Acute and chronic effects of desipramine administration to rhesus monkeys

Rhesus monkeys were studied for changes in noradrenergic functioning before and after chronic oral administration (28 days) of the tricyclic antidepressant desipramine (DMI). Decreases in cerebrospinal fluid concentration of the norepinephrine metabolite MHPG were evident following the first dose (5.0 mg/kg) of DMI, but not after chronic administration of the drug. The alpha 2-adrenoceptor agonist clonidine reduced plasma norepinephrine prior to DMI treatment, but not after 28 days of treatment with DMI. These adaptive changes in noradrenergic function were evident in spite of very low plasma levels of DMI due to rapid metabolism of the drug in the rhesus monkey. The development of changes compatible with alpha 2-adrenoceptor subsensitivity in the presence of plasma levels of the drug that are well below those considered therapeutic in the treatment of depression suggests that such a receptor change may be dissociated from the drug's antidepressant effect.     

Acute and chronic idazoxan in normal volunteers: biochemical, physiological and psychological effects

The acute and chronic effects of the selective a(2)-antagonist idazoxan were studied in 12 normal volunteers. Plasma 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), blood pressure and psychological responses to oral challenge doses of idazoxan 40 mg were measured twice, on the first and 22nd day of treatment with idazoxan 40 mg t.d.s. Changes in nocturnal melatonin output were studied on six occasions, before, during and after idazoxan treatment. Although baseline MHPG levels were significantly reduced after chronic treatment with idazoxan, idazoxan challenge did not alter MHPG concentrations on either test day. A small rise in systolic blood pressure occurred after acute but not chronic idazoxan challenge tests. Systolic blood pressure values were significantly lower during the chronic compared with the acute test. Diastolic blood pressure and heart rate were not affected by acute or chronic treatment. Subjects reported increases in self- ratings of arousal and reductions in sedation and anxiety of similar magnitude after acute and chronic idazoxan. Nocturnal plasma melatonin secretion was not altered by drug administration or withdrawal, although urinary 6-sulphatoxymelatonin excretion was significantly reduced on acute withdrawal. The increase in systolic blood pressure and arousal self-ratings after acute idazoxan are in accordance with the reported effects of other a(2)-antagonists, although we did not find increased anxiety or elevated plasma MHPG levels. Chronic idazoxan appears to reduce or normalize activity of noradrenergic systems, indicated by reduced baseline systolic blood pressure and MHPG, and loss of the pressor response to idazoxan. Withdrawal of idazoxan leads to an abrupt fall in noradrenergic activity, as demonstrated by the fall in urinary 6-sulphatoxymelatonin.     

Effects of chronic risperidone on central noradrenergic transmission

In the present work, we investigated the effects of chronic risperidone administration on the activity of locus coeruleus noradrenergic neurons. In addition, the effect of chronic risperidone administration on the basal level of norepinephrine in the prefrontal cortex was evaluated. Results of this research showed that chronic risperidone administration increased the activity of locus coeruleus noradrenergic neurons. The sensitivity of alpha(2)-adrenoceptors in the somatodendritic region of the locus coeruleus was assessed by using the ID(50) of clonidine. Results indicated that the firing rate of locus coeruleus noradrenergic neurons was the same in risperidone-treated rats and controls. Similarly, the ID(50) for (+/-)-2,5-dimetoxy-4-iodoamphetamine (DOI), an agonist of 5-HT(2) receptors which inhibits the activity of locus coeruleus neurons by acting on these receptors, did not show any differences between the firing rate of these neurons in risperidone treated rats and controls. Unlike controls, chronically treated rats showed a significant decrease in norepinephrine levels in the prefrontal cortex. The decreased release of norepinephrine following continuous risperidone administration could be explained by the sustained increase in locus coeruleus neuronal activity after chronic risperidone administration. This low norepinephrine level in the prefrontal cortex may contribute to the relief of certain negative schizophrenic symptoms and to the improvement of cognitive function.     

