1932

Abstract

In the past decade, emerging synthetic biology technologies such as chemogenetics have dramatically transformed how pharmacologists and systems biologists deconstruct the involvement of G protein–coupled receptors (GPCRs) in a myriad of physiological and translational settings. Here we highlight a specific chemogenetic application that extends the utility of the concept of RASSLs (receptors activated solely by synthetic ligands): We have dubbed it DREADDs (designer receptors exclusively activated by designer drugs). As we show in this review, DREADDs are now used ubiquitously to modulate GPCR activity noninvasively in vivo. Results from these studies have directly implicated GPCR signaling in a large number of therapeutically relevant contexts. We also highlight recent applications of DREADD technology that have illuminated GPCR signaling processes that control pathways relevant to the treatment of eating disorders, obesity, and obesity-associated metabolic abnormalities. Additionally, we provide an overview of the potential utility of chemogenetic technologies for transformative therapeutics.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pharmtox-010814-124803
2015-01-06
2024-06-15
Loading full text...

Full text loading...

/deliver/fulltext/pharmtox/55/1/annurev-pharmtox-010814-124803.html?itemId=/content/journals/10.1146/annurev-pharmtox-010814-124803&mimeType=html&fmt=ahah

Literature Cited

  1. Forkmann G, Dangelmayr B. 1.  1980. Genetic control of chalcone isomerase activity in flowers of Dianthus caryophyllus. Biochem. Genet. 18:519–27 [Google Scholar]
  2. Strobel SA, Ortoleva-Donnelly L, Ryder SP, Cate JH, Moncoeur E. 2.  1998. Complementary sets of noncanonical base pairs mediate RNA helix packing in the group I intron active site. Nat. Struct. Biol. 5:60–66 [Google Scholar]
  3. Bishop AC, Shah K, Liu Y, Witucki L, Kung C, Shokat KM. 3.  1998. Design of allele-specific inhibitors to probe protein kinase signaling. Curr. Biol. 8:257–66 [Google Scholar]
  4. Liu Y, Shah K, Yang F, Witucki L, Shokat KM. 4.  1998. Engineering Src family protein kinases with unnatural nucleotide specificity. Chem. Biol. 5:91–101 [Google Scholar]
  5. Collot J, Gradinaru J, Humbert N, Skander M, Zocchi A, Ward TR. 5.  2003. Artificial metalloenzymes for enantioselective catalysis based on biotin-avidin. J. Am. Chem. Soc. 125:9030–31 [Google Scholar]
  6. Häring D, Distefano MD. 6.  2001. Enzymes by design: chemogenetic assembly of transamination active sites containing lysine residues for covalent catalysis. Bioconjug. Chem. 12:385–90 [Google Scholar]
  7. Klein G, Humbert N, Gradinaru J, Ivanova A, Gilardoni F. 7.  et al. 2005. Tailoring the active site of chemzymes by using a chemogenetic-optimization procedure: towards substrate-specific artificial hydrogenases based on the biotin-avidin technology. Angew. Chem. Int. Ed. Engl. 44:7764–67 [Google Scholar]
  8. Strader CD, Gaffney T, Sugg EE, Candelore MR, Keys R. 8.  et al. 1991. Allele-specific activation of genetically engineered receptors. J. Biol. Chem. 266:5–8 [Google Scholar]
  9. Coward P, Wada HG, Falk MS, Chan SD, Meng F. 9.  et al. 1998. Controlling signaling with a specifically designed Gi-coupled receptor. Proc. Natl. Acad. Sci. USA 95:352–57 [Google Scholar]
