Advertisement

Regulation of Fear Responses by Striatal and Extrastriatal Adenosine A2A Receptors in Forebrain

  • Catherine J. Wei
    Affiliations
    Molecular Neuropharmacology Laboratory, Department of Neurology, and Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts
    Search for articles by this author
  • Elisabete Augusto
    Affiliations
    Molecular Neuropharmacology Laboratory, Department of Neurology, and Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts

    Center for Neuroscience and Cell Biology, CNC-University of Coimbra, Coimbra, Portugal

    Faculty of Medicine, University of Coimbra, Coimbra, Portugal
    Search for articles by this author
  • Catarina A. Gomes
    Affiliations
    Center for Neuroscience and Cell Biology, CNC-University of Coimbra, Coimbra, Portugal
    Search for articles by this author
  • Philipp Singer
    Affiliations
    R.S. Dow Neurobiology Laboratories, Legacy Research Institute, Portland, Oregon

    Laboratory of Behavioural Neurobiology, Swiss Federal Institute of Technology Zurich, Schwerzenbach, Switzerland
    Search for articles by this author
  • Yumei Wang
    Affiliations
    Molecular Neuropharmacology Laboratory, Department of Neurology, and Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts
    Search for articles by this author
  • Detlev Boison
    Affiliations
    R.S. Dow Neurobiology Laboratories, Legacy Research Institute, Portland, Oregon
    Search for articles by this author
  • Rodrigo A. Cunha
    Affiliations
    Center for Neuroscience and Cell Biology, CNC-University of Coimbra, Coimbra, Portugal

    Faculty of Medicine, University of Coimbra, Coimbra, Portugal
    Search for articles by this author
  • Benjamin K. Yee
    Affiliations
    R.S. Dow Neurobiology Laboratories, Legacy Research Institute, Portland, Oregon

    Laboratory of Behavioural Neurobiology, Swiss Federal Institute of Technology Zurich, Schwerzenbach, Switzerland
    Search for articles by this author
  • Jiang-Fan Chen
    Correspondence
    Address correspondence to Jiang-Fan Chen, M.D., Ph.D., Boston University School of Medicine, Department of Neurology, 715 Albany Street, C329, Boston, MA 02118
    Affiliations
    Molecular Neuropharmacology Laboratory, Department of Neurology, and Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts
    Search for articles by this author

      Background

      Adenosine A2A receptors (A2ARs) are enriched in the striatum but are also present at lower levels in the extrastriatal forebrain (i.e., hippocampus, cortex), integrating dopamine, glutamate, and brain-derived neurotrophic factor (BDNF) signaling, and are thus essential for striatal neuroplasticity and fear and anxiety behavior.

      Methods

      We tested two brain region-specific A2AR knockout lines with A2ARs selectively deleted either in the striatum (st-A2AR KO) or the entire forebrain (striatum, hippocampus, and cortex [fb-A2AR KO]) on fear and anxiety-related responses. We also examined the effect of hippocampus-specific A2AR deletion by local injection of adeno-associated virus type 5 (AAV5)-Cre into floxed-A2AR knockout mice.

      Results

      Selectively deleting A2ARs in the striatum increased Pavlovian fear conditioning (both context and tone) in st-A2AR KO mice, but extending the deletion to the rest of the forebrain apparently spared context fear conditioning and attenuated tone fear conditioning in fb-A2AR KO mice. Moreover, focal deletion of hippocampal A2ARs by AAV5-Cre injection selectively attenuated context (but not tone) fear conditioning. Deletion of A2ARs in the entire forebrain in fb-A2AR KO mice also produced an anxiolytic phenotype in both the elevated plus maze and open field tests, and increased the startle response. These extrastriatal forebrain A2AR behavioral effects were associated with reduced BDNF levels in the fb-A2AR KO hippocampus.

      Conclusions

      This study provides evidence that inactivation of striatal A2ARs facilitates Pavlovian fear conditioning, while inactivation of extrastriatal A2ARs in the forebrain inhibits fear conditioning and also affects anxiety-related behavior.

