Interaction of desipramine and amitriptyline with adrenergic mechanisms in the human iris in vivo

Summary Mydriatic responses of the pupil were evoked by locally instilled noradrenaline and methoxamine in eight healthy volunteers. The effects of three single oral doses (25 mg, 50 mg and 100 mg) of amitriptyline and desipramine were compared on the mydriatic responses. Both antidepressants potentiated the mydriasis evoked by noradrenaline; desipramine appeared to be approximately four times more potent than amitriptyline. Both antidepressants antagonised the mydriasis evoked by methoxamine, amitriptyline being approximately twice as potent as desipramine. It is suggested that the potentiation of the response to noradrenaline may reflect the blockade of the uptake of noradrenaline into adrenergic nerve terminals, whereas the antagonism of the response to methoxamine may reflect the blockade of postsynaptic -adrenoceptors by the antidepressants. It is argued that the interaction of the antidepressants with adrenergic mechanisms could explain why amitriptyline, a potent anticholinergic agent, causes no significant change in resting pupil diameter, while desipramine, a relatively weaker anticholinergic agent, produces a significant mydriasis.     

Consensual pupillary responses to mydriatic and miotic drugs.

1. Three experiments were conducted to examine whether mydriatic or miotic drugs instilled into one eye have any effect on the diameter of the pupil of the untreated fellow eye, in healthy volunteers. 2. In Experiment 1, the effects of four subjects, using photography in an illuminated room to assess pupil diameter. The drug evoked a dose-dependent mydriasis in the index eye which was accompanied by a simultaneous dose-dependent miosis in the fellow eye. 3. In Experiment 2, the same method was used to assess pupil diameter as in Experiment 1. The effects of mydriatic (methoxamine and tyramine) and of miotic (pilocarpine) drugs instilled into the fellow eye, were studied on the sizes of pupillary responses to the same drugs instilled into the index eye. The presence of a mydriatic drug in the fellow eye resulted in a decrease in the size of the mydriatic responses in the index eye. 4. In Experiment 3, the effects of three concentrations of phenylephrine hydrochloride (0.15-0.60 M) and of three concentrations of pilocarpine hydrochloride (0.002-0.008 M), were studied in darkness using an infra-red binocular television pupillometer, in seven subjects. Phenylephrine evoked dose-dependent mydriasis and pilocarpine evoked dose-dependent miosis. The pupillary responses of the index eye were not accompanied by any changes in the diameter of the pupil of the fellow eye. 5. It is concluded that drug-induced mydriasis in the index eye is accompanied by a consensual miosis in the fellow eye.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of the effects of clonidine on tyramine- and methoxamine-evoked mydriasis in man

