Marina Goldman

Dopamine transporter genotype modulation of neural responses to smoking cues: confirmation in a new cohort

Previously we demonstrated profound effects of dopamine transporter (DAT) SLC6A3 genotype on limbic responses to smoking cues (SCs). Probands carrying at least one copy of the 9‐repeat allele (9‐repeat carriers) had greater neural responses to SCs in the anatomically interconnected rostral ventral striatum/medial orbitofrontal cortex (VS/mOFC), compared with homozygotes for the 10‐repeat allele (10/10‐repeats). To test the reliability of the initial findings, we examined perfusion functional magnetic resonance images acquired during SC exposure in a new cohort of smokers (N = 26) who were genotyped for the SLC6A3 polymorphism. In smokers overall, activity was enhanced in the VS/mOFC (t = 3.77). Contrasts between allelic groups revealed that 9‐repeat carriers had a greater response to SCs in the VS (t = 3.12) and mOFC (t = 3.19). In separate groups, 9‐repeat carriers showed increased activity in the VS (t = 5.47) and mOFC (T = 4.96), while no increases were observed in 10‐repeats. Subjective reports of craving correlated with increased activity in reward‐related structures including the extended amygdala, insula and post‐central gyrus, and decreased activity in the dorsolateral prefrontal cortex, and were DAT‐genotype dependent (r = 0.63–0.96). In secondary analyses, we found that The Fagerström Test for Nicotine Dependence scores correlated with enhanced SC‐induced perfusion in 10/10‐repeats in the insula, mOFC, medial temporal and superior frontal gyri (r = 0.50–0.82), while correlations were absent in 9‐repeat carriers. Despite heterogeneity introduced by a host of factors, including variance in other genes involved in smoking behavior, we confirm that DAT genotype predicts the direction and location of neural responses to SCs.

Atomoxetine for treatment of marijuana dependence: A report on the efficacy and high incidence of gastrointestinal adverse events in a pilot study

Marijuana users consistently demonstrate impairments in attention, executive function and response inhibition, which resemble deficits seen in attention deficit hyperactivity disorder (ADHD). We hypothesized that targeting the cognitive deficits associated with chronic marijuana use through ADHD medications may help identify a therapeutic agent for marijuana dependence. Thirteen subjects participated in an 11-week open label study to determine the feasibility, safety and tolerability of atomoxetine for individuals seeking treatment for marijuana dependence. The Time-Line Follow-Back measured marijuana use 90 days prior to study entry (p-TLFB) and weekly during the study (s-TLFB) along with weekly qualitative urine drug screen (UDS). For the eight subjects who completed the trial, the TLFB data showed a trend toward reduction in use with an increase in percent days abstinent (p=0.06). Analysis of weekly UDSs did not confirm the TLFB trend with 94% of all possible UDSs positive for THC through out the study. Marijuana dependent subjects taking atomoxetine experienced an inordinate number of gastrointestinal (GI) adverse events. Overall, 10 of 13 subjects (77%) experienced a mild to moderate GI adverse event defined as nausea, vomiting, dyspepsia, and loose stools. Atomoxetine is of limited utility in the treatment of cannabis dependence and is associated with clinically significant GI adverse events.

Reward-related Brain Response and Craving Correlates of Marijuana Cue Exposure: A Preliminary Study in Treatment-Seeking Marijuana-Dependent Subjects

