Central Norepinephrine Neurons and Behavior

Trevor W. Robbins1 and Barry J. Everitt2
Depts. of 1Experimental Psychology and 2Anatomy
University of Cambridge
Downing Street
Cambridge, CB2 3EB  United Kingdom
fax:  (44)(1223) 314 547
e-mail:  twr.2@hermes.cam.ac.uk


1. Abercrombie ED, Keller RW,  Zigmond  MJ. Characterization of hippocampal norepinephrine release as measured by microdialysis perfusion: pharmacological and behavioral studies. Neuroscience  1988; 27: 897-904.

2 Acheson A, Zigmond MJ, Stricker EM. Compensatory increases in tyrosine hydroxylase activity in the rat brain after intraventricular injection of 6-hydroxydopamine. Science 1980;  207:  537-540.

3. AlZahrani SSA, AlRuwaitea ASA, Ho MY, Bradshaw CM, Szabadi E. Destruction of central noradrenergic neurones with DSP4 impairs the acquisition of temporal discrimination but does not affect memory for duration in a delayed conditional discrimination task. Psychopharmacology 1997; 130: 166-173.

4 Amaral DG, Sinnamon HM.  The locus coeruleus: neurobiology of a central noradrenergic nucleus. Prog. Neurobiol.  1977;  9 : 147-196.

5. Arnsten A. Catecholamine modulation of prefrontal cortical function. Trends in Cognitive Sciences,  1998; 2: 436-446.

6. Arnsten  AFT, Contant TA. Alpha-2 adrenergic agonists decrease distractibility in aged monkeys performing the delayed response task. Psychopharmacology 1992;108:159-169.

7.  Arnsten AFT, Goldman-Rakic PS.  Alpha 2-adrenergic mechanisms in prefrontal cortex associated with cognitive decline in aged non-human primates. Science 1985; 230: 1273-1276.

8. Arnsten AFT Jentsch JD. The alpha-1 adrenergic agonist, cirazoline, impairs spatial working memory performance in aged monkeys. Pharmacol. Biochem. Behav. 1997;  58: 55-59.

9. Arnsten AFT,  Cai JX,  Goldman-Rakic  PS.  The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects: evidence for alpha-2 receptor subtypes.   J.  Neurosci.;198 ;  8: 4287-4298.

10. Aston-Jones G, Chiang C, Alexinsky T. Discharge of noradrenergic locus coeruleus neurons in behaving rats and monkeys suggests a role in vigilance. Prog. Brain Res. 1991; 88:501-520.

11. Aston-Jones G, Rajkowski J, Kubiak, P, Alexinsky T. Locus coeruleus neurons in monkey are selectively activated by attended cues in a vigilance task. J. Neurosci. 1994; 14, 4467-4480.

12. Aston-Jones G, Rajkowski J, Kubiak P. Conditioned responses of monkey locus coeruleus neurons anticipate acquisition of discriminative behavior in a vigilance state. Neurosci. 1997: 80; 697-715.

13. Bedard MA, ElMassioui F, Malapani C, Dubois B, Pillon B, Renault B. Attentional deficits in Parkinson’s disease: Partial reversibility with naphtoxazine (SDZ NVI-085), a selective adrenergic alpha (1) agonist. Clinical Neuropharmacology 1998; 21: 108-117.

14. Borsini F, Rolls ET. Role of noradrenaline and serotonin in the basolateral regions of the amygdala in food preference and learned taste aversion in the rat. Physiol. Behav. 1984;  33:  37-43.

15. Britton DR, Ksir C, Thatcher-Britton K, Young D, Koob GF. Brain-norepinephrine-depleting lesions selectively enhance behavioral responses to novelty. Physiol. Behav. 1984; 33: 473-478.

16. Cahil, L, Prins B, Weber M, McGaugh JL. Beta-adrenergic activation and memory for emotional events. Nature 1994;  371: 702-704.

17. Carli M, Robbins TW, Evenden JL,  Everitt  BJ. Effects of lesions to ascending noradrenergic neurons on performance of a 5-choice serial reaction task in rats: implications for theories of dorsal noradrenergic bundle function based on selective attention and arousal. Behav. Brain Res. 1983;  9: 361-380.

