Analysis of pupillary dilation produced by analogs of clonidine

Pupillary responses to intravenous administration of clonidine and five congeneric derivatives of clonidine were observed in anesthetized cats. All of the agents tested produced a dose-dependent mydriasis of long duration. The order of potency for these compound was clonidine (St-155) > St-375 > St-606 > St-600 > St-608 > St-91. Pretreatment with yohimbine hydrochloride (0.5 mg/kg i.v.) shifted the dose-response curve for all of the compounds tested to the right. A CNS inhibition of parasympathetic nerve activity was demonstrated for clonidine and St-375 by means of direct recordings from the postganglionic ciliary nerves. An effect of high doses of St-91 on nerve activity was also observed. These results suggest that all the analogs of clonidine tested (with the possible exception of St-91) act like clonidine to produce mydriasis by a central α-adrenergic inhibition of parasympathetic outflow to the eye.     

Effects of clonidine and chlorpromazine on a sympathetic-cholinergic reflex

Intravenous administration of clonidine and chlorpromazine resulted in a dose-dependent inhibition of the amplitude of reflexly evoked electrodermal responses in intact and spinal cats. Yohimbine pretreatment (0.5 mg/kg, i.v.) antagonized the effects of clonidine but not chlorpromazine in both preparations. These findings confirm and expand previous observations that both clonidine and chlorpromazine inhibit the amplitude of centrally evoked responses in this sympathetic-cholinergic system. In addition, both drugs appeared to have a spinal site of action. The antagonism of the effects of clonidine by yohimbine suggests that the mechanism of the action of clonidine may be a result of activation of central inhibitory alpha-adrenergic receptors. The failure of yohimbine to antagonize the effects of chlorpromazine suggests that clonidine and chlorpromazine may depress these sympathetic reflexes by different mechanisms.     

Peripheral analgesic action of clonidine: mediation by release of endogenous enkephalin-like substances

Clonidine analgesia was tested on the hyperalgesia induced by intraplantar injection of prostaglandin E2 or carrageenin. The antinociceptive effect of clonidine was dose-dependent and was abolished by local administration of the selective alpha 2-adrenoceptor blocker, yohimbine or of the opioid antagonists naloxone or quaternary nalorphine. St-91, a clonidine analog which does not cross the blood-brain barrier also promoted significant antinociception. Repeated administration of drugs possessing a central mechanism of analgesic action leads to the development of tolerance in this test. Significant analgesic tolerance was observed following repeated (5 days) morphine (8 mg/kg) or high doses of clonidine (0.5 mg/kg). In contrast, no tolerance was detected to the analgesic effect of low doses of clonidine (0.15 mg/kg) or of St-91 (0.5 mg/kg). These results suggest that, in addition to its central analgesic action, clonidine can induce peripheral antinociception by an alpha 2-adrenoceptor-mediated local release of enkephalin-like substances.     

Central hypotensive action of bridge analogues of clonidine

The experimental compounds St-1913, St-1966 and St-1967 in which the bridging nitrogen atom, as found in clonidine, has been replaced by a methylene (--CH2--) function, an oxygen or a sulphur atom, respectively, have been investigated with respect to their acute hypotensive effects in anaesthetized cats. Attention was paid to a possible contribution of the central nervous system to the hypotensive action of the drugs by means of vertebral arterial infusions. Although less active than clonidine, St-1913 and St-1967 are centrally acting hypotensive drugs. Central alpha-adrenoceptors are presumably involved in a similar manner as in the mechanism of clonidine. The hypotensive potency of St-1966 was much lower compared to the aforementioned drugs. A central origin for its depressor effects could be established. However, central alpha-adrenoceptors probably do not participate. In spite of its structural similarity with clonidine the mechanism of action of St-1966 appears to be different.     

