Skip to main content
SpringerLink
Log in

The α2-adrenergic antagonist idazoxan counteracts prepulse inhibition deficits caused by amphetamine or dizocilpine in rats

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

Abstract

Rationale

Prepulse inhibition (PPI) is the reduction in startle response magnitude when intense stimuli are closely preceded by other weak stimuli. Animal models used to investigate sensorimotor gating deficits include both the stimulation of dopamine receptors (e.g., amphetamine or apomorphine) and the blockade of NMDA-glutamate receptors (e.g., dizocilpine or phencyclidine).

Objectives

We assessed the effects of idazoxan (an α2-adrenergic antagonist) on amphetamine- and dizocilpine-induced PPI disruptions in adult female Sprague–Dawley rats.

Methods

In experiment 1, rats were tested for PPI in a bimodal paradigm with an acoustic prepulse and a tactile startle stimulus. Interactions of amphetamine (1 mg/kg) and idazoxan (0.5, 1, and 2 mg/kg) were assessed, with all rats receiving all drug doses in a counterbalanced order. In experiment 2, dizocilpine (0.05 mg/kg) and idazoxan (0.5, 1, and 2 mg/kg) interactions were analyzed.

Results

Amphetamine (1 mg/kg) caused a significant reduction in PPI. Both the 1- and 2-mg/kg doses of idazoxan significantly counteracted this effect. Dizocilpine (.05 mg/kg) effectively inhibited PPI, and the 2-mg/kg idazoxan dose significantly counteracted this impairment.

Conclusions

These results suggest that the effectiveness of atypical antipsychotics such as clozapine in counteracting sensorimotor gating deficits reported in previous studies (e.g., Swerdlow and Geyer, Pharmacol Biochem Behav 44:741–744, 1993; Bakshi et al., J Pharmacol Exp Ther 271:787–794, 1994) may be related to their α2-antagonist effects, which may be a critical mechanism of the therapeutic effects of atypical antipsychotics in schizophrenia.

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

  • Bakshi VP, Geyer MA (1997) Phencyclidine-induced deficits in prepulse inhibition of startle are blocked by prazosin, an alpha-1 noradrenergic antagonist. J Pharmacol Exp Ther 283:666–674

    PubMed  CAS  Google Scholar 

  • Bakshi VP, Geyer MA (1998) Multiple limbic regions mediate the disruption of prepulse inhibition produced in rats by the noncompetitive NMDA antagonist dizocilpine. J Neurosci 18:8394–8401

    PubMed  CAS  Google Scholar 

  • Bakshi VP, Swerdlow NR, Geyer MA (1994) Clozapine antagonizes phencyclidine-induced deficits in sensorimotor gating of the startle response. J Pharmacol Exp Ther 271:787–794

    PubMed  CAS  Google Scholar 

  • Ballmaier M, Zoli M, Mazzoncini R, Gennarelli M, Spano F (2001) Combined alpha 2-adrenergic/D2 dopamine receptor blockade fails to reproduce the ability of clozapine to reverse phencyclidine-induced deficits in prepulse inhibition of startle. Psychopharmacol (Berl) 159:105–110

    Article  CAS  Google Scholar 

  • Bell DD, Zucker I (1971) Sex differences in body weight and eating: organization and activation by gonadal hormones in the rat. Physiol Behav 7:27–34

    Article  PubMed  CAS  Google Scholar 

  • Bortolato M, Aru GN, Fa M, Frau R, Orru M, Salis P, Casti A, Luckey GC, Mereu G, Gessa GL (2005) Activation of D1, but not D2 receptors potentiates dizocilpine-mediated disruption of prepulse inhibition of the startle. Neuropsychopharmacology 30:561–574

    Article  PubMed  CAS  Google Scholar 

  • Braff D, Stone C, Callaway E, Geyer M, Glick I, Bali L (1978) Prestimulus effects on human startle reflex in normals and schizophrenics. Psychophysiology 15:339–343

    Article  PubMed  CAS  Google Scholar 

  • Brown JS, Kalish HI, Farber IE (1951) Conditioned fear as revealed by magnitude of startle response to an auditory stimulus. J Exp Psychol 41:317–328

    Article  PubMed  CAS  Google Scholar 

  • Bubenikova V, Votava M, Horacek J, Palenicek T, Dockery C (2005) The effect of zotepine, risperidone, clozapine and olanzapine on MK-801-disrupted sensorimotor gating. Pharmacol Biochem Behav 80:591–596

