Alpha 2-adrenoceptor Sensitivity Research Articles

Altered Central α2-Adrenoceptor Sensitivity in Panic Disorder

The possibility that a disorder of brain alpha 2-adrenoceptor sensitivity might contribute to the etiology of panic disorder was examined using a challenge paradigm with the alpha 2-adrenoceptor agonist clonidine. The cardiovascular, psychological, and endocrine actions of 1.5-microgram/kg clonidine hydrochloride given intravenously were assessed in 16 patients and compared with age- and sex-matched controls. Patients with panic disorder showed an increased fall in blood pressure and decreased sedative and endocrine responses as compared with controls. These results suggest that there may be subsensitivity of some, and supersensitivity of other, brain alpha 2-adrenoceptors in panic disorder. In view of the increased cardiovascular responses seen in the present study and other reports of increased responses to the alpha 2-adrenoceptor antagonist yohimbine, there may exist an increased lability (decreased damping) of cardiovascular control mechanisms in panic disorder. Such a dysfunction could contribute to the symptoms of panic attacks, such as dizziness, palpitations, and faintness.

Alpha2-adrenergic receptor sensitivity in depressed patients: Relation between 3H-yohimbine binding to platelet membranes and clonidine-induced hypotension

Alpha 2-adrenergic receptor changes during antidepressant treatment were studied using 3H-yohimbine binding to human platelet membranes and clonidine-induced hypotension. Twenty-six patients with major depressive disorder (MDD) participated for 4–6 weeks in a trial of imipramine (2.5 mglkglday), tyrosine (100 mglkg/day), or placebo. Alpha 2-adrenergic receptors measured by 3H-yohimbine binding were not significantly changed following antidepressant treatment. Similarly, clonidine-induced hypotension did not differ significantly following treatment. No measure of alpha 2-adrenergic receptor sensitivity was significantly correlated with clinical improvement. The correlation between platelet receptor binding and clonidine-induced hypotension was not statistically significant, even though both tests are considered to be measures of alpha 2-adrenoceptor sensitivity.

The effects of acute and chronic desipramine on the thermogenic and hypoactivity responses to α2‐agonists in reserpinized and normal mice

1. The effects of acute and chronic (14 day) administration of the noradrenaline uptake inhibitor, desipramine (DMI), on the thermogenic responses to clonidine in reserpine-treated mice, and on the hypothermic and hypoactivity responses to the alpha 2-agonist, UK-14,304, in untreated mice were examined. 2. Taking the capacity of DMI to delay the onset of reserpine-induced hypothermia as an indicator of noradrenaline (NA) uptake inhibition, the lowest dose of DMI to inhibit uptake significantly for 12 h in the mouse was shown to be between 10 and 20 mg kg-1 orally. 3. Chronic (every 12 h for 14 days), but not acute treatment with DMI (15 mg kg-1, orally), attenuated the thermogenic responses to low doses (0.02-0.225 mg kg-1, i.p.) of clonidine (injected 20 h after the last dose of DMI) in reserpinized mice. 4. Acute DMI administration slightly attenuated the hypothermia and hypoactivity induced by UK-14,304 (0.25-1.0 mg kg-1, i.p.) when injected 2h, but not when injected 18-21h before the agonist. In contrast, 18-21h after withdrawal from chronic DMI both of these responses to UK-14, 304 were markedly attenuated. 5. As the thermogenic response to clonidine in reserpinized mice appears to involve central post-synaptic alpha 2-adrenoceptors, these results suggest that prolonged inhibition of NA uptake decreases the sensitivity of postsynaptic alpha 2-adrenoceptors. The results of the studies using UK-14,304 indicate that central alpha 2-adrenoceptors involved in mediating other behavioural and pharmacological responses to alpha 2-agonists are also down-regulated by chronic inhibition of NA uptake.

Binding of tritiated yohimbine to platelets in women with maternity blues.

