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TITLE: Neuroactivity in amygdala, nucleus accumbens and reward-related regions is modulated in smokers treated with the GABA B agonist, baclofen
AUTHORS: Franklin, Teresa1; Wang, Ze1,2; Hakun, Jonathan1; Harper, Derek1; Li, Yin1; Jens, Will1; O'Brien, Charles P1,3; Childress, Anna Rose1,3
1Department of Psychiatry
2Department of Radiology
3Philadelphia VA Medical Center
University of Pennsylvania, Philadelphia, PA USA
Support: Work supported by NIH grants DA015149, K01 DA 015426-011A1, 5-P60-DA-005186-18, and NS045839, BCS-0224007, RR02305 and the GCRC of the University of Pennsylvania
Presented at American College of Neuropsychopharmacology (ACNP) 2007, Boca Raton, FL
Teresa R. Franklin, Ph.D.
Research Assistant Professor of Neuroscience
Department of Psychiatry
University of Pennsylvania and VA Medical Center
Treatment Research Center
3900 Chestnut Street
Philadelphia, PA 19104
telephone: 215 222 3200 x119
FAX: 215 386 6770
Background: Few medications exist to treat cigarette dependence and those available are only partially effective. Surges in dopamine within the mesolimbic dopaminergic system are of primary importance in nicotine reward. GABAergic mechanisms act indirectly on this system to reduce dopamine. Thus, GABAergic compounds may be a viable smoking cessation treatment strategy. The short-acting GABA B agonist, baclofen has been studied with regard toits purported anti-craving properties in cocaine, alcohol, nicotine and other drug dependencies with variable results. Inadequate dose may be a factor in studies finding baclofen to be ineffective at preventing relapse.
Methods: In a double-blind placebo controlled study of smokers wishing to reduce and to eventually quit smoking, we utilized a higher dose than thatof other studies (20mgs q.i.d.). To reduce the possibility of drowsiness, a side effect of baclofen (15%), the dose was titrated upwards over a 12 day period. A five minute resting baseline (neuroactivity occurring in the brain at rest) MRI was collected on a subset of these smokers before treatment and then again following 3 weeks of treatment (N=10 baclofen, N=11 placebo). The quantitative technique of continuous arterial spin labeled (CASL) perfusion MRI enables a comparison of the Before and During medication scans.Subjects were smoking at both time points as Quit Dates were scheduled for 5 weeks
into treatment. The quantitative technique of continuous arterial spin labeled (CASL) perfusion MRI enables a comparison of the Before and During medication scans.
Results: Using SPM2, a paired t-test revealed (for all regions, -7.26 < t < +6.40, cluster corrected at p < 0.001) lower resting activity in reward-related regions (bilaterally in amygdala, nucleus accumbens shell, supragenual anterior cingulate, and ventral medial prefrontal cortex). Resting activity in regions known to modulate reward circuits was higher after three weeks of treatment (right lateral orbitofrontal, left superior frontal and posterior cingulate gyri). There were no differences in brain activity patterns after 3 weeks of treatment in the placebo group. There were no differences between groups in side effects or cigarettes smoked per day on on either scanning day, indicating that changes in the brain were not due to drowsiness induced by baclofen or changes in number of cigarettes smoked per day.
Discussion: Baclofen's modulatory actions on dopamine driven reward circuitry are reflected in the resting brain state and may account for its putative effectiveness as an anti-craving agent. These findings are a
seminal contribution to the drug addiction field and psychiatric illness in general. They highlight the feasibility of using the resting state as an indicator of therapeutic efficacy and as a tool for medications development in nicotine dependence. Longer acting GABAergics may have a greater ability to maintain modulation of the brain at rest.