1 It has been reported previously that clonidine can potentiate tyramine-evoked mydriasis on the pain-free side of cluster headache patients. We examined whether a single oral dose of clonidine (200 μg) can also potentiate tyramine-evoked mydriasis in healthy subjects, using mydriasis to methoxamine, a directly acting sympathomimetic amine, as a control. 2 Eight healthy male volunteers participated in four weekly sessions. In the first two sessions (Experiment 1) the effect of clonidine or placebo on the mydriasis to tyramine hydrochloride eyedrops (75 mm; 2×10 μl), and in the last two sessions (Experiment 2) the effect of clonidine or placebo on the mydriasis to methoxamine hydrochloride eyedrops (20 mm; 2×10 μl) was examined. In both experiments subjects were allocated to drugs and sessions according to a double-blind balanced design. In both experiments, pupil diameter of both the treated and the untreated eyes was recorded in standard ambient light and in the dark, before, and 2 h after clonidine/placebo, via binocular infrared television pupillometry. Salivation (dental roll technique), systolic and diastolic blood pressure (sitting), heart rate, and self-ratings of mood and feelings (visual analogue scales), were also measured before, and 2 h after the ingestion of clonidine or placebo. 3 Both tyramine and methoxamine produced a significant mydriasis, which was more prominent in the light condition (change in resting pupil size; mm±s.e.mean: tyramine/light 1.05±0.28; tyramine/dark: 0.73±0.15; methoxamine/light: 1.65±0.28; methoxamine/dark: 0.85±0.15). Clonidine produced a significant miosis in the untreated eye which was more prominent in the light condition (change in resting pupil size; mm±s.e.mean: Experiment 1, light: −1.34±0.19; Experiment 1, dark: −0.46±0.1; Experiment 2, light −0.97±0.18; Experiment 2, dark: −0.29±0.17). Clonidine had no significant effect on either tyramine- or methoxamine-evoked mydriasis. 4 In agreement with previous reports, clonidine significantly reduced salivation (g, mean±s.e.mean; Experiment 1: −0.84±0.22; Experiment 2: −0.55±0.11), systolic blood pressure (mm Hg; Experiment 1: −17.5±3.76; Experiment 2: −23.38±4.67), diastolic blood pressure (mm Hg; Experiment 2: −12.38±2.05), alertness (mm; Experiment 2: −24.19±5.40), and anxiety (mm; Experiment 1: −13.82±4.60), indicating the presence of pharmacodynamically effective tissue levels of the drug. 5 These results show that a single oral dose (200 μg) of clonidine causes significant miosis in human subjects, and fails to potentiate tyramine-evoked mydriasis. This indicates that the pupil on the asymptomatic side of cluster headache patients is affected differently from the pupils of healthy volunteers by tyramine and/or clonidine.     

The effects of alaproclate on the pupillary responses to tyramine,phenylephrine and pilocarpine in depressed patients

Nine depressed patients were treated with alaproclate, a selective 5-HT uptake inhibitor, for 3 weeks in a dose of 400 mg daily. The pupillary responses to tyramine, phenylephrine, and pilocarpine eye drops were measured on consecutive days before, after 1 week and after 3 weeks of treatment. The tyramine-induced mydriasis was unaffected by alaproclate, suggesting that it does not significantly inhibit the reuptake of noradrenaline. The pilocarpine-induced miosis and the phenylephrine-induced mydriasis were both enhanced after 1 week but not after 3 weeks of treatment. This suggests that alaproclate acutely increases the responsiveness of postsynaptic muscarinic and ₁ adrenoceptors.     

Evaluation of the antimuscarinic activity of atropine, terfenadine and mequitazine in healthy volunteers.

1 The anticholinergic effects of atropine and two antihistamines (terfenadine and mequitazine) were investigated vs placebo in a double-blind study. 2 Salivary secretion, basal pupil diameter, pilocarpine (0.25%) induced miosis and heart rate were determined in eight healthy volunteers, seven male and one female, aged between 23 and 35 years. Each volunteer received all four separate courses of treatment: i.e. terfenadine 60 mg or mequitazine 5 mg twice daily for 3 days, and one single dose on the day of the trial; for the placebo or atropine courses they received the placebo twice daily during 3 days and, on the morning of test day, either the placebo again or atropine 1 mg. Pupillary diameter was measured under standardized conditions using a pupil gauge (Smith and Nephew Pharmaceuticals Ltd). 3 Atropine significantly reduced salivary output (-2.25 +/- 0.36 ml from control values of 4.17 +/- 0.42 ml, P less than 0.001) and heart rate (-9.7 +/- 3.7 beats min-1 from 77.5 +/- 2.7, P less than 0.05). These maximal effects were observed 3 h after atropine dosing for salivary secretion and 1 h for heart rate. Atropine did not affect basal pupil diameter or pilocarpine-induced miosis. 4 Mequitazine and terfenadine did not affect salivary flow, heart rate or pilocarpine-induced miosis. 5 Terfenadine and mequitazine had no anticholinergic effect in these tests involving a limited number of subjects.     