Platelet alpha 2-adrenoceptor binding was measured in 108 women in the 36th week of pregnancy, at ten and twenty days and at three and six months post-partum. An age matched non-pregnant control group of women (N = 25) was also studied. The number (Bmax) of alpha 2-adrenoceptors was elevated antepartum but fell to control values on the tenth post-partum day. At three and six months post-partum, however, alpha 2-adrenoceptor Bmax was again increased. Women who developed maternity blues (N = 59) had significantly more platelet alpha 2-adrenoceptors than those who did not (N = 49) at both ten and twenty days post-partum. In addition their alpha 2-adrenoceptor Bmax was greater than controls at all time points measured except the tenth post-partum day. In contrast, the alpha 2-adrenoceptor Bmax of women without the blues did not differ from controls at any stage. It is suggested that women who develop maternity blues may have a relatively enduring abnormality in alpha 2-adrenoceptor sensitivity which is associated with psychological symptoms when concentrations of circulating sex-steroids suddenly change.

Effect of lithium treatment on the GH-clonidine test in affective disorders.

The effects of short-term lithium (Li) administration on alpha 2-adrenoceptor sensitivity was studied in 10 healthy volunteers and in 15 patients with normothymic, phasic depressive disorders. The GH-clonidine test was used to examine alpha 2-adrenoceptor sensitivity, administered before and after Li treatment (600 mg/day for 7 days in controls and for 15 days in patients). Before treatment, the GH response to clonidine in the patients was blunted, and afterwards it tended to increase in the patients and it was significantly decreased in the controls. The difference between the response in the two groups was significant and was correlated both with the diagnosis and the pretreatment GH response to the stimulus. The opposing pattern of the response in patients and controls to Li administration suggests that the drug exerts a modulatory effect on alpha 2-adrenoceptor sensitivity, with up or down regulation inversely correlated with pretreatment status.

Effects of antidepressant drug treatments on alpha 2-adrenoceptor control of [3H]noradrenaline release from hypothalamic synaptosomes.

KCl (16 mM) stimulated the release of [3H]noradrenaline ([3H]NA) from rat hypothalamic synaptosomes in a Ca2+-dependent manner; this release was attenuated by clonidine (0.01-100 microM). Changes in the release of [3H]NA and the functional status of alpha 2-adrenoceptors in the medial hypothalamus of rats treated acutely and chronically with clorgyline (1 mg/kg/day) or desipramine (DMI, 10 mg/kg/day) were assessed using superfused synaptosomes in which the attenuating effects of clonidine (1 microM) or the potentiating effects of yohimbine (1 microM) on K+-evoked release of [3H]NA were measured. After acute administration of DMI, significantly less [3H]NA was accumulated into synaptosomes. Although total (spontaneous + K+-evoked) [3H]NA release from these synaptosomes was unchanged, a significant reduction was apparent in the K+-evoked release from the DMI-treated tissue. Attenuation of K+-evoked release by clonidine was abolished in both these acute treatment groups. Following the chronic antidepressant drug regimens, [3H]NA uptake into DMI-treated tissue remained significantly reduced although total percent and K+-evoked [3H]NA release were unchanged. The K+-evoked release of [3H]NA in S1 was significantly enhanced (by 22%) in the clorgyline treatment group. Attenuation of K+-evoked [3H]NA release by clonidine in both chronic antidepressant-treated tissues was not significantly changed. It is concluded that the functional sensitivity of alpha 2-adrenoceptors on nerve endings in the medial hypothalamus is unchanged by these chronic antidepressant drug regimens. In synaptosomes from untreated tissue, yohimbine significantly potentiated K+-evoked release of [3H]NA; this effect was unchanged after acute regimens and reduced after chronic administration of both the antidepressants.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased central alpha 2-adrenoceptor sensitivity in panic disorder.

Cardiovascular responses to an intravenous challenge dose of clonidine (1.5 micrograms/kg) were measured in eight patients with DSM III panic disorder. In comparison with an age- and sex-matched control population panic patients showed significantly greater falls in systolic and diastolic blood pressure, with similar falls in heart rate. These observations support the view of a biological abnormality in panic disorder.

Studies on the Role of α2‐Adrenoceptors in the Control of Synaptosomal [3H]5‐Hydroxytryptamine Release: Effects of Antidepressant Drugs