    Article  PubMed  CAS  Google Scholar 

  • Bubser M, Koch M (1994) Prepulse inhibition of the acoustic startle response of rats is reduced by 6-hydroxydopamine lesions of the medial prefrontal cortex. Psychopharmacol (Berl) 113:487–492

    Article  CAS  Google Scholar 

  • Caceda R, Kinkead B, Owens MJ, Nemeroff CB (2005) Virally mediated increased neurotensin 1 receptor in the nucleus accumbens decreases behavioral effects of mesolimbic system activation. J Neurosci 25:11748–11756

    Article  PubMed  CAS  Google Scholar 

  • Castellanos FX, Fine EJ, Kaysen D, Marsh WL, Rapoport JL, Hallett M (1996) Sensorimotor gating in boys with Tourette's syndrome and ADHD: preliminary results. Biol Psychiatry 39:33–41

    Article  PubMed  CAS  Google Scholar 

  • Coward DM (1992) General pharmacology of clozapine. Br J Psychiatry Suppl (17):5–11

  • Davis M, Gendelman DS, Tischler MD, Gendelman PM (1982) A primary acoustic startle circuit: lesion and stimulation studies. J Neurosci 2:791–805

    PubMed  CAS  Google Scholar 

  • Eaton RC (1984) Neural mechanisms of startle behavior. Plenum, New York

    Google Scholar 

  • Fendt M, Koch M, Schnitzler HU (1994) Sensorimotor gating deficit after lesions of the superior colliculus. Neuroreport 5:1725–1728

    Article  PubMed  CAS  Google Scholar 

  • Geyer MA, Krebs-Thomson K, Braff DL, Swerdlow NR (2001) Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacol (Berl) 156:117–154

    Article  CAS  Google Scholar 

  • Graham FK (1975) Presidential Address, 1974. The more or less startling effects of weak prestimulation. Psychophysiology 12:238–248

    Article  PubMed  CAS  Google Scholar 

  • Grenhoff J, Nisell M, Ferre S, Aston-Jones G, Svensson TH (1993) Noradrenergic modulation of midbrain dopamine cell firing elicited by stimulation of the locus coeruleus in the rat. J Neural Transm Gen Sect 93:11–25

    Article  PubMed  CAS  Google Scholar 

  • Hertel P, Fagerquist MV, Svensson TH (1999) Enhanced cortical dopamine output and antipsychotic-like effects of raclopride by alpha2 adrenoceptor blockade. Science 286:105–107

    Article  PubMed  CAS  Google Scholar 

  • Hoffman HS, Ison JR (1980) Reflex modification in the domain of startle: I. Some empirical findings and their implications for how the nervous system processes sensory input. Psychol Rev 87:175–189

    Article  PubMed  CAS  Google Scholar 

  • Hoffman HS, Searle JL (1968) Acoustic and temporal factors in the evocation of startle. J Acoust Soc Am 43:269–282

    Article  PubMed  CAS  Google Scholar 

  • Honack D, Loscher W (1993) Sex differences in NMDA receptor mediated responses in rats. Brain Res 620:167–170

    Article  PubMed  CAS  Google Scholar 

  • Invernizzi RW, Garavaglia C, Samanin R (2003) The alpha 2-adrenoceptor antagonist idazoxan reverses catalepsy induced by haloperidol in rats independent of striatal dopamine release: role of serotonergic mechanisms. Neuropsychopharmacology 28:872–879

    PubMed  CAS  Google Scholar 

  • Karreman M, Moghaddam B (1996) The prefrontal cortex regulates the basal release of dopamine in the limbic striatum: an effect mediated by ventral tegmental area. J Neurochem 66:589–598

    Article  PubMed  CAS  Google Scholar 

  • Keith VA, Mansbach RS, Geyer MA (1991) Failure of haloperidol to block the effects of phencyclidine and dizocilpine on prepulse inhibition of startle. Biol Psychiatry 30:557–566

    Article  PubMed  CAS  Google Scholar 

  • Kleven MS, Barret-Grevoz C, Slot LB, Newman-Tancredi A (2005) Novel antipsychotic agents with 5-HT(1A) agonist properties: role of 5-HT(1A) receptor activation in attenuation of catalepsy induction in rats. Neuropharmacology 49:135–143