Cilazapril prevents hypertension in spontaneously hypertensive rats

Chronic daily administration of cilazapril (1 X 10 mg/kg/day p.o., from age 4 to 14 weeks) to young spontaneously hypertensive rats (SHR) prevented the development of hypertension. The antihypertensive effect of a single dose of cilazapril persisted greater than 24 h. Discontinuation of long-term treatment resulted in an increase of systolic arterial blood pressure (SAP) to control hypertensive levels within 4 days. Following 10 weeks of drug administration, comparative hemodynamic studies were carried out on age-matched (14 weeks) control SHR and cilazapril-treated SHR. Cilazapril-treated SHR had a significantly lower mean arterial blood pressure (MAP) and total peripheral vascular resistance than did control SHR. The antihypertensive effect of cilazapril was not associated with changes in heart rate (HR). The myocardial performance parameters, cardiac output, and stroke volume, were similar in treated and control SHR, suggesting that the antihypertensive effect of cilazapril following chronic administration to SHR is mainly due to a reduction in peripheral vascular resistance. Vasopressor responses to angiotensin I were significantly lower in cilazapril-treated SHR than in control SHR. By contrast, pressor responses to angiotensin II and a high dose of norepinephrine (1.0 microgram/kg i.v.) were significantly enhanced. Isoproterenol elicited a fall in blood pressure in both groups, the extent of which was dependent upon the magnitude of basal blood pressure levels. Chronic cilazapril treatment resulted in a reduction of heart weight, suggesting that the drug may prevent development of cardiac hypertrophy in SHR. Kidney and adrenal weights were unaffected by the chronic treatment. Specific renin activities (SRA) in tissues of SHR were increased by factors of 20 (plasma) or 2 (kidney and adrenal) following cilazapril administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Enhanced efficacy of both typical and atypical antipsychotic drugs by adjunctive alpha2 adrenoceptor blockade: experimental evidence

Adjunctive treatment with the selective alpha2 adrenoceptor antagonist idazoxan augments the effect of conventional antipsychotics in treatment-resistant schizophrenics comparing favourably with clozapine. Clozapine has high affinity for alpha2 adrenoceptors. Previously, we found that adjunctive idazoxan treatment to the dopamine (DA) D2/3 antagonist raclopride enhanced raclopride-induced effects in an animal model of antipsychotic activity (conditioned avoidance response, CAR) and, similarly to clozapine, reversed the disruption of working memory induced by N-methyl-D-aspartate receptor blockade in rats with a concomitant increase in prefrontal DA efflux. To further investigate the significance of alpha2 adrenoceptor affinity for antipsychotic efficacy, we here investigated, in rats, the effects of adjunctive idazoxan treatment to low doses of a typical (haloperidol) and an atypical (olanzapine) antipsychotic drug, both lacking appreciable alpha2 adrenoceptor affinity, on (i) CAR; (ii) catalepsy; and (iii) DA output in the prefrontal cortex and the nucleus accumbens using microdialysis. Adjunctive treatment with idazoxan to haloperidol or olanzapine enhanced suppression of CAR to a level predicting sufficient antipsychotic activity, increased DA output preferentially in the prefrontal cortex, and reversed haloperidol-induced catalepsy. Our data confirm and extend our previous findings as well as clinical observations, and suggest that adjunctive alpha2 adrenoceptor blockade both typical and atypical antipsychotic drugs, lacking appreciable affinity for the alpha2 adrenoceptor, may contribute to a more advantageous therapeutical profile of these drugs in schizophrenia treatment, allowing for reduced DA D2 occupancy and reduction of unwanted side-effects.     

