Effect of chronic administration of alprazolam and adinazolam on clonidine- or apomorphine-induced aggression in laboratory rodents

The activity of chronic (3 weeks) treatment with the triazolobenzodiazepines, alprazolam and adinazolam, on clonidine- and apomorphine-induced aggression were studied. Adinazolam, like desipramine, potentiated aggression induced by clonidine while diazepam and alprazolam completely abolished it. In the apomorphine-induced aggression, adinazolam suppressed both aggressivity and stereotypy, while diazepam slightly potentiated it. Alprazolam did not modify the effect of aggression induced by apomorphine. On the whole, while adinazolam seemed to develop an activity closer to that of a classical antidepressant like desipramine, alprazolam appeared to be more similar to the benzodiazepines on clonidine-induced aggression in mice. Compared to desipramine and diazepam, adinazolam left these two effects induced by apomorphine almost unchanged. The experiments performed showed differences between the profiles of action of the two triazolobenzodiazepines studied.     

Antidepressant and anxiolytic effects of alprazolam versus the conventional antidepressant desipramine and the anxiolytic diazepam in the forced swim test in rats.

The antidepressant and anxiolytic effects of alprazolam were compared to those of desipramine, diazepam and buspirone in the forced swim test. Subchronic alprazolam induced a reduction in immobility similar to that of desipramine in 'non-pretested' and 'pretested' rats. In 'non-pretested' rats, the anti-immobility effect of desipramine was potentiated by diazepam and alprazolam, given before subchronic desipramine, while the anti-immobility effect of subchronic alprazolam was counteracted by diazepam. Diazepam, administered before the pretest session, counteracted, 24 h later, the anti-immobility effect of subchronic desipramine and alprazolam; alprazolam counteracted the anti-immobility effect of alprazolam but not of desipramine, buspirone at the highest doses tested potentiated the anti-immobility effect of subchronic desipramine but not of alprazolam. These data provide further support for the hypothesis that the GABA/benzodiazepine/Cl complex is directly implicated in the action of antidepressants and that systems other than the GABA system are involved in the antidepressant and anxiolytic effects of alprazolam.     

Possible relationship of the locus coeruleus--hippocampal noradrenergic neurons to depression and mode of action of antidepressant drugs

Recent studies performed in our laboratory suggest involvement of locus coeruleus (LC) and hippocampal noradrenergic (NE) neurons in the mechanism of depression and mode of action of antidepressants. Both electrolytic and 6-OHDA lesions to the LC abolished desipramine action in forced swim test in rats. The action of desipramine was also reduced in rats pretreated with alpha 1 adrenolytic drugs -- phenoxybenzamine and prazosin. Electrical stimulation of the LC produced, like desipramine, activating effect in forced swim test, the phenomenon never observed in phenoxybenzamine-pretreated animals. Chronic (but not acute) administration of desipramine potentiated activatory effects of intrahippocampal injections of NE and phenylephrine but not isoprenaline in both open field and forced swim test. Depressant effect of intrahippocampal clonidine was reversed by chronic desipramine (in the open field test). The effect of desipramine was partially shared by citalopram.     

Intravenous alprazolam challenge in normal subjects

Alprazolam, a novel benzodiazepine derivative is thought to be effective in the treatment of anxiety, panic, and depressive disorders. There is considerable interest in alprazolam's mechanism of action, particularly whether its profile of actions might resemble that of the ₂ adrenore-ceptor agonist, clonidine. The present study assessed the biochemical, cardiovascular, and behavioral responses of healthy volunteers to acute intravenous infusions of alprazolam and placebo. Alprazolam reduced ACTH and cortisol while increasing growth hormone. There was a transient reduction in plasma norepinephrine and only modest effects on cardiovascular parameters. Subjects became quite sedated after intravenous alprazolam. This pharmacodynamic profile resembles that previously reported for traditional benzodiazepines, although alprazolam may be a more potent stimulator of growth hormone release. Alprazolam's effects on growth hormone resemble those of clonidine, but unlike clonidine, alprazolam has relatively little effect on plasma catecholamine and cardiovascular parameters. This suggests that ₂ mechanisms do not play a primary role in alprazolam's mode of action. Since alprazolam infusion affects three different measures (ACTH/cortisol, growth hormone, and plasma norepinephrine) thought to be dysregulated in depression, challenge with intravenous alprazolam may prove to be a useful probe in affective disorders.     