18. Chen MF, Chiu TH, Lee EH. Noradrenergic mediation of the memory enhancing effect of corticotrophin releasing factor in the locs coeruleus of rats. Psychoendocrin. 1992; 17: 113-124.

19.Clark CR, Geffen,GM, Geffen, LB. Catecholamines and attention II: Pharmacological studies in normal humans. Neurosci. Biobehav. Rev. 1987; 11: 353-364.

20. Clark CR,  Geffen GM,  Geffen LB. Catecholamines and the covert orienting of attention. Neuropsychologia 1986;  27:131-140.

21. Cole BJ, Robbins TW. Dissociable effects of lesions to the dorsal or ventral noradrenergic bundle on the acquisition, performance and extinction of aversive conditioning. Behav. Neurosci. 1987; 101:  476-488.

22. Cole BJ,  Robbins TW.  Amphetamine impairs the discrimination performance of rats with dorsal noradrenergic bundle lesions on a 5-choice serial reaction time task: new evidence for central dopaminergic-noradrenergic interactions.  Psychopharmacol. 1987; 91: 458-466.

23. Cole BJ, Robbins TW,  Everitt BJ.  Lesions of the dorsal noradrenergic bundle simultaneously enhance and reduce responsivity to novelty in a food preference test. Brain Res.  Rev. 1988; 13: 325-349.

24.Cole BJ, Robbins TW. Effects of 6-hydroxydopamine lesions of the nucleus accumbens septi on performance of a 5 choice serial reaction time task in rats; implications for theories of selective attention and arousal. Behav. Brain Res.1989; 33: 165-179.

25. Cole BJ,   Robbins  TW.  Forebrain norepinephrine: Role in controlled information processing in the rat. Neuropsychopharmacology,  1992; 7: 129-141.

26. Coull JT, Sahakian, BJ , Hodges JR. The alpha-2 antagonist idazoxan remediates certain attentional and executive forms of dysfunction in patients with dementia of the frontal-type. Psychopharmacology 1995;  123: 239-249.

27. Coull JT, Middleton HC, Robbins,  TW, Sahakian BJ. Contrasting effects of clonidine and diazepam on tests of working memory and planning.  Psychopharmacology 1995;  120: 311-321.

28.Coull JT , Middleton, HC,  Robbins TW, Sahakian B.J. Clonidine and diazepam have differential effects on tests of attention and learning. Psychopharmacology  1995;  120: 322-332.

29. Coull JT, Frith CD, Dolan RJ, Frackowiak RSJ, Grasby PM. The neural correlates of the noradrenergic modulation of human attention, arousal and learning. Eur. J. Neurosci. 1997; 9: 589-598.

30. Crowe SF, Shaw S. Salbutamol overcomes the effect of the noradrenergic neurotoxin DSP-4 on memory function in the day-old chick  Behavioral Pharmacology 1997; 8, 216-222.

31. Davis HP, Callahan MJ, Downs DA. Clonidine disrupts aged monkey delayed response performance. Drug Dev Res 1988; 12: 279-286.

32. Davis M, Hitchock JM, Rosen JB. Anxiety and the amygdala: pharmacological and anatomical analysis of the fear-potentiated startle paradigm. In: Bower G., ed.  The Psychology of Learning and Motivation.  New York: Academic Press, 1987;  263-305.

33. Devauges V, Sara SJ. Activation of the noradrenergic system facilitates an attentional shift in the rat. Behav. Brain Res. 1990; 39: 19-28.

34. Dooley DJ, Jones, GH, Robbins TW.  Noradrenaline- and time-dependent changes in neocortical a2- and b1- adrenoceptor binding in dorsal noradrenergic bundle-lesioned rats. Brain Res. 1987;  420: 152-156.

35. Dunn LT,  Everitt BJ . The effects of lesions to the noradrenergic projections from the locus ceruleus and lateral tegmental cell groups on conditioned taste aversion in the rat. Behav.Neurosci. 1987; 101: 409-422.

36. Ellis ME,  Kesner RP. The noradrenergic system of the amygdala and aversive information processing. Behav.  Neurosci. 1983; 97:  399-415.

