Skip to main content
SpringerLink
Log in

α2- and β-adrenoceptors involvement in nortriptyline modulation of auditory sustained attention and impulsivity

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

Abstract

Rationale

The catecholamine innervation of the prefrontal cortex controls attentional focus and inhibits inappropriate behavioral responses. The mechanism of action with which norepinephrine (NE) reuptake inhibitors modulate these cognitive functions has not been fully investigated.

Objective

We investigated the effect of systemic administration of the NE reuptake blocker nortriptyline (NT) on attention and impulsivity using an auditory sustained attention task. The task was designed to assess impulsive behavior and the maintenance of attentional focus to an auditory stimulus presented at interresponse time durations (IRT) between 5 and 80 s.

Results

NT (2.0 but not 3.0 mg/kg) improved sustained attention and decreased the percentage of premature responses without changing their latency. To better understand the adrenergic component of NT action, we tested the effect of noradrenergic receptor antagonists alone or together with NT. The α2-receptor antagonist yohimbine, the α1-receptor antagonist prazosin, or the β-receptor antagonist propranolol alone did not significantly affect attentive performance or premature responses. However, the beneficial effects of NT on sustained attention and premature responses were attenuated by pretreatment with either yohimbine or propranolol. On the contrary, prazosin did not affect the NT-mediated improvement in sustained attention.

Conclusions

We conclude that sustained attention displays an inverse U-shaped dependence on NT, mediated—at least in part—by α2- and β-adrenoceptors. We speculate that low doses of NT improve performance by maximizing the phasic release of NE, while higher doses of NT would elevate tonic levels of NE, thus producing suboptimal levels of phasically released NE.

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
Fig. 4

Similar content being viewed by others

References

  • Alexander JK, Hillier A, Smith RM, Tivarus ME, Beversdorf DQ (2007) Beta-adrenergic modulation of cognitive flexibility during stress. J Cogn Neurosci 19:468–478

    Article  PubMed  Google Scholar 

  • Aoki C, Venkatesan C, Go CG, Forman R, Kurose H (1998) Cellular and subcellular sites for noradrenergic action in the monkey dorsolateral prefrontal cortex as revealed by the immunocytochemical localization of noradrenergic receptors and axons. Cereb Cortex 8:266–277

    Article  Google Scholar 

  • Arnsten AF (1998) Catecholamine modulation of prefrontal cortical cognitive function. Trends Cogn Sci 2: 436-47

    Google Scholar 

  • Arnsten AFT, Goldman-Rakic PS (1984) Selective prefrontal cortical projections to the region of the locus coeruleus and raphe nuclei in the rhesus monkey. Brain Res 306:9–18

    Article  PubMed  CAS  Google Scholar 

  • Arnsten AFT, Goldman-Rakic PS (1985) Catecholamines and cognitive decline in aged nonhuman primates. Ann N Y Acad Sci 444:218–234

    Article  PubMed  CAS  Google Scholar 

  • Arnsten AFT, Li BM (2005) Neurobiology of executive functions: catecholamine influences of prefrontal cortical functions. Biol Psychiatry 57:1377–1384

    Google Scholar 

  • Arnsten AF, Steere JC, Hunt RD (1996) The contribution of α2-noradrenergic mechanisms to prefrontal cortical cognitive function. Arch Gen Psychiatry 53:448–455

    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 

  • Aston-Jones G, Iba M, Clayton E, Rajkowski J, Cohen J (2007) The locus coeruleus and regulation of behavioral flexibility and attention: clinical implications. In: Ordway GA, Schwartz MA, Frazer A (eds) Brain norepinephrine: neurobiology and therapeutics. Cambridge University Press, Cambridge, pp 196–235

    Chapter  Google Scholar 

  • Barkley RA (1997) Behavioral inhibition, sustained attention, and executive functions: constructing a unifying theory of ADHD. Psychol Bull 121:65–94

    Article  PubMed  CAS  Google Scholar 

  • Berridge CW, Waterhouse BD (2003) The locus coeruleus–noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res Brain Res Rev 42:33–84

    Article  PubMed  Google Scholar 

  • Biederman J, Spencer T (1999) Attention-deficit/hyperactivity disorder (ADHD) as a noradrenergic disorder. Biol Psychiatry 46:1234–1242

    Article  PubMed  CAS  Google Scholar 

  • Brennan AR, Arnsten AFT (2008) Neuronal mechanisms underlying attention deficit hyperactivity disorder: the influence of arousal on prefrontal cortical function. Ann N Y Acad Sci 1129:236–245

    Article  PubMed  Google Scholar 

  • Bruno KJ, Hess EJ (2006) The α2C-adrenergic receptor mediates hyperactivity of coloboma mice, a model of attention deficit hyperactivity disorder (2006). Neurobiol Dis 23:679–688