INFLUENCE OF BETA-BLOCKADE ON CIRCULATING PLASMA LEVELS OF 3-METHOXY-4-HYDROXY PHENYLETHYLENE GLYCOL (MHPG) DURING EXERCISE IN MODERATE HYPERTENSION

1. The effect of exercise testing and beta-blockade on plasma norepinephrine (PNE), and secretion of its metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), was assessed in 28 mild-to-moderate hypertensives before and after the administration of dilevalol, a new beta-blocker with beta 2-agonism. 2. This double blind, placebo-controlled study consisted of two successive submaximal exercise tests before and after the administration of a single oral dose of dilevalol (200 mg, 400 mg or 600 mg). Plasma norepinephrine levels were determined at rest, at 100 watts step of exercise and at maximal effort (Emax). 3. During the control test, mean PNE levels increased from 1.73 +/- 0.52 nmol/L (resting value) to 8.01 +/- 4.01 nmol/L at Emax (P less than 0.01) as MHPG levels increased from 11.18 +/- 1.33 nmol/L (rest) to 17.50 +/- 1.15 nmol/L (Emax, P less than 0.01). After dilevalol, PNE increased significantly as compared to controls (P less than 0.05), from 2.32 +/- 0.99 to 12.42 +/- 5.97 nmol/L (P less than 0.01). PNE and MHPG levels were correlated, both at rest and during exercise. PNE levels after beta-blockade were linearly related to the dose of beta-blocker administered. MHPG levels were unaltered by the administration of dilevalol, both before and after exercise. 4. The increase in MHPG that occurs during bicycle exercise is largely generated from an increase in central nervous system noradrenergic activity. While dilevalol increases the peripheral sympathetic nervous system, both at rest and during exercise (which is reflected by increases in PNE levels) the drug does not alter resting central nervous system noradrenergic activity nor amplify the increase in central noradrenergic activity that occurs during exercise.     

Effect of lithium upon desipramine enhanced shock-elicited fighting in rats

Rats were tested for changes in shock-elicited fighting (SEF) following the chronic administration of saline (IP); lithium (Li+) (20 mEq./l tap water) + saline (IP); desipramine (DMI) (15 mg/kg, IP); and DMI + Li+ for 14 days. The repeated test trials indicated a significant decrease in SEF in Li+-saline group (p less than 0.05), a significant increase (p less than p.05) in the DMI group, but no difference in the DMI + Li+ group in comparison to saline controls. Combined treatment with DMI + Li+ significantly reduced (p less than 0.05) SEF in comprison to the DMI group. These results suggest that enhanced aggressivity resulting from chronic DMI administration and measured by SEF can be a useful behavioral model to study the action of lithium.     

Differential noradrenergic influence on seizure expression in genetically Fast and Slow kindling rat strains during massed trial stimulation of the amygdala

The involvement of alpha(2) noradrenergic receptors during amygdala 'massed' stimulation (MS) was examined in rats that were selectively bred to be seizure-prone (Fast) or seizure-resistant (Slow) to amygdala kindling. The selective alpha(2) noradrenergic agonist guanfacine, or the antagonist idazoxan, was intraperitoneally injected during the MS procedure to study subsequent changes in afterdischarge (AD) threshold, AD duration and behavioral seizure expression. These measurements were again assessed weekly for 2 weeks after the MS treatment. Daily kindling began immediately thereafter. Following 6 stage-5 once daily convulsive seizures, guanfacine or idazoxan were re-administered. With idazoxan, the Slow rats expressed greater numbers of convulsive seizures and longer AD durations compared to guanfacine or saline controls during MS treatment. This pro-convulsive property of idazoxan was absent in Fast rats. By contrast, Fast rats showed enhanced convulsive expression in the presence of guanfacine. In the fully kindled rat, idazoxan and guanfacine differentially impacted seizure duration and severity in the Slow rats, but again not in the Fast rats. These data suggest that some aspect(s) of the alpha(2) noradrenergic system in the Fast and Slow rats are dissimilar and the mechanisms by which these receptors govern seizure genesis and propagation may be genetically controlled and distinct.     