Studies on the site of action of clonidine utilizing a sympathetic-cholinergic system

Clonidine (30 μg/kg, i.v.) reduced centrally evoked electrodermal responses (EDR) following stimulation of reactive loci in the hypothalamus and medulla. The responses were most depressed following low frequency stimulation. Similar results were observed on the EDR evoked by stimulation of the cervical cord in the spinal act. Little effect was seen following peripheral nerve stimulation. These results demonstrate that clonidine depresses the reactivity of this sympathetic-cholinergic system at all central levels including the cervical cord.     

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 11 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.     

Some cardiovascular effects of ST-91 and clonidine.

St-91, 2(2,6-diethylphenylamino)-2-imidazoline, is a clonidine derivative which does not penetrate the blood-brain barrier. In spontaneously hypertensive (SH) rats is acutely increased arterial pressure and reduced heart rate while at 8 to 12 h after oral administration, it slightly lowered arterial pressure. In contrast, clonidine had acute antihypertensive activity at all doses used. By intracerebroventricular administration to SH rats, both drugs (St-91 and clonidine) reduced arterial pressure and heart rate; in this respect, clonidine was more potent then St-91. Cardiac acceleration induced by low frequency electrical stimulation of right cardiac sympathetic nerves in anesthetized and vagotomized dogs was reduced by St-91 at the same doses by clonidine. Phenoxybenzamine, phentolamine and desipramine antagonized the inhibitory effects of St-91 on electrically induced cardiac acceleration. It was concluded that St-91, like clonidine, stimulates inhibitory alpha-adrenergic receptors at the sympathetic nerve endings but, unlike clonidine, is substantially devoid of acute antihypertensive activity. This suggests that stimulation of peripheral presynaptic inhibitory alpha-adrenergic receptors is not likely to represent the sole mechanism of antihypertensive action of clonidine.     

The pinna reflex and its inhibition by clonidine: relationship to sedation and quantitation of central alpha 2-antagonist potency

The relationship between sedation and pinna reflex inhibition has been measured for a range of centrally acting drugs. Ability to abolish the pinna reflex was not related to sedative activity as assessed by a behavioural method. Thus, at equisedative doses, diazepam, haloperidol, mianserin, prazosin and indoramin failed to abolish the pinna reflex while phenobarbitone and chlorpromazine caused partial- and clonidine complete-inhibition. At the ED50 for pinna reflex inhibition, guanabenz and guanfacine were significantly less sedative than clonidine. Mepyramine, yohimbine, RS-21361, idazoxan and phenylephrine produced little or no sedation and did not inhibit the reflex. When these agents (except for guanabenz and guanfacine) were tested for their ability to prevent clonidine-induced pinna reflex inhibition, all except the drugs with alpha 2-adrenoceptor antagonist activity were inactive. The potency order of the active agents was idazoxan greater than yohimbine greater than RS-21361 = mianserin. Antagonism of clonidine-induced pinna reflex inhibition may therefore prove to be a useful quantitative model for assessing the central potency of alpha 2-adrenoceptor antagonists.     

Studies on the mechanism of prazosin induced sympatho-inhibition

Intravenous administration of the alpha 1-adrenoceptor antagonist, prazosin (3-300 micrograms/kg), produced a depression of sympathetic-cholinergic electrodermal responses evoked by electrical stimulation of the posterior hypothalamus in pentobarbital anesthetized cats. Pretreatment with the alpha 2-adrenoceptor antagonists yohimbine (0.5 mg/kg) or idazoxan (0.1 mg/kg) significantly blocked the depressant effects of prazosin but had no effect on hypothalamic evoked electrodermal responses when given alone. Electrodermal responses were readily elicited in animals depleted of CNS monoamines. Monoamine depletion, however, totally abolished prazosin's depression of centrally evoked electrodermal responses. Prazosin also depressed the amplitude of electrodermal responses evoked by electrical stimulation of the cervical spinal cord in spinalized cats. In contrast to hypothalamic stimulation, yohimbine when given alone potentiated spinally evoked electrodermal responses which suggests that both excitatory and inhibitory mechanisms were being activated. Taken together these results suggest that prazosin produces its CNS sympatholytic effect by enhancing inhibition mediated by alpha 2-adrenoceptor mechanisms and not directly by blockade of excitatory alpha 1-adrenergic receptors in the central nervous system. A spinal cord site of action for prazosin is also implicated.     