    Article  PubMed  CAS  Google Scholar 

  • Bushnell PJ (1998) Behavioral approaches to the assessment of attention in animals. Psychopharmacology 138:231–259

    Article  PubMed  CAS  Google Scholar 

  • Carli M, Robbins TW, Evenden JL, Everitt BJ (1983) 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 9:361–380

    Article  PubMed  CAS  Google Scholar 

  • Cole SO, Michaleski A (1986) Dose-dependent impairment in the performance of a go-no go successive discrimination by chlordiazepoxide. Psychopharmacology 88:184–186

    Article  PubMed  CAS  Google Scholar 

  • Dagnino-Subiabre A, Muñoz-Llancao P, Terreros G, Wyneken U, Díaz-Véliz G, Porter B, Kilgard MP, Atzori M, Aboitiz F (2009) Chronic stress induces dendritic atrophy in the rat medial geniculate nucleus: effects on auditory conditioning. Behav Brain Res 203:88–96

    Google Scholar 

  • Dahlström A, Fuxe K (1964) Evidence for the existence of monoamine-containing neurons in the central nervous system: demonstration of monoamines in the cell bodies of brain stem neurons. Acta Physiol Scand Suppl 232:1–55

    Google Scholar 

  • Dalley JW, Cardinal RN, Robbins TW (2004) Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates. Neurosci Biobehav Rev 28:771–784

    Article  PubMed  CAS  Google Scholar 

  • Dekeyne A, Gobert A, Auclair A, Girardon S, Millan MJ (2002) Differential modulation of efficiency in a food-rewarded “differential reinforcement of low-rate” 72-s schedule in rats by norepinephrine and serotonin reuptake inhibitors. Psychopharmacology 162:156–167

    Article  PubMed  CAS  Google Scholar 

  • del Campo N, Chamberlain SR, Sahakian BR, Robbins TW (2011) The roles of dopamine and noradrenaline in the pathophysiology and treatment of attention-deficit/hyperactivity disorder. Biol Psychiatry 69:145–157

    Article  Google Scholar 

  • Devilbiss DM, Berridge CW (2006) Low-dose methylphenidate actions on tonic and phasic locus coeruleus discharge. J Pharmacol Exp Ther 319:1327–1335

    Article  PubMed  CAS  Google Scholar 

  • Donovan E (2010) Propranolol use in the prevention and treatment of posttraumatic stress disorder in military veterans: forgetting therapy revisited. Perspect Biol Med 53:61–74

    Article  PubMed  Google Scholar 

  • Dubocovich ML (1984) Presynaptic alpha-adrenoceptors in the central nervous system. Ann N Y Acad Sci 430:7–25

    Article  PubMed  CAS  Google Scholar 

  • Floody OR, Kilgard MP (2007) Differential reductions in acoustic startle document the discrimination of speech sounds in rats. J Acoust Soc Am 122:1884–1887

    Article  PubMed  Google Scholar 

  • Franowicz JS, Arnsten AFT (1998) The α2a noradrenergic agonist, guanfacine, improves delayed response performance in young adult rhesus monkeys. Psychopharmacology 136:8–14

    Article  PubMed  CAS  Google Scholar 

  • Frazer A (2001) Serotonergic and noradrenergic reuptake inhibitors: prediction of clinical effects and in vitro potencies. J Clin Psychiatry 12:16–23

    Google Scholar 

  • Gamo NJ, Wang M, Arnsten AF (2010) Methylphenidate and atomoxetine enhance prefrontal function through α2-adrenergic and dopamine D1 receptors. J Am Acad Child Adolesc Psychiatry 49:1011–1023

    Article  PubMed  Google Scholar 

  • Grilly DM, Gowans GC (1988) Effects of naltrexone, d-amphetamine, and their interaction on the stimulus control of choice behavior of rats. Psychopharmacology 96:73–80

    Article  PubMed  CAS  Google Scholar 

  • Haapalinna A, Viitamaa T, MacDonald E, Savola JM, Tuomisto L, Virtanen R, Heinonen E (1997) Evaluation of the effects of a specific α2-adrenoceptor antagonist, atipamezole, on α1-and α2-adrenoceptor subtype binding, brain neurochemistry and behaviour in comparison with yohimbine. Naunyn Schmiedebergs Arch Pharmacol 356:570–582

    Article  PubMed  CAS  Google Scholar 

  • Heal DJ, Smith SL, Kulkarni RS, Rowley HL (2008) New perspectives from microdialysis studies in freely-moving, spontaneously hypertensive rats on the pharmacology of drugs for the treatment of ADHD. Pharmacol Biochem Behav 90:184–197