37. Evenden JL, Marston HM, Jones GH, Giardini V, Lenard L, Everitt BJ, Robbins TW Effects of excitotoxic lesions of the substantia innominata, ventral and dorsal globus pallidus on visual discrimination acquisition, performance and reversal in the rat. Behav. Brain Res. 1989; 32: 129-149.

38. Everitt BJ, Robbins TW, Gaskin M,  Fray PJ.  The effects of lesions to noradrenergic neurons on discrimination learning and performance in the rat. Neuroscience 1983; 10: 397-410.

39. Eysenck MW Attention and Arousal. Berlin: Springer-Verlag, 1982.

40. Flicker C, Geyer M. Behavior during hippocampal microinfusions. I. Norepinephrine and diverse exploration. Brain Res. Rev. 1982; 4: 79-103.

41. Franowicz JCS, Arnsten AFT. The alpha-2A antagonist, guanfacine, improves delayed response performance in young adult rhesus monkeys. Psychopharmacol. 1998; 136:8-14.

42. French N, Lalies MD, Nutt DJ,  Pratt J. Idazoxan-induced reductions in cortical glucose use are accompanied by an increase in noradrenaline release-complementary (C-14) 2-deoxyglucose and microdialysis studies. Neuropharmacol. 1995; 34: 605-613.

43. Frith CD,  Dowdy J, Ferrier N, Crow TJ.  Selective impairment of paired associate learning after administration of a centrally-acting adrenergic agonist (clonidine), Psychopharmacol.   1985; 87: 490-493.

44. Gallagher M, Kapp BS, Musty RE,  Driscoll, P.A.  Memory formation: evidence for a specific neurochemical system in the amygdala. Science 1977; 198:  423-425.

45. Goodwin GM, Conway SC, Peyro-Saint-Paul H, Glabus MF, O’Carroll RE, Ebmeier KP. Executive function and uptake of 99mTc-exametrazine shown by single photon emission tomography after oral idazoxan in probable Alzheimer-type dementia. Psychopharmacol. 1997; 131: 371-378.

46. Gray JA.  The Neuropsychology of Anxiety.  Oxford, Clarendon Press, 1982.

47. Harley C.  Noradrenergic and locus coeruleus modulation of the perfornat path-evoked potential in the rat dentate gyrus supports a role for the locus coeruleus in attentional and memorial processes. Prog. Brain Res.  1991: 88: 307-321.

48. Hernandez L, Hoebel BG. Overeating after midbrain 6-hydroxydopamine: prevention by central injection of selective catecholamine re-uptake blockers. Brain Res. 1982; 245: 333-343.

49. Jackson WJ, Buccafusco JJ. Clonidine enhances delayed matching-to-sample performance by young and aged monkeys. Pharmacol Biochem Behav 1991; 39: 79-84.

50. Jacobs BL Central monoaminergic neurons: single unit studies in behaving animals. In Meltzer HY ed. Psychopharmacology: The Third Generation of Progress. New York: Raven Press, 1987; 159-169.

51. Kasamatsu T.  Neuronal plasticity maintained by the central norepinephrine system in the cat visual cortex. In:  Sprague JM, Epstein AN, eds. Progress in Psychobiology and Physiological Psychology Vol. 10. New York: Academic Press, 1983; 1-112.

52. Koger SM, Mair RG Depletion of cortical norepinephrine in rats by 6-hydroxydopamine does not impair performance of a delayed matching to sample task. Behav.  Neurosci. 1992; 106: 718-721.

53. Kolb B, Sutherland RJ. Noradrenaline depletion blocks behavioral sparing and alters cortical morphogenesis after neonatal frontal cortex damage in rats. J. Neuroscience 1992; 12: 2321-2330.

54. Koob GF, Thatcher-Britton K, Britton DR, Roberts DCS. Destruction of the locus coeruleus or the dorsal NE bundle does not alter the release of punished responding by ethanol and chlordiazepoxide. Physiol.Behav. 1984; 33: 479-485.

55. Langlais PJ, Connor DJ, Thal L. Comparison of the effects of single and combined lesions of the nucleus basalis magnocellularis and the dorsal noradrenergic bundle on learning and memory in the rat. Behav.  Brain Res. 1993; 54: 81-90.

56. Liang KC,  McGaugh JL,  Yao H-Y. Involvement of amygdala pathways in the influence of post-training amygdala norepinephrine and peripheral epinephrine on memory storage. Brain Res. 1990; 508: 225-233.

