Skip to main content

Advertisement

SpringerLink
Log in

Systemic and intrabasalis administration of the orexin-1 receptor antagonist, SB-334867, disrupts attentional performance in rats

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Orexin neurons project to a number of brain regions, including onto basal forebrain cholinergic neurons. Basal forebrain corticopetal cholinergic neurons are known to be necessary for normal attentional performance. Thus, the orexin system may contribute to attentional processing.

Objectives

We tested whether blockade of orexin-1 receptors would disrupt attentional performance.

Methods

Rats were trained in a two-lever sustained attention task that required discrimination of a visual signal (500, 100, 25 ms) from trials with no signal presentation. Rats received systemic or intrabasalis administration of the orexin-1 receptor antagonist, SB-334867, prior to task performance.

Results

Systemic administration of the orexin-1 receptor antagonist, SB-334867 (5.0 mg/kg), decreased detection of the longest duration signal. Intrabasalis SB-334867 (0.60 μg) decreased overall accuracy on trials with longer signal durations.

Conclusions

These findings suggest that orexins contribute to attentional processing, although neural circuits outside of basal forebrain corticopetal cholinergic neurons may mediate some of these effects.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Akbari E, Naghdi N, Motamedi F (2006) Functional inactivation of orexin 1 receptors in CA1 region impairs acquisition, consolidation and retrieval in Morris water maze task. Behav Brain Res 173:47–52

    Article  PubMed  CAS  Google Scholar 

  • Akbari E, Naghdi N, Motamedi F (2007) The selective orexin 1 receptor antagonist SB-334867-A impairs acquisition and consolidation but not retrieval of spatial memory in Morris water maze. Peptides 28:650–656

    Article  PubMed  CAS  Google Scholar 

  • Akbari E, Motamedi F, Naghdi N, Noorbakhshnia M (2008) The effect of antagonization of orexin 1 receptors in CA1 and dentate gyrus regions on memory processing in a passive avoidance task. Behav Brain Res 187:172–177

    PubMed  CAS  Google Scholar 

  • Arnold HM, Burk JA, Hodgson EM, Sarter M, Bruno JP (2002) Differential cortical acetylcholine release in rats performing a sustained attention task versus behavioral control tasks that do not explicitly tax attention. Neuroscience 114:451–460

    Article  PubMed  CAS  Google Scholar 

  • Aston-Jones G, Rajkowski J, Cohen J (1999) Role of locus coeruleus in attention and behavioral flexibility. Biol Psychiatry 46:1309–1320

    Article  PubMed  CAS  Google Scholar 

  • Baldo BA, Daniel RA, Berridge CW, Kelley AE (2003) Overlapping distributions of orexin/hypocretin- and dopamine beta-hydroxylase immunoreactive fibers in rat brain regions mediating arousal, motivation, and stress. J Comp Neurol 464:220–237

    Article  PubMed  Google Scholar 

  • Bentley P, Husain M, Dolan RJ (2004) Effects of cholinergic enhancement on visual stimulation, spatial attention, and spatial working memory. Neuron 41:969–982

    Article  PubMed  CAS  Google Scholar 

  • Burk JA (2004) Introduction of a retention interval in a sustained attention task in rats: effects of presenting a visual distracter and increasing the inter-trial interval. Behav Processes 67:521–531

    Article  PubMed  Google Scholar 

  • Burk JA, Sarter M (2001) Dissociation between the attentional functions mediated via basal forebrain cholinergic and GABAergic neurons. Neuroscience 105:899–909

    Article  PubMed  CAS  Google Scholar 

  • Bushnell PJ, Benignus VA, Case MW (2003) Signal detection behavior in humans and rats: a comparison with matched tasks. Behav Processes 64:121–129

    Article  PubMed  Google Scholar 

  • Cohen J (1988) Statistical power: analysis for the behavioral sciences. Erlbaum, Hillsdale

    Google Scholar 

  • Cutler DJ, Morris R, Sheridhar V, Wattam TA, Holmes S, Patel S, Arch JR, Wilson S, Buckingham RE, Evans ML, Leslie RA, Williams G (1999) Differential distribution of orexin-A and orexin-B immunoreactivity in the rat brain and spinal cord. Peptides 20:1455–1470

    Article  PubMed  CAS  Google Scholar 

  • Dalley JW, McGaughy J, O’Connell MT, Cardinal RN, Levita L, Robbins TW (2001) Distinct changes in cortical acetylcholine and noradrenaline efflux during contingent and noncontingent performance of a visual attentional task. J Neurosci 21:4908–4914

    PubMed  CAS  Google Scholar 

  • de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, Fukuhara C, Battenberg EL, Gautvik VT, Bartlett FS, Frankel WN, van del Pol AN, Bloom FE, Gautvik KM, Sutcliffe JG (1998) The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci U S A 95:322–3277

