Biological

Psychiatry Plenary and Symposium Abstracts

Background: Addiction is a chronically relapsing disorder. were evaluated by assessing operant self-administration,
Relapse can be precipitated by cues previously associated stress-induced reinstatement of alcohol seeking, and aversion-
with drug use. An underlying mechanism encompasses resistant alcohol seeking.
enhanced attention to drug-cues. Event-Related Potentials Results: In dependent rats, the RNA-seq screen identified,
(ERPs) objectively quantified motivated attention to drug cues qPCR confirmed decreased expression of PRDM2 that was
as a function of abstinence and self-regulation in individuals confined to neurons. Alcohol-induced PRDM2 repression was
with cocaine use disorder (iCUD). reversed by the DNA methyltransferase inhibitor RG108.
Methods: In the first study, 76 iCUD with varying durations of Conversely, PRDM2 knockdown in non-dependent rats
abstinence (2 days, 1 week, 1 month, 6 months, and 1 year) induced gene expression changes that overlapped with those
passively viewed cocaine-related pictures (drug cues) while found following alcohol dependence. These were associated
ERPs were acquired. In the second study, 37 iCUD and 23 with behavioral consequences otherwise seen following a
healthy controls either viewed cocaine-related pictures nor- history of dependence, including escalated alcohol intake,
mally or down-regulated their reactivity using cognitive reap- increased resistance to quinine adulteration, and enhanced
praisal. ERPs were acquired during the task and eye-tracking stress-induced reinstatement. Several genes that exhibited a
(during non-instructed picture gazing) was quantified immedi- significant decrease in H3K9me1 enrichment following
ately after each trial to assess change in motivated attention to dependence were identified in the ChIP-seq study, including
drug cues after self-regulation. synaptotagmin 1 (Syt1). We confirmed H3K9me1 enrichment in
Results: Amplitude of the late positive potential (LPP) controls compared to post-dependent rats using ChIP-PCR.
component of the ERP, a measure of motivated attention and a All n>7, all p<0.05
marker of drug-cue reactivity, showed an inverted U-shaped Conclusions: PRDM2 controls behaviors that are critical in
trajectory, such that it increased from 2 days to 1- and 6- alcoholism, and offers a novel therapeutic target.
months before declining at 1 year (quadratic contrast¼-1.13, Supported By: Swedish Research Council
p¼.002). LPPs were reduced during reappraisal compared to Keywords: Alcohol Addiction, Epigenetics, Stress
normal viewing of drug cues in iCUD (F¼6.56, p¼0.013);
reappraisal reduced spontaneous gaze duration during viewing 11. Orexin-1 Receptor Antagonists as Novel Smoking
of drug-cues in iCUD (t¼2.47, p¼0.02). Cessation Agents
Conclusions: Unlike self-reported craving, the LPP showed a Paul Kenny1, Theodore Kamenecka1, George Voren1,
pattern consistent with incubation of cue-induced reactivity Alexander Duncan1, Matthew Howe1, Jonathan Hollander2,
during abstinence. Using cognitive reappraisal strategies Diane Damez-Warno1, Qun Lu2, Purva Bali1, Roland Burli3,
reduced such reactivity and generalized to predict reductions Ian Gurrell3, Robert J. Mather3, and Nicholas J. Brandon3
in spontaneous attention to drug-cues in iCUD. Impact on
relapse prevention remains to be demonstrated. 1
Icahn School of Medicine at Mount Sinai, 2The Scripps
Supported By: NIDA R01
Research Institute, 3Neuroscience Innovative Medicines,
Keywords: Cocaine Addiction, Craving, Event Related Po-
AstraZeneca
tentials, Relapse, LPP

10. Epigenetic Enzymes as Novel Therapeutic Targets Background: Orexin-1 receptors (OX1Rs) regulate the moti-
in Alcohol Addiction vation to seek and consume nicotine in laboratory rodents, but
underlying mechanisms are unclear. Here, we identify a novel
Markus Heilig1, Claes Wahlestedt2, Estelle Barbier1, and brain circuit through which OX1Rs exerts control over nicotine-
Andrea Johnstone2 seeking behaviors. We also describe progress toward devel-
oping patient-ready OX1R antagonists as novel smoking
1
Linköping University, 2University of Miami Miller School of cessation agents.
Medicine Methods: Intravenous nicotine self-administration and Intra-
cranial self-stimulation thresholds were used to assess the
Background: Gene expression in the mPFC is dysregulated in motivational and reward-related properties of nicotine,
alcohol dependence. We have discovered epigenetic enzymes respectively. DREADDs were used to chemogenetically acti-
that take part in dependence-induced reprogramming of the vate or inhibit targeted neurons. Fiber photometry was used to
mPFC transcriptome, and may offer a novel class of thera- monitor orexin neuron activity. CHO cells stably expressing
peutic targets. OX1Rs were generated and intracellular calcium responses
Methods: Alcohol dependence was induced using chronic were used to identify novel OX1R antagonists.
intermittent alcohol vapor exposure. RNA-sequencing was Results: Pharmacological or genetic disruption of OX1 re-
used to screen the mPFC transcriptome for persistent differ- ceptor-mediated transmission decreased the motivation to
ential expression of epigenetic enzymes. PRDM2 was differ- consume nicotine, and attenuated reinstatement of extin-
entially expressed. Molecular consequences of its repression guished nicotine-seeking responses, in mice, rats and squirrel
were assessed by measuring H3K9 mono-methylation. monkeys. A population of previously unidentified OX1R-
PRMD2 expression was knocked down in the mPFC of non- regulated neurons in dorsal thalamus was shown to control
dependent rats using a lenti-viral shRNA vector. Chip-Seq was nicotine-seeking behaviors. These thalamic neurons do not
used to identify PRDM2 regulated target genes as downstream regulate reward-related actions of nicotine, but instead regu-
mediators. Functional consequences on addiction-like traits late the apparent “value” of the drug. Based on these findings,

S4 Biological Psychiatry May 1, 2018; 83:S1eS107 www.sobp.org/journal