title: Specific behavioral and cellular adaptations induced by chronic morphine are reduced by dietary omega-3 polyunsaturated fatty acids.
abstract: Opiates, one of the oldest known drugs, are the benchmark for treating pain. Regular opioid exposure also induces euphoria making these compounds addictive and often misused, as shown by the current epidemic of opioid abuse and overdose mortalities. In addition to the effect of opioids on their cognate receptors and signaling cascades, these compounds also induce multiple adaptations at cellular and behavioral levels. As omega-3 polyunsaturated fatty acids (n-3 PUFAs) play a ubiquitous role in behavioral and cellular processes, we proposed that supplemental n-3 PUFAs, enriched in docosahexanoic acid (DHA), could offset these adaptations following chronic opioid exposure. We used an 8 week regimen of n-3 PUFA supplementation followed by 8 days of morphine in the presence of this diet. We first assessed the effect of morphine in different behavioral measures and found that morphine increased anxiety and reduced wheel-running behavior. These effects were reduced by dietary n-3 PUFAs without affecting morphine-induced analgesia or hyperlocomotion, known effects of this opiate acting at mu opioid receptors. At the cellular level we found that morphine reduced striatal DHA content and that this was reversed by supplemental n-3 PUFAs. Chronic morphine also increased glutamatergic plasticity and the proportion of Grin2B-NMDARs in striatal projection neurons. This effect was similarly reversed by supplemental n-3 PUFAs. Gene analysis showed that supplemental PUFAs offset the effect of morphine on genes found in neurons of the dopamine receptor 2 (D2)-enriched indirect pathway but not of genes found in dopamine receptor 1(D1)-enriched direct-pathway neurons. Analysis of the D2 striatal connectome by a retrogradely transported pseudorabies virus showed that n-3 PUFA supplementation reversed the effect of chronic morphine on the innervation of D2 neurons by the dorsomedial prefontal and piriform cortices. Together these changes outline specific behavioral and cellular effects of morphine that can be reduced or reversed by dietary n-3 PUFAs.
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, California.|Brain Research Institute, University of California Los Angeles, Los Angeles, California.
authors.forename: Joshua
authors.initials: J
authors.lastname: Hakimian
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, California.|Brain Research Institute, University of California Los Angeles, Los Angeles, California.
authors.forename: Ani
authors.initials: A
authors.lastname: Minasyan
authors.affiliation: Brain Research Institute, University of California Los Angeles, Los Angeles, California.|UCLA Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, California.
authors.forename: Lily
authors.initials: L
authors.lastname: Zhe-Ying
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, California.|Brain Research Institute, University of California Los Angeles, Los Angeles, California.
authors.forename: Mariana
authors.initials: M
authors.lastname: Loureiro
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, California.|Brain Research Institute, University of California Los Angeles, Los Angeles, California.
authors.forename: Austin
authors.initials: A
authors.lastname: Beltrand
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, California.|Brain Research Institute, University of California Los Angeles, Los Angeles, California.
authors.forename: Camille
authors.initials: C
authors.lastname: Johnston
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, California.|Brain Research Institute, University of California Los Angeles, Los Angeles, California.
authors.forename: Alexander
authors.initials: A
authors.lastname: Vorperian
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, California.|Brain Research Institute, University of California Los Angeles, Los Angeles, California.
authors.forename: Nicole
authors.initials: N
authors.lastname: Romaneschi
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, California.|Brain Research Institute, University of California Los Angeles, Los Angeles, California.
authors.forename: Waleed
authors.initials: W
authors.lastname: Atallah
authors.affiliation: Brain Research Institute, University of California Los Angeles, Los Angeles, California.|UCLA Integrative Biology and Physiology, University of California Los Angeles, Los Angeles, California.
authors.forename: Fernando
authors.initials: F
authors.lastname: Gomez-Pinilla
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, California.|Brain Research Institute, University of California Los Angeles, Los Angeles, California.
authors.forename: Wendy
authors.identifier: http://orcid.org/0000-0003-1192-3065
authors.initials: W
authors.lastname: Walwyn
mesh_terms: D000818:Animals; D001007:Anxiety / Q000139:chemically induced; D003342:Corpus Striatum / Q000737:chemistry; D004334:Drug Administration Schedule; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology*; D005260:Female; D005625:Frontal Lobe / Q000737:chemistry; D008055:Lipids / Q000032:analysis; D008124:Locomotion / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D060888:Real-Time Polymerase Chain Reaction; D017470:Receptors, Glutamate / Q000032:analysis
chemical_list: D015525:Fatty Acids, Omega-3; D008055:Lipids; D017470:Receptors, Glutamate; D009020:Morphine