    Article  PubMed  Google Scholar 

  • Deadwyler SA, Porrino L, Siegel JM, Hampson RE (2007) Systemic and nasal delivery of orexin-A (hypocretin-1) reduces the effects of sleep deprivation on cognitive performance in nonhuman primates. J Neurosci 27:14239–14247

    Article  PubMed  CAS  Google Scholar 

  • Demeter E, Sarter M, Lustig C (2008) Rats and humans paying attention: cross-species task development for translational research. Neuropsychology 22:787–799

    Article  PubMed  Google Scholar 

  • Deutch AY, Bubser M (2007) The orexins/hypocretins and schizophrenia. Schizophr Bull 33:1277–1283

    Article  PubMed  Google Scholar 

  • Dong HL, Fukuda S, Murata E, Zhu Z, Higuchi T (2006) Orexins increase cortical acetylcholine release and electroencephalographic activation through orexin-1 receptor in the rat basal forebrain during isoflurane anesthesia. Anesthesiology 104:1023–1032

    Article  PubMed  CAS  Google Scholar 

  • Downs JL, Dunn MR, Borok E, Shanabrough M, Horvath TL, Kohama SG, Urbanski HF (2007) Orexin neuronal changes in the locus coeruleus of the aging rhesus macaque. Neurobiol Aging 28:1286–1295

    Article  PubMed  CAS  Google Scholar 

  • Duxon MS, Stretton J, Starr K, Jones DN, Holland V, Riley G, Jerman J, Brough S, Smart D, Johns A, Chan W, Porter RA, Upton N (2001) Evidence that orexin-A-evoked grooming in the rat is mediated by orexin-1 (OX1) receptors, with downstream 5-HT2C receptor involvement. Psychopharmacology (Berl) 153:203–209

    Article  CAS  Google Scholar 

  • Ebert U, Kirch W (1998) Scopolamine model of dementia: electroencephalogram findings and cognitive performance. Eur J Clin Invest 28:944–949

    Article  PubMed  CAS  Google Scholar 

  • España RA, Baldo BA, Kelley AE, Berridge CW (2001) Wake-promoting and sleep-suppressing actions of hypocretin (orexin): basal forebrain sites of action. Neuroscience 106:699–715

    Article  PubMed  Google Scholar 

  • Everitt BJ, Robbins TW (1997) Central cholinergic systems and cognition. Annu Rev Psychol 48:649–684

    Article  PubMed  CAS  Google Scholar 

  • Fadel J, Frederick-Duus D (2008) Orexin/hypocretin modulation of the basal forebrain cholinergic system: insights from in vivo microdialysis studies. Pharmacol Biochem Behav 90:156–162

    Article  PubMed  CAS  Google Scholar 

  • Fadel J, Sarter M, Bruno JP (2001) Basal forebrain glutamatergic modulation of cortical acetylcholine release. Synapse 39:201–212

    Article  PubMed  CAS  Google Scholar 

  • Fadel J, Pasumarthi R, Reznikov LR (2005) Stimulation of cortical acetylcholine release by orexin A. Neuroscience 130:541–547

    Article  PubMed  CAS  Google Scholar 

  • Foote SL, Berridge CW, Adams LM, Pineda JA (1991) Electrophysiological evidence for the involvement of the locus coeruleus in alerting, orienting, and attending. Prog Brain Res 88:521–532

    Article  PubMed  CAS  Google Scholar 

  • Frederick-Duus D, Guyton MT, Fadel J (2007) Food-elicited increases in cortical acetylcholine release require orexin transmission. Neuroscience 149:499–507

    Article  PubMed  CAS  Google Scholar 

  • Gritti I, Mainville L, Jones BE (1993) Codistribution of GABA- with acetylcholine-synthesizing neurons in the basal forebrain of the rat. J Comp Neurol 329:438–457

    Article  PubMed  CAS  Google Scholar 

  • Gritti I, Mainville L, Mancia M, Jones BE (1997) GABAergic and other non-cholinergic basal forebrain neurons, together with cholinergic neurons, project to the mesocortex and isocortex in the rat. J Comp Neurol 383:163–177

    Article  PubMed  CAS  Google Scholar 

  • Harris GC, Wimmer M, Aston-Jones G (2005) A role for lateral hypothalamic orexin neurons in reward seeking. Nature 437:556–559

    Article  PubMed  CAS  Google Scholar 

  • Harris GC, Wimmer M, Randall-Thompson JF, Aston-Jones G (2007) Lateral hypothalamic orexin neurons are critically involved in learning to associate an environment with morphine reward. Behav Brain Res 183:43–51

    Article  PubMed  CAS  Google Scholar 

  • Holley LA, Turchi J, Apple C, Sarter M (1995) Dissociation between the attentional effects of infusions of a benzodiazepine receptor agonist and an inverse agonist into the basal forebrain. Psychopharmacology (Berl) 120:99–108

