Loss of BDNF signaling in D1R-expressing NAc neurons enhances morphine reward by reducing GABA inhibition.
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.
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Ja Wook
JW
Koo
Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA.
Mary Kay
MK
Lobo
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.
Dipesh
D
Chaudhury
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Benoit
B
Labonté
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.
Allyson
A
Friedman
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Elizabeth
E
Heller
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Catherine Jensen
CJ
Peña
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.
Ming-Hu
MH
Han
Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Eric J
EJ
Nestler
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D059330:GABAergic Neurons / Q000187:drug effects* / Q000502:physiology; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000502:physiology; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D012201:Reward; D046509:Tissue Culture Techniques; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D058787:GABA-A Receptor Antagonists; D009294:Narcotics; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D009020:Morphine; D020813:Receptor, trkB