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Advanced Transgenic Approaches to Understand Alcohol-Related Phenotypes in Animals

  • Ainhoa BilbaoEmail author
Chapter
Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 13)

Abstract

During the past two decades, the use of genetically manipulated animal models in alcohol research has greatly improved the understanding of the mechanisms underlying alcohol addiction. In this chapter, we present an overview of the progress made in this field by summarizing findings obtained from studies of mice harboring global and conditional mutations in genes that influence alcohol-related phenotypes. The first part reviews behavioral paradigms for modeling the different phases of the alcohol addiction cycle and other alocohol-induced behavioral phenotypes in mice. The second part reviews the current data available using genetic models targeting the main neurotransmitter and neuropeptide systems involved in the reinforcement and stress pathways, focusing on the phenotypes modeling the alcohol addiction cycle. Finally, the third part will discuss the current findings and future directions, and proposes advanced transgenic mouse models for their potential use in alcohol research.

Keywords

Genetics Conditional knock-outs Behavior Alcohol addiction cycle Initiation Maintenance Craving Relapse Brain neurotransmitter systems 

Abbreviations

2AG

2-arachidonoyl glycerol

5HT

Serotonin

5HTT

Serotonin transporter

ADE

Alcohol deprivation effect

ACTH

Adrenocorticotropic hormone

AEA

Anandamide

CNS

Central nervous system

CORT

Cosrticosterone

CRF

Corticotropin releasing factor

CTA

Conditioned taste aversion

CPP

Conditioned place preference

DAGL

Diacylglycerol lipase

DAT

Dopamine transporter

DID

Drinking in the dark

ECS

Endocannabinoid system

FAAH

Fatty acid amide hidrolase

GP

Globus pallidus

HIC

Handling-induced convulsions

HPA

Hypothalamic-pituitary adrenal axis

KD

Knock-down

KI

Knock-in

KO

Knock-out

LORR

Loss of righting reflex

MAGL

Monoacyl glycerol lipase

Sert

Serotonin

THC

Delta (9)Tetrahydrocannabinol

Transg + 

Transgene overexpression

VTA

Ventral Tegmental Area

References

  1. Alsiö J, Nordenankar K, Arvidsson E, Birgner C, Mahmoudi S, Halbout B, Smith C, Fortin GM, Olson L, Descarries L, Trudeau LÉ, Kullander K, Lévesque D, Wallén-Mackenzie A (2011) Enhanced sucrose and cocaine self-administration and cue-induced drug seeking after loss of VGLUT2 in midbrain dopamine neurons in mice. J Neurosci 31:12593–12603PubMedGoogle Scholar
  2. Badanich KA, Doremus-Fitzwater TL, Mulholland PJ, Randall PK, Delpire E, Becker HC (2011) NR2B-deficient mice are more sensitive to the locomotor stimulant and depressant effects of ethanol. Genes Brain Behav 10:805–816Google Scholar
  3. Bahi A (2011) The pre-synaptic metabotropic glutamate receptor 7 “mGluR7” is a critical modulator of ethanol sensitivity in mice. Neuroscience 199C:13–23Google Scholar
  4. Basavarajappa BS, Yalamanchili R, Cravatt BF, Cooper TB, Hungund BL (2006) Increased ethanol consumption and preference and decreased ethanol sensitivity in female FAAH knock-out mice. Neuropharmacology 50:834–844PubMedGoogle Scholar
  5. Becker A, Grecksch G, Kraus J, Loh HH, Schroeder H, Höllt V (2002) Rewarding effects of ethanol and cocaine in mu opioid receptor-deficient mice. Naunyn Schmiedebergs Arch Pharmacol 365:296–302PubMedGoogle Scholar
  6. Belin D, Mar AC, Dalley JW, Robbins TW, Everitt BJ (2008) High impulsivity predicts the switch to compulsive cocaine-taking. Science 320:1352–1355PubMedCentralPubMedGoogle Scholar
  7. Bengel D, Murphy DL, Andrews AM, Wichems CH, Feltner D, Heils A, Mössner R, Westphal H, Lesch KP (1998) Altered brain serotonin homeostasis and locomotor insensitivity to 3, 4-methylenedioxymethamphetamine (“Ecstasy”) in serotonin transporter-deficient mice. Mol Pharmacol 53:649–655PubMedGoogle Scholar
  8. Berry RB, Chandra D, Diaz-Granados JL, Homanics GE, Matthews DB (2009) Investigation of ethanol-induced impairment of spatial memory in gamma2 heterozygous knock-out mice. Neurosci Lett 455:84–87PubMedCentralPubMedGoogle Scholar
  9. Bird MK, Kirchhoff J, Djouma E, Lawrence AJ (2008) Metabotropic glutamate 5 receptors regulate sensitivity to ethanol in mice. Int J Neuropsychopharmacol 11:765–774PubMedGoogle Scholar
  10. Blednov YA, Borghese CM, McCracken ML, Benavidez JM, Geil CR, Osterndorff-Kahanek E, Werner DF, Iyer S, Swihart A, Harrison NL, Homanics GE, Harris RA (2011) Loss of ethanol conditioned taste aversion and motor stimulation in knockin mice with ethanol-insensitive α2-containing GABA(A) receptors. J Pharmacol Exp Ther 336:145–154PubMedGoogle Scholar
  11. Blednov YA, Cravatt BF, Boehm SL 2nd, Walker D, Harris RA (2007) Role of endocannabinoids in alcohol consumption and intoxication: studies of mice lacking fatty acid amide hydrolase. Neuropsychopharmacology 32:1570–1582PubMedGoogle Scholar
  12. Blednov YA, Harris RA (2008) Metabotropic glutamate receptor 5 (mGluR5) regulation of ethanol sedation, dependence and consumption: relationship to acamprosateactions. Int J Neuropsychopharmacol 11:775–793PubMedCentralPubMedGoogle Scholar
  13. Blednov YA, Jung S, Alva H, Wallace D, Rosahl T, Whiting PJ, Harris RA (2003a) Deletion of the alpha1 or beta2 subunit of GABAA receptors reduces actions of alcohol and other drugs. J Pharmacol Exp Ther 304:30–36PubMedGoogle Scholar
  14. Blednov YA, Walker D, Alva H, Creech K, Findlay G, Harris RA (2003b) GABAA receptor alpha 1 and beta 2 subunit null mutant mice: behavioral responses to ethanol. J Pharmacol Exp Ther 305:854–863PubMedGoogle Scholar
  15. Blednov YA, Walker D, Martinez M, Harris RA (2006) Reduced alcohol consumption in mice lacking preprodynorphin. Alcohol 40:73–86PubMedCentralPubMedGoogle Scholar
  16. Blednov YA, Walker D, Osterndorf-Kahanek E, Harris RA (2004) Mice lacking metabotropic glutamate receptor 4 do not show the motor stimulatory effect of ethanol. Alcohol 34:251–259PubMedGoogle Scholar
  17. Blednov YA, Walker DL, Iyer SV, Homanics G, Harris AR (2010) Mice lacking Gad2 show altered behavioral effects of ethanol, flurazepam and gabaxadol. Addict Biol 15:45–61PubMedCentralPubMedGoogle Scholar
  18. Boehm SL 2nd, Schafer GL, Phillips TJ, Browman KE, Crabbe JC (2000) Sensitivity to ethanol-induced motor incoordination in 5-HT(1B) receptor null mutant mice is task-dependent: implications for behavioral assessment of genetically altered mice. Behav Neurosci 114:401–409PubMedGoogle Scholar
  19. Boehm SL 2nd, Peden L, Harris RA, Blednov YA (2004) Deletion of the fyn-kinase gene alters sensitivity to GABAergic drugs: dependence on beta2/beta3 GABAA receptor subunits. J Pharmacol Exp Ther 309(3):1154–1159 [Epub: 5 Feb, 2004]PubMedGoogle Scholar
  20. Bonasera SJ, Chu HM, Brennan TJ, Tecott LH (2006) A null mutation of the serotonin 6 receptor alters acute responses to ethanol. Neuropsychopharmacology 31:1801–1813 [Epub: 1 Feb, 2006]PubMedGoogle Scholar
  21. Borghese CM, Werner DF, Topf N, Baron NV, Henderson LA, Boehm SL 2nd, Blednov YA, Saad A, Dai S, Pearce RA, Harris RA, Homanics GE, Harrison NL (2006) An isoflurane- and alcohol-insensitive mutant GABA (A) receptor alpha (1) subunit with near-normal apparent affinity for GABA: characterization in heterologous systems and production of knockin mice. J Pharmacol Exp Ther 319:208–218 [Epub: 28 June, 2006]PubMedGoogle Scholar
  22. Bouwknecht JA, Hijzen TH, van der Gugten J, Maes RA, Hen R, Olivier B (2000) Ethanol intake is not elevated in male 5-HT (1B) receptor knock-out mice. Eur J Pharmacol 403:95–98PubMedGoogle Scholar