Asymmetric mydriatic response to topical tyramine in cluster headache relatives

A pupillometric study was performed to evaluate the mydriatic response to tyramine, a noradrenaline releaser. There were three groups of subjects: (a) 10 cluster headache patients, in an asymptomatic period; (b) 20 of their close relatives, exempt from this disease; (c) 10 healthy controls. The tyramine was instilled into both eyes of each subject. The controls displayed an isocoric tyramine-induced mydriasis but the cluster headache sufferers and their relatives showed an anisocoric mydriasis. This anisocoric mydriasis was caused by a deficient mydriatic response on one side, which in the cluster patients corresponded to the symptomatic side. The sympathetic abnormality of the iris may be the expression of a functional asymmetry in the hypothalamus. Central sympathetic asymmetry could thus represent a dysgenetic family predisposition to lateralized headache attacks.     

A comparison of various antidepressant drugs demonstrates rapid desensitisation of α2-adrenoceptors exclusively by sibutramine hydrochloride

The functional status of presynaptic and post-synaptic ₂-adrenoceptors in murine brain was respectively monitored using the hypoactivity (sedation) and mydriasis (pupil dilatation) responses to clonidine (0.1 mg/kg IP). Both responses were attenuated 24 h after 3 days of injection of sibutramine hydrochloride (3 mg/kg IP). To ascertain whether this property was exclusive to sibutramine, the following antidepressant drugs were also tested for their ability to down-regulate ₂-adrenoceptors rapidly: amitriptyline, doxepin, nomifensine, desipramine, amoxapine, fluoxetine, zimeldine, tranylcypromine and mianserin. When given for 3 or 5 days at the low dose of 3 mg/kg IP, none of the other antidepressants reduced clonidine-induced hypoactivity or mydriasis. Furthermore, increasing the dose of amitriptyline, doxepin, nomifensine, desipramine, amoxapine and tranylcypromine to 10 mg/kg IP did not enable these antidepressants to attenuate the ₂-adrenoceptor-mediated responses after 3 days of treatment. An electroconvulsive shock (ECS; 200 V, 2 s) given once daily attenuated clonidine-induced mydriasis, but not hypoactivity, when administered for 3 days and both responses when administered for 5 days. In conclusion, this comparative study using antidepressant treatments with differing pharmacological modes of action demonstrated that sibutramine was the only drug which rapidly down-regulated pre- and postsynaptic ₂-adrenoceptors. ECS down-regulated postsynaptic ₂-adrenoceptors when given for 3 days, but required 5 days to desensitise both ₂-adrenoceptor populations.     

Clinical studies of the effect of (+) and (−)-oxaprotiline upon noradrenaline uptake

In six normal male subjects the mydriatic effect of tyramine eye drops was inhibited by 1 day's treatment with desipramine and the (+)- but not the (-)-enantiomer of oxaprotiline. In the same experiment, the secretion of melatonin was increased after treatment with (+)- but not with (-)-oxaprotiline. The effects of (+)-oxaprotiline and of desipramine treatment were similar, as were those of (-)-oxaprotiline and placebo.These findings extend to clinical studies the demonstration in animal experiments of stereo-specificity for the effects of (+)- and (-)-oxaprotiline upon noradrenaline uptake. A comparison of the effects of the two enantiomers should provide an ideal strategy for studying effects of noradrenaline uptake blockade in clinical studies.     

Influence of ciclazindol on monoamine uptake and CNS function in normal subjects

The potential antidepressant drug ciclazindol inhibited dopamine uptake into human platelets without affecting 5-hydroxytryptamine uptake as compared with a control. It inhibited the tyramine pressor response less than desipramine after single 50-mg oral doses in 6 healthy volunteers under double-blind conditions. Compared with tandamine in a double-blind placebo-controlled study in nine healthy subjects, ciclazindol 50 mg orally caused no significant anticholinergic effects but reduced appetite according to an analysis of variance. Nonparametric analysis did not confirm the anorectic effect. Previous studies had shown that ciclazindol increased glucose uptake into isolated human skeletal muscle independently of insulin. Overall, ciclazindol resembles the antiobesity drug mazindol in molecular structure and pharmacological effects in man. Interactions with sympathomimetic amines and adrenergic neurone-blocking drugs cannot be excluded on the basis of these studies.     