    Article  CAS  Google Scholar 

  • Johnson RT, Burk JA (2006) Effects of gonadectomy and androgen supplementation on attention in male rats. Neurobiol Learn Mem 85:219–227

    Article  PubMed  CAS  Google Scholar 

  • Kiwaki K, Kotz CM, Wang C, Lanningham-Foster L, Levine JA (2004) Orexin A (hypocretin 1) injected into hypothalamic paraventricular nucleus and spontaneous physical activity in rats. Am J Physiol Endocrinol Metab 286:E551–E559

    Article  PubMed  CAS  Google Scholar 

  • Koelega HS, Brinkman JA, Zwep B, Verbaten MN (1990) Dynamic vs static stimuli and their effect on visual vigilance performance. Percept Mot Skills 70:823–831

    Article  PubMed  CAS  Google Scholar 

  • Lambe EK, Liu RJ, Aghajanian GK (2007) Schizophrenia, hypocretin (orexin), and the thalamocortical activating system. Schizophr Bull 33:1284–1290

    Article  PubMed  Google Scholar 

  • Lambe EK, Olausson P, Horst NK, Taylor JR, Aghajanian GK (2005) Hypocretin and nicotine excite the same thalamocortical synapses in prefrontal cortex: correlation with improved attention in rat. J Neurosci 25:5225–5229

    Article  PubMed  CAS  Google Scholar 

  • McGaughy J, Sarter M (1995) Behavioral vigilance in rats: task validation and effects of age, amphetamine, and benzodiazepine receptor ligands. Psychopharmacology (Berl) 117:340–357

    Article  CAS  Google Scholar 

  • McGaughy J, Sarter M (1998) Sustained attention performance in rats with intracortical infusions of 192 IgG-saporin-induced cortical cholinergic deafferentation: effects of physostigmine and FG 7142. Behav Neurosci 112:1519–1525

    Article  PubMed  CAS  Google Scholar 

  • McGaughy J, Kaiser T, Sarter M (1996) Behavioral vigilance following infusions of 192 IgG-saporin into the basal forebrain: selectivity of the behavioral impairment and relation to cortical AChE-positive fiber density. Behav Neurosci 110:247–265

    Article  PubMed  CAS  Google Scholar 

  • McGaughy J, Decker MW, Sarter M (1999) Enhancement of sustained attention performance by the nicotinic acetylcholine receptor agonist ABT-418 in intact but not basal forebrain-lesioned rats. Psychopharmacology 144:175–182

    Article  PubMed  CAS  Google Scholar 

  • McGaughy J, Dalley JW, Morrison CH, Everitt BJ, Robbins TW (2002) Selective behavioral and neurochemical effects of cholinergic lesions produced by intrabasalis infusions of 192 IgG-saporin on attentional performance in a five-choice serial reaction time task. J Neurosci 22:1905–1913

    PubMed  CAS  Google Scholar 

  • McQuail JA, Burk JA (2006) Evaluation of muscarinic and nicotinic receptor antagonists on attention and working memory. Pharmacol Biochem Behav 85:796–803

    Article  PubMed  CAS  Google Scholar 

  • Moore H, Sarter M, Bruno JP (1995) Bidirectional modulation of cortical acetylcholine efflux by infusion of benzodiazepine receptor ligands into the basal forebrain. Neurosci Lett 189:31–34

    Article  PubMed  CAS  Google Scholar 

  • National Research Council (1996) Guide for the care and use of laboratory animals. National Academy Press, Washington, D. C.

  • Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E (2000) Hypocretin (orexin) deficiency in human narcolepsy. Lancet 355:39–40

    Article  PubMed  CAS  Google Scholar 

  • Nuechterlein KH, Luck SJ, Lustig C, Sarter M (2009) CNTRICS final task selection: control of attention. Schizophr Bull 25:182–196

    Article  Google Scholar 

  • Parasuraman R, Warm JS, Dember WN (1987) Vigilance: taxonomy and utility. In: Mark LS, Warm JS, Huston RL (eds) Ergonomics and human factors. Springer, New York, pp 11–32

    Google Scholar 

  • Parikh V, Kozak R, Martinez V, Sarter M (2007) Prefrontal acetylcholine release controls cue detection on multiple timescales. Neuron 56:141–154

    Article  PubMed  CAS  Google Scholar 

  • Passetti F, Dalley JW, O’Connell MT, Everitt BJ, Robbins TW (2000) Increased acetylcholine release in the rat medial prefrontal cortex during performance of a visual attentional task. Eur J Neurosci 12:3051–3058

    Article  PubMed  CAS  Google Scholar 

  • Paxinos G, Watson C (2005) The rat brain in stereotaxic coordinates, 5th edn. Elsevier, Amsterdam