Comparison of the effects of clonidine and yohimbine on pupillary diameter at different illumination levels

AIMS: To evaluate the pupillary effects of single doses of the alpha2-adrenoceptor agonist clonidine and the alpha2-adrenoceptor antagonist yohimbine under several illumination conditions. METHODS: Sixteen healthy male volunteers received clonidine 0.2 mg, yohimbine 22 mg, clonidine 0.2 mg + yohimbine 22 mg in a double-blind placebo-controlled, cross-over study. 2 h post drug ingestion pupil diameter was recorded in darkness, and at luminance levels of 6 Cd m-2, 91 Cd m-2 and 360 Cd m-2. The effects of the active treatments on pupil diameter were also expressed as the differences from the placebo condition ('placebo-corrected' data; mean [95% CI]). RESULTS: Clonidine had little effect on pupil diameter in darkness; however, it caused a significant, light-dependent, miosis when the eye was illuminated. On the other hand yohimbine increased pupil size; this increase was significant at 91 and 360 Cd m-2. There were no significant differences between the effects of the combined treatment (clonidine 0.2 mg + yohimbine 22 mg) and the effect of placebo. CONCLUSIONS: The pupillary effects of clonidine and yohimbine are likely to reflect the interaction of these drugs with inhibitory alpha2-adrenoceptors located on central noradrenergic neurones, which in turn would lead to a decrease and an increase, respectively, in sympathetic outflow to the iris. The light dependence of the pupillary effects of these drugs, however, suggests that the parasympathetic light reflex pathway is also involved, which is known to be under inhibitory control from the central noradrenergic neurones. Modulation of parasympathetic outflow seems to play an important role since both drugs had relatively little effect on pupil diameter in darkness when sympathetic activity predominates.     

A study on the antagonism of the intestinal inhibitory effects of morphine and clonidine by yohimbine in mice

In mice, clonidine administered subcutaneously caused a dose-dependent inhibition of the intestinal motility as assayed by the movement of a charcoal meal. This inhibitory effect of clonidine was antagonized dose-dependently by prior subcutaneous or intracisternal administration of yohimbine. However, yohimbine given intracerebroventricularly was ineffective in antagonising the intestinal inhibitory action of clonidine. Clonidine administered centrally, either intracisternally or intracerebroventricularly, caused a dose-dependent inhibition of intestinal motility. Clonidine given by the intracisternal route appeared to be more effective than by the intracerebroventricular route. Centrally administered clonidine was antagonized by prior subcutaneous administration of yohimbine. The antagonism was related to the doses of yohimbine given. Subcutaneously administered morphine caused a dose-dependent inhibition of intestinal motility and this effect was antagonized by prior subcutaneous administration of yohimbine. However, administration of yohimbine centrally, either intracisternally or intracerebroventricularly, did not affect the intestinal inhibitory action of morphine. On the other hand, morphine injected centrally, either intracisternally or intracerebroventricularly, dose-dependently inhibited the motility of the intestine; such inhibitory action was antagonized by prior subcutaneous administration of yohimbine. The present study suggests that clonidine inhibits intestinal motility at both central and peripheral sites through alpha 2-adrenoceptors. Morphine also inhibits intestinal motility by both central and peripheral mechanisms but it appears that yohimbine only modifies the peripheral aspect of morphine's action.     

Effect of clonidine and chlorpromazine on centrally evoked electrodermal responses and their interaction with yohimbine

Both clonidine and chlorpromazine reduced the amplitude of electrodermal responses (EDR) evoked by stimulation of the hypothalamus at a constant submaximal frequency (10–16 Hz). The ED₅₀ for clonidine was approximately 5 μg/kg and that for chlorpromazine was about 1 mg/kg. Yohimbine pretreatment (0.5 mg/kg, i.v.) antagonized the effects of clonidine but did not alter the effectiveness of clorpromazine in inhibiting these responses. Yohimbine alone was without effect on these sympathetic-cholinergic responses. These results suggest that clonidine and chlorpromazine depress central sympathetic reactivity by different mechanisms.     