Sympathetic inhibition with methyldopa in heart failure

The hypothesis that withdrawal of increased sympathetic activity may be beneficial in heart failure was tested by administration of the centrally acting adrenergic inhibitor methyldopa. Fourteen subjects with chronic, stable New York Heart Association Functional Class 2 or 3 heart failure receiving digitalis and diuretics were randomized to methyldopa (n = 8) 500-1000 mg daily or placebo (n = 6). Clinical, hemodynamic, neurohumoral, and platelet alpha 2-receptor effects were studied after chronic (3 weeks) administration. Sympathetic inhibition did not alter symptom status or exercise duration but reduced plasma norepinephrine concentration during exercise and permitted the same level of exercise to be attained at a lower pressure-rate product, indicating reduced myocardial oxygen consumption. Left ventricular ejection fraction and stroke volume tended to increase, and systemic vascular resistance tended to decrease during exercise after methyldopa administration, suggesting enhanced vasodilation. Upright plasma renin activity increased from 8.2 +/- 2.2 to 13.3 +/- 3.0 ng/nl/h (p = 0.03) after methyldopa, but plasma antidiuretic hormone concentration changed insignificantly. In a subset of patients, platelet alpha 2-receptor density and affinity were unaltered. Renal function was also unchanged. Thus, sympathetic inhibition induced by methyldopa in selected patients with chronic, stable heart failure does not worsen symptom status or exercise performance, and may produce a beneficial effect by withdrawal of excess sympathetic activity with reduction of plasma norepinephrine levels.     

Plasma glucose levels predict the disrupting effects of adrenoceptor antagonists on enhancement of memory storage.

Adrenoceptor antagonists block the enhancement of memory storage produced by epinephrine injection, but not that produced by glucose injection. The present experiment determined whether adrenoceptor antagonists modify resting blood glucose levels or the magnitude of epinephrine-, glucose-, and footshock-induced increases in circulating glucose levels in a manner related to these previously observed effects on memory. The alpha- and beta-adrenoceptor antagonists, phenoxybenzamine and propranolol, respectively, were injected in rats 30 min prior to administration of epinephrine, glucose, or footshock. Plasma glucose levels were sampled during the next 30 min. Epinephrine-induced increases in plasma glucose levels were potentiated by phenoxybenzamine and were attenuated and delayed by propranolol. The adrenoceptor antagonists did not alter resting plasma glucose levels, or the increases in plasma glucose levels resulting from glucose injection or footshock. These findings suggest that phenoxybenzamine and propranolol alter blood glucose responses to epinephrine injection in a manner which may contribute to attenuation of epinephrine-induced enhancement of memory storage with peripheral injections of adrenoceptor antagonists.     

Evidence for a peripheral component in the sympatholytic effect of clonidine in rats.

In an attempt to assess separately the peripheral and central effects of clonidine on cardiovascular parameters and plasma catecholamine levels, the selective alpha 2-adrenoceptor antagonist idazoxan (RX 781094) was given either intravenously (i.v.) or intracerebroventricularly (i.c.v.) to anaesthetized rats before administration of intravenous clonidine. Plasma noradrenaline and plasma growth hormone concentrations were used as indices of peripheral sympathetic nervous activity and central alpha-adrenoceptor stimulation, respectively. Peripheral and central administration of idazoxan antagonized the cardiovascular responses to i.v. clonidine, 5 micrograms kg-1. However, idazoxan was more effective against the hypotension than the bradycardia induced by clonidine. Idazoxan 300 micrograms kg-1 i.v. and 50 micrograms i.c.v. prevented clonidine-induced falls in plasma noradrenaline and adrenaline. The results suggest that 50 micrograms idazoxan i.c.v. caused some blockade of peripheral as well as central alpha 2-adrenoceptors. Idazoxan, 10 micrograms i.c.v., caused similar inhibition of the hypotensive response to clonidine as 300 micrograms kg-1 i.v. and 50 micrograms i.c.v. but did not significantly inhibit the clonidine-induced fall in plasma noradrenaline concentration. Animals pretreated with i.v. or i.c.v. idazoxan had significantly lower levels of plasma growth hormone than vehicle-treated rats. Idazoxan 10 micrograms and 50 micrograms i.c.v. suppressed growth hormone secretion to the same extent. These results suggest that stimulation of peripheral, prejunctional alpha 2-adrenoceptors in anaesthetized rats may contribute to the fall in plasma catecholamines produced by i.v. clonidine, and confirm that the hypotensive effect is centrally mediated.     

Changes in tyrosine hydroxylase mRNA expression in the rat locus coeruleus following acute or chronic treatment with valproic acid.