  23. Boyce-Rustay JM, Holmes A (2006) Ethanol-related behaviors in mice lacking the NMDA receptor NR2A subunit. Psychopharmacology 187:455–466PubMedGoogle Scholar
  24. Boyce-Rustay JM, Holmes A (2005) Functional roles of NMDA receptor NR2A and NR2B subunits in the acute intoxicating effects of ethanol in mice. Synapse 56:222–225PubMedGoogle Scholar
  25. Boyce-Rustay JM, Risinger FO (2003) Dopamine D3 receptor knock-out mice and the motivational effects of ethanol. Pharmacol Biochem Behav 75:373–379PubMedGoogle Scholar
  26. Boyce-Rustay JM, Wiedholz LM, Millstein RA, Carroll J, Murphy DL, Daws LC, Holmes A (2006) Ethanol-related behaviors in serotonin transporter knock-out mice. Alcohol Clin Exp Res 30:1957–1965PubMedGoogle Scholar
  27. Buckley NE, McCoy KL, Mezey E, Bonner T, Zimmer A, Felder CC, Glass M, Zimmer A (2000) Immunomodulation by cannabinoids is absent in mice deficient for the cannabinoid CB (2) receptor. Eur J Pharmacol 396:141–149PubMedGoogle Scholar
  28. Bulwa ZB, Sharlin JA, Clark PJ, Bhattacharya TK, Kilby CN, Wang Y, Rhodes JS (2011) Increased consumption of ethanol and sugar water in mice lacking the dopamine D2 long receptor. Alcohol 45:631–639 [Epub: 31 July, 2011]PubMedCentralPubMedGoogle Scholar
  29. Cai YQ, Cai GQ, Liu GX, Cai Q, Shi JH, Shi J, Ma SK, Sun X, Sheng ZJ, Mei ZT, Cui D, Guo L, Wang Z, Fei J (2006) Mice with genetically altered GABA transporter subtype I (GAT1) expression show altered behavioral responses to ethanol. J Neurosci Res 84:255–267PubMedGoogle Scholar
  30. Camp MC, Feyder M, Ihne J, Palachick B, Hurd B, Karlsson RM, Noronha B, Chen YC, Coba MP, Grant SG, Holmes A (2011) A novel role for PSD-95 in mediating ethanol intoxication, drinking and place preference. Addict Biol 16:428–439PubMedCentralPubMedGoogle Scholar
  31. Chandra D, Jia F, Liang J, Peng Z, Suryanarayanan A, Werner DF, Spigelman I, Houser CR, Olsen RW, Harrison NL, Homanics GE (2006) GABAA receptor alpha 4 subunits mediate extrasynaptic inhibition in thalamus and dentate gyrus and the action of gaboxadol. Proc Natl Acad Sci USA 103:15230–15235PubMedGoogle Scholar
  32. Chandra D, Korpi ER, Miralles CP, De Blas AL, Homanics GE (2005) GABAA receptor gamma 2 subunit knock-down mice have enhanced anxiety-like behavior but unaltered hypnotic response to benzodiazepines. BMC Neurosci 6:30PubMedCentralPubMedGoogle Scholar
  33. Chandra D, Werner DF, Liang J, Suryanarayanan A, Harrison NL, Spigelman I, Olsen RW, Homanics GE (2008) Normal acute behavioral responses to moderate/high dose ethanol in GABAA receptor alpha 4 subunit knock-out mice. Alcohol Clin Exp Res 32:10–18PubMedCentralPubMedGoogle Scholar
  34. Chen J, Nam HW, Lee MR, Hinton DJ, Choi S, Kim T, Kawamura T, Janak PH, Choi DS (2010) Altered glutamatergic neurotransmission in the striatum regulates ethanol sensitivity and intake in mice lacking ENT1. Behav Brain Res 208:636–642PubMedCentralPubMedGoogle Scholar
  35. Choi DS, Cascini MG, Mailliard W, Young H, Paredes P, McMahon T, Diamond I, Bonci A, Messing RO (2004) The type 1 equilibrative nucleoside transporter regulates ethanol intoxication and preference. Nat Neurosci 7:855–861PubMedGoogle Scholar
  36. Chu K, Koob GF, Cole M, Zorrilla EP, Roberts AJ (2007) Dependence-induced increases in ethanol self-administration in mice are blocked by the CRF1 receptor antagonist antalarmin and by CRF1 receptor knock-out. Pharmacol Biochem Behav 86:813–821PubMedCentralPubMedGoogle Scholar
  37. Collison N, Kuenzi FM, Jarolimek W, Maubach KA, Cothliff R, Sur C, Smith A, Out FM, Howell O, Atack JR, McKernan RM, Seabrook GR, Dawson GR, Withing PJ, Rosahl TW (2002) Enhamced learning and memory and altered GABAergic synaptic transmission in mice lacking the alpha 5 subunit of the GABAA receptor. J Neurosc 22:5572–5580Google Scholar
  38. Coste SC, Kesterson RA, Heldwein KA, Stevens SL, Heard AD, Hollis JH, Murray SE, Hill JK, Pantely GA, Hohimer AR, Hatton DC, Phillips TJ, Finn DA, Low MJ, Rittenberg MB, Stenzel P, Stenzel-Poore MP (2000) Abnormal adaptations to stress and impaired cardiovascular function in mice lacking corticotropin-releasing hormone receptor-2. Nat Genet 24:403–409PubMedGoogle Scholar
  39. Cowen MS, Schroff KC, Gass P, Sprengel R, Spanagel R (2003) Neurobehavioral effects of alcohol in AMPA receptor subunit (GluR1) deficient mice. Neuropharmacology 45:325–333PubMedGoogle Scholar
  40. Crabbe JC, Bell RL, Ehlers CL (2010a) Human and laboratory rodent low response to alcohol: is better consilience possible? Addict Biol 15:125–144 ReviewGoogle Scholar
  41. Crabbe JC, Phillips TJ, Belknap JK (2010b) The complexity of alcohol drinking: studies in rodent genetic models. Behav Genet 40:737–750 ReviewGoogle Scholar
  42. Crabbe JC, Phillips TJ, Feller DJ, Hen R, Wenger CD, Lessov CN, Schafer GL (1996) Elevated alcohol consumption in null mutant mice lacking 5-HT1B serotonin receptors. Nat Genet 14:98–101PubMedGoogle Scholar
  43. Crabbe JC, Phillips TJ, Harris RA, Arends MA, Koob GF (2006) Alcohol-related genes: contributions from studies with genetically engineered mice. Addict Biol 11:195–269 ReviewGoogle Scholar
  44. Crabbe JC, Wahlsten D, Dudek BC (1999) Genetics of mouse behavior: interactions with laboratory environment. Science 284:1670–1672PubMedGoogle Scholar
  45. Cravatt BF, Demarest K, Patricelli MP, Bracey MH, Giang DK, Martin BR, Lichtman AH (2001) Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc Natl Acad Sci USA 98:9371–9376PubMedGoogle Scholar
  46. Cravatt BF, Saghatelian A, Hawkins EG, Clement AB, Bracey MH, Lichtman AH (2004) Functional disassociation of the central and peripheral fatty acid amide signaling systems. Proc Natl Acad Sci USA 101:10821–10826PubMedGoogle Scholar
  47. Cunningham CL, Howard MA, Gill SJ, Rubinstein M, Low MJ, Grandy DK (2000) Ethanol-conditioned place preference is reduced in dopamine D2 receptor-deficient mice. Pharmacol Biochem Behav 67:693–699PubMedGoogle Scholar
  48. Daws LC, Montañez S, Munn JL, Owens WA, Baganz NL, Boyce-Rustay JM, Millstein RA, Wiedholz LM, Murphy DL, Holmes A (2006) Ethanol inhibits clearance of brain serotonin by a serotonin transporter-independent mechanism. J Neurosci 26:6431–6438PubMedGoogle Scholar
  49. Deroche-Gamonet V, Belin D, Piazza PV (2004) Evidence for addiction-like behavior in the rat. Science 305:1014–1017PubMedGoogle Scholar
  50. Downing C, Marks MJ, Larson C, Johnson TE (2010) The metabotropic glutamate receptor subtype 5 mediates sensitivity to the sedative properties of ethanol. Pharmacogenet Genomics 20:553–564PubMedCentralPubMedGoogle Scholar
  51. Drago J, Gerfen CR, Lachowicz JE, Steiner H, Hollon TR, Love PE, Ooi GT, Grinberg A, Lee EJ, Huang SP et al (1994) Altered striatal function in a mutant mouse lacking D1A dopamine receptors. Proc Natl Acad Sci USA 91:12564–12568PubMedGoogle Scholar
  52. Dubreucq S, Kambire S, Conforzi M, Metna-Laurent M, Cannich A, Soria-Gomez E, Richard E, Marsicano G, Chaouloff F (2011) Cannabinoid type 1 receptors located on single-minded 1-expressing neurons control emotional behaviors. Neuroscience [Epub ahead of print]Google Scholar
  53. El-Ghundi M, George SR, Drago J, Fletcher PJ, Fan T, Nguyen T, Liu C, Sibley DR, Westphal H, O’Dowd BF (1998) Disruption of dopamine D1 receptor gene expression attenuates alcohol-seeking behavior. Eur J Pharmacol 353:149–158PubMedGoogle Scholar
  54. Engblom D, Bilbao A, Sanchis-Segura C, Dahan L, Perreau-Lenz S, Balland B, Parkitna JR, Luján R, Halbout B, Mameli M, Parlato R, Sprengel R, Lüscher C, Schütz G, Spanagel R (2008) Glutamate receptors on dopamine neurons control the persistence of cocaine seeking. Neuron 59:497–508PubMedGoogle Scholar
  55. Engel SR, Allan AM (1999) 5-HT3 receptor over-expression enhances ethanol sensitivity in mice. Psychopharmacology (Berl) 144:411–415Google Scholar