  10. Westkaemper RB, Hyde EG, Choudhary MS, Khan N, Gelbar EI. 10.  et al. 1999. Engineering in a region of bulk tolerance in the 5-HT2A receptor. Eur. J. Med. Chem. 34:441–47 [Google Scholar]
  11. Conklin BR, Hsiao EC, Claeysen S, Dumuis A, Srinivasan S. 11.  et al. 2008. Engineering GPCR signaling pathways with RASSLs. Nat. Methods 5:673–78 [Google Scholar]
  12. Jacobson KA, Gao ZG, Chen A, Barak D, Kim SA. 12.  et al. 2001. Neoceptor concept based on molecular complementarity in GPCRs: a mutant adenosine A3 receptor with selectively enhanced affinity for amine-modified nucleosides. J. Med. Chem. 44:4125–36 [Google Scholar]
  13. Armbruster B, Roth B. 13.  2005. Creation of designer biogenic amine receptors via directed molecular evolution. Neuropsychopharmacology 30:Suppl. S1S265 [Google Scholar]
  14. Armbruster BN, Li X, Pausch MH, Herlitze S, Roth BL. 14.  2007. Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand. Proc. Natl. Acad. Sci. USA 104:5163–68 [Google Scholar]
  15. Dong S, Rogan SC, Roth BL. 15.  2010. Directed molecular evolution of DREADDs: a generic approach to creating next-generation RASSLs. Nat. Protoc. 5:561–73 [Google Scholar]
  16. Abdul-Ridha A, Lane JR, Sexton PM, Canals M, Christopoulos A. 16.  2013. Allosteric modulation of a chemogenetically modified G protein-coupled receptor. Mol. Pharmacol. 83:521–30 [Google Scholar]
  17. Canals M, Lane JR, Wen A, Scammells PJ, Sexton PM, Christopoulos A. 17.  2012. A Monod-Wyman-Changeux mechanism can explain G protein-coupled receptor (GPCR) allosteric modulation. J. Biol. Chem. 287:650–59 [Google Scholar]
  18. Guettier JM, Gautam D, Scarselli M, Ruiz de Azua I, Li JH. 18.  et al. 2009. A chemical-genetic approach to study G protein regulation of β cell function in vivo. Proc. Natl. Acad. Sci. USA 106:19197–202 [Google Scholar]
  19. Alexander GM, Rogan SC, Abbas AI, Armbruster BN, Pei Y. 19.  et al. 2009. Remote control of neuronal activity in transgenic mice expressing evolved G protein-coupled receptors. Neuron 63:27–39 [Google Scholar]
  20. Agulhon C, Boyt KM, Xie AX, Friocourt F, Roth BL, McCarthy KD. 20.  2013. Modulation of the autonomic nervous system and behaviour by acute glial cell Gq protein-coupled receptor activation in vivo. J. Physiol. 591:5599–609 [Google Scholar]
  21. Li JH, Jain S, McMillin SM, Cui Y, Gautam D. 21.  et al. 2013. A novel experimental strategy to assess the metabolic effects of selective activation of a Gq-coupled receptor in hepatocytes in vivo. Endocrinology 154:3539–51 [Google Scholar]
  22. Jain S, Ruiz de Azua I, Lu H, White MF, Guettier JM, Wess J. 22.  2013. Chronic activation of a designer Gq-coupled receptor improves β cell function. J. Clin. Investig. 123:1750–62 [Google Scholar]
  23. Becnel J, Johnson O, Majeed ZR, Tran V, Yu B. 23.  et al. 2013. DREADDs in Drosophila: a pharmacogenetic approach for controlling behavior, neuronal signaling, and physiology in the fly. Cell Rep. 4:1049–59 [Google Scholar]
  24. Alvarez-Curto E, Ward RJ, Pediani JD, Milligan G. 24.  2011. Ligand regulation of the quaternary organization of cell surface M3 muscarinic acetylcholine receptors analyzed by fluorescence resonance energy transfer (FRET) imaging and homogeneous time-resolved FRET. J. Biol. Chem. 285:23318–30 [Google Scholar]