Valproate has proven effective in treating bipolar disorder. Though some biochemical effects of valproate are rapid, mood-stabilizing effects can take weeks, suggesting that regulatory changes in gene expression in brain neurotransmitter systems may be involved. Given a presumed role for norepinephrine (NE) in bipolar disorder, as well as the actions of mood-stabilizing drugs, we examined changes in mRNA expression for tyrosine hydroxylase (TH), the NE transporter (NET) and alpha 2A autoreceptor in the rat locus coeruleus after valproate treatment. TH mRNA increased slightly (16%) following acute treatment, and more so after chronic valproate treatment (26%), while neither NET nor alpha 2A mRNA expression changed. Further, chronic valproate treatment attenuated the elevation in TH mRNA expression induced in the LC in response to acute restraint stress. Both acute and chronic valproate treatment attenuated restraint stress-induced elevations in plasma ACTH secretion. These observations suggest that the therapeutic effects of valproate may involve regulatory alterations in TH message expression in the brain, and attenuation of stress-reactivity of the central noradrenergic system and the hypothalamic-pituitary-adrenal axis.     

Effects of chronic beta-adrenoceptor antagonism on plasma catecholamines and blood pressure in hypertension

Plasma catecholamines were measured before and after treatment with beta-adrenoceptor antagonists in 17 hypertensive patients. Chronic treatment with beta-adrenoceptor antagonists caused substantial reductions in heart rate and intra-arterial blood pressure recorded continuously during ambulation. Before treatment, a quantitative relationship was observed between plasma norepinephrine and blood pressure and heart rate during a variety of activities; a similar relationship was also observed after chronic treatment five of six patients, suggesting that plasma norepinephrine remains an index of sympathetic activity despite the influence of beta-adrenoceptor antagonism. After treatment, plasma norepinephrine tended to be higher at any level of blood pressure, although not significantly so. Chronic treatment caused no significant change in mean resting plasma levels of norepinephrine and epinephrine. During exercise, plasma norepinephrine and epinephrine levels were significantly elevated above control after acute but not after chronic treatment. These observations do not support the hypothesis that beta-adrenoceptor antagonist drugs lower blood pressure in hypertensive man through a sympatholytic mechanism in he central nervous system or at peripheral presynaptic receptors.     

Effects of idazoxan on dorsal raphe 5-hydroxytryptamine neuronal function.

The effects of the alpha 2-adrenoceptor antagonist idazoxan on 5-hydroxytryptamine (5-HT) neuronal firing and release have been investigated. Idazoxan, administered i.v. (10 micrograms/kg and 0.5 mg/kg) increased dorsal raphe nucleus (DRN)-5-HT neuronal firing rate in a dose-dependent fashion. At the higher dose, a voltammetric study revealed increases in extracellular 5-HT and 5-hydroxyindole acetic acid (5-HIAA) levels, there was no effect with the lower dose. Intra-raphe administration of idazoxan (1 ng) also elevated the firing rate of 5-HT neurones in the dorsal raphe, suggesting that idazoxan may produce the increase in firing by a direct effect in the DRN. However, microiontophoretic application of idazoxan did not increase the firing rate of 5-HT neurones in the DRN. Thus the increase in the firing rate of 5-HT neurones in the DRN observed with systemic and local administration of idazoxan is probably not due to a direct action of idazoxan on the 5-HT neurone. Possibly the idazoxan acted at alpha 2-adrenoceptors located on noradrenergic terminals thus stimulating noradrenaline release and consequently increased 5-HT activity. Chronic administration of idazoxan (0.8 mg/kg per h for 14 days), using osmotic mini-pumps, caused an elevation in basal firing rate and an attenuation of the inhibitory response of DRN 5-HT neurones to the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT) (10 micrograms/kg i.v.). This finding suggests that chronic infusion with idazoxan leads to desensitisation of the 5-HT1A somatodendritic autoreceptor.     

