Effects of clonidine and diazepam on prepulse inhibition of the acoustic startle response and the N1/P2 auditory evoked potential in man

Abstract

Contraction of the orbicularis oculi muscle in response to a sudden loud sound (acoustic startle response) and the N1/P2 component of the auditory evoked potential are both attenuated when a brief low-intensity stimulus is presented 30–500 ms before the ‘startle-eliciting’ stimulus (prepulse inhibition). We examined the effects of two sedative/anxiolytic drugs, diazepam and clonidine, on prepulse inhibition of these two responses in healthy volunteers. Fifteen males (aged 18–35 years) participated in three sessions in which they received oral doses of placebo, diazepam 10 mg and clonidine 0.2 mg according to a balanced double-blind protocol. Thirty-minute simultaneous recordings of the electromyographic (EMG) responses of the orbicularis oculi muscle of the right eye and the vertex auditory evoked potentials took place 120 min after ingestion of clonidine and 60 min after ingestion of diazepam. Sound stimuli (1 kHz) were presented in 60 trials separated by variable intervals (mean 25 s): (i) 40-ms 115-dB (‘pulse alone’, 20 trials); (ii) 40-ms 85-dB (20 trials); (iii) 40-ms 85-dB, followed after 120 ms by 40-ms 115-dB (‘prepulse/pulse’, 20 trials). Mean amplitudes of the EMG response and the N1/P2 potential were derived from the pulse-alone trials and, in each case, percentage prepulse inhibition was calculated. The amplitude of the EMG response was significantly reduced both by diazepam and by clonidine; neither drug significantly altered prepulse inhibition of the EMG response. Diazepam, but not clonidine, significantly reduced the amplitude of the N1/P2 potential; neither drug significantly affected prepulse inhibition of the N1/P2 potential. Both drugs reduced self-rated alertness and anxiety, and systolic blood pressure; clonidine, but not diazepam reduced diastolic blood pressure and salivation. The results confirm previous findings that sedative drugs can suppress the startle response without affecting prepulse inhibition of this response, and provide new information on the effects of these drugs on the N1/P2 potential and its inhibition by prepulses.

Keywords

acousticstartleresponse clonidine diazepam N1/P2auditoryevokedpotential prepulseinhibition

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References

Abduljawad K A J , Langley R W , Bradshaw C M , Szabadi E (1997) Effects of clonidine and diazepam on the acoustic startle response and on its inhibition by ‘prepulses’ in man. J Psychopharmacol 11: 29–34

Abduljawad K A J , Langley R W , Bradshaw C M , Szabadi E (1999) Effects of bromocriptine and haloperidol on prepulse inhibition: comparison of the acoustic startle eyeblink response and the N1/P2 auditory-evoked response in man. J Psycho-pharmacol 13: 3–9

Adler L E , Pachtman E , Franks R D , Pecevich M , Waldo M C , Freedman R (1982) Neurophysiological evidence for a defect in neuronal mechanisms involved in sensory gating in schizophrenia. Biol Psychiatry 17: 639–654

Bender S , Schall U , Wolstein J , Grzella I , Zerbin D , Oades R D (1999) A topographic event-related potential follow-up study on ‘prepulse inhibition’ in first and second episode patients with schizophrenia. Psychiatr Res Neuroimag Sect 90: 41–53

Bitsios P , Philpott A , Langley R W , Bradshaw C M , Szabadi E (1999) Comparison of the effects of diazepam on the fear-potentiated startle reflex and the fear-inhibited light reflex in man. J Psychopharmacol 13: 226–234

Bond AJ , Lader M H (1974) The use of analogue scales in rating subjective feelings. Br J Med Psychol 47: 211–218

Davis M (1980) Neurochemical modulation of sensory-motor reactivity: acoustic and tactile startle reflexes. Neurosci Biobehav Rev 4: 791–805

Davis M , Cederbaum J M , Abhajanian G K , Gendelman D S (1977) Effects of clonidine on habituation and sensitization of the acoustic startle in normal, decerebrate and locus coeruleus lesioned rats. Psychopharmacology 51: 243–253

Greenblatt D J , Allen M D , Harmatz J S , Shader R I (1980) Diazepam disposition determinants. Clin Pharmacol Ther 27: 301–312

10.

Judd L L , McAdams L , Budnick B , Braff D L (1992) Sensory gating deficits in schizophrenia: new results. Am J Psychiatry 149: 488–493

11.

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

12.