On the role of noradrenergic neurotransmission in the action of desipramine and amitriptyline in animal models of depression

Three weeks of treatment with desipramine (DMI) and amitriptyline (AMI) reduced the hypothermic action of clonidine in rats. Both electrolytic and 6-hydroxydopamine lesions of the locus coeruleus (LC) and administration of DSP-4 counteracted the reduction of clonidine hypothermia produced by antidepressants. Lesions of the LC and DSP-4 administration also antagonized the anti-immobility action of single doses of DMI but failed to modulate the action of AMI in the forced swim test. Chronic DMI action on the rat immobility was reduced by 6-hydroxydopamine lesions of the LC: other lesions (electrolytic, DSP-4) were ineffective. Electrical stimulation of the LC increased the rat activity in the forced swim paradigm, producing an effect similar to that of antidepressants. The anti-immobility effect of DMI as well as LC stimulation were antagonized by drugs blocking alpha-adrenoceptors (phenoxybenzamine, prazosin) but not by propranolol, a non-selective antagonist of beta-adrenoceptors. On the other hand, the anti-immobility action of AMI was unchanged by all adrenolytics used in that study. The results indicate that the LC system and alpha 1-adrenoceptors play an important role in the antidepressive action of DMI, but not AMI, in the forced swim test.     

Behavioural responsiveness to picrotoxin and desipramine in adult rats prenatally exposed to different benzodiazepine receptor agonists

The behavioural responsiveness to picrotoxin and desipramine was investigated in adult rats prenatally exposed to different benzodiazepine receptor agonists such as diazepam, alprazolam and zolpidem. Prenatal exposure to diazepam and alprazolam similarly potentiated the anti-immobility effect on the forced swimming test and the inhibitory effect on spontaneous motor activity of picrotoxin and desipramine and increased the seizure sensitivity to picrotoxin. Prenatal zolpidem seems to be ineffective. These data suggest that, despite the differences in their pharmacodynamic profile, prenatal exposure to diazepam and alprazolam, but not zolpidem, may have similar permanent consequences on the behavioural effects of drugs acting on the GABA_A receptors.     

The effect of 5,7-DHT-induced lesions of the median raphe nucleus and chronic desipramine administration upon motor behaviour of rats given intrahippocampal clonidine injection

The role of serotonergic (5-HT) innervation of rat hippocampus in clonidine- induced behavioural effects was studied in naive and desipramine-pretreated animals. 5,7- DHT-lesions of the median raphe nucleus (MR) produced about 50 per cent decrease of serotonin and 5-hydroxyindoloacetic acid (5-HIAA) content in the rat cortex and hippocampus. Lesions of the MR also accelerated the attenuating effect of desipramine upon locomotor inhibition produced by intrahippocampal clonidine injections. In the forced swim test (FST) the MR lesion revealed the stimulatory potency of clonidine upon rat active behaviour, which was statistically significant. However, no further potentiation by MR lesions of DMI effects upon behavioural action of clonidine could be observed in this test. It is concluded that hippocampal serotonergic innervation plays a minor role in the antidepressant-induced changes in behavioural effects of clonidine, which probably occur via modulation of local alpha-adrenoceptors. It is also conceivable that the stimulatory effect of intrahippocampal clonidine injections in the forced swim test in MR-lesioned rats, may be due to the increase in the alpha-(1)-adrenoceptor function in this brain area.     

Clonidine causes antidepressant-like effects in rats by activating alpha 2-adrenoceptors outside the locus coeruleus.

Clonidine, 0.05, 0.1 and 0.5 mg/kg administered i.p. as a three-injection course but not as single doses, significantly reduced the immobility of rats in the forced swimming test. Doses of 0.1 and 0.5, administered the same way, significantly reduced activity in an open field. The effect of 0.05 and 0.5 mg/kg clonidine on immobility was prevented by 1 mg/kg idazoxan, an alpha 2-adrenoceptor antagonist, but not by 3 mg/kg prazosin, which blocks alpha 1-adrenoceptors. An infusion of 6 micrograms/microliters 6-hydroxydopamine in the locus coeruleus, which markedly depleted noradrenaline in terminal regions, did not modify the effect of 0.05 and 0.5 mg/kg clonidine on immobility. Chronic treatment with 5 mg/kg i.p. desipramine or 0.1 mg/kg i.p. clonidine, twice daily for 15 days, did not modify the effect of a three-injection course with 0.1 mg/kg clonidine. It is suggested that clonidine exerts antidepressant-like effects on rats in the forced swimming test by acting on central alpha 2-adrenoceptors outside the locus coeruleus and presumably postsynaptically to noradrenaline-containing neurons. No tolerance or sensitization of the clonidine effect was found after chronic treatment with desipramine or clonidine. These findings are of significance for the effects of clonidine in subgroups of depressed patients.     