  25. Alvarez-Curto E, Prihandoko R, Tautermann CS, Zwier JM, Pediani JD. 25.  et al. 2011. Developing chemical genetic approaches to explore G protein-coupled receptor function: validation of the use of a receptor activated solely by synthetic ligand (RASSL). Mol. Pharmacol. 80:1033–46 [Google Scholar]
  26. Krashes MJ, Koda S, ChianPing Y, Rogan SC, Adams AC. 26.  et al. 2011. Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J. Clin. Investig. 121:41424–28 [Google Scholar]
  27. Krashes MJ, Shah BP, Koda S, Lowell BB. 27.  2013. Rapid versus delayed stimulation of feeding by the endogenously released AgRP neuron mediators GABA, NPY, and AgRP. Cell Metab. 18:588–95 [Google Scholar]
  28. Kong D, Tong Q, Ye C, Koda S, Fuller PM. 28.  et al. 2012. GABAergic RIP-Cre neurons in the arcuate nucleus selectively regulate energy expenditure. Cell 151:645–57 [Google Scholar]
  29. Atasoy D, Betley JN, Su HH, Sternson SM. 29.  2012. Deconstruction of a neural circuit for hunger. Nature 488:172–77 [Google Scholar]
  30. Pei Y, Rogan SC, Yan F, Roth BL. 30.  2008. Engineered GPCRs as tools to modulate signal transduction. Physiology 23:313–21 [Google Scholar]
  31. Rogan SC, Roth BL. 31.  2011. Remote control of neuronal signaling. Pharmacol. Rev. 63:291–315 [Google Scholar]
  32. Nawaratne V, Leach K, Suratman N, Loiacono RE, Felder CC. 32.  et al. 2008. New insights into the function of M4 muscarinic acetylcholine receptors gained using a novel allosteric modulator and a DREADD (designer receptor exclusively activated by a designer drug). Mol. Pharmacol. 74:1119–31 [Google Scholar]
  33. Reuveny E, Slesinger PA, Inglese J, Morales JM, Iniguez-Lluhi JA. 33.  et al. 1994. Activation of the cloned muscarinic potassium channel by G protein βγ subunits. Nature 370:143–46 [Google Scholar]
  34. Kunkel MT, Peralta EG. 34.  1995. Identification of domains conferring G protein regulation on inward rectifier potassium channels. Cell 83:443–49 [Google Scholar]
  35. Ferguson SM, Eskenazi D, Ishikawa M, Wanat MJ, Phillips PE. 35.  et al. 2011. Transient neuronal inhibition reveals opposing roles of indirect and direct pathways in sensitization. Nat. Neurosci. 14:22–24 [Google Scholar]
  36. Yagi H, Tan W, Dillenburg-Pilla P, Armando S, Amornphimoltham P. 36.  et al. 2011. A synthetic biology approach reveals a CXCR4-G13-Rho signaling axis driving transendothelial migration of metastatic breast cancer cells. Sci. Signal 4:ra60 [Google Scholar]
  37. Stachniak TJ, Ghosh A, Sternson SM. 37.  2013. Chemical genetic presynaptic inhibition selectively silences axon collaterals in a central hunger circuit Presented at Soc. Neurosci. Annu. Meet., Nov. 9–13, San Diego [Google Scholar]
  38. Farrell MS, Pei Y, Wan Y, Yadav PN, Daigle TL. 38.  et al. 2013. A Gαs DREADD mouse for selective modulation of cAMP production in striatopallidal neurons. Neuropsychopharmacology 38:854–62 [Google Scholar]
  39. Ferguson SM, Phillips PE, Roth BL, Wess J, Neumaier JF. 39.  2013. Direct-pathway striatal neurons regulate the retention of decision-making strategies. J. Neurosci. 33:11668–76 [Google Scholar]
  40. Majeed ZR, Nichols CD, Cooper RL. 40.  2013. 5-HT stimulation of heart rate in Drosophila does not act through cAMP as revealed by pharmacogenetics. J. Appl. Physiol. 115:1656–65 [Google Scholar]