    Article  PubMed  CAS  Google Scholar 

  • Koch M (1998) Sensorimotor gating changes across the estrous cycle in female rats. Physiol Behav 64:625–628

    Article  PubMed  CAS  Google Scholar 

  • Koch M (1999) The neurobiology of startle. Prog Neurobiol 59:107–128

    Article  PubMed  CAS  Google Scholar 

  • Koch M, Kungel M, Herbert H (1993) Cholinergic neurons in the pedunculopontine tegmental nucleus are involved in the mediation of prepulse inhibition of the acoustic startle response in the rat. Exp Brain Res 97:71–82

    Article  PubMed  CAS  Google Scholar 

  • Landis C, Hunt WA, Strauss H (1939) The startle pattern. Farrar & Rinehart, New York

    Google Scholar 

  • Larrauri JA, Levin ED (2010) PPI deficit induced by amphetamine is attenuated by the histamine H1 antagonist pyrilamine, but is exacerbated by the serotonin 5HT2 antagonist ketanserin. Psychopharmacology 212:551–558

    Article  PubMed  CAS  Google Scholar 

  • Levin ED, Caldwell DP, Perraut C (2007) Clozapine treatment reverses dizocilpine-induced deficits of pre-pulse inhibition of tactile startle response. Pharmacol Biochem Behav 86:597–605

    Article  PubMed  CAS  Google Scholar 

  • Litman RE, Su TP, Potter WZ, Hong WW, Pickar D (1996) Idazoxan and response to typical neuroleptics in treatment-resistant schizophrenia. Comparison with the atypical neuroleptic, clozapine. Br J Psychiatry 168:571–579

    Article  PubMed  CAS  Google Scholar 

  • Luttinger D, Durivage ME (1986) Alpha 2-adrenergic antagonists effect on amphetamine-induced behaviors. Pharmacol Biochem Behav 25:155–160

    Article  PubMed  CAS  Google Scholar 

  • Mallard NJ, Hudson AL, Nutt DJ (1992) Characterization and autoradiographical localization of non-adrenoceptor idazoxan binding sites in the rat brain. Br J Pharmacol 106:1019–1027

    PubMed  CAS  Google Scholar 

  • Mansbach RS, Geyer MA (1989) Effects of phencyclidine and phencyclidine biologs on sensorimotor gating in the rat. Neuropsychopharmacology 2:299–308

    Article  PubMed  CAS  Google Scholar 

  • Mansbach RS, Geyer MA, Braff DL (1988) Dopaminergic stimulation disrupts sensorimotor gating in the rat. Psychopharmacol (Berl) 94:507–514

    Article  CAS  Google Scholar 

  • McAlonan GM, Daly E, Kumari V, Critchley HD, van Amelsvoort T, Suckling J, Simmons A, Sigmundsson T, Greenwood K, Russell A, Schmitz N, Happe F, Howlin P, Murphy DG (2002) Brain anatomy and sensorimotor gating in Asperger's syndrome. Brain 125:1594–1606

    Article  PubMed  Google Scholar 

  • McGrath JJ (2006) Variations in the incidence of schizophrenia: data versus dogma. Schizophr Bull 32:195–197

    Article  PubMed  Google Scholar 

  • Meredith MA, Wallace MT, Stein BE (1992) Visual, auditory and somatosensory convergence in output neurons of the cat superior colliculus: multisensory properties of the tecto-reticulo-spinal projection. Exp Brain Res 88:181–186

    Article  PubMed  CAS  Google Scholar 

  • Milesi-Halle A, McMillan DE, Laurenzana EM, Byrnes-Blake KA, Owens SM (2007) Sex differences in (+)-amphetamine- and (+)-methamphetamine-induced behavioral response in male and female Sprague–Dawley rats. Pharmacol Biochem Behav 86:140–149

    Article  PubMed  CAS  Google Scholar 

  • Miller LJ, Nielsen DM, Schoen SA, Brett-Green BA (2009) Perspectives on sensory processing disorder: a call for translational research. Front Integr Neurosci 3:1–12

    Article  Google Scholar 

  • Moghaddam B, Bunney BS (1990) Acute effects of typical and atypical antipsychotic drugs on the release of dopamine from prefrontal cortex, nucleus accumbens, and striatum of the rat: an in vivo microdialysis study. J Neurochem 54:1755–1760