Effects of alprazolam on anxiety-related behavior of rats in a modified forced-swim test employing straw suspension.

The present study was undertaken to examine how the triazolobenzodiazepine derivative, alprazolam, which possesses anxiolytic activity in man and anticonflict effects in animals, could affect both the duration of immobility and the incidence of straw-climbing behavior of rats in a modified forced-swim (MFS) test. After a 5-min test of forced swimming, four straws were suspended just above the surface of the water and subsequently the straw-climbing trials were counted for 5 min as an index of escape behaviors induced by negative emotionality (anxiety and/or fear). Rats were injected IP with either alprazolam (0.1, 0.2, 1, and 2 mg/kg) or its vehicle 30 min before testing. Alprazolam prolonged the duration of immobility and inhibited the straw-climbing counts in a dose-dependent manner. This effect is in the same direction as the effect shown by an anxiolytic benzodiazepine such as diazepam. The results suggest that alprazolam may possess anxiolytic effects at lower doses, whereas at a high dose of 2 mg/kg this compound might elicit sedation, concomitantly with its anxiolytic and/or antipanic effects. In addition, it appears that alprazolam is more potent than diazepam in the MFS test following a single-injection protocol.     

Effects of neurotropin and other drugs on EEG alterations in SART-stressed (repeated cold-stressed) rats

SART-stressed (repeated cold-stressed) rats, experimental model animals for vagotonic-type dysautonomia, have been reported to show EEG with lower-amplitude fast waves during resting-arousal and higher-amplitude slow waves during slow-wave sleep compared to normal rats. In this report, the effects of certain drugs on EEG alterations were investigated using the power spectral analysis. EEG was measured 60 min after a single dose of drugs and on the day following the final dose of 6 administrations. Neurotropin, a sedative analgesic, slightly increased faster waves on resting-arousal EEG and slower waves on slow-wave sleep EEG in normal rats, and it prevented SART stress-induced EEG alterations during both resting-arousal and slow-wave sleep. Alprazolam, a minor tranquilizer, and GABOB, a GABA related compound, were also effective on SART stress-induced EEG alterations. Alprazolam produced remarkable but transient high-amplitude fast waves in the resting-arousal EEG of normal rats, and GABOB produced lasting low-amplitude fast waves in the slow-wave sleep EEG of normal rats. From the above results, it appears that Neurotropin may have an effect on EEG alterations caused by SART stress and that its action is likely due to mechanisms different from those of alprazolam and GABOB.     

Studies on the locus coeruleus system in an animal model for antidepressive activity

The present study was performed in order to evaluate the role of brain noradrenergic system of the locus coeruleus (LC) in mediating the effect of desipramine (DMI) in the behavioral despair (immobility) induced by forced swim in rats. Both single and repetitive doses of DMI significantly reduced the immobility. The effect of single dose of drug was reduced in LC lesioned rats. On the other hand, lesions failed to influence the action of repetitive doses of DMI. A lesion of the LC alone failed to influence animals' behavior in the immobility test. Electrical stimulation of the LC (either unilateral or bilateral) significantly reduced the immobility i.e. produced an effect similar to that produced by DMI. The possible involvement of the LC in action of DMI and mechanisms of depression is discussed.     

A double-blind clinical trial of alprazolam, imipramine, or placebo in the depressed elderly.

The efficacy and safety of alprazolam as compared to imipramine or a placebo added to weekly interpersonal psychotherapy was compared in a 6-week double-blind randomized clinical trial of 35 ambulatory elderly patients with major depression. The average maximum dosage of alprazolam was 2.2 mg and the average maximum dosage of imipramine was 97.5 mg. The findings showed a rapid onset of action of alprazolam within 1 week on symptoms of depression and anxiety. The effects for imipramine were seen later in the study. There were no serious side effects that interfered with treatment. The anticholinergic effects of imipramine were the ones that most commonly interfered with treatment. Alprazolam produced the greatest number of symptoms with discontinuation, most of which were alleviated within a week. We conclude that alprazolam may be useful as an antidepressant for the elderly. More clinical trials are needed to test its efficacy in the depressed elderly with concomitant medical problems, using plasma levels. A double-blind discontinuation study of alprazolam is needed to determine the degree of symptom return.     

