PMID- 24853771 OWN - NLM STAT- MEDLINE DCOM- 20150615 LR - 20211021 IS - 1740-634X (Electronic) IS - 0893-133X (Print) IS - 0893-133X (Linking) VI - 39 IP - 11 DP - 2014 Oct TI - Loss of BDNF signaling in D1R-expressing NAc neurons enhances morphine reward by reducing GABA inhibition. PG - 2646-53 LID - 10.1038/npp.2014.118 [doi] AB - The nucleus accumbens (NAc) has a central role in the mechanism of action of drugs of abuse. The major neuronal type within the NAc is the GABAergic medium spiny neuron (MSN), with two major subpopulations defined-termed D1-type and D2-type MSNs-based on the predominant dopamine receptor expressed. However, very little is known about the contribution of altered GABAergic function in NAc MSNs to the neural and behavioral plasticity that contributes to the lasting actions of drugs of abuse. In the present study, we show that GABAergic activity is selectively modulated in D1-type MSNs of the NAc by signaling of brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine receptor kinase B (TrkB), and that such adaptations control rewarding responses to morphine. Optical activation of D1-type MSNs, or the knockout of TrkB from D1-type MSNs (D1-TrkB KO), enhances morphine reward, effects not seen for D2-type MSNs. In addition, D1-TrkB KO mice, but not D2-TrkB KO mice, display decreased GABAA receptor (GABAAR) subunit expression and reduced spontaneous inhibitory postsynaptic currents (sIPSCs) in D1-type, but not D2-type, MSNs in the NAc. Furthermore, we found that GABAAR antagonism in the NAc enhances morphine reward and that morphine exposure decreases TrkB expression as well as GABAergic activity in D1-type MSNs. Together, these data provide evidence for the enhancement of morphine reward through reduction of inhibitory GABAAR responses, an adaptation mediated by morphine-induced reduction of BDNF-TrkB signaling in D1-type MSNs. FAU - Koo, Ja Wook AU - Koo JW AD - Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Lobo, Mary Kay AU - Lobo MK AD - Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA. FAU - Chaudhury, Dipesh AU - Chaudhury D AD - 1] Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA [2] Departments of Psychiatry and of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Labonte, Benoit AU - Labonte B AD - Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Friedman, Allyson AU - Friedman A AD - 1] Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA [2] Departments of Psychiatry and of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Heller, Elizabeth AU - Heller E AD - Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Pena, Catherine Jensen AU - Pena CJ AD - Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Han, Ming-Hu AU - Han MH AD - 1] Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA [2] Departments of Psychiatry and of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, NY, USA. FAU - Nestler, Eric J AU - Nestler EJ AD - Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. LA - eng GR - R01 MH092306/MH/NIMH NIH HHS/United States GR - R01 AA022445/AA/NIAAA NIH HHS/United States GR - R01 DA038613/DA/NIDA NIH HHS/United States GR - R01 DA014133/DA/NIDA NIH HHS/United States GR - T32 DA007135/DA/NIDA NIH HHS/United States GR - P01 DA008227/DA/NIDA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20140523 PL - England TA - Neuropsychopharmacology JT - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology JID - 8904907 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (GABA-A Receptor Antagonists) RN - 0 (Narcotics) RN - 0 (Receptors, Dopamine D1) RN - 0 (Receptors, Dopamine D2) RN - 0 (Receptors, GABA-A) RN - 56-12-2 (gamma-Aminobutyric Acid) RN - 76I7G6D29C (Morphine) RN - EC 2.7.10.1 (Receptor, trkB) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/*metabolism MH - GABA-A Receptor Antagonists/pharmacology MH - GABAergic Neurons/*drug effects/physiology MH - Inhibitory Postsynaptic Potentials/drug effects/physiology MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Morphine/*pharmacology MH - Narcotics/*pharmacology MH - Nucleus Accumbens/*drug effects/physiology MH - Receptor, trkB/genetics/metabolism MH - Receptors, Dopamine D1/*metabolism MH - Receptors, Dopamine D2/metabolism MH - Receptors, GABA-A/metabolism MH - Reward MH - Tissue Culture Techniques MH - gamma-Aminobutyric Acid/metabolism PMC - PMC4207344 EDAT- 2014/05/24 06:00 MHDA- 2015/06/16 06:00 PMCR- 2015/10/01 CRDT- 2014/05/24 06:00 PHST- 2014/03/03 00:00 [received] PHST- 2014/05/03 00:00 [revised] PHST- 2014/05/05 00:00 [accepted] PHST- 2014/05/24 06:00 [entrez] PHST- 2014/05/24 06:00 [pubmed] PHST- 2015/06/16 06:00 [medline] PHST- 2015/10/01 00:00 [pmc-release] AID - npp2014118 [pii] AID - 10.1038/npp.2014.118 [doi] PST - ppublish SO - Neuropsychopharmacology. 2014 Oct;39(11):2646-53. doi: 10.1038/npp.2014.118. Epub 2014 May 23.