    Google Scholar 

  • Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG, Kilduff TS (1998) Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 18:9996–10015

    PubMed  CAS  Google Scholar 

  • Peyron C, Faraco J, Rogers W, Ripley B, Overeem S, Charnay Y, Nevsimalova S, Aldrich M, Reynolds D, Albin R, Li R, Hungs M, Pedrazzoli M, Padigaru M, Kucherlapati M, Fan J, Maki R, Lammers GJ, Bouras C, Kucherlapati R, Nishino S, Mignot E (2000) A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 6:991–997

    Article  PubMed  CAS  Google Scholar 

  • Porkka-Heiskanen T, Alanko L, Kalinchuk A, Heiskanen S, Stenberg D (2004) The effect of age on prepro-orexin expression and contents of orexin A and B in the rat brain. Neurobiol Aging 25:231–238

    Article  PubMed  CAS  Google Scholar 

  • Rieger M, Mayer G, Gauggel S (2003) Attention deficits in patients with narcolepsy. Sleep 26:36–43

    PubMed  Google Scholar 

  • Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richarson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92:573–585

    Article  PubMed  CAS  Google Scholar 

  • Sarter M, Bruno JP (2002) The neglected constituent of the basal forebrain corticopetal projection system: GABAergic projections. Eur J Neurosci 15:1867–1873

    Article  PubMed  Google Scholar 

  • Sarter M, Hasselmo ME, Bruno JP, Givens B (2005) Unraveling the attentional functions of cortical cholinergic inputs: interactions between signal-driven and cognitive modulation of signal detection. Brain Res Brain Res Rev 48:98–111

    Article  PubMed  CAS  Google Scholar 

  • Smart D, Sabido-David C, Brough SJ, Jewitt F, Johns A, Porter RA, Jerman JC (2001) SB-33867-A: the first selective orexin-1 receptor antagonist. Br J Pharmacol 132:1179–1182

    Article  PubMed  CAS  Google Scholar 

  • Terao A, Apte-Deshpande A, Morairty S, Freund YR, Kilduff TS (2002) Age-related decline in hypocretin (orexin) receptor 2 messenger RNA levels in the mouse brain. Neurosci Lett 332:190–194

    Article  PubMed  CAS  Google Scholar 

  • Thakkar MM, Ramesh V, Strecker RE, McCarley RW (2001) Microdialysis perfusion of orexin-A in the basal forebrain increases wakefulness in freely behaving rats. Arch Ital Biol 139:313–328

    PubMed  CAS  Google Scholar 

  • Thannickal TC, Moore RY, Nienhuis R, Ramanathan L, Gulyani S, Aldrich M, Cornford M, Siegel JM (2000) Reduced number of hypocretin neurons in human narcolepsy. Neuron 27:469–474

    Article  PubMed  CAS  Google Scholar 

  • Turchi J, Sarter M (2001) Bidirectional modulation of basal forebrain N-methyl-D-aspartate receptor function differentially affects visual attention but not visual discrimination performance. Neuroscience 104:407–417

    Article  PubMed  CAS  Google Scholar 

  • Zaborszky L, Gaykema RP, Swanson DJ, Cullinan WE (1997) Cortical input to the basal forebrain. Neuroscience 79:1051–1079

    Article  PubMed  CAS  Google Scholar 

  • Zar JH (1974) Biostatistical analysis. Prentice Hall, Englewood Cliffs

    Google Scholar 

  • Zhang JH, Sampogna S, Morales FR, Chase MH (2002) Age-related changes in hypocretin (orexin) immunoreactivity in the cat brainstem. Brain Res 930:206–211

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by AG030646 (JRF and JAB) and awards from the Jeffress Memorial Trust (JAB). The authors wish to thank Andrea Robinson, Usmaan Bashir, Sarah Baum, Will Bleser, Fuad Bohsali, Aileen Kim, David Mangini, Puja Parekh, Jon Weeks, and Bethany Wilson for technical assistance.

Author information

Authors and Affiliations

  1. Department of Psychology, College of William & Mary, Williamsburg, VA, 23187, USA

    Karen E. Boschen & Joshua A. Burk

  2. Department of Pharmacology, Physiology and Neuroscience, School of Medicine, University of South Carolina, Columbia, SC, 29208, USA

    Jim R. Fadel

Authors
  1. Karen E. Boschen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jim R. Fadel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joshua A. Burk
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joshua A. Burk.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Boschen, K.E., Fadel, J.R. & Burk, J.A. Systemic and intrabasalis administration of the orexin-1 receptor antagonist, SB-334867, disrupts attentional performance in rats. Psychopharmacology 206, 205–213 (2009). https://doi.org/10.1007/s00213-009-1596-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-009-1596-2

Keywords

Search

Navigation