The sensitivity of alpha 2-adrenoceptors on 5-hydroxytryptamine (5-HT) nerve endings obtained from rat cerebral cortex was investigated following treatment with the antidepressant drugs desipramine (10 mg/kg/day for 21-28 days) or clorgyline (1 mg/kg/day for 21-28 days). [3H]5-HT (100 nM) was used to load cortical synaptosomes (P2) after experiments with uptake inhibitors confirmed that this concentration of amine ensured exclusive uptake into 5-HT nerve terminals. The sensitivity of K+-stimulated release of [3H]5-HT to alpha 2-adrenoceptor occupancy was assessed in a superfusion system by means of the dose-dependent inhibition of [3H]5-HT release by clonidine. This is blocked by yohimbine (1 microM), which, when administered alone, enhances release, suggesting that endogenous catecholamines released from other synaptosomes act on these alpha 2-heteroreceptors. The effect of addition of citalopram (1 microM) to superfusates suggests that some reuptake of [3H]5-HT occurs during superfusion. Of the tritium released into superfusates during "background" and K+-stimulated release, 17 and 90%, respectively is [3H]5-HT. The attenuation of K+-stimulated release by clonidine is apparently diminished by the chronic clorgyline regimen but not by desipramine. However, clorgyline elevates catecholamine levels, and this might increase endogenous noradrenaline (NA) efflux, which by competition with clonidine could appear to alter alpha 2-adrenoceptor sensitivity. This possibility was investigated by depleting NA with the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4). These studies showed that the apparent effect of chronic clorgyline on alpha 2-adrenoceptor sensitivity to clonidine was due to competition with increased levels of endogenous NA.(ABSTRACT TRUNCATED AT 250 WORDS)

Biological aspects of depression.

Several neuroendocrine studies with the clonidine-growth hormone stimulation test show endogenous depressive patients to have a reduced GH response as compared to neurotic depressives, schizophrenics and controls. The blunted GH response to clonidine seems to be a trait marker or vulnerability factor for mono- and bipolar endogenous depression. It could be explained by a reduced postsynaptic alpha 2-adrenoceptor sensitivity or of structures related to them. The sensitivity of alpha 2-adrenoceptors is influenced by both, the endorphinergic and cholinergic systems. First results supporting this concept are presented and discussed.

Presynaptic and transynaptic mechanisms involved in the subsensitivity of rat cortical noradrenergic system after long-term antidepressant treatment.

Chronic treatment with antidepressants has been shown to produce a subsensitivity of noradrenergic neurons, both at presynaptic and postsynaptic sites. Important mechanisms, whereby the activity of noradrenergic neurons is regulated, could be the sensitivity of presynaptic alpha 2-adrenoceptors and the participation of transynaptic mechanisms involving other neurons. In this report we demonstrate that transynaptic factors involving the serotonergic system may be relevant to the regulation of the function of alpha 2-receptors in antidepressant chronically treated animals. In fact, we provide evidence of a markedly deminished responsiveness of noradrenergic neurons to an alpha 2-agonist (clonidine) or antagonist (mianserin) in biochemical and behavioral studies following serotonergic denervation with 5,7-dihydroxytryptamine. These results indicate that a functional interrelationship between serotonergic and noradrenergic systems might play an important role in the adaptive changes which bring the noradrenergic neurons to a lower level of activity after chronic antidepressant administration.

Clonidine induced sedation is not altered by repeated stress in the RHA/iop and RLA/iop strains of rats.

An hypothesis that repeated stress results in central changes in alpha 2-adrenoceptor sensitivity was investigated using a behavioural test. Stressed (immobilisation for 2 h/day for 7 days) and unstressed rats from the RHA/iop and RLA/iop strains were tested for the sedative effects of the alpha 2-adrenoceptor agonist clonidine on Y-maze behaviour. The measures used were number of lines crossed, arm entries and rearing. The stressed animals showed higher scores for line crossings and rearing; but the only significant difference between the strains was for rearing, which was higher for RHA/iop. Clonidine significantly depressed all the measures of activity. However, there was no evidence of an interaction of the drug with stress for any of the measures. It is concluded that neither repeated stress nor genetic differences in the ability to cope with stress influence the behavioural effects of clonidine. This suggests that stress responses are not related to the central alpha 2-adrenoceptor system.

Effects of desipramine on stimulation-induced contractions of the vas deferens of rats pretreated either chronically with desipramine or acutely with idazoxan.