  56. Engel SR, Lyons CR, Allan AM (1998) 5-HT3 receptor over-expression decreases ethanol self administration in transgenic mice. Psychopharmacology (Berl) 140:243–248Google Scholar
  57. Falzone TL, Gelman DM, Young JI, Grandy DK, Low MJ, Rubinstein M (2002) Absence of dopamine D4 receptors results in enhanced reactivity to unconditioned, but not conditioned, fear. Eur J Neurosci 15:158–164PubMedGoogle Scholar
  58. Femenía T, Manzanares J (2011) Increased ethanol intake in prodynorphin knock-out mice is associated to changes in opioid receptor function and dopamine transmission. Addict Biol [Epub ahead of print]Google Scholar
  59. Ferguson C, Hardy SL, Werner DF, Hileman SM, Delorey TM, Homanics GE (2007) New insight into the role of the beta3 subunit of the GABAA-R in development, behavior, body weight regulation, and anesthesia revealed by conditional gene knock-out. BMC Neurosci 10(8):85Google Scholar
  60. Filliol D, Ghozland S, Chluba J, Martin M, Matthes HW, Simonin F, Befort K, Gavériaux-Ruff C, Dierich A, LeMeur M, Valverde O, Maldonado R, Kieffer BL (2000) Mice deficient for delta- and mu-opioid receptors exhibit opposing alterations of emotional responses. Nat Genet 25:195–200PubMedGoogle Scholar
  61. Gao Y, Vasilyev DV, Goncalves MB, Howell FV, Hobbs C, Reisenberg M, Shen R, Zhang MY, Strassle BW, Lu P, Mark L, Piesla MJ, Deng K, Kouranova EV, Ring RH, Whiteside GT, Bates B, Walsh FS, Williams G, Pangalos MN, Samad TA, Doherty P (2010) Loss of retrograde endocannabinoid signaling and reduced adult neurogenesis in diacylglycerol lipase knock-out mice. J Neurosci 30:2017–2024PubMedGoogle Scholar
  62. Gaveriaux-Ruff C, Nozaki C, Nadal X, Hever XC, Weibel R, Matifas A, Reiss D, Filliol D, Nassar MA, Wood JN, Maldonado R, Kieffer BL (2011) Genetic ablation of delta opioid receptors in nociceptive sensory neurons increases chronic pain and abolishes opioid analgesia. Pain 152:1238–1248PubMedGoogle Scholar
  63. Ghozland S, Chu K, Kieffer BL, Roberts AJ (2005) Lack of stimulant and anxiolytic-like effects of ethanol and accelerated development of ethanol dependence in mu-opioid receptor knock-out mice. Neuropharmacology 49:493–501PubMedGoogle Scholar
  64. Giros B, Jaber M, Jones SR, Wightman RM, Caron MG (1996) Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter. Nature 379:606–612PubMedGoogle Scholar
  65. Gorwood P, Aissi F, Batel P, Adès J, Cohen-Salmon C, Hamon M, Boni C, Lanfumey L (2002) Reappraisal of the serotonin 5-HT(1B) receptor gene in alcoholism: of mice and men. Brain Res Bull 57:103–107PubMedGoogle Scholar
  66. Grahame NJ, Low MJ, Cunningham CL (1998) Intravenous self-administration of ethanol in beta-endorphin-deficient mice. Alcohol Clin Exp Res 22:1093–1098PubMedGoogle Scholar
  67. Grahame NJ, Mosemiller AK, Low MJ, Froehlich JC (2000) Naltrexone and alcohol drinking in mice lacking beta-endorphin by site-directed mutagenesis. Pharmacol Biochem Behav 67:759–766PubMedGoogle Scholar
  68. Grisel JE, Bartels JL, Allen SA, Turgeon VL (2008) Influence of beta-Endorphin on anxious behavior in mice: interaction with EtOH. Psychopharmacology (Berl) 200:105–115Google Scholar
  69. Grisel JE, Mogil JS, Grahame NJ, Rubinstein M, Belknap JK, Crabbe JC, Low MJ (1999) Ethanol oral self-administration is increased in mutant mice with decreased beta-endorphin expression. Brain Res 835:62–67PubMedGoogle Scholar
  70. Gyetvai B, Simonyi A, Oros M, Saito M, Smiley J, Vadász C (2011) mGluR7 genetics and alcohol: intersection yields clues for addiction. Neurochem Res 36:1087–1100PubMedGoogle Scholar
  71. Hall FS, Sora I, Uhl GR (2001) Ethanol consumption and reward are decreased in mu-opiate receptor knock-out mice. Psychopharmacology (Berl) 154:43–49Google Scholar
  72. Hall FS, Sora I, Uhl GR (2003) Sex-dependent modulation of ethanol consumption in vesicular monoamine transporter 2 (VMAT2) and dopamine transporter (DAT) knock-out mice. Neuropsychopharmacology 28:620–628PubMedGoogle Scholar
  73. Haller C, Casanova E, Müller M, Vacher CM, Vigot R, Doll T, Barbieri S, Gassmann M, Bettler B (2004) Floxed allele for conditional inactivation of the GABAB(1) gene. Genesis 40:125–130PubMedGoogle Scholar
  74. Hansen HH, Krutz B, Sifringer M, Stefovska V, Bittigau P, Pragst F, Marsicano G, Lutz B, Ikonomidou C (2008) Cannabinoids enhance susceptibility of immature brain to ethanol neurotoxicity. Ann Neurol 64:42–52PubMedGoogle Scholar
  75. Harris RA, Osterndorff-Kahanek E, Ponomarev I, Homanics GE, Blednov YA (2011) Testing the silence of mutations: transcriptomic and behavioral studies of GABA(A) receptor α1 and α2 subunit knock-in mice. Neurosci Lett 488:31–35 [Epub: 5 Nov, 2010]PubMedCentralPubMedGoogle Scholar
  76. Harrison SJ, Nobrega JN (2009) Differential susceptibility to ethanol and amphetamine sensitization in dopamine D3 receptor-deficient mice. Psychopharmacology (Berl) 204:49–59Google Scholar
  77. Hayward MD, Hansen ST, Pintar JE, Low MJ (2004) Operant self-administration of ethanol in C57BL/6 mice lacking beta-endorphin and enkephalin. Pharmacol Biochem Behav 79(1):171–181PubMedGoogle Scholar
  78. Helinski S, Spanagel R (2011) Publication trends in addiction research. Addict Biol 16:532–539PubMedGoogle Scholar
  79. Heilig M, Egli M, Crabbe JC, Becker HC (2010) Acute withdrawal, protracted abstinence and negative affect in alcoholism: are they linked? Addict Biol 15:169–184 ReviewGoogle Scholar
  80. Heilig M, Koob GF (2007) A key role for corticotropin-releasing factor in alcohol dependence. Trends Neurosci 30:399–406 ReviewGoogle Scholar
  81. Hodge CW, Kelley SP, Bratt AM, Iller K, Schroeder JP, Besheer J (2004) 5-HT(3A) receptor subunit is required for 5-HT3 antagonist-induced reductions in alcohol drinking. Neuropsychopharmacology 29:1807–1813PubMedGoogle Scholar
  82. Homanics GE, DeLorey TM, Firestone LL, Quinlan JJ, Handforth A, Harrison NL, Krasowski MD, Rick CE, Korpi ER, Mäkelä R, Brilliant MH, Hagiwara N, Ferguson C, Snyder K, Olsen RW (1997) Mice devoid of gamma-aminobutyrate type a receptor beta3 subunit have epilepsy, cleft palate, and hypersensitive behavior. Proc Natl Acad Sci USA 94:4143–4148PubMedGoogle Scholar
  83. Homanics GE, Harrison NL, Quinlan JJ, Krasowski MD, Rick CE, de Blas AL, Mehta AK, Kist F, Mihalek RM, Aul JJ, Firestone LL (1999) Normal electrophysiological and behavioral responses to ethanol in mice lacking the long splice variant of the gamma2 subunit of the gamma-aminobutyrate type a receptor. Neuropharmacology 38:253–265PubMedCentralPubMedGoogle Scholar
  84. Homanics GE, Le NQ, Kist F, Mihalek R, Hart AR, Quinlan JJ (1998) Ethanol tolerance and withdrawal responses in GABA(A) receptor alpha 6 subunit null allele mice and in inbred C57BL/6 J and strain 129/SvJ mice. Alcohol Clin Exp Res 22:259–265PubMedGoogle Scholar
  85. Houchi H, Babovic D, Pierrefiche O, Ledent C, Daoust M, Naassila M (2005) CB1 receptor knock-out mice display reduced ethanol-induced conditioned place preference and increased striatal dopamine D2 receptors. Neuropsychopharmacology 30:339–349PubMedGoogle Scholar
  86. Hu JH, Ma YH, Yang N, Mei ZT, Zhang MH, Fei J, Guo LH (2004) Up-regulation of gamma-aminobutyric acid transporter I mediates ethanol sensitivity in mice. Neuroscience 123:807–812PubMedGoogle Scholar
  87. Hungund BL, Szakall I, Adam A, Basavarajappa BS, Vadasz C (2003) Cannabinoid CB1 receptor knock-out mice exhibit markedly reduced voluntary alcohol consumption and lack alcohol-induced dopamine release in the nucleus accumbens. J Neurochem 84:698–704PubMedGoogle Scholar