Kumari V , Cotter P , Corr P J , Gray J A , Checkley S A (1996) Effect of clonidine on the human acoustic startle reflex. Psycho-pharmacology 132: 352–360

13.

Lader M (1977) Effects of psychotropic drugs on auditory evoked potentials in man. In Desmedt J E (ed.), Auditory evoked potentials in man: psychopharmacology correlates of evoked potentials. Progress in clinical neurophysiology, vol. 2. Karger, Basel

14.

Lowenthal D T , Matzek K M , MacGregor T R (1988) Clinical pharmacokinetics of clonidine. Clin Pharmacokinet 14: 287–310

15.

Mauguière F , Cooper R , Holder G E , Luxon L M , Murray N M F (1995) Evoked potentials: normal findings by modality. In Osselton J W (ed.) Clinical neurophysiology. Butterworth-Heinneman, Oxford

16.

McDowd J M , Filion D L , Harris M J , Braff D L (1993) Sensory gating and inhibitory function in late-life schizophrenia. Schizophr Bull 19: 733–746

17.

Nagamoto H T , Adler L E , Hea R A , Griffith J M , McRae K A , Freedman R (1996) Gating of auditory P50 in schizophrenia: unique effects of clozapine. Biol Psychiatry 40: 181–188

18.

Norris H (1971) The action of sedation on brain-stem oculomotor systems in man. Neuropharmacology 10: 181–191

19.

Patrick C J , Bertholt B D , Moore J D (1996) Diazepam blocks fear-potentiated startle in humans. J Abnorm Psychol 105: 89–96

20.

Peck R E (1959) The SHP test – an aid to the detection and measurement of depression. Arch Gen Psychiatry 1: 35–40

21.

Perlstein W M , Simons R F , Graham F K (2001) Prepulse effects as a function of cortical projection system. Biol Psychol, 56: 83–111

22.

Phillips M A , Langley R W , Bradshaw C M , Szabadi E (2000a) The effect of some antidepressant drugs on prepulse inhibition of the acoustic startle (eyeblink) response and the N1/P2 auditory evoked potential. J Psychopharmacol 14: 40–45

23.

Phillips M A , Langley R W , Bradshaw C M , Szabadi E (2000b) Effect of acute tryptophan depletion on prepulse inhibition of the acoustic startle (eyeblink) response and the N1/P2 auditory evoked potential in man. J Psychopharmacol 14: 258–265

24.

Rodriguez-Fornells A , Riba J , Gironell A , Kulisevsky J , Barbanoj M J (1999) Effects of alprazolam on the acoustic startle response in man. Psychopharmacology 143: 280–285

25.

Schächinger H , Müller B U , Strobel W , Langewitz , Ritz R (1999) Midazolam effects on prepulse inhibition of the acoustic blink reflex. Br J Clin Pharmacol 47: 421–426

26.

Schall U , Schon A , Zerbin D , Eggers C , Oades R D (1996) Event-related potentials during an auditory discrimination with prepulse inhibition in patients with schizophrenia, obsessive-compulsive disorder and healthy subjects. Int J Neurosci 84: 15–33

27.

Schwarzkopf S B , Lanberti J S , Smith D A (1993) Concurrent assessment of acoustic startle and auditory P50 evoked potential measures of sensory inhibition. Biol Psychiatry 33: 815–828

28.

Swerdlow N R , Caine S B , Braff D L , Geyer M A (1992) The neural substrates on sensorimotor gating of the startle reflex: a review. J Psychopharmacol 6: 176–190

29.

Swerdlow N R , Fillon D , Geyer M A , Braff D L (1995) ‘Normal’ personality correlates of sensorimotor, cognitive, and visuo-spatial gating. Biol Psychiatry 37: 286–299

30.

Swerdlow N R , Hartman P L , Auerbach P P (1997) Changes in sensorimotor inhibition across the menstrual cycle: implications for neuropsychiatric disorders. Biol Psychiatry 41: 452–460

31.

Swerdlow N R , Braff D L , Geyer M A (2000) Animla 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

32.

Szabadi E , Bradshaw C M (1996) The role of α2-adrenoceptors in the autonomic control of bodily functions in man. J Psycho-pharmacol 10 (Suppl.): 6–18

33.

Young D A , Waldo M , Rutledge J H , Freedman R (1996) Hereditability of inhibitory gating of the P50 auditory-evoked potential in monozygotic and dizygotic twins. Neuro-psychobiology 33: 113–117