57. Lorden JF, Rickert EJ, Dawson RJ Jr., Pelleymounter M. Forebrain norepinephrine and the selective processing of information. Brain Res.  1980; 190: 569-573.

58.  McGaugh JL, Liang KC, Bennett C, Sternberg DB. Adrenergic influences on memory storage: interaction of peripheral and central systems. In: Lynch G, McGaugh JL,  Weinberger NM, eds.  Neurobiology of Learning and Memory. New York: The Guilford Press, 1984; 313-332.

59. McGaughy J, Sandstrom M, Ruland S, Bruno JP, Sarter M (1997) Lack of effects of lesions of the dorsal noradrenergic bundle on behavioral vigilance. Behav. Neurosci. 1997; 111: 646-652.

60. Mair RG, McEntee WJ. Cognitive enhancement in Korsakoff's psychosis by clonidine: a comparison with L-DOPA and ephedrine. Psychopharmacol. 1986; 88: 374-380.

61. Mason ST,  Iversen SD. Theories of the dorsal bundle extinction effect. Brain Res. Rev.  1979, 1, 107-137.

62.  Mason ST, Lin D. Dorsal noradrenergic bundle and selective attention. J. Comp.Physiol. Psychol. 1980; 94: 819-832.

63.  Muir JL, Everitt, BJ,  Robbins TW. The cerebral cortex of the rat and visual attentional function: dissociable effects of mediofrontal, cingulate, anterior dorsolateral and parietal cortex lesions on a 5-choice serial reaction time task. Cerebral Cortex  1995;  6: 470-481

64. Ohno M, Yoshimatsu A, Kobayashi M, Watanabe S. Noradrenergic DSP-4 lesions aggravate impairment of working memory produced by muscarinic blockade in rats. Pharmacol. Biochem. Behav. 57: 257-261.

65. Pineda JA, Foote SL, Neville HJ. Effects of locus coeruleus lesions on auditory, lon-latency, event-related potentials in monkey. J. Neurosci.  1989; 9: 81-93.

66. Pisa M, Fibiger HC. Evidence against a role of the rat's dorsal noradrenergic bundle in selective attention and place memory. Brain Res. 1983; 272: 319-329.

67. Rauschecker JP. Mechanisms of visual plasticity: Hebb synapses, NMDA receptors and beyond. Physiol. Rev.  1991; 71: 587-615.

68. Redmond DE.  New and old evidence for the involvement of a brain norepinephrine system in anxiety, In:  Fann WG, I. Karacan, Pokorny D, Williams RL, eds.) Phenomenology and Treatment of Anxiety.  New York: Spectrum 1979; 153-203.

69. Robbins TW. Cortical noradrenaline, attention and arousal. Psychol. Med. 1984; 14: 13-21.

70. Robbins TW, Everitt BJ, Cole BJ, Archer T,  Mohammed A.  Functional hypotheses of the coeruleo-cortical noradrenergic projection: a review of recent experimentation and theory. Physiol. Psychol.1985 ; 13:  127-150.

71. Roberts DCS, Price MTC, Fibiger HC. The dorsal tegmental noradrenergic projection: an analysis of its role in maze learning. J. Comp. Physiol. Psychol. 1976; 90: 363-372.

72. Rowe J., Durantou, F, Saunders, J , Robbins, TW. Systemic idazoxan impairs performance in a non-reversal shift test: implications for the role of the cerebral noradrenergic systems in selective attention. 1996;  J. Psychopharmacol . 10: 188-194.

73. Sahakian BJ, Winn P, Robbins TW, Dooley RJ, Everitt BJ, Dunn LT, Wallace M, James WPT.  Changes in body weight and food-related behaviour induced by destruction of the ventral or dorsal noradrenergic bundle. Neuroscience 1983; 10: 1405-1420.

74. Sara SJ, Dyon-Laurent G, Gilbert B, Leviel V. Noradrenergic hyperactivity after partial fornix section; role in cholinergic dependent memory performance. Exp. Brain Res.  1992; 89: 125-132.

75. Sara SJ, Segal M. Plasticity of sensory responses of locus coeruleus neurons in the behaving rat; behavioral implications. Prog. in Brain Res.  1991;  88: 571-585.