  88. Iyer SV, Benavides RA, Chandra D, Cook JM, Rallapalli S, June HL, Homanics GE (2011) α4-Containing GABA(A) Receptors are Required for Antagonism of Ethanol-Induced Motor Incoordination and Hypnosis by the Imidazobenzodiazepine Ro15-4513. Front Pharmacol 2:18PubMedCentralPubMedGoogle Scholar
  89. Job MO, Ramachandra V, Anders S, Low MJ, Gonzales RA (2006) Reduced basal and ethanol stimulation of striatal extracellular dopamine concentrations in dopamine D2 receptor knock-out mice. Synapse 60:158–164PubMedGoogle Scholar
  90. Job MO, Tang A, Hall FS, Sora I, Uhl GR, Bergeson SE, Gonzales RA (2007) Mu (mu) opioid receptor regulation of ethanol-induced dopamine response in the ventral striatum: evidence of genotype specific sexual dimorphic epistasis. Biol Psychiatry 62:627–634PubMedCentralPubMedGoogle Scholar
  91. Jones A, Korpi ER, McKernan RM, Pelz R, Nusser Z, Mäkelä R, Mellor JR, Pollard S, Bahn S, Stephenson FA, Randall AD, Sieghart W, Somogyi P, Smith AJ, Wisden W (1997) Ligand-gated ion channel subunit partnerships: GABAA receptor alpha6 subunit gene inactivation inhibits delta subunit expression. J Neurosci 17:1350–1362PubMedGoogle Scholar
  92. June HL Sr, Foster KL, Eiler WJ 2nd, Goergen J, Cook JB, Johnson N, Mensah-Zoe B, Simmons JO, June HL Jr, Yin W, Cook JM, Homanics GE (2007) Dopamine and benzodiazepine-dependent mechanisms regulate the EtOH-enhanced locomotor stimulation in the GABAA alpha1 subunit null mutant mice. Neuropsychopharmacology 32:137–152PubMedGoogle Scholar
  93. Jurd R, Arras M, Lambert S, Drexler B, Siegwart R, Crestani F, Zaugg M, Vogt KE, Ledermann B, Antkowiak B, Rudolph U (2002) General anesthetic actions in vivo strongly attenuated by a point mutation in the GABA(A) receptor beta3 subunit. FASEB J 17:250–252PubMedGoogle Scholar
  94. Kang-Park MH, Kieffer BL, Roberts AJ, Roberto M, Madamba SG, Siggins GR, Moore SD (2009) Mu-opioid receptors selectively regulate basal inhibitory transmission in the central amygdala: lack of ethanol interactions. J Pharmacol Exp Ther 328:284–293PubMedGoogle Scholar
  95. Kang-Park MH, Kieffer BL, Roberts AJ, Siggins GR, Moore SD (2007) Presynaptic delta opioid receptors regulate ethanol actions in central amygdala. J Pharmacol Exp Ther 320:917–925PubMedGoogle Scholar
  96. Karlsson RM, Adermark L, Molander A, Perreau-Lenz S, Singley E, Solomon M, Holmes A, Tanaka K, Lovinger DM, Spanagel R, Heilig M (2012) Reduced alcohol intake, lack of alcohol reward and impaired endocannabinoid signaling in mice with a deletion of the glutamate transporter GLAST. Neuropharmacology. [Epub ahead of Print]Google Scholar
  97. Kasanetz F, Deroche-Gamonet V, Berson N, Balado E, Lafourcade M, Manzoni O, Piazza PV (2010) Transition to addiction is associated with a persistent impairment in synaptic plasticity. Science 328:1709–1712PubMedGoogle Scholar
  98. Kash SF, Johnson RS, Tecott LH, Noebels JL, Mayfield RD, Hanahan D, Baekkeskov S (1997) Epilepsy in mice deficient in the 65-kDa isoform of glutamic acid decarboxylase. Proc Natl Acad Sci USA 94:14060–14065PubMedGoogle Scholar
  99. Kaur S, Li J, Stenzel-Poore MP, Ryabinin AE (2012) Corticotropin-releasing factor acting on corticotropin-releasing factor receptor type 1 is critical for binge alcohol drinking in mice. Alcohol Clin Exp Res 36:369–376PubMedCentralPubMedGoogle Scholar
  100. Kelaï S, Aïssi F, Lesch KP, Cohen-Salmon C, Hamon M, Lanfumey L (2003) Alcohol intake after serotonin transporter inactivation in mice. Alcohol Alcohol 38:386–389PubMedGoogle Scholar
  101. Kelly MA, Rubinstein M, Asa SL, Zhang G, Saez C, Bunzow JR, Allen RG, Hnasko R, Ben-Jonathan N, Grandy DK (1997) Low MJ (1997) Pituitary lactotroph hyperplasia and chronic hyperprolactinemia in dopamine D2 receptor-deficient mice. Neuron 19:103–113PubMedGoogle Scholar
  102. Kelly MA, Rubinstein M, Phillips TJ, Lessov CN, Burkhart-Kasch S, Zhang G, Bunzow JR, Fang Y, Gerhardt GA, Grandy DK, Low MJ (1998) Locomotor activity in D2 dopamine receptor-deficient mice is determined by gene dosage, genetic background, and developmental adaptations. J Neurosci 18:3470–3479PubMedGoogle Scholar
  103. Kim JH, Karpyak VM, Biernacka JM, Nam HW, Lee MR, Preuss UW, Zill P, Yoon G, Colby C, Mrazek DA, Choi DS (2011) Functional role of the polymorphic 647 T/C variant of ENT1 (SLC29A1) and its association with alcohol withdrawal seizures. PLoS One 6(1):e16331PubMedCentralPubMedGoogle Scholar
  104. Kleppisch T, Wolfsgruber W, Feil S, Allmann R, Wotjak CT, Goebbels S, Nave KA, Hofmann F, Feil R (2003) Hippocampal cGMP-dependent protein kinase I supports an age- and protein synthesis-dependent component of long-term potentiation but is not essential for spatial reference and contextual memory. J Neurosci 23:6005–6012PubMedGoogle Scholar
  105. Koenig HN, Olive MF (2002) Ethanol consumption patterns and conditioned place preference in mice lacking preproenkephalin. Neurosci Lett 325:75–78PubMedGoogle Scholar
  106. Kolodziejska-Akiyama KM, Cha YM, Jiang Y, Loh HH, Chang SL (2005) Ethanol-induced FOS immunoreactivity in the brain of mu-opioid receptor knock-out mice. Drug Alcohol Depend 80:161–168PubMedGoogle Scholar
  107. König M, Zimmer AM, Steiner H, Holmes PV, Crawley JN, Brownstein MJ, Zimmer A (1996) Pain responses, anxiety and aggression in mice deficient in pre-proenkephalin. Nature 383:535–638PubMedGoogle Scholar
  108. Kovacs KM, Szakall I, O’Brien D, Wang R, Vinod KY, Saito M, Simonin F, Kieffer BL, Vadasz C (2005) Decreased oral self-administration of alcohol in kappa-opioid receptor knock-out mice. Alcohol Clin Exp Res 29:730–738PubMedGoogle Scholar
  109. Kralic JE, Wheeler M, Renzi K, Ferguson C, O’Buckley TK, Grobin AC, Morrow AL, Homanics GE (2003) Deletion of GABAA receptor alpha 1 subunit-containing receptors alters responses to ethanol and other anesthetics. J Pharmacol Exp Ther 305:600–607PubMedGoogle Scholar
  110. LaBuda CJ, Fuchs PN (2001) The anxiolytic effect of acute ethanol or diazepam exposure is unaltered in mu-opioid receptor knock-out mice. Brain Res Bull 55:755–760PubMedGoogle Scholar
  111. Lallemand F, De Witte P (2005) Ethanol induces higher BEC in CB1 cannabinoid receptor knock-out mice while decreasing ethanol preference. Alcohol Alcohol 40:54–62PubMedGoogle Scholar
  112. Lee MR, Hinton DJ, Wu J, Mishra PK, Port JD, Macura SI, Choi DS (2011) Acamprosate reduces ethanol drinking behaviors and alters the metabolite profile in mice lacking ENT1. Neurosci Lett 490:90–95PubMedCentralPubMedGoogle Scholar
  113. Lee S, Smith GW, Vale W, Lee KF, Rivier C (2001) Mice that lack corticotropin-releasing factor (CRF) receptors type 1 show a blunted ACTH response to acute alcohol despite up-regulated constitutive hypothalamic CRF gene expression. Alcohol Clin Exp Res 25:427–433PubMedGoogle Scholar
  114. Leeman RF, Heilig M, Cunningham CL, Stephens DN, Duka T, O’Malley SS (2010) Ethanol consumption: how should we measure it? Achieving consilience between human and animal phenotypes. Addict Biol 15:109–124 ReviewGoogle Scholar
  115. Liang J, Suryanarayanan A, Chandra D, Homanics GE, Olsen RW, Spigelman I (2008) Functional consequences of GABAA receptor alpha 4 subunit deletion on synaptic and extrasynaptic currents in mouse dentate granule cells. Alcohol Clin Exp Res 32:19–26PubMedGoogle Scholar
  116. Loh HH, Liu HC, Cavalli A, Yang W, Chen YF, Wei LN (1998) mu Opioid receptor knock-out in mice: effects on ligand-induced analgesia and morphine lethality. Brain Res Mol Brain Res 54:321–326PubMedGoogle Scholar
  117. Lu YM, Jia Z, Janus C, Henderson JT, Gerlai R, Wojtowicz JM, Roder JC (1997) Mice lacking metabotropic glutamate receptor 5 show impaired learning and reduced CA1 long-term potentiation (LTP) but normal CA3 LTP. J Neurosci 17:5196–5205PubMedGoogle Scholar