    Article  PubMed  CAS  Google Scholar 

  • Jodo E, Aston-Jones G (1997) Activation of locus coeruleus by prefrontal cortex by excitatory amino acid inputs. Brain Res 768:327–332

    Article  PubMed  CAS  Google Scholar 

  • Koskinen T, Haapalinna A, Sirviö J (2003) α-adrenoceptor-mediated modulation of 5-HT2 receptor agonist induced impulsive responding in a 5-choice serial reaction time task. Pharmacol Toxicol 92:214–225

    Article  PubMed  CAS  Google Scholar 

  • Li BM, Mei ZT (1994) Delayed-response deficit induced by local injection of the alpha-2 adrenergic antagonist yohimbine into the dorsolateral prefrontal cortex in young adult monkeys. Behav Neural Biol 62:134–139

    Article  PubMed  CAS  Google Scholar 

  • Liu YP, Lin YL, Chuang CH, Kao YT, Chang ST, Tung CS (2009) Alpha adrenergic modulation on effects of norepinephrine transporter inhibitor reboxetine in five-choice serial reaction time task. J Biomed Sci 16:72–83

    Article  PubMed  Google Scholar 

  • Lovejoy DW, Ball JD, Keats M, Stutts ML, Spain EH, Janda L, Janusz J (1999) Neuropsychological performance of adults with attention deficit hyperactivity disorder (ADHD): diagnostic classification of estimates for measures of frontal lobe/executive functioning. J Int Neuropsychol Soc 5:222–233

    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 117:340–357

    Article  PubMed  CAS  Google Scholar 

  • Merriam AE (2000) Tricyclic antidepressants. In: Spencer PS, Schaumburg HH (eds) Experimental and clinical neurotoxicology. Oxford University Press, New York, pp 1203–1206

    Google Scholar 

  • Milstein JA, Lehmann O, Theobald DE, Dalley JW, Robbins TW (2007) Selective depletion of cortical noradrenaline by anti-dopamine beta-hydroxylase-saporin impairs attentional function and enhances the effects of guanfacine in the rat. Psychopharmacology 190:51–63

    Article  PubMed  CAS  Google Scholar 

  • Milstein JA, Dalley JW, Robbins TW (2008) Methylphenidate-induced impulsivity: pharmacological antagonism by β-adrenoceptor blockade. J Psychopharmacol 24:309–321

    Article  PubMed  Google Scholar 

  • Mirsky AF, Duncan CC (2001) A nosology of disorders of attention. In: Wasserstein J, Wolf LE, Lefever FF (eds) Adult attention deficit disorder: brain mechanisms and life outcomes. The New York Academy of Sciences, New York, pp 17–32

    Google Scholar 

  • Mishima K, Fujii M, Aoo N, Yoshikawa T, Fukue Y, Honda Y, Egashira N, Iwasaki K, Shoyama Y, Fujiwara M (2002) The pharmacological characterization of attentional processes using two-lever reaction time task in rats. Biol Pharm Bull 25:1570–1576

    Article  PubMed  CAS  Google Scholar 

  • Navarra R, Graf R, Huang Y, Logue S, Comery T, Hughes Z, Day M (2008) Effects of atomoxetine and methylphenidate on attention and impulsivity in the 5-choice serial reaction time test. Prog Neuropsychopharmacol Biol Psychiatry 32:34–41

    Article  PubMed  CAS  Google Scholar 

  • O’Donnell JM, Seiden LS (1983) Differential-reinforcement-of-low-rate 72-second schedule: selective effects of antidepressant drugs. J Pharmacol Exp Ther 224:80–88

    PubMed  Google Scholar 

  • Pattij T, Schetters D, Schoffelmeer AN, van Gaalen MM (2011) On the improvement of inhibitory response control and visuospatial attention by indirect and direct adrenoceptor agonists. Psychopharmacology 219:327–420

    Google Scholar 

  • Pitman RK, Sanders KM, Zusman RM, Healy AR, Cheema F, Lasko NB, Cahill L, Orr SP (2002) Pilot study of secondary prevention of posttraumatic stress disorder with propranolol. Biol Psychiatry 51:189–192

    Article  PubMed  CAS  Google Scholar 

  • Pliszka SR, McCracken JT, Maas JW (1996) Catecholamines in attention-deficit hyperactivity disorders: current perspectives. J Am Acad Child Adolesc Psychiatry 35:264–272

    Article  PubMed  CAS  Google Scholar 

  • Prince JB, Wilens TE, Biederman J, Spencer TJ, Millstein R, Polisner DA, Bostic JQ (2000) A controlled study of nortriptyline in children and adolescents with attention deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 10:193–204