      Key Words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Schiffmann S.N.
        • Fisone G.
        • Moresco R.
        • Cunha R.A.
        • Ferré S.
        Adenosine A2A receptors and basal ganglia physiology.
        Prog Neurobiol. 2007; 83: 277-292
        • Svenningsson P.
        • Le Moine C.
        • Fisone G.
        • Fredholm B.B.
        Distribution, biochemistry and function of striatal adenosine A2A receptors.
        Prog Neurobiol. 1999; 59: 355-396
        • Rebola N.
        • Lujan R.
        • Cunha R.A.
        • Mulle C.
        Adenosine A2A receptors are essential for long-term potentiation of NMDA-EPSCs at hippocampal mossy fiber synapses.
        Neuron. 2008; 57: 121-134
      1. Costenla AR, Digenes MJ, Canas PM, Rodrigues RJ, Nogueira C, Maroco J, et al. (2011): Enhanced role of adenosine A(2A) receptors in the modulation of LTP in the rat hippocampus upon ageing. Eur J Neurosci 34:12–21.

        • d'Alcantara P.
        • Ledent C.
        • Swillens S.
        • Schiffmann S.N.
        Inactivation of adenosine A2A receptor impairs long term potentiation in the accumbens nucleus without altering basal synaptic transmission.
        Neuroscience. 2001; 107: 455-464
        • Flajolet M.
        • Wang Z.
        • Futter M.
        • Shen W.
        • Nuangchamnong N.
        • Bendor J.
        • et al.
        FGF acts as a co-transmitter through adenosine A(2A) receptor to regulate synaptic plasticity.
        Nat Neurosci. 2008; 11: 1402-1409
        • Sebastião A.M.
        • Ribeiro J.A.
        Triggering neurotrophic factor actions through adenosine A2A receptor activation: Implications for neuroprotection.
        Br J Pharmacol. 2009; 158: 15-22
        • Cunha R.A.
        • Agostinho P.M.
        Chronic caffeine consumption prevents memory disturbance in different animal models of memory decline.
        J Alzheimers Dis. 2010; 20: S95-S116
        • Takahashi R.N.
        • Pamplona F.A.
        • Prediger R.D.
        Adenosine receptor antagonists for cognitive dysfunction: A review of animal studies.
        Front Biosci. 2008; 13: 2614-2632
        • Dall'igna O.P.
        • Fett P.
        • Gomes M.W.
        • Souza D.O.
        • Cunha R.A.
        • Lara D.R.
        Caffeine and adenosine A(2a) receptor antagonists prevent beta-amyloid (25-35)-induced cognitive deficits in mice.
        Exp Neurol. 2007; 203: 241-245
        • Kopf S.R.
        • Melani A.
        • Pedata F.
        • Pepeu G.
        Adenosine and memory storage: Effect of A(1) and A(2) receptor antagonists.
        Psychopharmacology (Berl). 1999; 146: 214-219
        • Pereira G.S.
        • Rossato J.I.
        • Sarkis J.J.
        • Cammarota M.
        • Bonan C.D.
        • Izquierdo I.
        Activation of adenosine receptors in the posterior cingulate cortex impairs memory retrieval in the rat.
        Neurobiol Learn Mem. 2005; 83: 217-223
        • El Yacoubi M.
        • Ledent C.
        • Parmentier M.
        • Costentin J.
        • Vaugeois J.M.
        The anxiogenic-like effect of caffeine in two experimental procedures measuring anxiety in the mouse is not shared by selective A(2A) adenosine receptor antagonists.
        Psychopharmacology (Berl). 2000; 148: 153-163
        • Ledent C.
        • Vaugeois J.M.
        • Schiffmann S.N.
        • Pedrazzini T.
        • El Yacoubi M.
        • Vanderhaeghen J.J.
        • et al.
        Aggressiveness, hypoalgesia and high blood pressure in mice lacking the adenosine A2a receptor.
        Nature. 1997; 388: 674-678
        • Shen H.Y.
        • Coelho J.E.
        • Ohtsuka N.
        • Canas P.M.
        • Day Y.J.
        • Huang Q.Y.
        • et al.
        A critical role of the adenosine A2A receptor in extrastriatal neurons in modulating psychomotor activity as revealed by opposite phenotypes of striatum and forebrain A2A receptor knock-outs.
        J Neurosci. 2008; 28: 2970-2975
        • Bastia E.
        • Xu Y.H.
        • Scibelli A.C.
        • Day Y.J.
        • Linden J.
        • Chen J.F.
        • Schwarzschild M.A.
        A crucial role for forebrain adenosine A(2A) receptors in amphetamine sensitization.
        Neuropsychopharmacology. 2005; 30: 891-900
        • Wei C.J.
        • Singer P.
        • Coelho J.
        • Boison D.
        • Feldon J.
        • Yee B.K.
        • Chen J.F.
        Selective inactivation of adenosine A(2A) receptors in striatal neurons enhances working memory and reversal learning.
        Learn Mem. 2011; 18: 459-474
        • Yu L.
        • Shen H.Y.
        • Coelho J.E.
        • Araujo I.M.
        • Huang Q.Y.
        • Day Y.J.
        • et al.
        Adenosine A2A receptor antagonists exert motor and neuroprotective effects by distinct cellular mechanisms.
        Ann Neurol. 2008; 63: 338-346
        • Schmittgen T.D.
        • Livak K.J.
        Analyzing real-time PCR data by the comparative C(T) method.
        Nat Protoc. 2008; 3: 1101-1108
      2. Hagenbuch N, Feldon J, Yee BK (2006): Use of the elevated plus-maze test with opaque or transparent walls in the detection of mouse strain differences and the anxiolytic effects of diazepam. Behav Pharmacol 17:31–41