Inhibition and possible induction of rat CYP2D after short- and long-term treatment with antidepressants

The aim of this study was to investigate the influence of tricyclic antidepressants (imipramine, amitriptyline, clomipramine, desipramine), selective serotonin reuptake inhibitors (SSRIs: fluoxetine, sertraline) and novel antidepressant drugs (mirtazapine, nefazodone) on the activity of CYP2D, measured as a rate of ethylmorphine O-deethylation. The reaction was studied in control liver microsomes in the presence of the antidepressants, as well as in microsomes of rats treated intraperitoneally for one day or two weeks (twice a day) with pharmacological doses of the drugs (imipramine, amitriptyline, clomipramine, nefazodone 10 mg kg(-1) i.p.; desipramine, fluoxetine, sertraline 5 mg kg(-1) i.p.; mirtazapine 3 mg kg(-1) i.p.), in the absence of the antidepressants in-vitro. Antidepressants decreased the activity of the rat CYP2D by competitive inhibition of the enzyme, the potency of their inhibitory effect being as follows: clomipramine (K(i) = 14 microM) > sertraline approximate, equals fluoxetine (K(i) = 17 and 16 microM, respectively) > imipramine approximate, equals amitriptyline (K(i) = 26 and 25 microM, respectively) > desipramine (K(i) = 44 microM) > nefazodone (K(i) = 55 microM) > mirtazapine (K(i) = 107 microM). A one-day treatment with antidepressants caused a significant decrease in the CYP2D activity after imipramine, fluoxetine and sertraline. After prolonged administration of antidepressants, the decreased CYP2D activity produced by imipramine, fluoxetine and sertraline was still maintained. Moreover, amitriptyline and nefazodone significantly decreased, while mirtazapine increased the activity of the enzyme. Desipramine and clomipramine did not produce any effect when administered in-vivo. The obtained results indicate three different mechanisms of the antidepressants-CYP2D interaction: firstly, competitive inhibition of CYP2D shown in-vitro, the inhibitory effects of tricyclic antidepressants and SSRIs being stronger than those of novel drugs; secondly, in-vivo inhibition of CYP2D produced by both one-day and chronic treatment with tricyclic antidepressants (except for desipramine and clomipramine) and SSRIs, which suggests inactivation of the enzyme apoprotein by reactive metabolites; and thirdly, in-vivo inhibition by nefazodone and induction by mirtazapine of CYP2D produced only by chronic treatment with the drugs, which suggests their influence on the enzyme regulation.     

Effects of the substance P antagonist [D-Arg1,D-Pro2,D-Trp7,9,Leu11]SP on miosis caused by echothiophate iodide or pilocarpine hydrochloride

The anticholinesterase agent echothiophate iodide (EI) and the cholinergic agent pilocarpine hydrochloride (pilocarpine), drugs commonly used in glaucoma therapy, cause miosis in rabbits as well as in man. In rabbits the miotic effect decreases after a few days of treatment, a phenomenon possibly due to a drug-induced decrease in the number of muscarinic receptors. However, the muscarinic pupillary contraction caused by stimulation of the retina with light is intact. In this investigation the miosis caused by the doses of EI was found to be very resistant to muscarinic or nerve blockade but inhibited by the substance P (SP) analog [D-Arg1,D-Pro2,D-Trp7,9, Leu11]SP, which seems to be a SP/SPLI blocker in the rabbit pupillary sphincter. Miosis caused by pilocarpine was partly inhibited by muscarinic blockade and partly by the SP blocker. In eyes treated with EI topically twice daily for three weeks, SP or the red pepper extract capsaicin, a releaser of SP-like immunoreactivity (SPLI), had less miotic effect than in control eyes. Capsaicin caused more pronounced miosis in eyes treated with topical pilocarpine for three weeks than in controls. The radioimmunoassay technique did not reveal a significant change in the amount of SPLI in the retinas or iris-ciliary bodies from EI-treated eyes as compared with the controls. It is concluded that, besides cholinergic miosis, EI causes non-muscarinic miosis, probably by release of SP or a related substance and that pilocarpine may have similar effects.     