Alpha 2-adrenoreceptors on human platelets: selective labelling by [3H]clonidine and [3H]yohimbine and competitive inhibition by antidepressant drugs

[3H]Clonidine and [3H]yohimbine have been used to characterize alpha 2-adrenoreceptors on human platelets. At 25 degrees C binding was rapid (t 1/2 of association, 1.8 and 2.7 min) and reversible (t 1/2 of dissociation, 0.5 and 8.2 min). The binding sites for [3H]clonidine and ]3H]yohimbine showed the specificity required for an alph 2-adrenoreceptor. The rank order of potency of inhibitors of [3h[clonidine binding was clonidine greater than yohimbine greater than phenylephrine greater than prazosin and of [3H]yohimbine binding was yohimbine greater than clonidine greater than phenylephrine greater than prazosin. Scatchard analysis of [3H]yohimbine binding indicated the existence of a single population of noninteracting sites (KD = 3.0 nM; Bmax = 188 fmol/mg protein). The high-affinity binding of [3H-clonidine had a lower affinity and a lower number of sites (KD = 5.0 nM; Bmax = 35 fmol/mg protein). [3H]Clonidine binding also showed evidence of a second site of much lower affinity and greater number (KD = 18.6 nM; Bmax = 77 fmol/mg protein) in 40% of the normal population. In vitro, antidepressant drugs competed with [3H]clonidine and [3H]yohimbine for the platelet alpha 2-adrenoreceptor. The rank order of potency of inhibitors of [3H]clonidine binding was mianserin greater than amitriptyline greater than iprindole greater than desipramine and of [3H]yohimbine binding was mianserin greater than amitriptyline greater than desipramine greater than iprindole. The inhibition constants (Ki) of adrenergic drugs and of various antidepressant drugs in competing with [3H]clonidine were correlated with the inhibition constants of these drugs in competing with [3H]yohimbine (r = 0.970; P less than 0.001) which suggests that both radioligands labelled the same alpha 2-adrenoreceptor on the human platelet. The inhibition of binding induced by all antidepressant drugs was competitive. In contrast, long-term administration of tricyclic antidepressant drugs to patients was recently found to be associated with a decrease in the number of binding sites for [3H]clonidine on platelet membranes. The present results indicate that both [3H]clonidine and [3H]yohimbine are useful tools for the quantification of alpha 2-adrenoreceptors on blood platelets and suggests that the specific binding of radiolabelled alpha 2-adrenoreceptor ligands to human platelet membranes might be used to monitor changes in alpha 2-adrenoreceptors during tricyclic antidepressant drug treatment.     

A quantitative assessment of CNS sympatho-inhibition produced by psychotropic drugs

As one index of sympathetic reactivity, electrodermal responses (EDR) were evoked from central (hypothalamic) and peripheral (ulnar nerve) sites in pentobarbital-anesthetized cats. When compared with intravenous chlorpromazine (ED₅₀ ～ 1.0 mg/kg), only thioridazine, trifluoperazine and pimozide were less potent than chlorpromazine in reducing the amplitude of these centrally-evoked sympathetic-cholinergic responses. Perphenazine and methotrimeprazine (a non-neuroleptic phenothiazine) were about twice as potent as chlorpromazine. Haloperidol and triflupromazine were about 5 times as potent and chlorprothixine was more than 10 times as potent. None of these agents reduced the peripherally-evoked electrodermal response, indicating a CNS mode of action. Diazepam was without effect at either site. In addition, pretreatment with yohimbine (0.5 mg/kg, i.v.) did not significantly alter the ED₅₀ for any of the above drugs. These results demonstrate that all of the phenothiazines and non-phenothiazine neuroleptics tested produced a dose-dependent central sympatho-inhibition and that diazepam does not. The results also suggest that there is no significant correlation between central symphatho-inhibition and the antipsychotic potency of these compounds and that their depression of central sympathetic outflow is independent of α-adrenergic mechanisms in the CNS.     