  118. Ma YH, Zhou XG, Duan SH, Hu JH, Lu BF, Yu Y, Mei ZT, Fei J, Guo LH (2001) Overexpression of gamma-aminobutyric acid transporter subtype I leads to cognitive deterioration in transgenic mice. Acta Pharmacol Sin 22:340–348PubMedGoogle Scholar
  119. Mameli M, Halbout B, Creton C, Engblom D, Parkitna JR, Spanagel R, Lüscher C (2009) Cocaine-evoked synaptic plasticity: persistence in the VTA triggers adaptations in the NAc. Nat Neurosci 12:1036–1041PubMedGoogle Scholar
  120. Marsicano G, Goodenough S, Monory K, Hermann H, Eder M, Cannich A, Azad SC, Cascio MG, Gutiérrez SO, van der Stelt M, López-Rodriguez ML, Casanova E, Schütz G, Zieglgänsberger W, Di Marzo V, Behl C, Lutz B (2003) CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 302:84–88PubMedGoogle Scholar
  121. Masugi M, Yokoi M, Shigemoto R, Muguruma K, Watanabe Y, Sansig G, van der Putten H, Nakanishi S (1999) Metabotropic glutamate receptor subtype 7 ablation causes deficit in fear response and conditioned taste aversion. J Neurosci 19:955–963PubMedGoogle Scholar
  122. Mathews TA, John CE, Lapa GB, Budygin EA, Jones SR (2006) No role of the dopamine transporter in acute ethanol effects on striatal dopamine dynamics. Synapse 60:288–294PubMedGoogle Scholar
  123. Matthes HW, Maldonado R, Simonin F, Valverde O, Slowe S, Kitchen I, Befort K, Dierich A, Le Meur M, Dollé P, Tzavara E, Hanoune J, Roques BP, Kieffer BL (1996) Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene. Nature 383:819–823PubMedGoogle Scholar
  124. McKenzie-Quirk SD, Girasa KA, Allan AM, Miczek KA (2005) 5-HT (3) receptors, alcohol and aggressive behavior in mice. Behav Pharmacol 16:163–169PubMedGoogle Scholar
  125. McQuade JA, Xu M, Woods SC, Seeley RJ, Benoit SC (2003) Ethanol consumption in mice with a targeted disruption of the dopamine-3 receptor gene. Addict Biol 8:295–303PubMedGoogle Scholar
  126. Metz AV, Chynoweth J, Allan AM (2006) Influence of genetic background on alcohol drinking and behavioral phenotypes of 5-HT3 receptor over-expressing mice. Pharmacol Biochem Behav 84:120–127PubMedGoogle Scholar
  127. Mihalek RM, Banerjee PK, Korpi ER, Quinlan JJ, Firestone LL, Mi ZP, Lagenaur C, Tretter V, Sieghart W, Anagnostaras SG, Sage JR, Fanselow MS, Guidotti A, Spigelman I, Li Z, DeLorey TM, Olsen RW, Homanics GE (1999) Attenuated sensitivity to neuroactive steroids in gamma-aminobutyrate type A receptor delta subunit knock-out mice. Proc Natl Acad Sci USA 96:12905–12910PubMedGoogle Scholar
  128. Mihalek RM, Bowers BJ, Wehner JM, Kralic JE, VanDoren MJ, Morrow AL, Homanics GE (2001) GABA(A)-receptor delta subunit knock-out mice have multiple defects in behavioral responses to ethanol. Alcohol Clin Exp Res 25:1708–1718PubMedGoogle Scholar
  129. Mittleman G, Call SB, Cockroft JL, Goldowitz D, Matthews DB, Blaha CD (2011) Dopamine dynamics associated with, and resulting from, schedule-induced alcohol self-administration: analyses in dopamine transporter knock-out mice. Alcohol 45:325–339PubMedCentralPubMedGoogle Scholar
  130. Molander A, Vengeliene V, Heilig M, Wurst W, Deussing JM, Spanagel R (2011) Brain-specific inactivation of Crhr1 gene inhibits post-dependent and stress-induced alcohol intake but does not affect relapse-like drinking. Neuropsychopharmacology [Epub ahead of print]Google Scholar
  131. Monory K, Blaudzun H, Massa F, Kaiser N, Lemberger T, Schütz G, Wotjak CT, Lutz B, Marsicano G (2007) Genetic dissection of behavioral and autonomic effects of Delta(9) tetrahydrocannabinol in mice. PLoS Biol 5:e269PubMedCentralPubMedGoogle Scholar
  132. Monory K, Massa F, Egertová M, Eder M, Blaudzun H, Westenbroek R, Kelsch W, Jacob W, Marsch R, Ekker M, Long J, Rubenstein JL, Goebbels S, Nave KA, During M, Klugmann M, Wölfel B, Dodt HU, Zieglgänsberger W, Wotjak CT, Mackie K, Elphick MR, Marsicano G, Lutz B (2006) The endocannabinoid system controls key epileptogenic circuits in the hippocampus. Neuron 51:455–466PubMedCentralPubMedGoogle Scholar
  133. Morice E, Denis C, Giros B, Nosten-Bertrand M (2010) Evidence of long-term expression of behavioral sensitization to both cocaine and ethanol in dopamine transporter knock-out mice. Psychopharmacology (Berl) 208:57–66Google Scholar
  134. Muglia L, Jacobson L, Dikkes P, Majzoub JA (1995) Corticotropin-releasing hormone deficiency reveals major fetal but not adult glucocorticoid need. Nature 373:427–432PubMedGoogle Scholar
  135. Müller MB, Zimmermann S, Sillaber I, Hagemeyer TP, Deussing JM, Timpl P, Kormann MS, Droste SK, Kühn R, Reul JM, Holsboer F, Wurst W (2003) Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress. Nat Neurosci 6:1100–1107PubMedGoogle Scholar
  136. Naassila M, Pierrefiche O, Ledent C, Daoust M (2004) Decreased alcohol self-administration and increased alcohol sensitivity and withdrawal in CB1 receptor knock-out mice. Neuropharmacology 46:243–253PubMedGoogle Scholar
  137. Nakao H, Nakao K, Kano M, Aiba A (2007) Metabotropic glutamate receptor subtype-1 is essential for motor coordination in the adult cerebellum. Neurosci Res 57:538–543PubMedGoogle Scholar
  138. Nam HW, Lee MR, Hinton DJ, Choi DS (2010) Reduced effect of NMDA glutamate receptor antagonist on ethanol-induced ataxia and striatal glutamate levels in mice lacking ENT1. Neurosci Lett 479:277–281PubMedCentralPubMedGoogle Scholar
  139. Nam HW, Lee MR, Zhu Y, Wu J, Hinton DJ, Choi S, Kim T, Hammack N, Yin JC, Choi DS (2011) Type 1 equilibrative nucleoside transporter regulates ethanol drinking through accumbal N-methyl-D-aspartate receptor signaling. Biol Psychiatry 69:1043–1051PubMedCentralPubMedGoogle Scholar
  140. Narboux-Nême N, Sagné C, Doly S, Diaz SL, Martin CB, Angenard G, Martres MP, Giros B, Hamon M, Lanfumey L, Gaspar P, Mongeau R (2011) Severe serotonin depletion after conditional deletion of the vesicular monoamine transporter 2 gene in serotonin neurons: neural and behavioral consequences. Neuropsychopharmacology 36:2538–2550 [Epub: 3 Aug, 2011]Google Scholar
  141. Narita M, Soma M, Tamaki H, Narita M, Suzuki T (2002) Intensification of the development of ethanol dependence in mice lacking dopamine D(3) receptor. Neurosci Lett 324:129–132PubMedGoogle Scholar
  142. Nie Z, Schweitzer P, Roberts AJ, Madamba SG, Moore SD, Siggins GR (2004) Ethanol augments GABAergic transmission in the central amygdala via CRF1 receptors. Science 303:1512–1514PubMedGoogle Scholar
  143. Novak M, Halbout B, O’Connor EC, Rodriguez Parkitna J, Su T, Chai M, Crombag HS, Bilbao A, Spanagel R, Stephens DN, Schütz G, Engblom D (2010) Incentive learning underlying cocaine-seeking requires mGluR5 receptors located on dopamine D1 receptor-expressing neurons. J Neurosci 30:11973–11982PubMedGoogle Scholar
  144. Olive MF, Mehmert KK, Koenig HN, Camarini R, Kim JA, Nannini MA, Ou CJ, Hodge CW (2003) A role for corticotropin releasing factor (CRF) in ethanol consumption, sensitivity, and reward as revealed by CRF-deficient mice. Psychopharmacology (Berl) 165:181–187Google Scholar
  145. Palachick B, Chen YC, Enoch AJ, Karlsson RM, Mishina M, Holmes A (2008) Role of major NMDA or AMPA receptor subunits in MK-801 potentiation of ethanol intoxication. Alcohol Clin Exp Res 32:1479–1492PubMedCentralPubMedGoogle Scholar
  146. Palmer AA, Low MJ, Grandy DK, Phillips TJ (2003) Effects of a Drd2 deletion mutation on ethanol-induced locomotor stimulation and sensitization suggest a role for epistasis. Behav Genet 33:311–324PubMedGoogle Scholar
  147. Palmer AA, Sharpe AL, Burkhart-Kasch S, McKinnon CS, Coste SC, Stenzel-Poore MP, Phillips TJ (2004) Corticotropin-releasing factor overexpression decreases ethanol drinking and increases sensitivity to the sedative effects of ethanol. Psychopharmacology (Berl) 176:386–397Google Scholar