        • Pietropaolo S.
        • Mintz M.
        • Feldon J.
        • Yee B.K.
        The behavioral sequela following the prevention of home-cage grid-climbing activity in C57BL/6 mice.
        Behav Neurosci. 2007; 121: 345-355
        • Yee B.K.
        • Singer P.
        • Chen J.F.
        • Feldon J.
        • Boison D.
        Transgenic overexpression of adenosine kinase in brain leads to multiple learning impairments and altered sensitivity to psychomimetic drugs.
        Eur J Neurosci. 2007; 26: 3237-3252
        • Yee B.K.
        • Chang D.L.
        • Feldon J.
        The effects of dizocilpine and phencyclidine on prepulse inhibition of the acoustic startle reflex and on prepulse-elicited reactivity in C57BL6 mice.
        Neuropsychopharmacology. 2004; 29: 1865-1877
        • Szapacs M.E.
        • Mathews T.A.
        • Tessarollo L.
        • Ernest Lyons W.
        • Mamounas L.A.
        • Andrews A.M.
        Exploring the relationship between serotonin and brain-derived neurotrophic factor: analysis of BDNF protein and extraneuronal 5-HT in mice with reduced serotonin transporter or BDNF expression.
        J Neurosci Methods. 2004; 140: 81-92
        • Singer P.
        • Zhang C.C.
        • Boison D.
        • Yee B.K.
        Dysregulation of brain adenosine is detrimental to the expression of conditioned freezing but not general Pavlovian learning.
        Pharmacol Biochem Behav. 2013; 104: 80-89
        • Ma L.
        • Wang D.D.
        • Zhang T.Y.
        • Yu H.
        • Wang Y.
        • Huang S.H.
        • et al.
        Region-specific involvement of BDNF secretion and synthesis in conditioned taste aversion memory formation.
        J Neurosci. 2011; 31: 2079-2090
        • Zhou S.J.
        • Zhu M.E.
        • Shu D.
        • Du X.P.
        • Song X.H.
        • Wang X.T.
        • et al.
        Preferential enhancement of working memory in mice lacking adenosine A(2A) receptors.
        Brain Res. 2009; 1303: 74-83
        • White N.M.
        • Salinas J.A.
        Mnemonic functions of dorsal striatum and hippocampus in aversive conditioning.
        Behav Brain Res. 2003; 142: 99-107
        • White N.M.
        • Viaud M.
        Localized intracaudate dopamine D2 receptor activation during the post-training period improves memory for visual or olfactory conditioned emotional responses in rats.
        Behav Neural Biol. 1991; 55: 255-269
        • Durieux P.F.
        • Schiffmann S.N.
        • de Kerchove d'Exaerde A.
        Differential regulation of motor control and response to dopaminergic drugs by D1R and D2R neurons in distinct dorsal striatum subregions.
        EMBO J. 2012; 31: 640-653
        • Lobo M.K.
        • Covington 3rd, H.E.
        • Chaudhury D.
        • Friedman A.K.
        • Sun H.
        • Damez-Werno D.
        • et al.
        Cell type-specific loss of BDNF signaling mimics optogenetic control of cocaine reward.
        Science. 2010; 330: 385-390
        • Bateup H.S.
        • Santini E.
        • Shen W.
        • Birnbaum S.
        • Valjent E.
        • Surmeier D.J.
        • et al.
        Distinct subclasses of medium spiny neurons differentially regulate striatal motor behaviors.
        Proc Natl Acad Sci U S A. 2010; 107: 14845-14850
        • Hikida T.
        • Kimura K.
        • Wada N.
        • Funabiki K.
        • Nakanishi S.
        Distinct roles of synaptic transmission in direct and indirect striatal pathways to reward and aversive behavior.
        Neuron. 2010; 66: 896-907
        • Biedenkapp J.C.
        • Rudy J.W.
        Hippocampal and extrahippocampal systems compete for control of contextual fear: Role of ventral subiculum and amygdala.
        Learn Mem. 2009; 16: 38-45
        • Bissiére S.
        • Plachta N.
        • Hoyer D.
        • McAllister K.H.
        • Olpe H.R.
        • Grace A.A.
        • Cryan J.F.
        The rostral anterior cingulate cortex modulates the efficiency of amygdala-dependent fear learning.
        Biol Psychiatry. 2008; 63: 821-831
        • Sacchetti B.
        • Baldi E.
        • Lorenzini C.A.
        • Bucherelli C.
        Differential contribution of some cortical sites to the formation of memory traces supporting fear conditioning.
        Exp Brain Res. 2002; 146: 223-232
        • McHugh S.B.
        • Fillenz M.
        • Lowry J.P.
        • Rawlins J.N.
        • Bannerman D.M.
        Brain tissue oxygen amperometry in behaving rats demonstrates functional dissociation of dorsal and ventral hippocampus during spatial processing and anxiety.