Mechanism of ketanserin-induced sympatho-inhibition.

Experiments were undertaken to determine if sympatho-inhibition produced by ketanserin is due to antagonism of central nervous system alpha 1-adrenoceptors rather than central 5-HT2 receptors and if (like prazosin) it produces sympatho-inhibition indirectly via a central (presynaptic) alpha 2-adrenoceptor mechanism. Administration of ketanserin (0.03-3.0 mg/kg i.v.) caused a dose-related depression of sympathetic-cholinergic electrodermal responses evoked by electrical stimulation of the hypothalamus in pentobarbital anesthetized cats. No effect of ketanserin was observed on electrodermal responses evoked by preganglionic sympathetic nerve stimulation nor did the more specific 5-HT2 receptor antagonist, cinanserin, produce a central sympatholytic effect at dosages up to 3 mg/kg i.v. Pretreatment with alpha 2-adrenoceptor blockers yohimbine, idazoxan, or rauwolscine significantly antagonized ketanserin-induced sympatho-inhibition. Depletion of central nervous system (CNS) monoamines totally prevented ketanserin-induced sympatho-inhibition although clonidine (30 micrograms/kg i.v.) continued to be effective. These results suggest that ketanserin acts in the CNS to reduce sympathetic reactivity by blocking alpha 1-adrenoceptors and not 5-HT2 receptors. In this regard, ketanserin appears to act in a manner similar to other alpha 1-adrenoceptor antagonists (e.g. prazosin and indoramin) by an apparent presynaptic facilitation of alpha 2-adrenoceptor mediated tonic inhibition descending from the lower brainstem.     

Analysis of CNS sympatho-inhibition produced by guanabenz

The effects of guanabenz on several autonomic systems were observed in vagotomized, anesthetized cats with the aim of determining, in a quantitative sense, the degree to which guanabenz produces a clonidine-like central nervous system action. Guanabenz given as a single dose (50 μg/kg i.v.) produced a transient hypertension associated with a more sustained bradycardia and depression of centrally (hypothalamic) evoked electrodermal responses (EDR). Increasing cumulative doses of guanabenz (3–1000 μg/kg i.v.) also resulted in a dose-related depression of EDR amplitude, transient hypertension followed by hypotension, sustained bradycardia, and mydriasis. All responses were antagonized by pretreatment with yohimbine (0.5 mg/kg i.v.). The ED₅₀ for depression of the centrally evoked EDR was in the range of 50–100 μg/kg i.v. in the non-pretreated preparations. Guanabenz (100 μg/kg i.v.) was shown to be devoid of significant ganglionic blocking properties. These experiments suggest that guanabenz acts like clonidine in the CNS and that an α₂-adrenergic inhibitory mechanism is involved in its myriad of central autonomic effects.     

Potentiation of two sympathetic reflexes by yohimbine hydrochloride.

Yohimbine hydrochloride (0.5 $\text{mg}\text{kg}$ i.v.) resulted in a pronounced increase in electrodermal (sympathetic-cholinergic) and nictitating membrane reflexes in intact anaesthetized and decerebrate unanaesthetized cats. Potentiation by yohimbine of these two sympathetic reflexes was not an indirect action due to lowering of blood pressure as the effect was still observed in baroreceptor denervated cats. Yohimbine had no effect on electrodermal reflexes evoked in spinal preparations nor did it alter the peripheral frequency-response curves for either effector. Yohimbine also appeared to increase central tonic activity with regard to basal skin potential, nictitating membrane basal tone and heart rate levels. These results suggest that yohimbine may be acting to antagonize central inhibitory tone to both of these autonomic systems. With regard to the electrodermal system, yohimbine may be acting at the level of the spinal cord to block tonic inhibition descending from the lower brain stem.     