A study of the effects of clonidine on the EEG in rats treated with single and multiple doses of antidepressants

The influence of repeated and single administrations of desipramine, amitryptiline, and mianserin on the EEG effects of clonidine has been investigated in rats implanted with chronic cortical electrodes. Clonidine induced a dose-dependent EEG synchronization in control animals. Signs of behavioral depression occurred after administration of moderate (0.1 mg/kg) and higher (0.2 mg/kg) doses of clonidine. Single doses of desipramine and amitryptiline attenuated the clonidine effect, while mianserine potentiated clonidine-induced synchronization. Antidepressants given once daily for 14 days completely (desipramine and amitryptiline) or partially (mianserin) reduced the effect of clonidine. Antidepressants alone produced only a slight effect on cortical EEG pattern.     

Chronic treatment with desipramine facilitates its effect on extracellular noradrenaline in the rat hippocampus: studies on the role of presynaptic α2-adrenoceptors

Adaptive phenomena such as desensitization of autoreceptors are considered an important factor in the achievement of therapeutic efficacy of antidepressant drugs after chronic treatment. We have studied whether a chronic treatment with desipramine had a greater effect than a single dose on the extracellular concentrations of noradrenaline in the dorsal hippocampus. Administration of 10 mg/kg i.p. desipramine once daily for 14 days significantly raised the basal extracellular noradrenaline in the dorsal hippocampus 24 h but not 48 h after the last drug injection. A challenge dose of desipramine increased extracellular noradrenaline in rats treated chronically with vehicle and desipramine. The effect was significantly higher in rats treated chronically with desipramine 48 h but not 24 h after the last injection. An intraperitoneal administration of the alpha2-adrenoceptor agonist clonidine at the dose of 10 microg/kg significantly reduced extracellular noradrenaline in the control group but not in animals chronically treated with desipramine whereas 30 microg/kg clonidine produced a similar decrease in both groups. Three concentrations of clonidine (0.05, 0.5 and 1 microM) infused into the hippocampus significantly reduced extracellular noradrenaline to a similar extent in rats chronically treated with saline or desipramine. Fourty-eight hours after the last injection of the chronic treatment, [3H]RX-821002 binding to alpha2-adrenoceptors in the rat locus coeruleus measured by autoradiography was not significantly modified. A slight (17%) but significant decrease of neuronal uptake of [3H]noradrenaline was found in synaptosome preparations from dorsal hippocampus of rats chronically treated with desipramine, but this was likely due to a decrease in affinity. The results suggest that a repeated treatment with desipramine (10 mg/kg i.p. once daily for 14 days) facilitates its effect on extracellular noradrenaline in the dorsal hippocampus and induces adaptive changes probably involving desensitization of alpha2-adrenoceptors, with no changes in their density, on noradrenergic neurons in the locus coeruleus.     

Alprazolam: Review of pharmacological,pharmacokinetic, and clinical data

Alprazolam is a recently marketed triazolobenzodiazepine. The animal pharmacological data reviewed here suggest a potent anxiolytic action. But, in addition, an antidepressant activity was revealed in clinical studies and subsequently studied in animal assays. As an extension of these activities, alprazolam also displays efficacy in panic and phobic disorders. Data relating to a wide range of pharmacological activities and pharmacokinetics of alprazolam are also reviewed.     

Synergistic antinociception of intrathecal sildenafil with clonidine in the rat formalin test