        Eur J Neurosci. 2011; 33: 322-337
        • Adhikari A.
        • Topiwala M.A.
        • Gordon J.A.
        Synchronized activity between the ventral hippocampus and the medial prefrontal cortex during anxiety.
        Neuron. 2010; 65: 257-269
        • Bannerman D.M.
        • Rawlins J.N.
        • McHugh S.B.
        • Deacon R.M.
        • Yee B.K.
        • Bast T.
        • et al.
        Regional dissociations within the hippocampus--memory and anxiety.
        Neurosci Biobehav Rev. 2004; 28: 273-283
        • Cunha R.A.
        • Ferre S.
        • Vaugeois J.M.
        • Chen J.F.
        Potential therapeutic interest of adenosine A2A receptors in psychiatric disorders.
        Curr Pharm Des. 2008; 14: 1512-1524
        • Hamilton S.P.
        • Slager S.L.
        • De Leon A.B.
        • Heiman G.A.
        • Klein D.F.
        • Hodge S.E.
        • et al.
        Evidence for genetic linkage between a polymorphism in the adenosine 2A receptor and panic disorder.
        Neuropsychopharmacology. 2004; 29: 558-565
        • Hohoff C.
        • Mullings E.L.
        • Heatherley S.V.
        • Freitag C.M.
        • Neumann L.C.
        • Domschke K.
        • et al.
        Adenosine A(2A) receptor gene: Evidence for association of risk variants with panic disorder and anxious personality.
        J Psychiatr Res. 2010; 44: 930-937
        • Deckert J.
        • Nöthen M.M.
        • Franke P.
        • Delmo C.
        • Fritze J.
        • Knapp M.
        • et al.
        Systematic mutation screening and association study of the A1 and A2a adenosine receptor genes in panic disorder suggest a contribution of the A2a gene to the development of disease.
        Mol Psychiatry. 1998; 3: 81-85
        • Hince D.A.
        • Martin-Iverson M.T.
        Differences in prepulse inhibition (PPI) between Wistar and Sprague-Dawley rats clarified by a new method of PPI standardization.
        Behav Neurosci. 2005; 119: 66-77
        • Martin-Iverson M.T.
        • Stevenson K.N.
        Apomorphine effects on emotional modulation of the startle reflex in rats.
        Psychopharmacology (Berl). 2005; 181: 60-70
        • Stoddart C.W.
        • Noonan J.
        • Martin-Iverson M.T.
        Stimulus quality affects expression of the acoustic startle response and prepulse inhibition in mice.
        Behav Neurosci. 2008; 122: 516-526
        • Hauber W.
        • Koch M.
        Adenosine A2a receptors in the nucleus accumbens modulate prepulse inhibition of the startle response.
        Neuroreport. 1997; 8: 1515-1518
        • Nagel J.
        • Schladebach H.
        • Koch M.
        • Schwienbacher I.
        • Müller C.E.
        • Hauber W.
        Effects of an adenosine A2A receptor blockade in the nucleus accumbens on locomotion, feeding, and prepulse inhibition in rats.
        Synapse. 2003; 49: 279-286
        • Decker M.W.
        • Curzon P.
        • Brioni J.D.
        Influence of separate and combined septal and amygdala lesions on memory, acoustic startle, anxiety, and locomotor activity in rats.
        Neurobiol Learn Mem. 1995; 64: 156-168
        • Poo M.M.
        Neurotrophins as synaptic modulators.
        Nat Rev Neurosci. 2001; 2: 24-32
        • Chao M.V.
        Neurotrophins and their receptors: A convergence point for many signalling pathways.
        Nat Rev Neurosci. 2003; 4: 299-309
        • Heldt S.A.
        • Stanek L.
        • Chhatwal J.P.
        • Ressler K.J.
        Hippocampus-specific deletion of BDNF in adult mice impairs spatial memory and extinction of aversive memories.
        Mol Psychiatry. 2007; 12: 656-670
        • Bozdagi O.
        • Rich E.
        • Tronel S.
        • Sadahiro M.
        • Patterson K.
        • Shapiro M.L.
        • et al.
        The neurotrophin-inducible gene Vgf regulates hippocampal function and behavior through a brain-derived neurotrophic factor-dependent mechanism.
        J Neurosci. 2008; 28: 9857-9869
        • Yee B.K.
        • Zhu S.W.
        • Mohammed A.H.
        • Feldon J.
        Levels of neurotrophic factors in the hippocampus and amygdala correlate with anxiety- and fear-related behaviour in C57BL6 mice.
        J Neural Transm. 2007; 114: 431-444
      3. Texel SJ, Camandola S, Ladenheim B, Rothman SM, Mughal MR, Unger EL, et al. (2012): Ceruloplasmin deficiency results in an anxiety phenotype involving deficits in hippocampal iron, serotonin, and BDNF. J Neurochem 120:125–134.