  41. Nakajima KI, Wess J. 41.  2012. Design and functional characterization of a novel, arrestin-biased designer G protein-coupled receptor. Mol. Pharmacol. 82:4575–82 [Google Scholar]
  42. Schnütgen F, Doerflinger N, Calléja C, Wendling O, Chambon P, Ghyselinck NB. 42.  2003. A directional strategy for monitoring Cre-mediated recombination at the cellular level in the mouse. Nat. Biotechnol. 21:562–65 [Google Scholar]
  43. Atasoy D, Aponte Y, Su HH, Sternson SM. 43.  2008. A FLEX switch targets channelrhodopsin-2 to multiple cell types for imaging and long-range circuit mapping. J. Neurosci. 28:7025–30 [Google Scholar]
  44. Kuhlman SJ, Huang ZJ. 44.  2008. High-resolution labeling and functional manipulation of specific neuron types in mouse brain by Cre-activated viral gene expression. PLoS ONE 3:e2005 [Google Scholar]
  45. Aponte Y, Atasoy D, Sternson SM. 45.  2011. AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nat. Neurosci. 14:351–55 [Google Scholar]
  46. Sasaki K, Suzuki M, Mieda M, Tsujino N, Roth B, Sakurai T. 46.  2011. Pharmacogenetic modulation of orexin neurons alters sleep/wakefulness states in mice. PLoS ONE 6:e20360 [Google Scholar]
  47. Michaelides M, Anderson SA, Ananth M, Smirnov D, Thanos PK. 47.  et al. 2013. Whole-brain circuit dissection in free-moving animals reveals cell-specific mesocorticolimbic networks. J. Clin. Investig. 123:5342–50 [Google Scholar]
  48. Anderson SA, Michaelides M, Zarnegar P, Ren Y, Fagergren P. 48.  et al. 2013. Impaired periamygdaloid-cortex prodynorphin is characteristic of opiate addiction and depression. J. Clin. Investig. 123:5334–41 [Google Scholar]
  49. Carter ME, Soden ME, Zweifel LS, Palmiter RD. 49.  2013. Genetic identification of a neural circuit that suppresses appetite. Nature 503:111–14 [Google Scholar]
  50. Ray RS, Corcoran AE, Brust RD, Soriano LP, Nattie EE, Dymecki SM. 50.  2012. Egr2-neurons control the adult respiratory response to hypercapnia. Brain Res. 1511:115–25 [Google Scholar]
  51. Ray RS, Corcoran AE, Brust RD, Kim JC, Richerson GB. 51.  et al. 2011. Impaired respiratory and body temperature control upon acute serotonergic neuron inhibition. Science 333:637–42 [Google Scholar]
  52. Zhan C, Zhou J, Feng Q, Zhang JE, Lin S. 52.  et al. 2013. Acute and long-term suppression of feeding behavior by POMC neurons in the brainstem and hypothalamus, respectively. J. Neurosci. 33:3624–32 [Google Scholar]
  53. Halford JC, Lawton CL, Blundell JE. 53.  1997. The 5-HT2 receptor agonist MK-212 reduces food intake and increases resting but prevents the behavioural satiety sequence. Pharmacol. Biochem. Behav. 56:41–46 [Google Scholar]
  54. Clineschmidt BV, Hanson HM, Pflueger AB, McGuffin JC. 54.  1977. Anorexigenic and ancillary actions of MK-212 (6-chloro-2-[1-piperazinyl]-pyrazine; CPP). Psychopharmacology 55:27–33 [Google Scholar]
  55. Wurtman JJ, Wurtman RJ. 55.  1977. Fenfluramine and fluoxetine spare protein consumption while suppressing caloric intake by rats. Science 198:1178–80 [Google Scholar]
  56. Fletcher PJ, Tampakeras M, Sinyard J, Slassi A, Isaac M, Higgins GA. 56.  2009. Characterizing the effects of 5-HT2C receptor ligands on motor activity and feeding behaviour in 5-HT2C receptor knockout mice. Neuropharmacology 57:259–67 [Google Scholar]
