Modulation of the Acoustic Startle Response by the Level of Arousal: Comparison of Clonidine and Modafinil in Healthy Volunteers

Abstract

A sudden loud sound evokes an electromyographic (EMG) response from the orbicularis oculi muscle in humans together with an auditory evoked potential (AEP) and an increase in skin conductance (SC). Startle responses are inhibited by weak prepulses (prepulse inhibition, (PPI)) and may also be modified by the level of alertness. We compared the sedative drug clonidine and the alerting drug modafinil on sound-evoked EMG, AEP, and SC responses, on the PPI of these responses and on level of arousal and autonomic functions. Sixteen healthy male volunteers participated in four weekly sessions (clonidine 0.2 mg, modafinil 400 mg, their combination, placebo) in a double-blind, cross-over, balanced design. Responses were evoked by sound pulses of 115 and 85 dB (PPI) for 40 ms and recorded conventionally. Level of alertness, autonomic functions (pupil diameter, blood pressure, heart rate, salivation, temperature) and the plasma levels of the hormones prolactin, thyroid-stimulating hormone and growth hormone were also measured. Data were analyzed with analysis of variance with multiple comparisons. Both prepulses and clonidine attenuated all three startle responses and modafinil antagonized clonidine's effects on the EMG and AEP responses. None of the drugs affected PPI. Clonidine showed sedative and sympatholytic effects, and modafinil showed alerting and sympathomimetic effects. In conclusion, startle responses were susceptible not only to PPI but also to the level of arousal. Keywords: acoustic startle response; auditory evoked potential; skin conductance; prepulse inhibition; clonidine; modafinil INTRODUCTIONThe startle response involves rapid involuntary contractions of facial and skeletal musculature in response to a sudden intense stimulus. In the case of the acoustic startle response, this reaction occurs in response to a sudden loud sound and is measurable in humans as an electromyographic (EMG) response from the orbicularis oculi muscle (eyeblink startle response). This response is believed to be mediated via a pathway below the level of the diencephalon consisting of between three and five central synapses, originating from the sensory receptors and terminating on the motor neurons, where the principal relay is the caudal pontine reticular nucleus (Davis et al, 1982; for review, see Yeomans and Frankland, 1996;Koch, 1999). In addition to this muscular response, changes in electroencephalographic (EEG) activity can be observed in response to the auditory stimulus, and these changes are termed auditory evoked potentials (AEP). In particular, the N1/P2 component of the AEP is measurable following the presentation of the acoustic startle stimulus (for examples, see Abduljawad et al, 1999Abduljawad et al, , 2001 Phillips et al, 2000a, b;Graham et al, 2001Graham et al, , 2004Scaife et al, 2005Scaife et al, , 2006. Both the muscular and the AEP responses are fast responses; longer-latency responding to the startle stimulus can be observed in autonomic activity, in particular in sympathetically mediated skin conductance...

Correspondence arising: Modafinil for cognitive neuroenhancement in health non-sleep-deprived-subjects

“…A preliminary literature search reveals at least nine more articles that provide data on effects of modafinil on the mood of healthy individuals. (Warot et al, 1993;Hou et al, 2005;Hou et al, 2007;Samuels et al, 2006;Samuels et al, 2007;Taneja et al, 2007;Volkow et al, 2009) Among these are two studies that were published before 1990 and not taken into account due to an arbitrary time span set by the authors for literature search (Saletu et al, 1989a;1989b). The same criticism applies to their report on side effects.…”

Relationship Between Cardiac Autonomic Regulation and Auditory Mechanisms: Importance for Growth and Development

“…Além disso, os autores sugeriram que apenas certos tipos de música afetam a atividade simpática renal e pressão arterial em ratos. Animais com lesões bilaterais no córtex auditivo podem discriminar um som simples, sugerindo que existe uma outra via auditiva de detecção que não é mediado pelo córtex auditivo 25 mas lesões da cóclea ou do córtex auditivo eliminaram alterações induzidas pela música na atividade simpática renal e na pressão arterial 24 , indicando que as alterações na atividade simpática renal e na pressão arterial dependem de sinalização através do sistema auditivo.…”

The 5-min pupillary alertness test is sensitive to modafinil: a placebo controlled study in patients with sleep apnea

“…In healthy alert individuals, modafinil has little or no mydriatic effect in darkness (Samuels et al 2006(Samuels et al , 2007, but it is possible that a ceiling effect in the pupils of alert subjects militates against the detection of such an effect in the dark. Indeed, a mydriatic effect of modafinil is more apparent in the light (Hou et al 2005Samuels et al 2007). This effect may be mediated by sympathetic activation by the drug, as modafinil failed to inhibit the amplitude of the light reflex (Hou et al 2005, while it increased the velocity of the darkness reflex, a sympathetically mediated response (Hou et al 2005).…”

“…The pupillary light reflex may help to elucidate the effects of a drug on the sympathetic and parasympathetic inputs to the iris, as the time-course of the light reflex response is determined by the successive activation of the parasympathetic and sympathetic inputs; the amplitude (the depth of pupillary constriction in response to a light stimulus) reflects activation of the midbrain parasympathetic Edinger-Westphal nucleus (Gamlin et al 1997;Barbur 2004) and the recovery time (the redilation of the pupil to its original size in response to light stimulus offset) reflects mainly sympathetic activation (Smith and Smith 1999;Loewenfeld 1999;Bitsios et al 1998). In healthy alert individuals, modafinil has little or no mydriatic effect in darkness (Samuels et al 2006(Samuels et al , 2007, but it is possible that a ceiling effect in the pupils of alert subjects militates against the detection of such an effect in the dark. Indeed, a mydriatic effect of modafinil is more apparent in the light (Hou et al 2005Samuels et al 2007).…”