Objective: Determining the brain substrates underlying the motivation to abuse addictive drugs is critical for understanding and treating addictive disorders. Laboratory neuroimaging studies have demonstrated differential activation of limbic and motivational circuitry (eg, amygdala, hippocampus, ventral striatum, insula, and orbitofrontal cortex) triggered by cocaine, heroin, nicotine, and alcohol cues. The literature on neural responses to marijuana cues is sparse. Thus, the goals of this study were to characterize the brains response to marijuana cues, a major motivator underlying drug use and relapse, and determine whether these responses are linked to self-reported craving in a clinically relevant population of treatment-seeking marijuana-dependent subjects. Methods: Marijuana craving was assessed in 12 marijuana-dependent subjects using the Marijuana Craving Questionnaire–Short Form. Subsequently, blood oxygen level dependent functional magnetic resonance imaging data were acquired during exposure to alternating 20-second blocks of marijuana-related versus matched nondrug visual cues. Results: Brain activation during marijuana cue exposure was significantly greater in the bilateral amygdala and the hippocampus. Significant positive correlations between craving scores and brain activation were found in the ventral striatum and the medial and lateral orbitofrontal cortex (P < 0.0001). Conclusions: This study presents direct evidence for a link between reward-relevant brain responses to marijuana cues and craving and extends the current literature on marijuana cue reactivity. Furthermore, the correlative relationship between craving and brain activity in reward-related regions was observed in a clinically relevant sample (treatment-seeking marijuana-dependent subjects). Results are consistent with prior findings in cocaine, heroin, nicotine, and alcohol cue studies, indicating that the brain substrates of cue-triggered drug motivation are shared across abused substances.

Brief Report: “Spiders-No, Puppies-Go”, Introducing a Novel Go NoGo Task tested in Inner City Adolescents at Risk for Poor Impulse Control

In adolescents, externalizing disorders and the syndrome of neurobehavioral disinhibition are a broad spectrum of disorders involving poor impulse control as a cardinal feature. These disorders are linked to substance use disorder (SUD), thus possibly representing a vulnerability to addiction (Kuperman et al., 2001; Tarter et al., 2003). With the eventual goal of assessing whether deficits of impulse control predate and/or potentially predispose to drug use, our laboratory studies impulsivity in adolescents who are at high risk for poor impulse control. The traditional Go NoGo task measures “rapid-response” impulsivity by evaluating the ability of a subject to inhibit a prepotent response when the subject is asked to respond to a series of rapidly presented Go stimuli and to withhold responding to less frequently presented NoGo stimuli (Horn, Dolan, Elliott, Deakin, & Woodruff, 2003). Responding to a NoGo stimulus, an error of commission, represents a failure to suppress the prepotent Go response, i.e. a failure of response inhibition, with more commission errors indicating greater impairment in response inhibition. Poor performance on a Go NoGo task has been demonstrated in populations with SUD (e.g. cocaine, opioids, and cigarette smoking) (Fillmore & Rush, 2002; Forman et al., 2004; Kaufman, Ross, Stein, & Garavan, 2003; Luijten, Littel, & Franken, 2011). We observed that the typical Go NoGo task was not engaging to our study populations, who typically have low levels of education and/or attention deficits. We suggest that this is because typical Go NoGo tasks utilize abstract stimuli such as letters of the alphabet (e.g. Go=X and NoGo=Y) or shapes (e.g. Go=circle and NoGo=square) (Mostofsky et al., 2003). Thus, we developed a Go NoGo task that uses approach/avoidance congruent pictures, e.g. appealing/ pleasant objects (baby animals) on Go trials, and unappealing/unpleasant objects (spiders) on NoGo trials. These stimuli have inherent ecological validity, as choosing the appropriate response to environmental stimuli is critical for survival (Chen & Bargh, 1999). We hypothesized that the use of approach/avoidance congruent pictures, rather than abstract stimuli (commonly used in the typical Go NoGo task) would facilitate better task engagement in our adolescent ‘at risk’ population. In this paper, we describe the development, reliability and construct validity of an Approach-Avoidance (A-A) Go NoGo task. The A-A Go NoGo task incorporates three levels of difficulty. This multi-level approach allows us to assess the validity of the task design because the number of commission errors should increase as the level of difficulty increases (de Zubicaray, Andrew, Zelaya, Williams, & Dumanoir, 2000; Durston, Thomas, Worden, Yang, & Casey, 2002). We piloted the A-A Go NoGo task in a cohort of socioeconomically deprived, inner city adolescents with low average IQ, at risk for poor impulse control, and examined whether the novel task correlated with observation based measures of impulsivity.