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Modulation of the acoustic startle response by the level of arousal: Comparison of clonidine and modafinil in healthy volunteers

Division of Psychiatry, Psychopharmacology Section, Medical School, Queen's Medical Centre, University of Nottingham, Nottingham, UK.
Neuropsychopharmacology (Impact Factor: 7.83). 12/2007; 32(11):2405-21. DOI: 10.1038/sj.npp.1301363
Source: PubMed

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.

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    • "Interestingly, the autonomic component of the startle reflex, like the motor component (see above), is subject to prepulse modulation (Samuels et al., 2007; Eder et al., 2009). Although the exact connections of this " sensorysympathetic reflex " are not known, it is likely that a number of premotor sympathetic nuclei, including the ventrolateral medulla (Holand et al., 1999), the LC and the hypothalamic paraventricluar nucleus (Samuels et al., 2007) are involved. "
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    ABSTRACT: The locus coeruleus is activated by noxious stimuli, and this activation leads to inhibition of perceived pain. As two physiological reflexes, the acoustic startle reflex and the pupillary light reflex, are sensitive to noxious stimuli, this sensitivity, at least to some extent, may be mediated by the locus coeruleus. The acoustic startle reflex, contraction of a large body of skeletal muscles in response to a sudden loud acoustic stimulus, can be enhanced by both directly (“sensitization”) and indirectly (“fear conditioning”) applied noxious stimuli. The enhancement of the startle response by conditioned fear (“fear-potentiated startle”) involves the activation of the amygdala. The locus coeruleus may also be involved in both sensitization and fear potentiation: pain signals activate the locus coeruleus both directly and indirectly via the amygdala, which results in enhanced motoneurone activity, leading to an enhanced muscular response. The light reflex response is constriction of the pupil evoked by a light stimulus. The pupil is dilated by the sympathetic and constricted by the parasympathetic output to the iris. The locus coeruleus contributes to the sympathetic outflow to the iris and attenuates the parasympathetic output by inhibiting the Edinger-Westphal nucleus, the preganglionic cholinergic nucleus in the light reflex pathway. Noxious stimulation results in pupil dilation (“reflex dilation”), without any change in the light reflex response, consistent with sympathetic activation via the locus coeruleus. Conditioned fear, on the other hand, results in the attenuation of the light reflex response (“fear-inhibited light reflex”), consistent with the inhibition of the parasympathetic light reflex via the locus coeruleus. Directly applied pain and fear conditioning may affect different populations of autonomic neurones in the locus coeruleus, directly applied pain activating sympathetic and fear conditioning parasympathetic premotor neurones.
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    • "The rise of BP and heart rate (within 10 s) to acoustic startle stimuli suggested an autonomic involvement within this reflex. In a recent study, a paradigm of acoustic startle response was proposed and the locus coeruleus was regarded as the central control of the regulation of autonomic function responding to the acoustic stimuli (Samuels et al., 2007). In addition, cortical centers and also subcortical processing centers were thought to be involved in the cardiovascular and hormonal responses to a long-term stress activation by the environmental noises even though the noise intensity was as low as Lmax of 53 dBA (Spreng, 2004). "
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    • "For example, the P300 potential, generated during cognitive discrimination tasks, varies with negatively valenced stimuli such as fear-inducing images (Williams et al. 2006). Pharmaceutical manipulations have similarly demonstrated that the alerting drug modaWnil signiWcantly reduced the latency of P2 cortical potentials induced by an acoustic startle stimulus (Samuels et al. 2007). Converging evidence from functional imaging and anatomical data also provides support for links between cortical and autonomic activity. "
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