Further support for the central origin of the gastric antisecretory properties of clonidine in conscious rats

The effects of clonidine (CL) on interdigestive gastric acid secretion were studied in chronic gastric fistula rats and compared with those of St 91, a CL-like drug which does not cross the blood-brain barrier. CL induced a dose-dependent inhibition of gastric acid output when administered s.c. (ED50 13.5 micrograms X kg-1), in the lateral ventricle of the brain (ED50 5.80 micrograms X kg-1) or in the cisterna magna (ED50 0.49 micrograms X kg-1). St 91 and several alpha-adrenergic antagonists administered subcutaneously also inhibited gastric acid secretion dose dependently. Decreasing activities were prazosin greater than St 91 greater than phentolamine greater than yohimbine greater than piperoxan; phenoxybenzamine was a poor inhibitor. The anti-secretory properties of CL on basal secretion were antagonized by yohimbine and piperoxan. Other drugs either did not antagonize (phentolamine) or potentiated (phenoxybenzamine, prazosin) the CL effect, while yohimbine and phenoxybenzamine potentiated the response to St. 91. CL had no activity on methacholine while it drastically inhibited 2-DG-, histamine- and pentagastrin-stimulated gastric secretion. The inhibitory activity of CL on histamine stimulation was significantly decreased by yohimbine but not by phentolamine. These results confirm that the CL inhibition of the gastric acid secretion in unanesthetized rats is mediated at least partly through the stimulation of alpha 2-adrenergic receptors. Most of the data favour a major role of the CNS in the antisecretory activity of CL and suggest the possibility that most of the receptors involved are located in the medulla oblongata.     

Comparison of alpha-adrenoceptor involvement in the antinociceptive action of tizanidine and clonidine in the mouse

The effect of drugs that influence the opioidergic and monoaminergic neuronal systems on the antinociceptive action of tizanidine [5-chloro-4-(2-imidazolin-2-yl-amino)-2,1, 3-benzothiodiazole] was compared with their effect on the action of clonidine. The potency of the clonidine-induced antinociceptive action was 1.83 and 7.75 times greater than that of tizanidine in the tail-flick and acetic acid-induced writhing tests, respectively. The action of tizanidine and clonidine was completely antagonized by pretreatment with yohimbine, an alpha 2-adrenoceptor blocker, but not by prazosin, an alpha 1-adrenoceptor blocker. Other alpha-adrenoceptor blockers, phenoxybenzamine and phentolamine, also attenuated the action of tizanidine and clonidine but the potency of these drugs was less than that of yohimbine. An opioid antagonist (naloxone), drugs influencing the serotonergic neuronal system (p-chlorophenylalanine, 5,6-dihydroxytryptamine, cyproheptadine), and drugs influencing the catecholaminergic system (alpha-methyl-p-tyrosine, diethyl-dithiocarbamate, 6-hydroxydopamine, haloperidol) showed no effect on the action of tizanidine and clonidine. From these results, it appears that alpha 2-adrenoceptors might be of importance in mediating the tizanidine and clonidine antinociceptive action in the tail-flick test.     

The effect of clonidine and yohimbine on audiogenic seizures (AGS) in rats

Clonidine in high doses (0.5,1.0 mg/kg) significantly increased the latency for audiogenic seizures (AGS) in rats and reduced seizure severity. At a dose (0.05 mg/kg) which acts more specifically on presynaptic alpha 2-receptors, clonidine did not affect seizure latency, but showed a slight proconvulsant action. Yohimbine tended to decrease seizure-latency at all doses, but statistical significance (p less than 0.05) was only reached at 10 mg/kg. Smaller doses of yohimbine (0.5 and 1.0 mg/kg) showed a proconvulsant effect, while a high dose (10 mg/kg) markedly reduced the severity of AGS. The effect of clonidine on seizure-latency was only antagonized by high-dose yohimbine (10 mg/kg), the combination of these drugs being of marked anticonvulsant efficacy. From these results it can be concluded that the anticonvulsant effect of clonidine does not seem to be mediated through presynaptic alpha 2-receptors. Action on other central noradrenergic receptors, and influences on other transmitters must be taken into account when interpreting the effect of clonidine and yohimbine on AGS in rats.