    CAS  Google Scholar 

  • Ramos BP, Arnsten AFT (2007) Adrenergic pharmacology and cognition: focus on the prefrontal cortex. Pharmacol Ther 113:523–536

    Article  PubMed  CAS  Google Scholar 

  • Robbins TW (2002) The 5-choice serial reaction time task: behavioural pharmacology and functional neurochemistry. Psychopharmacology 163:362–380

    Article  PubMed  CAS  Google Scholar 

  • Sagvolden T (2006) The alpha-2A adrenoceptor agonist guanfacine improves sustained attention and reduces overactivity and impulsiveness in an animal model of attention-deficit/hyperactivity disorder. Behav Brain Funct 2:41

    Article  PubMed  Google Scholar 

  • Schubert J, Nybäck H, Sedvall G (1970) Effect of antidepressant drugs on accumulation and disappearance of monoamines formed in vivo from labelled precursors in mouse brain. J Pharm Pharmacol 22:136–139

    Article  PubMed  CAS  Google Scholar 

  • Sessions GR, Kant GJ, Koob GF (1976) Locus coeruleus lesions and learning in the rat. Physiol Behav 17:853–859

    Article  PubMed  CAS  Google Scholar 

  • Sonuga-Barke EJ (2005) Causal models of attention-deficit/hyperactivity disorder: from common simple deficits to multiple developmental pathways. Biol Psychiatry 57:1231

    Article  PubMed  Google Scholar 

  • Tait DS, Brown VJ, Farovik A, Theobald DE, Dalley JW, Robbins TW (2007) Lesions of the dorsal noradrenergic bundle impair attentional set-shifting in the rat. Eur J Neurosci 25:3719–3724

    Article  PubMed  Google Scholar 

  • Taube HD, Starke K, Borowski E (1977) Presynaptic receptor systems of the noradrenergic neurons of rat brain. Naunyn Schmiedebergs Arch Pharmacol 299:123–141

    Article  PubMed  CAS  Google Scholar 

  • Vaiva G, Ducrocq F, Jezequel K, Averland B et al (2003) Immediate treatment with propranolol decreases posttraumatic stress disorder two months after trauma. Biol Psychiatry 54:947–949

    Article  PubMed  CAS  Google Scholar 

  • Valsamis B, Schmid S (2011) Habituation and prepulse inhibition of acoustic startle in rodent. J Vis Exp 55:e3446

    PubMed  Google Scholar 

  • Wilens TE, Biederman J, Spencer T, Geist DE (1993) A retrospective study of serum levels and electrocardiographic effects of nortriptyline in children and adolescents. J Am Acad Child Adolesc Psychiatry 32:270–277

    Article  PubMed  CAS  Google Scholar 

  • Wong CC, Mill J, Fernandes C (2011) Drug and addiction: an introduction to epigenetics. Addiction 106:480–489

    Article  PubMed  Google Scholar 

  • Zhang HT, Whisler LR, Huang Y, Xiang Y et al (2009) Postsynaptic α2-adrenergic receptors are critical for the antidepressant-like effects of desipramine on behavior. Neuropsychopharmacology 34:1067–1077

    Article  PubMed  CAS  Google Scholar 

  • Zhu J, Spencer TJ, Liu-Chen LY, Biederman J, Bhide PJ (2011) Methylphenidate and μ opioid receptor interactions: a pharmacological target for prevention of stimulant abuse. Neuropharmacology 61:283–292

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We would like to thank Mr. Jevin Jackson for thorough review of the manuscript. This work has been funded by a BBS/UTD Research Fund grant to M.A. None of the authors have any conflict of interest related to this study.

Author information

Authors and Affiliations

  1. Laboratory of Synaptic and Cellular Physiology, School of Behavioral and Brain Sciences, University of Texas at Dallas/GR41, 800 West Campbell Road, Richardson, TX, 75080, USA

    Swagata Roychowdhury, Zulma Peña-Contreras, Jason Tam, Amulya Yadlapalli, Lu Dinh, Justin Andrew Nichols, Debarshi Basu & Marco Atzori

  2. Electron Microscopy Center, University of Los Andes, Mérida, Venezuela

    Zulma Peña-Contreras

  3. Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA

    Justin Andrew Nichols

Authors
  1. Swagata Roychowdhury
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zulma Peña-Contreras
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jason Tam
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Amulya Yadlapalli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lu Dinh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Justin Andrew Nichols
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Debarshi Basu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Marco Atzori
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Marco Atzori.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Roychowdhury, S., Peña-Contreras, Z., Tam, J. et al. α2- and β-adrenoceptors involvement in nortriptyline modulation of auditory sustained attention and impulsivity. Psychopharmacology 222, 237–245 (2012). https://doi.org/10.1007/s00213-012-2635-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-012-2635-y

Keywords

Search

Navigation