  148. Pan B, Wang W, Zhong P, Blankman JL, Cravatt BF, Liu QS (2011) Alterations of endocannabinoid signaling, synaptic plasticity, learning, and memory in monoacylglycerol lipase knock-out mice. J Neurosci 31:13420–13430PubMedCentralPubMedGoogle Scholar
  149. Pastor R, McKinnon CS, Scibelli AC, Burkhart-Kasch S, Reed C, Ryabinin AE, Coste SC, Stenzel-Poore MP, Phillips TJ (2008) Corticotropin-releasing factor-1 receptor involvement in behavioral neuroadaptation to ethanol: an urocortin1-independent mechanism. Proc Natl Acad Sci USA 105:9070–9075PubMedGoogle Scholar
  150. Pastor R, Reed C, Burkhart-Kasch S, Li N, Sharpe AL, Coste SC, Stenzel-Poore MP, Phillips TJ (2011) Ethanol concentration-dependent effects and the role of stress on ethanol drinking in corticotropin-releasing factor type 1 and double type 1 and 2 receptor knock-out mice. Psychopharmacology (Berl) 218:169–177Google Scholar
  151. Pattij T, Groenink L, Oosting RS, van der Gugten J, Maes RA, Olivier B (2002) GABA(A)-benzodiazepine receptor complex sensitivity in 5-HT(1A) receptor knock-out mice on a 129/Sv background. Eur J Pharmacol 447:67–74PubMedGoogle Scholar
  152. Pekhletski R, Gerlai R, Overstreet LS, Huang XP, Agopyan N, Slater NT, Abramow-Newerly W, Roder JC, Hampson DR (1996) Impaired cerebellar synaptic plasticity and motor performance in mice lacking the mGluR4 subtype of metabotropic glutamate receptor. J Neurosci 16:6364–6373PubMedGoogle Scholar
  153. Perreau-Lenz S, Zghoul T, de Fonseca FR, Spanagel R, Bilbao A (2009) Circadian regulation of central ethanol sensitivity by the mPer2 gene. Addict Biol 14:253–259PubMedGoogle Scholar
  154. Phillips TJ, Brown KJ, Burkhart-Kasch S, Wenger CD, Kelly MA, Rubinstein M, Grandy DK, Low MJ (1998) Alcohol preference and sensitivity are markedly reduced in mice lacking dopamine D2 receptors. Nat Neurosci 1:610–615PubMedGoogle Scholar
  155. Poncelet M, Maruani J, Calassi R, Soubrié P (2003) Overeating, alcohol and sucrose consumption decrease in CB1 receptor deleted mice. Neurosci Lett 343:216–218PubMedGoogle Scholar
  156. Quinlan JJ, Homanics GE, Firestone LL (1998) Anesthesia sensitivity in mice that lack the beta3 subunit of the gamma-aminobutyric acid type A receptor. Anesthesiology 88:775–780PubMedGoogle Scholar
  157. Radwanska K, Kaczmarek L (2011) Characterization of an alcohol addiction-prone phenotype in mice. Addict Biol [Epub ahead of print]Google Scholar
  158. Racz I, Bilkei-Gorzo A, Toth ZE, Michel K, Palkovits M, Zimmer A (2003) A critical role for the cannabinoid CB1 receptors in alcohol dependence and stress-stimulated ethanol drinking. J Neurosci 23:2453–2458Google Scholar
  159. Racz I, Schürmann B, Karpushova A, Reuter M, Cichon S, Montag C, Fürst R, Schütz C, Franke PE, Strohmaier J, Wienker TF, Terenius L, Osby U, Gunnar A, Maier W, Bilkei-Gorzó A, Nöthen M, Zimmer A (2008) The opioid peptides enkephalin and beta-endorphin in alcohol dependence. Biol Psychiatry 64:989–997PubMedCentralPubMedGoogle Scholar
  160. Ramachandra V, Kang F, Kim C, Nova AS, Bajaj A, Hall FS, Uhl GR, Gonzales RA (2011) The mu opioid receptor is not involved in ethanol-stimulated dopamine release in the ventral striatum of C57BL/6 J mice. Alcohol Clin Exp Res 35:929–938PubMedCentralPubMedGoogle Scholar
  161. Ramboz S, Oosting R, Amara DA, Kung HF, Blier P, Mendelsohn M, Mann JJ, Brunner D, Hen R (1998) Serotonin receptor 1A knock-out: an animal model of anxiety-related disorder. Proc Natl Acad Sci USA 95:14476–14481PubMedGoogle Scholar
  162. Ramboz S, Saudou F, Amara DA, Belzung C, Segu L, Misslin R, Buhot MC, Hen R (1996) 5-HT1B receptor knock out–behavioral consequences. Behav Brain Res 73:305–312PubMedGoogle Scholar
  163. Refojo D, Schweizer M, Kuehne C, Ehrenberg S, Thoeringer C, Vogl AM, Dedic N, Schumacher M, von Wolff G, Avrabos C, Touma C, Engblom D, Schütz G, Nave KA, Eder M, Wotjak CT, Sillaber I, Holsboer F, Wurst W, Deussing JM (2011) Glutamatergic and dopaminergic neurons mediate anxiogenic and anxiolytic effects of CRHR1. Science 333:1903–1907PubMedGoogle Scholar
  164. Risinger FO, Bormann NM, Oakes RA (1996) Reduced sensitivity to ethanol reward, but not ethanol aversion, in mice lacking 5-HT1B receptors. Alcohol Clin Exp Res 20:1401–1405PubMedGoogle Scholar
  165. Risinger FO, Doan AM, Vickrey AC (1999) Oral operant ethanol self-administration in 5-HT1b knock-out mice. Behav Brain Res 102:211–215PubMedGoogle Scholar
  166. Risinger FO, Freeman PA, Rubinstein M, Low MJ, Grandy DK (2000) Lack of operant ethanol self-administration in dopamine D2 receptor knock-out mice. Psychopharmacology (Berl) 152:343–350Google Scholar
  167. Roberts AJ, Gold LH, Polis I, McDonald JS, Filliol D, Kieffer BL, Koob GF (2001) Increased ethanol self-administration in delta-opioid receptor knock-out mice. Alcohol Clin Exp Res 25:1249–1256PubMedGoogle Scholar
  168. Roberts AJ, McDonald JS, Heyser CJ, Kieffer BL, Matthes HW, Koob GF, Gold LH (2000) mu-Opioid receptor knock-out mice do not self-administer alcohol. J Pharmacol Exp Ther 293:1002–1008PubMedGoogle Scholar
  169. Rodríguez de Fonseca F, Del Arco I, Bermudez-Silva FJ, Bilbao A, Cippitelli A, Navarro M (2005) The endocannabinoid system: physiology and pharmacology. Alcohol Alcohol 40:2–14PubMedGoogle Scholar
  170. Rubinstein M, Mogil JS, Japón M, Chan EC, Allen RG, Low MJ (1996) Absence of opioid stress-induced analgesia in mice lacking beta-endorphin by site-directed mutagenesis. Proc Natl Acad Sci USA 93:3995–4000PubMedGoogle Scholar
  171. Rubinstein M, Phillips TJ, Bunzow JR, Falzone TL, Dziewczapolski G, Zhang G, Fang Y, Larson JL, McDougall JA, Chester JA, Saez C, Pugsley TA, Gershanik O, Low MJ, Grandy DK (1997) Mice lacking dopamine D4 receptors are supersensitive to ethanol, cocaine, and methamphetamine. Cell 90:991–1001PubMedGoogle Scholar
  172. Saarelainen KS, Ranna M, Rabe H, Sinkkonen ST, Möykkynen T, Uusi-Oukari M, Linden AM, Lüddens H, Korpi ER (2008) Enhanced behavioral sensitivity to the competitive GABA agonist, gaboxadol, in transgenic mice over-expressing hippocampal extrasynaptic alpha6beta GABA(A) receptors. J Neurochem 105:338–350PubMedGoogle Scholar
  173. Sakimura K, Kutsuwada T, Ito I, Manabe T, Takayama C, Kushiya E, Yagi T, Aizawa S, Inoue Y, Sugiyama H et al (1995) Reduced hippocampal LTP and spatial learning in mice lacking NMDA receptor epsilon 1 subunit. Nature 373:151–155PubMedGoogle Scholar
  174. Sanchis-Segura C, Borchardt T, Vengeliene V, Zghoul T, Bachteler D, Gass P, Sprengel R, Spanagel R (2006) Involvement of the AMPA receptor GluR-C subunit in alcohol-seeking behavior and relapse. J Neurosci 26:1231–1238PubMedGoogle Scholar
  175. Sanchis-Segura C, Cline B, Jurd R, Rudolph U, Spanagel R (2007) Etomidate and propofol-hyposensitive GABAA receptor beta3 (N265 M) mice show little changes in acute alcohol sensitivity but enhanced tolerance and withdrawal. Neurosci Lett 416:275–278PubMedGoogle Scholar
  176. Sanchis-Segura C, Spanagel R (2006) Behavioral assessment of drug reinforcement and addictive features in rodents: an overview. Addict Biol 11:2–38 ReviewGoogle Scholar
  177. Sato Y, Seo N, Kobayashi E (2006) Ethanol-induced hypnotic tolerance is absent in N-methyl-D-aspartate receptor epsilon 1 subunit knock-out mice. Anesth Analg 103:117–120PubMedGoogle Scholar
  178. Saudou F, Amara DA, Dierich A, LeMeur M, Ramboz S, Segu L, Buhot MC, Hen R (1994) Enhanced aggressive behavior in mice lacking 5-HT1B receptor. Science 265:1875–1878PubMedGoogle Scholar
  179. Savelieva KV, Caudle WM, Findlay GS, Caron MG, Miller GW (2002) Decreased ethanol preference and consumption in dopamine transporter female knock-out mice. Alcohol Clin Exp Res 26:758–764PubMedGoogle Scholar