In the present studies the effects of desipramine on the functional sensitivity of the prejunctional alpha 2-adrenoceptors of the vas deferens were studied in pithed rats; contractions of the tissue were evoked by electrical stimulation (6 Hz) of the spinal sympathetic outflow. Twenty-four hours after a single dose of desipramine (10 mg/kg, intraperitoneally) the inhibitory dose-response curves to either UK 14 304 or desipramine itself did not differ significantly from those seen in control animals, whereas both were displaced significantly to the right after 15 days pretreatment with desipramine. Thus the functional responsiveness of the prejunctional alpha 2-adrenoceptors of the vas deferens was reduced by chronic but not acute pretreatment with desipramine. In acute studies desipramine (0.3-4.3 mg/kg, intravenously) inhibited electrically induced contractions of the vas deferens of pithed rats. In the presence of the selective alpha 2-adrenoceptor antagonist idazoxan (1 mg/kg, intravenously) desipramine potentiated nerve stimulation. Although idazoxan (10-1440 micrograms/kg, intravenously) itself potentiated electrically induced contractions of the vas deferens the potentiation observed was markedly less than that obtained in rats pretreated acutely with desipramine (0.3 mg/kg, intravenously). Acute simultaneous blockade of both prejunctional alpha 2-adrenoceptors and uptake into nerve terminals can produce maximal potentiation of the contraction of the vas deferens to sympathetic nerve stimulation. Results are discussed in relation to the hypothesis that the combination of an uptake inhibitor and a prejunctional alpha 2-adrenoceptor antagonist, by enhancing noradrenergic transmission, may provide an antidepressant therapy with rapid onset of action.

Presynaptic alpha 2- and postsynaptic beta-adrenoceptor sensitivity in slices of rat neocortex after chronic treatment with various antidepressant drugs

The effect of chronic (4 weeks) treatment of rats with the antidepressant drugs desipramine, maprotiline, chlorimipramine, zimelidine or iprindol on the sensitivity of presynaptic alpha 2- and postsynaptic beta-adrenoceptors in neocortical slices was investigated. Acute (1 day) treatment with the antidepressants did not affect the efflux of cyclic-AMP induced by isoprenaline (1 microM) from neocortical slices, while after chronic treatment the efflux of cyclic AMP was consistently reduced. Following acute administration the electrically-evoked release of [3H]noradrenaline (NA) from radiolabelled cortical slices remained unchanged. Upon chronic treatment with desipramine the release of [3H]NA was enhanced by about 45%. In contrast, after chronic treatment with maprotiline or chlorimipramine the electrically-evoked release of [3H]NA was not affected, whereas release was even slightly reduced after chronic administration of zimelidine or iprindol. In all cases, however, a similar inhibitory effect of exogenous NA (0.1 microM) on the release of [3H]NA was found. These data indicate that the desensitization of postsynaptic beta-adrenoceptors in rat brain after chronic treatment with antidepressant drugs is not paralleled by a reduction of presynaptic alpha 2-adrenoceptor sensitivity.

Some effects of chronic antidepressant treatments on rat brain monoaminergic systems.

A range of established and putative antidepressant therapies were studied for the effect of their long-term administration on two facets of presynaptic monoaminergic functioning in rat brain, namely NE, DA, and 5-HT turnover and alpha 2-adrenoceptor sensitivity. Unless stated otherwise drugs (10 mg/kg) were injected i.p. twice daily for 14 days. ECT (100 mA for 1 s) was applied once daily for 10 days. Changes in turnover were indirectly assessed by measuring levels of metabolites. Brain levels of MHPG-SO4 were unchanged by chronic amitriptyline, imipramine, nisoxetine (20 mg/kg), nortriptyline, salbutamol (5 mg/kg), and ECT. Amitriptyline elicited a slight, but significant, increase in brain DOPAC content. Brain levels of 5-HIAA were increased by amitriptyline, imipramine, salbutamol, and ECT. An overall view of the results indicates that no common pattern of change was elicited by the range of antidepressant therapies studied. Central alpha 2-adrenoceptor sensitivity was assessed by investigating the effect of various therapies on the ability of clonidine (25 mg/kg i.p.) to decrease rat brain MHPG-SO4 content. The clonidine-induced fall was attenuated by desipramine, imipramine, and ECT. Amitriptyline, iprindole, mianserin, nisoxetine, nortriptyline, Org 6582 (10 mg/kg once daily), pargyline (25 mg/kg once daily), salbutamol, and trazodone were ineffective. The following chronic antidepressant therapies were investigated for their effect on rat frontal cortex 3H-clonidine binding: amitriptyline, desipramine, imipramine, iprindole, mianserin, nisoxetine, nortriptyline, pargyline, salbutamol, and ECT. CHronic, but not acute, pargyline decreased 3H-clonidine binding and this was due to a diminished number of binding sites. The induction of subsensitive presynaptic alpha 2-adrenoceptors in rat brain is not a property common to all forms of antidepressant therapies. Hence it cannot be the fundamental mode of action of antidepressants. No correlation exists between the changes in rat cortical 3H-clonidine binding and the observed changes in the sensitivity of central presynaptic alpha 2-adrenoceptors.