  57. Weintraub M, Hasday JD, Mushlin AI, Lockwood DH. 57.  1984. A double-blind clinical trial in weight control: use of fenfluramine and phentermine alone and in combination. Arch. Intern. Med. 144:1143–48 [Google Scholar]
  58. Berger M, Gray JA, Roth BL. 58.  2009. The expanded biology of serotonin. Annu. Rev. Med. 60:355–66 [Google Scholar]
  59. Meltzer HY, Roth BL. 59.  2013. Lorcaserin and pimavanserin: emerging selectivity of serotonin receptor subtype-targeted drugs. J. Clin. Investig. 123:4986–91 [Google Scholar]
  60. Vickers SP, Clifton PG, Dourish CT, Tecott LH. 60.  1999. Reduced satiating effect of d-fenfluramine in serotonin 5-HT2C receptor mutant mice. Psychopharmacology 143:309–14 [Google Scholar]
  61. Rothman RB, Baumann MH, Savage JE, Rauser L, McBride A. 61.  et al. 2000. Evidence for possible involvement of 5-HT2B receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation 102:2836–41 [Google Scholar]
  62. Setola V, Hufeisen SJ, Grande-Allen KJ, Vesely I, Glennon RA. 62.  et al. 2003. 3,4-Methylenedioxy-methamphetamine (MDMA, “Ecstasy”) induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro. Mol. Pharmacol. 63:1223–29 [Google Scholar]
  63. Setola V, Dukat M, Glennon RA, Roth BL. 63.  2005. Molecular determinants for the interaction of the valvulopathic anorexigen norfenfluramine with the 5-HT2B receptor. Mol. Pharmacol. 68:20–33 [Google Scholar]
  64. Huang XP, Setola V, Yadav PN, Allen JA, Rogan SC. 64.  et al. 2009. Parallel functional activity profiling reveals valvulopathogens are potent 5-hydroxytryptamine2B receptor agonists: implications for drug safety assessment. Mol. Pharmacol. 76:710–22 [Google Scholar]
  65. Roth BL. 65.  2007. Drugs and valvular heart disease. N. Engl. J. Med. 356:6–9 [Google Scholar]
  66. Fidler MC, Sanchez M, Raether B, Weissman NJ, Smith SR. 66.  et al. 2011. A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: the BLOSSOM trial. J. Clin. Endocrinol. Metab. 96:3067–77 [Google Scholar]
  67. Smith SR, Weissman NJ, Anderson CM, Sanchez M, Chuang E. 67.  et al. 2010. Multicenter, placebo-controlled trial of lorcaserin for weight management. N. Engl. J. Med. 363:245–56 [Google Scholar]
  68. Thomsen WJ, Grottick AJ, Menzaghi F, Reyes-Saldana H, Espitia S. 68.  et al. 2008. Lorcaserin, a novel selective human 5-hydroxytryptamine2C agonist: in vitro and in vivo pharmacological characterization. J. Pharmacol. Exp. Ther. 325:577–87 [Google Scholar]
  69. Heisler LK, Cowley MA, Tecott LH, Fan W, Low MJ. 69.  et al. 2002. Activation of central melanocortin pathways by fenfluramine. Science 297:609–11 [Google Scholar]
  70. Xu Y, Jones JE, Kohno D, Williams KW, Lee CE. 70.  et al. 2008. 5-HT2CRs expressed by pro-opiomelanocortin neurons regulate energy homeostasis. Neuron 60:582–89 [Google Scholar]
  71. Xu Y, Jones JE, Lauzon DA, Anderson JG, Balthasar N. 71.  et al. 2010. A serotonin and melanocortin circuit mediates D-fenfluramine anorexia. J. Neurosci. 30:14630–34 [Google Scholar]
  72. Conn PJ, Sanders-Bush E, Hoffman BJ, Hartig PR. 72.  1986. A unique serotonin receptor in choroid plexus is linked to phosphatidylinositol turnover. Proc. Natl. Acad. Sci. USA 83:4086–88 [Google Scholar]
  73. Ren H, Orozco IJ, Su Y, Suyama S, Gutierrez-Juarez R. 73.  et al. 2012. FoxO1 target Gpr17 activates AgRP neurons to regulate food intake. Cell 149:1314–26 [Google Scholar]