  180. Savelieva KV, Caudle WM, Miller GW (2006) Altered ethanol-associated behaviors in vesicular monoamine transporter heterozygote knock-out mice. Alcohol 40:87–94PubMedGoogle Scholar
  181. Schmidt MV, Deussing JM, Oitzl MS, Ohl F, Levine S, Wurst W, Holsboer F, Müller MB, de Kloet ER (2006) Differential disinhibition of the neonatal hypothalamic-pituitary-adrenal axis in brain-specific CRH receptor 1-knock-out mice. Eur J Neurosci 24:2291–2298PubMedGoogle Scholar
  182. Shannon EE, Shelton KL, Vivian JA, Yount I, Morgan AR, Homanics GE, Grant KA (2004) Discriminative stimulus effects of ethanol in mice lacking the gamma-aminobutyric acid type A receptor delta subunit. Alcohol Clin Exp Res 28:906–913PubMedGoogle Scholar
  183. Sharifi N, Diehl N, Yaswen L, Brennan MB, Hochgeschwender U (2001) Generation of dynorphin knock-out mice. Brain Res Mol Brain Res 86:70–75PubMedGoogle Scholar
  184. Sharpe AL, Coste SC, Burkhart-Kasch S, Li N, Stenzel-Poore MP, Phillips TJ (2005) Mice deficient in corticotropin-releasing factor receptor type 2 exhibit normal ethanol-associated behaviors. Alcohol Clin Exp Res 29:1601–1609PubMedGoogle Scholar
  185. Shelton KL, Dukat M, Allan AM (2004) Effect of 5-HT3 receptor over-expression on the discriminative stimulus effects of ethanol. Alcohol Clin Exp Res 28:1161–1171PubMedGoogle Scholar
  186. Short JL, Ledent C, Drago J, Lawrence AJ (2006) Receptor crosstalk: characterization of mice deficient in dopamine D1 and adenosine A2A receptors. Neuropsychopharmacology 31:525–534PubMedGoogle Scholar
  187. Silberstein S, Vogl AM, Refojo D, Senin SA, Wurst W, Holsboer F, Deussing JM, Arzt E (2009) Amygdaloid pERK1/2 in corticotropin-releasing hormone overexpressing mice under basal and acute stress conditions. Neuroscience 159:610–617PubMedGoogle Scholar
  188. Sillaber I, Rammes G, Zimmermann S, Mahal B, Zieglgänsberger W, Wurst W, Holsboer F, Spanagel R (2002) Enhanced and delayed stress-induced alcohol drinking in mice lacking functional CRH1 receptors. Science 296:931–933PubMedGoogle Scholar
  189. Simonin F, Valverde O, Smadja C, Slowe S, Kitchen I, Dierich A, Le Meur M, Roques BP, Maldonado R, Kieffer BL (1998) Disruption of the kappa-opioid receptor gene in mice enhances sensitivity to chemical visceral pain, impairs pharmacological actions of the selective kappa-agonist U-50,488H and attenuates morphine withdrawal. EMBO J 17:886–897PubMedGoogle Scholar
  190. Smith GW, Aubry JM, Dellu F, Contarino A, Bilezikjian LM, Gold LH, Chen R, Marchuk Y, Hauser C, Bentley CA, Sawchenko PE, Koob GF, Vale W, Lee KF (1998) Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development. Neuron 20:1093–1102PubMedGoogle Scholar
  191. Sonner JM, Cascio M, Xing Y, Fanselow MS, Kralic JE, Morrow AL, Korpi ER, Hardy S, Sloat B, Eger EI 2nd, Homanics GE (2005) Alpha 1 subunit-containing GABA type a receptors in forebrain contribute to the effect of inhaled anesthetics on conditioned fear. Mol Pharmacol 68:61–68PubMedCentralPubMedGoogle Scholar
  192. Sora I, Takahashi N, Funada M, Ujike H, Revay RS, Donovan DM, Miner LL, Uhl GR (1997) Opiate receptor knock-out mice define mu receptor roles in endogenous nociceptive responses and morphine-induced analgesia. Proc Natl Acad Sci USA 94:1544–1549PubMedGoogle Scholar
  193. Sora I, Wichems C, Takahashi N, Li XF, Zeng Z, Revay R, Lesch KP, Murphy DL, Uhl GR (1998) Cocaine reward models: conditioned place preference can be established in dopamine- and in serotonin-transporter knock-out mice. Proc Natl Acad Sci USA 95:7699–7704PubMedGoogle Scholar
  194. Spanagel R (2009) Alcoholism: a systems approach from molecular physiology to addictive behavior. Physiol Rev 89:649–705 ReviewGoogle Scholar
  195. Spanagel R, Kiefer F (2008) Drugs for relapse prevention of alcoholism: ten years of progress. Trends Pharmacol Sci 29:109–115PubMedGoogle Scholar
  196. Spanagel R, Pendyala G, Abarca C, Zghoul T, Sanchis-Segura C, Magnone MC, Lascorz J, Depner M, Holzberg D, Soyka M, Schreiber S, Matsuda F, Lathrop M, Schumann G, Albrecht U (2005) The clock gene Per2 influences the glutamatergic system and modulates alcohol consumption. Nat Med 11:35–42PubMedGoogle Scholar
  197. Sperling RE, Gomes SM, Sypek EI, Carey AN, McLaughlin JP (2010) Endogenous kappa-opioid mediation of stress-induced potentiation of ethanol-conditioned place preference and self-administration. Psychopharmacology (Berl) 210:199–209Google Scholar
  198. Steiner H, Fuchs S, Accili D (1997) D3 dopamine receptor-deficient mouse: evidence for reduced anxiety. Physiol Behav 63:137–141PubMedGoogle Scholar
  199. Stenzel-Poore MP, Cameron VA, Vaughan J, Sawchenko PE, Vale W (1992) Development of Cushing’s syndrome in corticotropin-releasing factor transgenic mice. Endocrinology 130:3378–3386PubMedGoogle Scholar
  200. Stephens DN, Duka T, Crombag HS, Cunningham CL, Heilig M, Crabbe JC (2010) Reward sensitivity: issues of measurement, and achieving consilience between human and animal phenotypes. Addict Biol 15:145-168 ReviewGoogle Scholar
  201. Stephens DN, Pistovcakova J, Worthing L, Atack JR, Dawson GR (2005) Role of GABAA alpha5-containing receptors in ethanol reward: the effects of targeted gene deletion, and a selective inverse agonist. Eur J Pharmacol 526:240–50 [Epub: 25 Oct, 2005]Google Scholar
  202. Sung KW, Engel SR, Allan AM, Lovinger DM (2000) 5-HT (3) receptor function and potentiation by alcohols in frontal cortex neurons from transgenic mice overexpressing the receptor. Neuropharmacology 39:2346–2351PubMedGoogle Scholar
  203. Sur C, Wafford KA, Reynolds DS, Hadingham KL, Bromidge F, Macaulay A, Collinson N, O’Meara G, Howell O, Newman R, Myers J, Atack JR, Dawson GR, McKernan RM, Whiting PJ, Rosahl TW (2001) Loss of the major GABA (A) receptor subtype in the brain is not lethal in mice. J Neurosci 21:3409–3418PubMedGoogle Scholar
  204. Suryanarayanan A, Liang J, Meyer EM, Lindemeyer AK, Chandra D, Homanics GE, Sieghart W, Olsen RW, Spigelman I (2011) Subunit compensation and plasticity of synaptic GABA(A) receptors induced by ethanol in α4 subunit knock-out mice. Front Neurosci 5:110PubMedCentralPubMedGoogle Scholar
  205. Thanos PK, Dimitrakakis ES, Rice O, Gifford A, Volkow ND (2005a) Ethanol self-administration and ethanol conditioned place preference are reduced in mice lacking cannabinoid CB1 receptors. Behav Brain Res 164:206–213PubMedGoogle Scholar
  206. Thanos PK, Gopez V, Delis F, Michaelides M, Grandy DK, Wang GJ, Kunos G, Volkow ND (2011) Upregulation of cannabinoid type 1 receptors in dopamine D2 receptor knock-out mice is reversed by chronic forced ethanol consumption. Alcohol Clin Exp Res 35:19–27PubMedCentralPubMedGoogle Scholar
  207. Thanos PK, Rivera SN, Weaver K, Grandy DK, Rubinstein M, Umegaki H, Wang GJ, Hitzemann R, Volkow ND (2005b) Dopamine D2R DNA transfer in dopamine D2 receptor-deficient mice: effects on ethanol drinking. Life Sci 77:130–139PubMedGoogle Scholar
  208. Timpl P, Spanagel R, Sillaber I, Kresse A, Reul JM, Stalla GK, Blanquet V, Steckler T, Holsboer F, Wurst W (1998) Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1. Nat Genet 19:162–166PubMedGoogle Scholar
  209. Ting-A-Kee R, Dockstader C, Heinmiller A, Grieder T, van der Kooy D (2009) GABA(A) receptors mediate the opposing roles of dopamine and the tegmental pedunculopontine nucleus in the motivational effects of ethanol. Eur J Neurosci 29:1235–1244PubMedGoogle Scholar
  210. Trebicka J, Racz I, Siegmund SV, Cara E, Granzow M, Schierwagen R, Klein S, Wojtalla A, Hennenberg M, Huss S, Fischer HP, Heller J, Zimmer A, Sauerbruch T (2011) Role of cannabinoid receptors in alcoholic hepatic injury: steatosis and fibrogenesis are increased in CB2 receptor-deficient mice and decreased in CB1 receptor knock-outs. Liver Int 31:860–870PubMedGoogle Scholar