        • Aso E.
        • Ozaita A.
        • Valdizán E.M.
        • Ledent C.
        • Pazos A.
        • Maldonado R.
        • Valverde O.
        BDNF impairment in the hippocampus is related to enhanced despair behavior in CB1 knockout mice.
        J Neurochem. 2008; 105: 565-572
        • Takei S.
        • Morinobu S.
        • Yamamoto S.
        • Fuchikami M.
        • Matsumoto T.
        • Yamawaki S.
        Enhanced hippocampal BDNF/TrkB signaling in response to fear conditioning in an animal model of posttraumatic stress disorder.
        J Psychiatr Res. 2011; 45: 460-468
        • Kozlovsky N.
        • Matar M.A.
        • Kaplan Z.
        • Kotler M.
        • Zohar J.
        • Cohen H.
        Long-term down-regulation of BDNF mRNA in rat hippocampal CA1 subregion correlates with PTSD-like behavioural stress response.
        Int J Neuropsychopharmacol. 2007; 10: 741-758
        • Tebano M.T.
        • Martire A.
        • Potenza R.L.
        • Gró C.
        • Pepponi R.
        • Armida M.
        • et al.
        Adenosine A(2A) receptors are required for normal BDNF levels and BDNF-induced potentiation of synaptic transmission in the mouse hippocampus.
        J Neurochem. 2008; 104: 279-286
        • Lee F.S.
        • Chao M.V.
        Activation of Trk neurotrophin receptors in the absence of neurotrophins.
        Proc Natl Acad Sci U S A. 2001; 98: 3555-3560
        • Assaife-Lopes N.
        • Sousa V.C.
        • Pereira D.B.
        • Ribeiro J.A.
        • Chao M.V.
        • Sebastiao A.M.
        Activation of adenosine A2A receptors induces TrkB translocation and increases BDNF-mediated phospho-TrkB localization in lipid rafts: Implications for neuromodulation.
        J Neurosci. 2010; 30: 8468-8480