Clonidine exerted sympatholytic and sedative effects, whereas modafinil had sympathomimetic and some alerting effects. Modafinil may activate noradrenergic neurones in the LC involved in arousal and pupillary control, without affecting extracoerulear noradrenergic neurones involved in cardiovascular and salivary regulation.

It has been shown previously that the amplitude of the acoustic startle reflex is enhanced, and the amplitude of the light reflex reduced, when subjects anticipate an aversive event, compared to periods when subjects are resting ('fear-potentiated startle reflex' and 'fear-inhibited light reflex'). We examined whether the anxiolytic diazepam would reverse the effects of threat on the startle and pupillary reflexes. Twelve male volunteers participated in three weekly sessions in which they received oral treatment with placebo, diazepam 5 mg and diazepam 10 mg, according to a balanced crossover double-blind design. One hour after ingestion of the treatments, miotic responses to light pulses and electromyographic responses of the orbicularis oculi muscle to sound pulses were elicited during alternating periods in which the threat of an electric shock (electrodes attached to the subject's wrist) was present (THREAT) and absent (SAFE). The THREAT condition was associated with a significant increase in the amplitude of the electromyographic (EMG) response, a significant reduction of the miotic response amplitude, and an increase in self-rated anxiety. Diazepam attenuated all these effects of THREAT. Diazepam did not affect the amplitude of the miotic response under the SAFE condition, but did suppress the EMG response under this condition. These results confirm the validity of the fear-potentiated startle reflex and fear-inhibited light reflex as laboratory models of human anxiety, and reveal some differences between the effects of diazepam on the two reflexes.

This experiment examined the effects of two sedative/anxiolytic drugs, diazepam and clonidine, on the eyeblink component of the acoustic startle response in healthy volunteers. Twelve males (18-30 years), screened for normal hearing thresholds, participated in three sessions in which they received oral doses of placebo, diazepam 10mg and clonidine 200 microg according to a balanced double-blind protocol. Thirty-minute electromyographic recordings from the orbicularis oculi muscle of the right eye were carried out 120 min after ingestion of clonidine and 60 min after ingestion of diazepam. Subjects received 36 40-msec sound pulses (115 dB), separated by variable intervals (mean 25 sec); in 24 of the trials the pulse was preceded by a 40-msec prepulse (75 dB in 12 trials and 85 dB in 12 trials; prepulse-pulse interval, 120 msec). The amplitude of the startle response was significantly reduced both by diazepam (mean+/-SEM: -43.9+/-7.4%) and by clonidine (-75.7+/-4.7%). Under the placebo condition, the 75 and 85dB prepulses inhibited the startle response by 38.6+/-6.5 and 70.3+/-2.9%, respectively. Neither drug significantly altered the degree of prepulse inhibition. Both drugs reduced self-rated alertness; clonidine reduced systolic blood pressure and salivation. The results confirm the suppressant effect of clonidine on the startle response and show a qualitatively similar effect of diazepam; the results also demonstrate the insensitivity of prepulse inhibition of the startle response to doses of sedative drugs that are sufficient to attenuate the startle response itself.

The noradrenergic locus coeruleus is a major wakefulness-promoting nucleus of the brain, which is also involved in the regulation of autonomic and endocrine functions. The activity of the locus coeruleus is believed to be tonically enhanced by a mesocoerulear dopaminergic pathway arising from the ventral tegmental area of the midbrain. Both modafinil, a wakefulness-promoting drug, and pramipexole, a D(2)/D(3)receptor agonist with sedative properties, may act on this pathway, with modafinil increasing and pramipexole decreasing locus coeruleus activity. The aim of this study was to compare the two drugs on alertness, autonomic and endocrine functions in healthy volunteers. Pramipexole (0.5mg), modafinil (200mg), and their combination were administered to 16 healthy males in a double-blind, placebo-controlled design. Methods included tests of alertness (pupillographic sleepiness test, critical flicker fusion frequency, visual analogue scales), autonomic functions (resting pupil diameter, light and darkness reflex responses, heart rate, blood pressure, salivation, core temperature), and endocrine functions (blood concentrations of prolactin, growth hormone, and thyroid stimulating hormone). Data were analysed by ANOVA. Pramipexole reduced alertness, caused pupil dilatation, increased heart rate, reduced prolactin and thyroid stimulating hormone, and increased growth hormone level. Modafinil caused small increases in blood pressure and core temperature, and reduced prolactin levels. The sedative effect of pramipexole and the autonomic effects of modafinil are consistent with altered activity in the mesocoerulear pathway; the pupil dilatation following pramipexole suggests reduced dopaminergic excitation of the Edinger-Westphal nucleus.