  74. Hennen S, Wang H, Peters L, Merten N, Simon K. 74.  et al. 2013. Decoding signaling and function of the orphan G protein–coupled receptor GPR17 with a small-molecule agonist. Sci. Signal 6:ra93 [Google Scholar]
  75. Gomes I, Aryal DK, Wardman JH, Gupta A, Gagnidze K. 75.  et al. 2013. GPR171 is a hypothalamic G protein-coupled receptor for BigLEN, a neuropeptide involved in feeding. Proc. Natl. Acad. Sci. USA 110:16211–16 [Google Scholar]
  76. Doyle JP, Dougherty JD, Heiman M, Schmidt EF, Stevens TR. 76.  et al. 2008. Application of a translational profiling approach for the comparative analysis of CNS cell types. Cell 135:749–62 [Google Scholar]
  77. Heiman M, Schaefer A, Gong S, Peterson JD, Day M. 77.  et al. 2008. A translational profiling approach for the molecular characterization of CNS cell types. Cell 135:738–48 [Google Scholar]
  78. Spaethling JM, Piel D, Dueck H, Buckley PT, Morris JF. 78.  et al. 2014. Serotonergic neuron regulation informed by in vivo single-cell transcriptomics. FASEB J. 28:771–80 [Google Scholar]
  79. Snead AN, Insel PA. 79.  2012. Defining the cellular repertoire of GPCRs identifies a profibrotic role for the most highly expressed receptor, protease-activated receptor 1, in cardiac fibroblasts. FASEB J. 26:4540–47 [Google Scholar]
  80. Lovatt D, Ruble BK, Lee J, Dueck H, Kim TK. 80.  et al. 2014. Transcriptome in vivo analysis (TIVA) of spatially defined single cells in live tissue. Nat. Methods 11:190–96 [Google Scholar]
  81. Deisseroth K, Schnitzer MJ. 81.  2013. Engineering approaches to illuminating brain structure and dynamics. Neuron 80:3568–77 [Google Scholar]
  82. Lee H, Brott BK, Kirkby LA, Adelson JD, Cheng S. 82.  et al. 2014. Synapse elimination and learning rules co-regulated by MHC class I H2-Db. Nature 509:7499195–200 [Google Scholar]
  83. Brancaccio M, Maywood ES, Chesham JE, Loudon AS, Hastings MH. 83.  2013. A Gq-Ca2+ axis controls circuit-level encoding of circadian time in the suprachiasmatic nucleus. Neuron 78:714–28 [Google Scholar]
  84. Saito YC, Tsujino N, Hasegawa E, Akashi K, Abe M. 84.  et al. 2013. GABAergic neurons in the preoptic area send direct inhibitory projections to orexin neurons. Front. Neural Circuits 7:192 [Google Scholar]
  85. Kuhlman SJ, Olivas ND, Tring E, Ikrar T, Xu X, Trachtenberg JT. 85.  2013. A disinhibitory microcircuit initiates critical-period plasticity in the visual cortex. Nature 501:543–46 [Google Scholar]
  86. Kozorovitskiy Y, Saunders A, Johnson CA, Lowell BB, Sabatini BL. 86.  2012. Recurrent network activity drives striatal synaptogenesis. Nature 485:646–50 [Google Scholar]
  87. Jann MW, Lam YW, Chang WH. 87.  1994. Rapid formation of clozapine in guinea-pigs and man following clozapine-N-oxide administration. Arch. Int. Pharmacodyn. Ther. 328:243–50 [Google Scholar]
  88. Bender D, Holschbach M, Stocklin G. 88.  1994. Synthesis of n.c.a. carbon-11 labelled clozapine and its major metabolite clozapine-N-oxide and comparison of their biodistribution in mice. Nucl. Med. Biol. 21:921–25 [Google Scholar]
  89. Boyden ES, Zhang F, Bamberg E, Nagel G, Deisseroth K. 89.  2005. Millisecond-timescale, genetically targeted optical control of neural activity. Nat. Neurosci. 8:1263–68 [Google Scholar]