Pharmacokinetic and pharmacodynamic interactions between almorexant,a dual orexin receptor antagonist,and desipramine

Almorexant is a dual orexin receptor antagonist (DORA) with sleep-enabling effects in humans. Insomnia is often associated with mental health problems, including depression. Hence, potential interactions with antidepressants deserve attention. Desipramine was selected as a model drug because it is mainly metabolized by CYP2D6, which is inhibited by almorexant in vitro. A single-center, randomized, placebo-controlled, two-way crossover study in 20 healthy male subjects was conducted to evaluate the pharmacokinetic and pharmacodynamic interactions between almorexant and desipramine. Almorexant 200 mg or matching placebo (double-blind) was administered orally once daily in the morning for 10 days, and a single oral dose of 50 mg desipramine (open-label) was administered on Day 5. Almorexant increased the exposure to desipramine 3.7-fold, suggesting that almorexant is a moderate inhibitor of desipramine metabolism through inhibition of CYP2D6. Conversely, desipramine showed no relevant effects on the pharmacokinetics of almorexant. Pharmacodynamic evaluations indicated that almorexant alone reduced visuomotor coordination, postural stability, and alertness, and slightly increased calmness. Desipramine induced a reduction in subjective alertness and an increase in pupil/iris ratio. Despite the increase in exposure to desipramine, almorexant and desipramine in combination showed the same pharmacodynamic profile as almorexant alone, except for prolonging reduced alertness and preventing the miotic effect of almorexant. Co-administration also prolonged the mydriatic effect of desipramine. Overall, repeated administration of almorexant alone or with single-dose desipramine was well tolerated. The lack of a relevant interaction with antidepressants, if confirmed for other DORAs, would be a key feature for a safer class of hypnotics.     

Antagonism by tricyclic antidepressants of reserpine-induced hypothermia in mice. Involvement of postsynaptic alpha 2-adrenoceptors

The effects of adrenoceptor blocking agents and cyproheptadine on the antagonism by the antidepressants imipramine, desipramine and maprotiline, of reserpine-induced hypothermia in mice were studied. The anti-reserpine effect of the antidepressants was reduced by phenoxybenzamine, prazosin, yohimbine and d,1-propranolol, the two latter drugs exhibiting the strongest effect. Practolol was ineffective, while cyproheptadine potentiated the effect of maprotiline and was inactive towards imipramine and desipramine. Furthermore, the anti-reserpine effect of desipramine (the other antidepressants not being studied) was also reduced by piperoxan and l-propranolol, but not by d-propranolol. The reserpine-induced hypothermia was antagonized by clonidine and this effect was completely blocked by yohimbine and partly reduced by prazosin. These results confirm that the antagonism by tricyclic antidepressants of reserpine-induced hypothermia depends on the activation of noradrenergic mechanisms and indicate that this effect is mediated not only by alpha 1- and beta-, but also by postsynaptic alpha 2-adrenoceptors.     

Determining Pharmacological Selectivity of the Kappa Opioid Receptor Antagonist LY2456302 Using Pupillometry as a Translational Biomarker in Rat and Human

Background:

Selective kappa opioid receptor antagonism is a promising experimental strategy for the treatment of depression. The kappa opioid receptor antagonist, LY2456302, exhibits ~30-fold higher affinity for kappa opioid receptors over mu opioid receptors, which is the next closest identified pharmacology.

Methods:

Here, we determined kappa opioid receptor pharmacological selectivity of LY2456302 by assessing mu opioid receptor antagonism using translational pupillometry in rats and humans.

Results:

In rats, morphine-induced mydriasis was completely blocked by the nonselective opioid receptor antagonist naloxone (3mg/kg, which produced 90% mu opioid receptor occupancy), while 100 and 300mg/kg LY2456302 (which produced 56% and 87% mu opioid receptor occupancy, respectively) only partially blocked morphine-induced mydriasis. In humans, fentanyl-induced miosis was completely blocked by 50mg naltrexone, and LY2456302 dose-dependently blocked miosis at 25 and 60mg (minimal-to-no blockade at 4–10mg).

