evidence suggests that an anxiety-prone cue-vulnerable subtype will respond to baclofen, which we have shown has efficacy in a smoking reduction study and blunts both brain activity in reward-related neural activity in the brain in ‘at rest’ and during smoking cue exposure.
Additional studies include the use of the imaging technique, single photon emission computed tomography (SPECT), and the DAT-specific radiotracer, TRODAT to examine whether the DAT-mediated effects on smoking cue reactivity are due to less available or less functional DATs.
Ultimately, the goal for contemporary medicine is to establish brain/behavioral/genetic endophenotypes of medication response, so that treatment strategies can be tailored to manage individual vulnerabilities to aid in conquering this devastating and difficult to treat addiction.
Franklin, T.R., Wang, Z., Wang, J., Sciortino, N., Harper, D., Li, Y., Ehrman, R., Kampman, K., O'Brien, C.P., Detre, J.A., Childress, A.R.: Limbic activation to cigarette smoking cues independent of nicotine withdrawal: a perfusion fMRI study. Neuropsychopharmacology 32(11): 2301-2309, 2007.
Franklin, T.R., Harper, D., Kampman, K., Kildea-McCrea, S., Jens, W., Lynch, K.G., O'Brien, C.P., Childress, A.R.: The GABA B agonist baclofen reduces cigarette consumption in a preliminary double-blind placebo-controlled smoking reduction study. Drug and Alcohol Dependence 103(1-2): 30-36, 2009.
Franklin, T.R., Allen, S.S.: Influence of menstrual cycle phase on smoking cessation treatment outcome: a hypothesis regarding the discordant findings in the literature. Addiction (Abingdon, England) 104(11): 1941-1942, 2009.
Franklin, T.R., Wang, Z., Sciortino, N., Harper, D., Li, Y., Hakun, J., Kildea, S., Kampman, K., Ehrman, R., Detre, J.A., O'Brien, C.P., Childress, A.R.: Modulation of resting brain cerebral blood flow by the GABA B agonist, baclofen: A longitudinal perfusion fMRI study. Drug and alcohol dependence 117(2-3): 176-183, 2011.
Franklin, T.R., Wang, Z., Li, Y., Suh, J., Goldman, M., Lohoff, F., Cruz, J., Hazan, R., Jens, W., Detre, J.A., Berrettini, W., O'Brien, C.P., Childress, A.R.: Dopamine transporter genotype modulation of neural responses to smoking cues: Confirmation in a new cohort. Addiction Biology 16(2): 308-322, 2011.
14. Franklin, T.R., Wang, Z., Suh, J.J., Hazan, R., Cruz, J., Li, Y., Goldman, M., Detre, J.A., O'Brien, C.P., Childress, A.R.: Effects of varenicline on smoking cue-triggered neural and craving responses. Archives of General Psychiatry 68(5): 516-526, 2011.
Franklin, T.R., Wang, Z., Shin, J., Jagannathan, K., Suh, J.J., Detre, J.A., O'Brien, C.P., Childress, A.R.: A VBM study demonstrating ‘apparent’ effects of a singe dose of medication on T1-weighted MRIs. Brain Structure and Function 218(1): 97-104, 2013.
Wetherill, R.R., Childress, A.R., Jagannathan, K., Bender, J., Young, K.A., Suh, J.J., O’Brien, C.P., Franklin, T.R.: Neural responses to subliminally presented cannabis and other emotionally evocative cues in cannabis-dependent individuals. Psychopharmacology 231(7): 1397-1407, 2014.
Wetherill, R.R., Jagannathan, K., Shin, J., Franklin, T.R.: Sex Differences in Resting State Neural Networks of Nicotine-Dependent Cigarette Smokers. Addictive Behaviors 2014 Notes: AOL January 23, 2014; http://www.sciencedirect.com/science/article/pii/S0306460314000070.
Young, K., Franklin, T.R., Roberts, D., Jagannathan, K., Suh, J.J., Wetherill, R.R., Wang, Z., Kampman, K., O’Brien, C.P., Childress, AR.: Nipping cue reactivity in the bud: Baclofen prevents limbic activation elicited by subliminal drug cues. Journal of Neuroscience 34(14): 5038-5043, 2014.
back to top
Last updated: 06/25/2014
The Trustees of the University of Pennsylvania