My ultimate goal as an Addictions’ Researcher is to aid in characterizing pharmaco-responsive endophenotypes in smokers to help them in achieving successful smoking cessation. There are two major factors that motivate relapse to smoking:
a) Craving induced by pharmacological withdrawal from nicotine.
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. I focus on cue-vulnerable subtypes of smokers and pharmacotherapies that show promise to reduce relapse rates in these subtypes. The tools I am using to identify the subtypes are:
a) Appetitive smoking cue videos in a withdrawal versus 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 cognitive bias tasks, cigarette consumption and treatment outcome.
f) A candidate gene approach of functional polymorphisms involved in smoking behavior.
I 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 contribution to continued smoking in males is influenced more by the maintenance of nicotine levels in the brain (withdrawal). My preliminary neuroimaging data support this hypothesis: females show greater responses during smoking cue exposure compared to males. 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 (Franklin et al., Nicotine and Tobacco Research. 2004). 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 (Franklin et al., Journal of Women's Health. 2008).
In addition to studying genetic and male/female/menstrual cycle influences on smoking cue responsivity, I also examine the brain and behavioral responses to smoking cues in smokers with co-morbidities such as Attention Deficit Hyperactivity Disorder (ADHD), anxiety disorder, and marijuana and/or alcohol 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. I 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. To our knowledge ours is the first human study that has elucidated the mechanisms underlying the effectiveness of a medication in blunting both brain and behavioral cue reactivity. The action of varenicline to increase activity in the reward-evaluating lateral orbitofrontal cortex predicts its actions to reduce activity in the reward-responsive ventral striatum/medial orbitofrontal cortex.
In other studies, we have data showing that both marijuana cues and smoking cues activate the same reward-related brain circuitry, suggesting similar brain vulnerabilities, and further, 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 cigarette smoking reduction study, and blunts both brain activity in reward-related neural activity in the brain in ‘at rest’ and during smoking cue exposure. Because of the similar brain signature, and possibly similar brain vulnerabilities, we are currently acquiring data to examine the effects of baclofen on marijuana smokers who also smoke cigarettes.
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 addiction.
Click on the article titles below to see brain data in all three planes for each publication.