  90. Li X, Gutierrez DV, Hanson MG, Han J, Mark MD. 90.  et al. 2005. Fast noninvasive activation and inhibition of neural and network activity by vertebrate rhodopsin and green algae channelrhodopsin. Proc. Natl. Acad. Sci. USA 102:17816–21 [Google Scholar]
  91. Zhang F, Wang LP, Brauner M, Liewald JF, Kay K. 91.  et al. 2007. Multimodal fast optical interrogation of neural circuitry. Nature 446:633–39 [Google Scholar]
  92. Drago J, Padungchaichot P, Wong JY, Lawrence AJ, McManus JF. 92.  et al. 1998. Targeted expression of a toxin gene to D1 dopamine receptor neurons by Cre-mediated site-specific recombination. J. Neurosci. 18:9845–57 [Google Scholar]
  93. Vrontou S, Wong AM, Rau KK, Koerber HR, Anderson DJ. 93.  2013. Genetic identification of C fibres that detect massage-like stroking of hairy skin in vivo. Nature 493:669–73 [Google Scholar]
  94. Bock R, Shin JH, Kaplan AR, Dobi A, Markey E. 94.  et al. 2013. Strengthening the accumbal indirect pathway promotes resilience to compulsive cocaine use. Nat. Neurosci. 16:632–38 [Google Scholar]
  95. Wang S, Tan Y, Zhang JE, Luo M. 95.  2013. Pharmacogenetic activation of midbrain dopaminergic neurons induces hyperactivity. Neurosci. Bull. 29:517–24 [Google Scholar]
  96. Cassataro D, Bergfeldt D, Malekian C, Van Snellenberg JX, Thanos PK. 96.  et al. 2013. Reverse pharmacogenetic modulation of the nucleus accumbens reduces ethanol consumption in a limited access paradigm. Neuropsychopharmacology 39:283–90 [Google Scholar]
  97. Alam MR, Ming X, Nakagawa O, Jin J, Juliano RL. 97.  2013. Covalent conjugation of oligonucleotides with cell-targeting ligands. Bioorg. Med. Chem. 21:6217–23 [Google Scholar]
  98. Garner AR, Rowland DC, Hwang SY, Baumgaertel K, Roth BL. 98.  et al. 2012. Generation of a synthetic memory trace. Science 335:1513–16 [Google Scholar]
  99. Parnaudeau S, O'Neill PK, Bolkan SS, Ward RD, Abbas AI. 99.  et al. 2013. Inhibition of mediodorsal thalamus disrupts thalamofrontal connectivity and cognition. Neuron 77:1151–62 [Google Scholar]
  100. Li H, Penzo MA, Taniguchi H, Kopec CD, Huang ZJ, Li B. 100.  2013. Experience-dependent modification of a central amygdala fear circuit. Nat. Neurosci. 16:332–39 [Google Scholar]
  101. Gremel CM, Costa RM. 101.  2013. Orbitofrontal and striatal circuits dynamically encode the shift between goal-directed and habitual actions. Nat. Commun. 4:2264 [Google Scholar]
  102. Nunez-Parra A, Maurer RK, Krahe K, Smith RS, Araneda RC. 102.  2013. Disruption of centrifugal inhibition to olfactory bulb granule cells impairs olfactory discrimination. Proc. Natl. Acad. Sci. USA 110:14777–82 [Google Scholar]
  103. Silva BA, Mattucci C, Krzywkowski P, Murana E, Illarionova A. 103.  et al. 2013. Independent hypothalamic circuits for social and predator fear. Nat. Neurosci. 16:1731–33 [Google Scholar]
  104. Ferguson SM, Eskenazi D, Ishikawa M, Wanat MJ, Phillips PEM. 104.  et al. 2011. Transient neuronal inhibition reveals opposing roles of indirect and direct pathways in sensitization. Nat. Neurosci. 14:122–24 [Google Scholar]
/content/journals/10.1146/annurev-pharmtox-010814-124803
Loading
/content/journals/10.1146/annurev-pharmtox-010814-124803
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error