Conclusions:

We demonstrate, for the first time, the use of translational pupillometry in the context of receptor occupancy to identify a clinical dose of LY2456302 achieving maximal kappa opioid receptor occupancy without evidence of significant mu receptor antagonism.     

The interaction between alpha-methyl-dopa and tricyclic antidepressants.

The central hypotensive action of alpha-methyl-DOPA is antagonized by tricyclic antidepressants like desipramine and imipramine. This antagonism has been demostrated in chloralose-anaesthetized cats. The drugs to be tested were infused into the left vertebral artery. The antagonism pProbably takes place in the pons-medulla region of the CNS. Probably, the alpha-adrenolytic properties of the tricyclic antidepressants bring about the blockade of central alpha-adrenergic receptors that are stimulated by alpha-methyl-noradrenaline, the biotransformation product of alpha-methyl-DOPA.     

The relationship between pupil diameter and pain by the administration of morphine and antidepressant drugs in mice.

Because the pain sensation is subjective, it is difficult to evaluate the responses to analgesic drugs. Some analgesics that affect the central nervous system are known to change the pupil diameter. The pupil diameter is a more objective criterion that shows the drug effect. We studied the relation between the pupil diameter and analgesia responses to morphine and antidepressants by using the selective micro-receptor agonist morphine (2 and 4 mg/kg), the noradrenaline reuptake inhibitor desipramine (7.5 and 10 mg/kg), the mixed serotonergic and noradrenergic uptake inhibitor and cholinergic receptor antagonist amitriptyline (2.5 and 5 mg/kg), and the selective serotonin reuptake inhibitor sertraline (2.5 and 5 mg/kg) in mice. Both monocular microscopy to assess pupil measurement and the hot-plate test to assess nociceptive thresholds were used in the same animals. We found that morphine played an important role in both mydriasis and analgesia, whereas amitriptyline and desipramine had a greater effect on pupil response than on nociception. Sertraline produced antinociception without causing a change in pupil diameter. As a result, although the pupil response is an important criterion in evaluating the analgesic effect of morphine, it is not possible to put forward the same criterion for the antidepressant drugs. Because different neurotransmitters are involved in pupil and pain mechanisms of antidepressant drugs, it is difficult to evaluate the analgesic response with the pupil diameter.     

alpha-Methyldopa produces mydriasis in the rat by stimulation of CNS alpha 2-adrenoceptors.

1. The effects of i.v. administration of alpha-methyldopa (MD) on rat pupil diameter were investigated. All experiments were carried out in rats in which vagosympathetic nerve trunks were sectioned bilaterally at the cervical level. 2. In anaesthetized rats MD produced a marked dose-related increase in pupil diameter. The onset of pupillary response to MD was gradual and reached maximal levels 2-3 h after administration. 3. Pretreatment with alpha 2-adrenoceptor antagonists yohimbine (1.5 mg kg-1, i.v.) or idazoxan (0.5 mg kg-1, i.v.) blocked the pupillary response to MD. In contrast, the alpha 1-antagonists prazosin (1.0 mg kg-1, i.v.) and phenoxybenzamine (1.5 mg kg-1, i.v.) did not significantly alter the pupillary effects of MD. 4. Selective enzymatic blockade with 3-hydroxy-benzyl-hydrazine (NSD-1015; 25 mg kg-1, i.p.), a dopa-decarboxylase inhibitor, as well as bis (4-methyl-homopiperazinyl-thiocarbonyl) disulphide (FLA-63, 5.0 mg kg-1, i.p.), a dopamine-beta-hydroxylase inhibitor, prevented the mydriatic effect of MD. 5. The above findings support the hypothesis that MD produces a clonidine-like CNS mydriasis in the rat. This effect appears to be mediated primarily by the MD metabolite, alpha-methylnoradrenaline. 6. These results indicate that MD produces mydriasis in the rat by a CNS action. The mydriatic action of MD appears to be produced by its metabolite alpha-methylnoradrenaline which in turn stimulates CNS postsynaptic alpha 2-adrenoceptors.     