    Article  PubMed  CAS  Google Scholar 

  • Palsson E, Fejgin K, Wass C, Klamer D (2008) Agmatine attenuates the disruptive effects of phencyclidine on prepulse inhibition. Eur J Pharmacol 590:212–216

    Article  PubMed  CAS  Google Scholar 

  • Perry W, Minassian A, Lopez B, Maron L, Lincoln A (2007) Sensorimotor gating deficits in adults with autism. Biol Psychiatry 61:482–486

    Article  PubMed  Google Scholar 

  • Roegge CS, Perraut C, Hao X, Levin ED (2007) Histamine H1 receptor involvement in prepulse inhibition and memory function: relevance for the antipsychotic actions of clozapine. Pharmacol Biochem Behav 86:686–692

    Article  PubMed  CAS  Google Scholar 

  • Sallinen J, Hoglund I, Engstrom M, Lehtimaki J, Virtanen R, Sirvio J, Wurster S, Savola JM, Haapalinna A (2007) Pharmacological characterization and CNS effects of a novel highly selective alpha2C-adrenoceptor antagonist JP-1302. Br J Pharmacol 150:391–402

    Article  PubMed  CAS  Google Scholar 

  • Schmid A, Koch M, Schnitzler HU (1995) Conditioned pleasure attenuates the startle response in rats. Neurobiol Learn Mem 64:1–3

    Article  PubMed  CAS  Google Scholar 

  • Schwabe K, Koch M (2004) Role of the medial prefrontal cortex in N-methyl-d-aspartate receptor antagonist induced sensorimotor gating deficit in rats. Neurosci Lett 355:5–8

    Article  PubMed  CAS  Google Scholar 

  • Sills TL (1999) Amphetamine dose dependently disrupts prepulse inhibition of the acoustic startle response in rats within a narrow time window. Brain Res Bull 48:445–448

    Article  PubMed  CAS  Google Scholar 

  • Swerdlow NR, Geyer MA (1993) Clozapine and haloperidol in an animal model of sensorimotor gating deficits in schizophrenia. Pharmacol Biochem Behav 44:741–744

    Article  PubMed  CAS  Google Scholar 

  • Swerdlow NR, Braff DL, Masten VL, Geyer MA (1990) Schizophrenic-like sensorimotor gating abnormalities in rats following dopamine infusion into the nucleus accumbens. Psychopharmacol (Berl) 101:414–420

    Article  CAS  Google Scholar 

  • Swerdlow NR, Auerbach P, Monroe SM, Hartston H, Geyer MA, Braff DL (1993a) Men are more inhibited than women by weak prepulses. Biol Psychiatry 34:253–260

    Article  PubMed  CAS  Google Scholar 

  • Swerdlow NR, Benbow CH, Zisook S, Geyer MA, Braff DL (1993b) A preliminary assessment of sensorimotor gating in patients with obsessive compulsive disorder. Biol Psychiatry 33:298–301

    Article  PubMed  CAS  Google Scholar 

  • Swerdlow NR, Paulsen J, Braff DL, Butters N, Geyer MA, Swenson MR (1995) Impaired prepulse inhibition of acoustic and tactile startle response in patients with Huntington's disease. J Neurol Neurosurg Psychiatry 58:192–200

    Article  PubMed  CAS  Google Scholar 

  • Swerdlow NR, Braff DL, Geyer MA (2000) Animal models of deficient sensorimotor gating: what we know, what we think we know, and what we hope to know soon. Behav Pharmacol 11:185–204

    Article  PubMed  CAS  Google Scholar 

  • Swerdlow NR, Kuczenski R, Goins JC, Crain SK, Ma LT, Bongiovanni MJ, Shoemaker JM (2005) Neurochemical analysis of rat strain differences in the startle gating-disruptive effects of dopamine agonists. Pharmacol Biochem Behav 80:203–211

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Box #104790, Durham, NC, 27710, USA

    José A. Larrauri & Edward D. Levin

Authors
  1. José A. Larrauri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Edward D. Levin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Edward D. Levin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Larrauri, J.A., Levin, E.D. The α2-adrenergic antagonist idazoxan counteracts prepulse inhibition deficits caused by amphetamine or dizocilpine in rats. Psychopharmacology 219, 99–108 (2012). https://doi.org/10.1007/s00213-011-2377-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-011-2377-2

Keywords

Search

Navigation