Increased sensitivity of alpha2-adrenoceptors mediating pressor response in spontaneously hypertensive rats

Increased sensitivity of alpha2-adrenoceptors mediating pressor response in spontaneously hypertensive rats

Spontaneously hypertensive rats exhibit an enhanced mydriatic response to clonidine. Evidence for enhanced sensitivity of central alpha 2-adrenoceptors.

Comparisons among spontaneously hypertensive (SHR), Kyoto Wistar (KW), and Wistar (W) rats were made of the functional states of central nervous system (CNS) alpha 2-adrenoceptors (clonidine-induced mydriasis) and nonvascular peripheral presynaptic alpha 2-adrenoceptors (clonidine-induced inhibition of the neurogenic twitch of the isolated vas deferens). While there were no differences among the strains of rats in the concentration of clonidine required to produce a 50% inhibition of the electrically evoked contractile response of the vas deferens, there was a significant reduction in the mean effective concentration (ED50) of clonidine to induce mydriasis in SHR as compared with KW and W rats. These observations indicate that CNS alpha 2-adrenoceptors may be functionally more sensitive in SHR. The data also suggest that the sensitivity of nonvascular presynaptic alpha 2-adrenoceptors, at least in the vas deferens, is not altered in hypertensive animals.

Biochemical pharmacology of paradoxical sleep.

The role of noradrenergic cells in the regulation of paradoxical sleep is still controversial, and experimental data have given rise to contradictory interpretations. Early investigations focused primarily on chemical neurotransmissions. However, the process of information transmission between cells involves many other factors, and the cell surface is an important site for transduction of messages into modifications of the activity of postsynaptic cells. alpha-adrenoceptors are believed to play an important role in the control of wakefulness and paradoxical sleep. Experimental evidence suggests that physiological modulation of receptor sensitivity, possibly by specific neuro-modulators, may be a key mechanism in synaptic transmission. In the investigation of the mechanisms involved in paradoxical sleep regulation, lesions of the locus coeruleus have given equivocal results. Collateral inhibition, probably mediated by alpha 2-adrenoceptors, appears to be a powerful mechanism. The exact temporal relationship between noradrenergic cell activation and paradoxical sleep production is not established, but 5-HT appears to be involved. Differences between paradoxical sleep and waking may be related to a physiological modulation of alpha 2-adrenoceptor sensitivity.

Tricyclic antidepressants vary in decreasing alpha 2-adrenoceptor sensitivity with chronic treatment: assessment with clonidine inhibition of acoustic startle.

1 Clonidine inhibition of the acoustic startle reflex in the rat was used as a behavioural measure of alpha 2-adrenoceptor sensitivity following acute or chronic administration of tricyclic antidepressants. 2 Chronic (14 day) administration of desipramine (10 mg/kg, i.p.) attenuated the depressant effect of clonidine (20 or 40 microgram/kg) on the startle reflex. 3 No change in response to clonidine was obtained after chronic treatment with two other tricyclic antidepressants, amitriptyline (10 mg/kg) or iprindole (5 mg/kg). 4 Acute administration of these tricyclics (1 h) did not modify the effect of clonidine on startle. 5 It is suggested that the development of alpha 2-adrenoceptor subsensitivity produced by chronic tricyclics may be unique to those compounds, such as desipramine, which are active in blocking the uptake of noradrenaline.

A study of the sensitivity of rat brain alpha 2-adrenoceptors during chronic antidepressant treatments.

Two experimental approaches were used to study the effect of chronic antidepressant treatments on the functioning of central alpha2-adrenoceptors. In one, the effect of antidepressant treatment on the ability of a low dose of clonidine (25 μg/kg) to lower rat brain 3-methoxy-4-hydroxyphenylethyleneglycol sulphate (MHPG-SO4) levels was studied. In the other, potential treatment-induced alterations in rat frontal cortex 3H-clonidine binding were determined. The same cortical tissue was also studied in parallel for 3H-dihydroalprenolol binding.