Comparison of the effects of clonidine and yohimbine on spontaneous pupillary fluctuations in healthy human volunteers

Rationale: Spontaneous fluctuations in the size of the pupil in darkness are a recognized index of sleepiness, and these fluctuations can be quantitatively measured using the pupillographic sleepiness test (PST). The central noradrenergic system is believed to play a role in the maintenance of alertness, and there is evidence that alpha(2)-adrenoceptor agonists (e.g. clonidine) decrease the activity of central noradrenergic neurones, whereas alpha(2)-adrenoceptor antagonists (e.g. yohimbine) have the opposite effect. Objective: To evaluate the effects of single oral doses of clonidine and yohimbine on spontaneous pupillary fluctuations in healthy volunteers. Methods: Sixteen healthy male volunteers (18-25 years) participated in four weekly sessions, each associated with one oral drug condition (clonidine hydrochloride 0.2 mg, yohimbine hydrochloride 22 mg, clonidine hydrochloride 0.2 mg+yohimbine hydrochloride 22 mg), according to a balanced double-blind design. Pupil diameter was recorded continuously over Il min in darkness using a dedicated monocular video pupillometer. Average pupil diameter, power of pupil diameter fluctuations (obtained by fast Fourier transformation), and the pupillary unrest index (PUI), a measure of cumulative changes in pupil size, were computed. Autonomic functions known to be sensitive to centrally acting noradrenergic drugs (blood pressure, heart rate and salivary output) were recorded. Subjective "alertness", "anxiety" and "Contentedness" were rated using visual analogue scales. Measurements were carried out 2 h after drug ingestion. Data were analyzed by ANOVA followed by Dunnett's corrected t-test (criterion of significance P<0.05). Results: Clonidine decreased systolic and diastolic blood pressure, salivation and subjectively rated alertness, and tended to decrease pupil diameter, and to increase the power of pupillary fluctuations and PUI. On the other hand, yohimbine increased systolic and diastolic blood pressure, salivation, pupil diameter and decreased PUI. When the two drugs were given in combination they reduced each other's effects. Conclusions: These results confirm the alerting effect of the centrally acting noradrenergic activating drug yohimbine and the opposite effect of clonidine, and the suitability of the PST to detect these effects.