Biological
Psychiatry
Background: Addiction is a chronically relapsing disorder.
Relapse can be precipitated by cues previously associated
with drug use. An underlying mechanism encompasses
enhanced attention to drug-cues. Event-Related Potentials
(ERPs) objectively quantified motivated attention to drug cues
as a function of abstinence and self-regulation in individuals
with cocaine use disorder (iCUD).
Methods: In the first study, 76 iCUD with varying durations of
abstinence (2 days, 1 week, 1 month, 6 months, and 1 year)
passively viewed cocaine-related pictures (drug cues) while
ERPs were acquired. In the second study, 37 iCUD and 23
healthy controls either viewed cocaine-related pictures nor-
mally or down-regulated their reactivity using cognitive reap-
praisal. ERPs were acquired during the task and eye-tracking
(during non-instructed picture gazing) was quantified immedi-
ately after each trial to assess change in motivated attention to
drug cues after self-regulation.
Results: Amplitude of the late positive potential (LPP)
component of the ERP, a measure of motivated attention and a
marker of drug-cue reactivity, showed an inverted U-shaped
trajectory, such that it increased from 2 days to 1- and 6-
months before declining at 1 year (quadratic contrast¼-1.13,
p¼.002). LPPs were reduced during reappraisal compared to
normal viewing of drug cues in iCUD (F¼6.56, p¼0.013);
reappraisal reduced spontaneous gaze duration during viewing
of drug-cues in iCUD (t¼2.47, p¼0.02).
Conclusions: Unlike self-reported craving, the LPP showed a
pattern consistent with incubation of cue-induced reactivity
during abstinence. Using cognitive reappraisal strategies
reduced such reactivity and generalized to predict reductions
in spontaneous attention to drug-cues in iCUD. Impact on
relapse prevention remains to be demonstrated.
Supported By: NIDA R01
Keywords: Cocaine Addiction, Craving, Event Related Po-
tentials, Relapse, LPP
10. Epigenetic Enzymes as Novel Therapeutic Targets
in Alcohol Addiction
Markus Heilig1, Claes Wahlestedt2, Estelle Barbier1, and
Andrea Johnstone2
1
Linköping University, 2University of Miami Miller School of
Medicine
Background: Gene expression in the mPFC is dysregulated in
alcohol dependence. We have discovered epigenetic enzymes
that take part in dependence-induced reprogramming of the
mPFC transcriptome, and may offer a novel class of thera-
peutic targets.
Methods: Alcohol dependence was induced using chronic
intermittent alcohol vapor exposure. RNA-sequencing was
used to screen the mPFC transcriptome for persistent differ-
ential expression of epigenetic enzymes. PRDM2 was differ-
entially expressed. Molecular consequences of its repression
were assessed by measuring H3K9 mono-methylation.
PRMD2 expression was knocked down in the mPFC of non-
dependent rats using a lenti-viral shRNA vector. Chip-Seq was
used to identify PRDM2 regulated target genes as downstream
mediators. Functional consequences on addiction-like traits
S4 Biological Psychiatry May 1, 2018; 83:S1eS107 www.sobp.org/journal
Plenary and Symposium Abstracts
were evaluated by assessing operant self-administration,
stress-induced reinstatement of alcohol seeking, and aversion-
resistant alcohol seeking.
Results: In dependent rats, the RNA-seq screen identified,
qPCR confirmed decreased expression of PRDM2 that was
confined to neurons. Alcohol-induced PRDM2 repression was
reversed by the DNA methyltransferase inhibitor RG108.
Conversely, PRDM2 knockdown in non-dependent rats
induced gene expression changes that overlapped with those
found following alcohol dependence. These were associated
with behavioral consequences otherwise seen following a
history of dependence, including escalated alcohol intake,
increased resistance to quinine adulteration, and enhanced
stress-induced reinstatement. Several genes that exhibited a
significant decrease in H3K9me1 enrichment following
dependence were identified in the ChIP-seq study, including
synaptotagmin 1 (Syt1). We confirmed H3K9me1 enrichment in
controls compared to post-dependent rats using ChIP-PCR.
All n>7, all p<0.05
Conclusions: PRDM2 controls behaviors that are critical in
alcoholism, and offers a novel therapeutic target.
Supported By: Swedish Research Council
Keywords: Alcohol Addiction, Epigenetics, Stress
11. Orexin-1 Receptor Antagonists as Novel Smoking
Cessation Agents
Paul Kenny1, Theodore Kamenecka1, George Voren1,
Alexander Duncan1, Matthew Howe1, Jonathan Hollander2,
Diane Damez-Warno1, Qun Lu2, Purva Bali1, Roland Burli3,
Ian Gurrell3, Robert J. Mather3, and Nicholas J. Brandon3
1
Icahn School of Medicine at Mount Sinai, 2The Scripps
Research Institute, 3Neuroscience Innovative Medicines,
AstraZeneca
Background: Orexin-1 receptors (OX1Rs) regulate the moti-
vation to seek and consume nicotine in laboratory rodents, but
underlying mechanisms are unclear. Here, we identify a novel
brain circuit through which OX1Rs exerts control over nicotine-
seeking behaviors. We also describe progress toward devel-
oping patient-ready OX1R antagonists as novel smoking
cessation agents.
Methods: Intravenous nicotine self-administration and Intra-
cranial self-stimulation thresholds were used to assess the
motivational and reward-related properties of nicotine,
respectively. DREADDs were used to chemogenetically acti-
vate or inhibit targeted neurons. Fiber photometry was used to
monitor orexin neuron activity. CHO cells stably expressing
OX1Rs were generated and intracellular calcium responses
were used to identify novel OX1R antagonists.
Results: Pharmacological or genetic disruption of OX1 re-
ceptor-mediated transmission decreased the motivation to
consume nicotine, and attenuated reinstatement of extin-
guished nicotine-seeking responses, in mice, rats and squirrel
monkeys. A population of previously unidentified OX1R-
regulated neurons in dorsal thalamus was shown to control
nicotine-seeking behaviors. These thalamic neurons do not
regulate reward-related actions of nicotine, but instead regu-
late the apparent “value” of the drug. Based on these findings,