Blockade of postsynaptic alpha 2-adrenoceptors enhances responses to mixed alpha 1/alpha 2-agonists in rat submaxillary gland

The effects of selective blockade of alpha 2-adrenoceptors with idazoxan on salivary secretion elicited by several alpha-adrenoceptor agonists known to differ in their alpha 1/alpha 2 potency ratios were studied in the submaxillary gland. Doses of idazoxan ranging between 0.01 to 10 000 micrograms/kg did not produce secretion in anaesthetized rats. Idazoxan (3 micrograms/kg) effectively blocked the inhibitory action of clonidine, 10 micrograms/kg, on the responses to methacholine but did not change the sialagogic responses to either phenylephrine or isoprenaline. On the other hand, idazoxan enhanced the secretion elicited by other agonists known to have mixed alpha 1/alpha 2-agonistic properties. The degree of augmentation of the responses observed after alpha 2 blockade was: clonidine much greater than alpha-methyl-norepinephrine greater than norepinephrine. Guanabenz did not elicit secretory responses in either the presence or absence of idazoxan. These results argue that two components determine the magnitude of the sialagogic response induced by agonists with mixed alpha 1/alpha 2 activity: (a) an alpha 1-mediated secretory effect and (2) an alpha 2-mediated inhibitory effect, both being localized at postsynaptic level.     

DSP4-induced noradrenergic lesions increase beta-adrenergic receptors and hippocampal electrophysiological responsiveness

Following profound (greater than 90%) depletions of norepinephrine (NE) by the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4), the numbers of beta-adrenergic receptors were significantly increased (20-25%) in rat hippocampal and somatosensory cortical membranes; however, the numbers of alpha 1-adrenergic receptors and the affinities of both types of receptors were unaffected. This selective up-regulation of beta-adrenergic receptors was evident 1 week after DSP4 administration and was maintained for at least 2 more weeks. In electrophysiological experiments in the hippocampal slice preparation, responses to threshold as well as maximal concentrations of isoproterenol were enhanced 150% and 33%, respectively, in the DSP4-lesioned animals. The results demonstrate that nearly complete depletion of brain NE produced by administration of DSP4, like that produced by 6-hydroxydopamine, results in increased numbers of beta- but not alpha-adrenergic receptors, and suggest that the density of the former are regulated by afferent noradrenergic fibers. Furthermore, the functional significance of the increased number of hippocampal beta-adrenergic receptors is directly manifested in a greater electrophysiological responsiveness to an exogenously administered beta-adrenergic receptor agonist.     

Possible role of alpha-2 and alpha-1 adrenoceptors in the experimentally-induced depression of the central nervous system

The alpha-2 adrenoceptor agonists clonidine and xylazine were employed in chicks and rats to induce a loss of the righting reflex, a sign for depression of the central nervous system. These effects of clonidine and xylazine were antagonized by yohimbine, idazoxan and CH-38083 (7,8-(methylenedioxi)-14-alpha-hydroxyalloberbane HCl), compounds having alpha-2 adrenoceptor antagonist properties. Prazosin, an antagonist for alpha-1 adrenoceptors, enforced the alpha-2 adrenoceptor agonist-induced depression in both species. 6-Hydroxydopamine treatment, which reduced the norepinephrine concentrations in the rat cerebral cortex by 76%, increased the duration of the loss of righting reflex induced by xylazine indicating that central postsynaptic alpha-2 adrenoceptors might also be involved in this behavioral alteration. The electrically-stimulated tritium release was also determined from the isolated rat cerebral cortex slices which had been preloaded with 3H-norepinephrine. Clonidine and xylazine inhibited the stimulation-induced tritium release and this inhibition was counteracted by yohimbine, idazoxan or CH-38083, but not by prazosin. We have concluded from the present data that stimulation of alpha-2 adrenoceptors with pre- and postsynaptic locations or inhibition of alpha-1 adrenoceptors in the central nervous system may shift the depression/vigilance balance to the direction of depression which might be accompanied by a decreased activity of cortical noradrenergic neural transmission.     