Determination of the role of noradrenergic and 5-hydroxytryptaminergic neurones in postsynaptic alpha 2-adrenoceptor desensitization by desipramine and ECS.

1. Experiments were conducted to determine the respective roles which noradrenergic and 5-hydroxytryptaminergic neurones play in the down-regulation of postsynaptic alpha 2-adrenoceptors by desipramine and electroconvulsive shock (ECS). The functional status of these receptors was monitored by use of clonidine-induced mydriasis in conscious mice. 2. Mydriasis to clonidine (0.1 mg kg-1, i.p.) was markedly attenuated by administration of either desipramine (10 mg kg-1, i.p.) for 14 days or ECS (200 V, 2s) given five times over ten days confirming our previous observations. 3. The neurotoxin, DSP-4 (100 mg kg-1, i.p. X 2), reduced brain noradrenaline levels by 64% and abolished the mydriasis induced by the noradrenaline releasing agent and reuptake inhibitor, methamphetamine, without significantly altering the response to clonidine, confirming our earlier results. This lesion prevented the attenuation of clonidine mydriasis by repeated administration of desipramine, but not ECS. 4. Lesioning of central 5-hydroxytryptaminergic neurones with 5,7-dihydroxytryptamine (75 micrograms, i.c.v.) had no influence on the reduction in clonidine mydriasis produced by repeated administration of either desipramine or ECS. 5. Since noradrenergic neurones are essential for the desensitization of postsynaptic alpha 2-adrenoceptors by desipramine, it indicates that this effect is probably the result of increased synaptic noradrenaline levels. This mechanism is not responsible for the change induced by ECS because this adaptation is independent of an intact noradrenergic input. 5-HT-containing neurones do not play a permissive role in the down-regulation of postsynaptic alpha 2-adrenoceptors by either antidepressant treatment.     

The effect of tricyclic antidepressants on cholinergic responses of single cortical neurones.

1 The technique of microelectrophoresis was used in order to study the effects of tricyclic antidepressants on responses of single cortical neurones to acetylcholine. 2 Both potentiation and antagonism of excitatory responses to acetylcholine could be observed after a brief application of imipramine or desipramine. A higher dose of the antidepressant was required to evoke antagonism than to evoke potentiation. 3 Responses to carbachol were affected by desipramine similarly, suggesting the inhibition of cholinesterase is not responsible for the potentiation of cholinergic responses. 4 A brief application of atropine also had a dual effect on responses to acetylcholine. 5 It is suggested that the potentiation of excitatory cholinergic responses by atropine and the antidepressants may be due to the blockade of masked inhibitory receptors.     

Rapid down-regulation of serotonin2 receptor binding during combined administration of tricyclic antidepressant drugs and alpha 2 antagonists

Recent studies have shown that chronic, but not acute, treatment with several different antidepressant drugs decreases the density of serotonin2 (5HT2) receptors in the cerebral cortex (Peroutka and Snyder, 1980a). It was found that combined administration of antidepressant drugs with alpha 2 antagonists could accelerate this down-regulation of 5HT2 receptors induced by antidepressants. Amitriptyline (10 mg/kg, twice daily) in combination with yohimbine (5 mg/kg, twice daily) decreased 5HT2 receptor binding after 4 days of treatment, whereas amitriptyline alone required 10 days to decrease the density of 5HT2 receptors. Other antidepressant--alpha-antagonist combinations which rapidly decreased the density of 5HT2 receptors were desipramine-phenoxybenzamine, amitriptyline-phenoxybenzamine, iprindole-phenoxybenzamine, mianserin-phenoxybenzamine and desipramine-dihydroergotamine. Treatment with desipramine in combination with prazosin, an alpha 1 antagonist, did not accelerate the down-regulation of 5HT2 receptors induced by antidepressants. These results suggest that blockade of central alpha 2 receptors can accelerate the down-regulation of 5HT2 receptors by antidepressants. A combination of antidepressant and alpha antagonist treatment could represent a new, rapid onset antidepressant drug therapy.