76. Segal M, Bloom FE. The action of norepinephrine in the rat hippocampus. IV. The effects of locus coeruleus stimulation on evoked hippocampal activity. Brain Res. 1976;   107: 513-525.

77. Selden NRW, Robbins TW,  Everitt BJ.  Enhanced behavioral conditioning to context and impaired behavioral and neuroendocrine responses to conditioning stimuli following ceruleo-cortical noradrenergic lesions: support for an attentional hypothesis of central noradrenergic function. J. Neurosci. 1990; 10: 531-539.

78. Selden NRW, Cole  BJ, Everitt BJ, Robbins TW. Damage to ceruleo-cortical noradrenergic projections impairs locally cued but enhances spatially cued water maze acquisition. Behav. Brain Res. 1990;  39: 29-52.

79. Selden  NRW,  Everitt BJ,  Jarrard LE,   Robbins  TW.  Complementary roles for the amygdala and hippocampus  in aversive conditioning to explicit and contextual cues. Neuroscience 1991; 2: 335-350.

80. Selden NRW, Everitt BJ, Robbins TW. Telencephalic but not diencephalic noradrenaline depletion enhances behavioral but not endocrine measures of fear conditioning to contextual stimuli. Behav. Brain Res. 1992; 43: 139-154.

81. Selden NRW, Robbins TW, Everitt  BJ.  Diencephalic noradrenaline depletion impairs the corticosterone response to footshock but does not affect conditioned fear. J. Neuroendocrin. 1993; 4 : 773-779.

82. Simson PG, Weiss JM, Hoffman LJ, Ambrose MJ. Reversal of behavioral depression by infusion of an alpha-2 adrenergic agonist into the locus ceruleus. Neuropharmacol.  1986; 25: 385-389

83. Sirvio J, Mazurkiewicz M, Haaplinna A, Riekkinen P, Lahtinen H, Riekkinen PJ. The effects of selective alpha-2-adrenergic agents on the performance of rats in a 5-choice serial reaction time task. Brain Res.Bull.  1994, 451-455.

84. Smith AP, Nutt D. Noradrenaline and attention lapses. Nature  1996; 380: 291.

85. Smith AP, Wilson SJ, Glue P, Nutt DJ. The effects and after-effects of the alpha-2-adrenoceptor antagonist idazoxan on mood, memory and attention in normal volunteers. J. Psychopharmacol.  1992; 6:385-389.

86. Steketee JD, Silverman PB, Swann AC. Noradrenergic mechanisms in neophobia. Psychopharmacol. 1992; 106: 136-142.

87. Tassin J-P, Herve D,  Vezina P,  Trovero F,  Blanc G, Glowinski  J. Relationships between mesocortical and mesolimbic dopamine neurons: functional correlates of D1 receptor heteroregulation. In:  Willner  P,   Scheel-Kruger J,  eds.The Mesolimbic  Dopamine System: From Motivation to Action.  Chichester: Wiley 1991; 175-196.

88. Taylor JR, Elsworth JD, Garcia EJ, Grant SJ, Roth RH, Redmond DE Jr. Clonidine infusions into the locus coeruleus attenuate behavioral and neurochemical changes associated with naloxone-precipitated withdrawal. Psychopharmacol. 1988; 96: 121-134.

89. Tsaltas E, Preston GC,  Gray JA . The effects of dorsal bundle lesions on serial and trace conditioning. Behav. Brain Res.  1983; 10: 361-374.

90. van Stegeren AH, Everaerd W, Cahill L, McGaugh JL, Gooren LJG. Memory for emotional events: differential effects of centrally versus peripherally acting B-blocking agents. Psychopharmacology  1998; 138, 305-310.

91. Wenk G, Hughey D, Boundy V, Kim A, Walker L, Olton D. Neurotransmitters and memory; Role of cholinergic, serotonergic and noradrenergic systems. Behav. Neurosci. 1987; 101: 325-332.

92. Witte EA, Marrocco RT. Alteration of brain noradrenergic activity in rhesus monkeys affects the alerting component of covert orienting. Psychopharmacol. 1997; 132: 315-323.

Back to Chapter

published 2000