Effects of the alpha 2-antagonist idazoxan on monoaminergic parameters measured in the cerebrospinal fluid of rabbits

The alpha 2-antagonist idazoxan was administered intravenously to rabbits. The increase in central noradrenergic, dopaminergic and serotonergic activity was followed as a function of time by determining neuronal parameters in the cerebrospinal fluid (CSF) and was compared with changes previously determined after yohimbine. These parameters include the enzyme dopamine-beta-hydroxylase (D beta H), the noradrenergic metabolites 3-methoxy-4-hydroxyphenylmandelic acid (VMA) and 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), the dopaminergic metabolite 3-methoxy-4-hydroxyphenylacetic acid (HVA) and the serotonergic metabolite 5-hydroxyindole acetic acid (5-HIAA). Control experiments with physiological saline were also performed. D beta H activity increased to 211% in control experiments, and to 570 and 530%, respectively after yohimbine and idazoxan. Compared to the control experiments yohimbine was able to elevate VMA, MHPG and HVA concentrations, but 5-HIAA levels were reduced. Idazoxan caused increased MHPG concentrations, slight increases in VMA, little effect on HVA and no effect on 5-HIAA levels. We conclude that idazoxan was as potent as yohimbine as an alpha 2-antagonist in our in vivo experiments and that idazoxan shows a much greater selectivity with regard to the noradrenergic system.     

Effects of acute and chronic reboxetine treatment on stress-induced monoamine efflux in the rat frontal cortex.

Reboxetine is a selective noradrenergic reuptake inhibitor that displays an antidepressant profile in both animal tests and in clinical trials. The present study examined the ability of reboxetine to alter stress-induced increases in norepinephrine, serotonin and dopamine efflux in the frontal cortex in awake behaving rats. Acute systemic administration of reboxetine (0.3-20.0 mg/kg) dose-dependently increased extracellular norepinephrine in the frontal cortex while having no effect on extracellular serotonin. At 20 mg/kg, reboxetine also increased extracellular dopamine. Application of a 20-min tailpinch stress increased extracellular norepinephrine. This effect was greatly potentiated in rats pretreated with reboxetine. Tailpinch did not elicit increases in dopamine in saline treated animals but this stimulus increased dopamine levels following reboxetine pretreatment. Furthermore, chronic administration of reboxetine for 14 days resulted in elevated basal concentrations of extracellular norepinephrine and dopamine and a greater net increase of extracellular norepinephrine and dopamine, but not serotonin, in response to tailpinch compared with vehicle control animals. Taken together, these data support the view that the noradrenergic and dopaminergic systems are modified by reboxetine treatment and may be important factors in the mechanism of action of antidepressant compounds.     

Effect of dexfenfluramine treatment on body weight,blood pressure and noradrenergic activity in obese hypertensive patients

Summary The effect of dexfenfluramine (dF) on body weight, blood pressure and noradrenergic activity were studied in 30 obese hypertensive patients randomly divided into two groups and treated for 3 months either with dF (30 mg daily; 16 subjects) or placebo (Pl; 14 subjects). 11 patients from the dF group and 9 patients given Pl completed the entire experimental protocol, including monthly visits for metabolic and hormonal measurements, as well as a bicycle exercise test with arterial catheterisation for haemodynamic and catecholamine measurements performed before and after 3 months of treatment.A progressive significant decrease in body weight, averaging 6.0 kg after 3 months was observed in the dF-treated group, whereas loss of weight in the placebo group (1.4 kg) was not significant. While blood pressure and noradrenergic activity, assessed as changes in the plasma levels and urinary excretion of norepinephrine, remained unaffected in the Pl group, a significant drop in the supine systolic and diastolic blood pressures, as well as in the resting venous norepinephrine level and in urinary norepinephrine excretion was found after the first month of dF administration. In addition, the exercise-induced rise in systolic and diastolic blood pressure, as well as in arterial plasma norepinephrine and epinephrine concentrations, was significantly reduced after 3 months of dF administration; there were no such changes in the Pl-treated group.The results of the present study indicate that, in addition to the weight-reducing effect of dexfenfluramine, its hypotensive effect may be mediated by a decrease in noradrenergic activity.