Spinal sildenafil (phosphodiesterase 5 inhibitor) and clonidine (alpha-2 adrenoceptor agonist) have shown antinociception. The author examined the properties of drug interaction after concurrent administration of intrathecal sildenafil-clonidine, and further clarified the reciprocity of sildenafil and clonidine. Catheters were inserted into the intrathecal space of male Sprague-Dawley rats. The formalin test was used as a nociceptive test, which was induced by subcutaneous injection of 50 µl of 5% formalin solution into the hindpaw. The pharmacological interaction was characterized using an isobolographic analysis. Intrathecal sildenafil and clonidine dose-dependently suppressed the flinching response observed during phase 1 and phase 2 in the formalin test. Isobolographic analysis revealed a synergistic interaction after intrathecal delivery of sildenafil-clonidine in both phases. Intrathecal yohimbine antagonized the antinociceptive action of intrathecal sildenafil during both phases in the formalin test. However, intrathecal ODQ failed to antagonize the antinociceptive action of intrathecal clonidine. These results suggest that sildenafil and clonidine, and the mixture of the two are effective against acute pain and facilitated pain state at the spinal level. Furthermore, synergism was noted after delivery of sildenafil-clonidine mixture. The antinociception of sildenafil can be modulated by spinal alpha-2 adrenoceptor, while the effect of clonidine is independent on the guanyly cyclase.     

The interference of tricyclic antidepressants with the central hypotensive effect of clonidine

From clinical experience it is known that the hypotensive action of clonidine may be antagonized by simultaneously administrated desipramine. In the present experiments it has been demonstrated that pretreatment of anaesthetized cats with desipramine, imipramine, amitryptyline and protryptyline reduced the central hypotensive action of clonidine. Since both clonidine and the tricyclic antidepressive drugs were administered via the vertebral artery in low doses it may be concluded that the interaction occurs in the CNS, i.e. the rhombencephalon. The experiments suggest that interaction between tricyclic antidepressants and clonidine is not restricted to desmethylimipramine. Therefore combination of clonidine with these drugs should be avoided.     

Double-blind clinical assessment of alprazolam, a new benzodiazepine derivative, in the treatment of moderate to severe anxiety

This four-week, double-blind, placebo-controlled clinical trial assessed the new benzodiazepine derivative alprazolam (Xanax) treatment of moderate to severe anxiety characteristic of anxiety neurosis. Sixty-two outpatients participated; 8 per cent of those taking drug and 52 per cent of those taking placebo discontinued participation due to side effects or lack of efficacy. The mean total daily alprazolam dose was 1.35 mg taken in divided doses. Alprazolam significantly improved scores on five anxiety rating scales--Hamilton Anxiety Rating Scale, Physician's Global Impressions, Target Symptoms Record, Self-Rating Symptom Scale, and Patient's Global Impressions. Alprazolam patients experienced no clinically significant changes in vital signs and laboratory values; they reported drowsiness as the most frequent side effect. We conclude that alprazolam is an effective and safe anxiolytic agent.     

Effects of anxiogenic drugs in rat forced swimming test.

The effect of antidepressants and anxiogenics in the forced swimming (Porsolt') test was investigated in rats. On the second day of an experiment, desipramine (10 mg/kg), pentylenetetrazole (20 mg/kg), picrotoxin (2.5 mg/kg), and clonidine (1.0 mg/kg) shortened while buspirone (1.0 mg/kg), yohimbine (2.5 mg/kg), DMCM (1.0 mg/kg), and Ro-15-4513 (1.0 mg/kg) prolonged the time of immobility or behavioral despair; fluoxetine (10 and 20 mg/kg), citalopram (10 mg/kg), and flumazenil (10 mg/kg) were ineffective. While clonidine, given in a subeffective dose (0.1 mg/kg), augmented the effect of desipramine (10 mg/kg), buspirone (1.0 mg/kg) had an opposite effect. The picrotoxin (2.5 mg/kg) challenge prominently shortened the time of immobility after desipramine (10 mg/kg) or citalopram (10 mg/kg) treatment. In conclusion, our results indicate that pharmacologically enhanced anxiety interacts with the effects of acute drug treatment in the forced swimming test.     

Effects of single doses of alprazolam and diazepam,alone and in combination with ethanol,on psychomotor and cognitive performance and on autonomic nervous system reactivity in healthy volunteers

Summary Effects of alprazolam, alone and in combination with ethanol, on psychomotor and cognitive performance were studied in healthy male volunteers and compared to effects of diazepam. Alprazolam 2 mg produced relatively long-lasting impairments on tests of tracking, verbal and nonverbal information processing, and memory, and decreased blood pressure without a change in heart rate or plasma norepinephrine levels. Although ethanol consumption was demonstrated to produce additive decrements in performance on certain tasks, there was little evidence to support a synergistic effect. Alprazolam 2 mg was accompanied by increased selfreports of side effects, especially drowsiness. Low dose alprazolam, diazepam, and ethanol produced significantly fewer side effects than 2 mg alprazolam, but significantly more than placebo.