BDNF Is a Negative Modulator of Morphine Action

Koo, Ja Wook; Mazei-Robison, Michelle S.; Chaudhury, Dipesh; Juarez, Barbara; LaPlant, Quincey; Ferguson, Deveroux; Feng, Jian; Sun, HaoSheng; Scobie, Kimberly N.; Damez-Werno, Diane; Crumiller, Marshall; Ohnishi, Yoshinori N.; Mouzon, Ezekiell; Dietz, David M.; Lobo, Mary Kay; Neve, Rachael L.; Russo, Scott J.; Han, Ming; Nestler, Eric J.

doi:10.1126/science.1222265

Cited by 164 publications

(167 citation statements)

References 56 publications

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“…Mice were given 1-week recovery before conditioned place preference (CPP) experiments. For in vivo optical stimulation, a modified 200-mm core optic fiber (Thor labs, with B50 mm of the stripped optic fiber exposed below the cannula) were attached through an FC/PC adaptor to a 473-nm blue laser diode (BCL-473-050-M, Crystal Lasers), and light pulses were generated through a stimulator (33220A, Agilent; Koo et al, 2012;Lobo et al, 2010). Ten Hertz blue light pulses (100 ms square width) were delivered for four 3-min periods (one period consists of 3 min on and 5 min off) during the 30-min conditioning.…”

Section: Stereotaxic Surgery Virus and Drug Infusion And Optogenetimentioning

confidence: 99%

“…An unbiased CPP paradigm was used as previously described (Koo et al, 2012;Lobo et al, 2010). Mice were evaluated for morphine or morphine/blue light CPP in a three-chamber CPP box using the Med Associates software.…”

Section: Morphine Cppmentioning

confidence: 99%

“…For standard morphine CPP, mice were conditioned to one chamber for 45 min in the morning (saline) and to the opposite chamber in the afternoon (15 mg/kg morphine, sc or ip) over 3 days. The dose was chosen based on a dose-response analysis of morphine CPP in a previous study (Koo et al, 2012). On day 5, the CPP test day, mice were allowed to freely explore all three chambers for 20 min.…”

Section: Morphine Cppmentioning

confidence: 99%

“…Although a growing body of evidence demonstrates some shared and some distinct molecular, cellular, and circuit mechanisms between psychostimulant and opiate action (Albertson et al, 2006;Badiani et al, 2011;Chang et al, 1998;Koo et al, 2012;Nestler, 2005), the contribution of D1-type vs D2-type NAc MSNs to morphine reward remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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Loss of BDNF Signaling in D1R-Expressing NAc Neurons Enhances Morphine Reward by Reducing GABA Inhibition

Koo

Lobo

Chaudhury

et al. 2014

Neuropsychopharmacol

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102

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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 GABA A receptor (GABA A R) subunit expression and reduced spontaneous inhibitory postsynaptic currents (sIPSCs) in D1-type, but not D2-type, MSNs in the NAc. Furthermore, we found that GABA A R 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 GABA A R responses, an adaptation mediated by morphine-induced reduction of BDNF-TrkB signaling in D1-type MSNs.

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Section: Stereotaxic Surgery Virus and Drug Infusion And Optogenetimentioning

confidence: 99%

Section: Morphine Cppmentioning

confidence: 99%

Section: Morphine Cppmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Loss of BDNF Signaling in D1R-Expressing NAc Neurons Enhances Morphine Reward by Reducing GABA Inhibition

Koo

Lobo

Chaudhury

et al. 2014

Neuropsychopharmacol

Self Cite

102

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show abstract

“…5 In the present work we focus our analysis on another popular gene in behavioral genetics, highly important in neurodevelopment and in system-level neural phenotypes and sensitive to environmental factors, the gene coding for the Brain Derived Neurotrophic Factor (BDNF). BDNF is a highly regulated protein, a crucial factor for the development of the feto-placental unit 6 and of the brain, 7 as well as for neural plasticity, energy metabolism, learning, episodic and working memory (WM) [7][8][9][10][11][12] and cancer. 13 The effects of BDNF on synaptic plasticity and neuron survival strongly suggest a role for this factor in schizophrenia, a neurodevelopmental disorder whose risk is heritable and characterized by physiological prefrontal cortex (PFC) dysfunction during WM, [14][15][16] as well as reduced prefrontal levels of BDNF.…”

Section: Introductionmentioning

confidence: 99%

BDNF rs6265 methylation and genotype interact on risk for schizophrenia

et al. 2016

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Epigenetic mechanisms can mediate gene-environment interactions relevant for complex disorders. The BDNF gene is crucial for development and brain plasticity, is sensitive to environmental stressors, such as hypoxia, and harbors the functional SNP rs6265 (Val 66 Met), which creates or abolishes a CpG dinucleotide for DNA methylation. We found that methylation at the BDNF rs6265 Val allele in peripheral blood of healthy subjects is associated with hypoxia-related early life events (hOCs) and intermediate phenotypes for schizophrenia in a distinctive manner, depending on rs6265 genotype: in ValVal individuals increased methylation is associated with exposure to hOCs and impaired working memory (WM) accuracy, while the opposite is true for ValMet subjects. Also, rs6265 methylation and hOCs interact in modulating WM-related prefrontal activity, another intermediate phenotype for schizophrenia, with an analogous opposite direction in the 2 genotypes. Consistently, rs6265 methylation has a different association with schizophrenia risk in ValVals and ValMets. The relationships of methylation with BDNF levels and of genotype with BHLHB2 binding likely contribute to these opposite effects of methylation. We conclude that BDNF rs6265 methylation interacts with genotype to bridge early environmental exposures to adult phenotypes, relevant for schizophrenia. The study of epigenetic changes in regions containing genetic variation relevant for human diseases may have beneficial implications for the understanding of how genes are actually translated into phenotypes.

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Neuronal Network Plasticity and Recovery From Depression

2013

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The brain processes sensory information in neuronal networks that are shaped by experience, particularly during early life, to optimally represent the internal and external milieu. Recent surprising findings have revealed that antidepressant drugs reactivate a window of juvenile-like plasticity in the adult cortex. When antidepressant-induced plasticity was combined with appropriate rehabilitation, it brought about a functional recovery of abnormally wired neuronal networks. These observations suggest that antidepressants act permissively to facilitate environmental influence on neuronal network reorganization and so provide a plausible neurobiological explanation for the enhanced effect of combining antidepressant treatment with psychotherapy. The results emphasize that pharmacological and psychological treatments of mood disorders are closely entwined: The effect of antidepressant-induced plasticity is facilitated by rehabilitation, such as psychotherapy, that guides the plastic networks, and psychotherapy benefits from the enhanced plasticity provided by the drug treatment. Optimized combinations of pharmacological and psychological treatments might help make best use of existing antidepressant drugs and reduce the number of treatment-resistant patients. The network hypothesis of antidepressant action presented here proposes that recovery from depression and related mood disorders is a gradual process that develops slowly and is facilitated by structured guidance and rehabilitation.

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BDNF Is a Negative Modulator of Morphine Action

Cited by 164 publications

References 56 publications

Loss of BDNF Signaling in D1R-Expressing NAc Neurons Enhances Morphine Reward by Reducing GABA Inhibition

Loss of BDNF Signaling in D1R-Expressing NAc Neurons Enhances Morphine Reward by Reducing GABA Inhibition

BDNF rs6265 methylation and genotype interact on risk for schizophrenia

Neuronal Network Plasticity and Recovery From Depression

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