  211. Umhau JC, Momenan R, Schwandt ML, Singley E, Lifshitz M, Doty L, Adams LJ, Vengeliene V, Spanagel R, Zhang Y, Shen J, George DT, Hommer D, Heilig M (2010) Effect of acamprosate on magnetic resonance spectroscopy measures of central glutamate in detoxified alcohol-dependent individuals: a randomized controlled experimental medicine study. Arch Gen Psychiatry 67:1069–1077PubMedCentralPubMedGoogle Scholar
  212. Vadasz C, Saito M, Gyetvai BM, Oros M, Szakall I, Kovacs KM, Prasad VV, Toth R (2007) Glutamate receptor metabotropic 7 is cis-regulated in the mouse brain and modulates alcohol drinking. Genomics 90:690–702PubMedGoogle Scholar
  213. Van Rijn RM, Whistler JL (2009) The delta (1) opioid receptor is a heterodimer that opposes the actions of the delta (2) receptor on alcohol intake. Biol Psychiatry 66:777–784PubMedCentralPubMedGoogle Scholar
  214. Vengeliene V, Bilbao A, Molander A, Spanagel R (2008) Neuropharmacology of alcohol addiction. Br J Pharmacol 154:299–315 ReviewGoogle Scholar
  215. Vengeliene V, Celerier E, Chaskiel L, Penzo F, Spanagel R (2009) Compulsive alcohol drinking in rodents. Addict Biol 14:384–396 ReviewGoogle Scholar
  216. Vicini S, Ferguson C, Prybylowski K, Kralic J, Morrow AL, Homanics GE (2001) GABA(A) receptor alpha1 subunit deletion prevents developmental changes of inhibitory synaptic currents in cerebellar neurons. J Neurosci 21:3009–3016PubMedGoogle Scholar
  217. Vinod KY, Yalamanchili R, Thanos PK, Vadasz C, Cooper TB, Volkow ND, Hungund BL (2008a) Genetic and pharmacological manipulations of the CB(1) receptor alter ethanol preference and dependence in ethanol preferring and nonpreferring mice. Synapse 62:574–581PubMedCentralPubMedGoogle Scholar
  218. Vinod KY, Sanguino E, Yalamanchili R, Manzanares J, Hungund BL (2008b) Manipulation of fatty acid amide hydrolase functional activity alters sensitivity and dependence to ethanol. J Neurochem 104:233–243PubMedGoogle Scholar
  219. Wallén-Mackenzie A, Wootz H, Englund H (2010) Genetic inactivation of the vesicular glutamate transporter 2 (VGLUT2) in the mouse: what have we learnt about functional glutamatergic neurotransmission? Ups J Med Sci 115:11–20 ReviewGoogle Scholar
  220. Wang L, Liu J, Harvey-White J, Zimmer A, Kunos G (2003) Endocannabinoid signalling via cannabinoid receptor 1 is involved in ethanol preference and its age-dependent decline in mice. Proc Natl Acad Sci USA 100:1393–1398PubMedGoogle Scholar
  221. Wang Y, Xu R, Sasaoka T, Tonegawa S, Kung MP, Sankoorikal EB (2000) Dopamine D2 long receptor-deficient mice display alterations in striatum-dependent functions. J Neurosci 20:8305–8314PubMedGoogle Scholar
  222. Wang YM, Gainetdinov RR, Fumagalli F, Xu F, Jones SR, Bock CB, Miller GW, Wightman RM, Caron MG (1997) Knock-out of the vesicular monoamine transporter 2 gene results in neonatal death and supersensitivity to cocaine and amphetamine. Neuron 19:1285–1296PubMedGoogle Scholar
  223. Warnault V, Houchi H, Barbier E, Pierrefiche O, Vilpoux C, Ledent C, Daoust M, Naassila M (2007) The lack of CB1 receptors prevents neuroadapatations of both NMDA and GABA (A) receptors after chronic ethanol exposure. J Neurochem 102:741–752PubMedGoogle Scholar
  224. Watase K, Hashimoto K, Kano M, Yamada K, Watanabe M, Inoue Y, Okuyama S, Sakagawa T, Ogawa S, Kawashima N, Hori S, Takimoto M, Wada K, Tanaka K (1998) Motor discoordination and increased susceptibility to cerebellar injury in GLAST mutant mice. Eur J Neurosci 10:976–988PubMedGoogle Scholar
  225. Werner DF, Blednov YA, Ariwodola OJ, Silberman Y, Logan E, Berry RB, Borghese CM, Matthews DB, Weiner JL, Harrison NL, Harris RA, Homanics GE (2006) Knockin mice with ethanol-insensitive alpha1-containing gamma-aminobutyric acid type A receptors display selective alterations in behavioral responses to ethanol. J Pharmacol Exp Ther 319:219–227PubMedGoogle Scholar
  226. Werner DF, Swihart A, Rau V, Jia F, Borghese CM, McCracken ML, Iyer S, Fanselow MS, Oh I, Sonner JM, Eger EI 2nd, Harrison NL, Harris RA, Homanics GE (2011) Inhaled anesthetic responses of recombinant receptors and knockin mice harboring α2 (S270H/L277A) GABA(A) receptor subunits that are resistant to isoflurane. J Pharmacol Exp Ther 336:134–144PubMedGoogle Scholar
  227. Werner DF, Swihart AR, Ferguson C, Lariviere WR, Harrison NL, Homanics GE (2009) Alcohol-induced tolerance and physical dependence in mice with ethanol insensitive alpha1 GABA A receptors. Alcohol Clin Exp Res 33:289–299PubMedCentralPubMedGoogle Scholar
  228. Wick MJ, Radcliffe RA, Bowers BJ, Mascia MP, Lüscher B, Harris RA, Wehner JM (2000) Behavioral changes produced by transgenic overexpression of gamma2L and gamma2S subunits of the GABAA receptor. Eur J Neurosci 12:2634–2638PubMedGoogle Scholar
  229. Wu J, Lee MR, Choi S, Kim T, Choi DS (2010) ENT1 regulates ethanol-sensitive EAAT2 expression and function in astrocytes. Alcohol Clin Exp Res 34:1110–1117PubMedCentralPubMedGoogle Scholar
  230. Xu M, Koeltzow TE, Santiago GT, Moratalla R, Cooper DC, Hu XT, White NM, Graybiel AM, White FJ, Tonegawa S (1997) Dopamine D3 receptor mutant mice exhibit increased behavioral sensitivity to concurrent stimulation of D1 and D2 receptors. Neuron 19:837–848PubMedGoogle Scholar
  231. Yao WD, Gainetdinov RR, Arbuckle MI, Sotnikova TD, Cyr M, Beaulieu JM, Torres GE, Grant SG, Caron MG (2004) Identification of PSD-95 as a regulator of dopamine-mediated synaptic and behavioral plasticity. Neuron 41:625–638PubMedGoogle Scholar
  232. Yoshino H, Miyamae T, Hansen G, Zambrowicz B, Flynn M, Pedicord D, Blat Y, Westphal RS, Zaczek R, Lewis DA, Gonzalez-Burgos G (2011) Postsynaptic diacylglycerol lipase mediates retrograde endocannabinoid suppression of inhibition in mouse prefrontal cortex. J Physiol 589(Pt 20):4857–4884PubMedGoogle Scholar
  233. Zamanillo D, Sprengel R, Hvalby O, Jensen V, Burnashev N, Rozov A, Kaiser KM, Köster HJ, Borchardt T, Worley P, Lübke J, Frotscher M, Kelly PH, Sommer B, Andersen P, Seeburg PH, Sakmann B (1999) Importance of AMPA receptors for hippocampal synaptic plasticity but not for spatial learning. Science 284:1805–1811PubMedGoogle Scholar
  234. Zapata A, Shippenberg TS (2006) Endogenous kappa opioid receptor systems modulate the responsiveness of mesoaccumbal dopamine neurons to ethanol. Alcohol Clin Exp Res 30:592–597PubMedGoogle Scholar
  235. Zeitz KP, Guy N, Malmberg AB, Dirajlal S, Martin WJ, Sun L, Bonhaus DW, Stucky CL, Julius D, Basbaum AI (2002) The 5-HT3 subtype of serotonin receptor contributes to nociceptive processing via a novel subset of myelinated and unmyelinated nociceptors. J Neurosci 22:1010–1019PubMedGoogle Scholar
  236. Zheng B, Larkin DW, Albrecht U, Sun ZS, Sage M, Eichele G, Lee CC, Bradley A (1999) The mPer2 gene encodes a functional component of the mammalian circadian clock. Nature 400:169–173PubMedGoogle Scholar
  237. Zhong P, Pan B, Gao XP, Blankman JL, Cravatt BF, Liu QS (2011) Genetic deletion of monoacylglycerol lipase alters endocannabinoid-mediated retrograde synaptic depression in the cerebellum. J Physiol 589(Pt 20):4847–4855PubMedGoogle Scholar
  238. Zimmer A, Zimmer AM, Hohmann AG, Herkenham M, Bonner TI (1999) Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knock-out mice. Proc Natl Acad Sci USA 96:5780–5785PubMedGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.Faculty of Medicine MannheimInstitute of Psychopharmacology, Central Institute of Mental Health, University of HeidelbergMannheimGermany

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