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PubMed1990

Unusual behavioral profile of alprazolam in squirrel monkeys.

Alprazolam was studied for its effects on schedule-controlled behavior of squirrel monkeys. Monkeys responded by pressing a lever under fixed-ratio or two separate fixed-interval (FI) schedules. Responding was maintained by the presentation of food under all three schedules and was suppressed under one of the FI schedules by electric shock. Unlike lorazepam, alprazolam did not increase rates of either suppressed or nonsuppressed responding under the two FI schedules after acute administration. When given for 3 (at 0.03 mg/kg) or 11 (at 0.1 mg/kg) consecutive days immediately before test sessions, alprazolam also did not increase suppressed responding. Under all three schedules, alprazolam (0.03-3.0 mg/kg) produced dose-dependent decreases in response rate. The rate-decreasing effects of alprazolam were attenuated by drugs known to have benzodiazepine (BZ) antagonist action: Ro 15-1788 (0.01 and 0.3 mg/kg), Ro 15-4513 (0.01 and 0.1 mg/kg) and 3-(methoxycarbonyl)amino-beta-carboline (10.0 and 30.0 mg/kg). These latter drugs alone either had no effect on or decreased fixed-ratio responding. Alprazolam also was tested in combination with lorazepam under the two FI schedules. In general, low doses of lorazepam, equal to or less than those having little effect on response rate when given alone, increased suppressed and nonsuppressed responding when combined with low to moderate doses of alprazolam. The results show that although the rate-decreasing effects of alprazolam probably are due to actions at BZ recognition sites, alprazolam alone does not have typical BZ-like agonist effects on FI responding; it did, however, potentiate the behavioral effects of lorazepam.

Alprazolam↗
PubMed1995

Abecarnil and alprazolam in humans: behavioral, subjective and reinforcing effects.

Abecarnil, a novel beta-carboline, is under development for the treatment of Generalized Anxiety Disorder. This study compared the behavioral, subjective and reinforcing effects of abecarnil to those of the benzodiazepine alprazolam in 14 healthy males with histories of sedative drug abuse. Placebo, abecarnil (10, 20, 40 mg) and alprazolam (1.0, 2.0, 4.0 mg) were administered p.o. in a double-blind, cross-over design. Abecarnil and alprazolam produced comparable dose-dependent decreases in behavioral performance on balance, circular lights, digit-recall and digit-symbol-substitution tasks that peaked 2-4 hr after drug administration. Both drugs produced a profile of sedative effects and were categorized by subjects as predominantly barbiturate- or benzodiazepine-like. However, the high dose of alprazolam increased subject-ratings of sleepy, fatigued and tired; these ratings were significantly different from both placebo and all doses of abecarnil. Abecarnil and alprazolam produced comparable dose-dependent increases in ratings of drug strength. The highest dose of alprazolam produced increases in Next Day ratings of drug liking, good effects, monetary value of the drug, and desire to take the drug again that were significantly greater than placebo and the highest dose of abecarnil. Abecarnil, but not alprazolam, produced increases in Next Day ratings of "bad effects" that were significantly greater than placebo. The highest dose of alprazolam produced increases in a direct measure of drug reinforcement (drug vs. money Multiple-Choice Procedure) that were significantly greater than placebo and all doses of abecarnil. Collectively, these data suggest that abecarnil may have less potential for abuse than alprazolam in a sedative-abusing population.

Adult↗
PubMed1997

Pharmacokinetic-pharmacodynamic modeling of stimulatory and sedative effects of alprazolam: timing performance deficits.

Alprazolam decreased the reinforcement rate and increased the shorter-response rate of contingency-controlled timing behavior under a differential reinforcement of low-rate schedule (DRL 45-s) in rats. An integrated pharmacokinetic-pharmacodynamic (PK-PD) model was developed to describe and characterize the effects of i.v. and s. c. administration of alprazolam. The onset, peak and disappearance of alprazolam effects were evaluated during a 3-hr session. After s. c. alprazolam administration, two peak increases in shorter-response rate occurred at moderate alprazolam serum levels, first in the ascending and then in the descending limb of the concentration-time profile. We used a stimulation-sedation PD model incorporating two opposing effect-link sigmoidal Emax functions to model the two peaks after s.c. alprazolam administration. The model suggested that alprazolam possesses both stimulatory and sedative effects in a continuous but sequential fashion, which corresponded to low- and high-concentration effects as indicated by the EC50 values of 0.09 and 0.18 microg/ml, respectively. Owing to the rapid onset of i.v. administration, the first peak (a transition phase before the onset of the sedative effect) was absent, with the presence of the second peak again coinciding with the offset of the sedative effect. The reinforcement rate (IC50 = 0.02 microg/ml) characterized by the indirect response model to account for the initial hysteresis is an index for evaluating the deficit in timing performance. Although the effects of alprazolam can be described in behavioral terms, simultaneous PK-PD optimization numerically defines the performance and hypothesizes the coexistence of stimulation and sedation components for alprazolam. The stimulation-sedation model may help in delineating the possible mechanisms for adverse rebound side effects and of tolerance in humans.

Alprazolam↗
PubMed1998

Effect of venlafaxine on the pharmacokinetics of alprazolam.

Potential pharmacokinetic effects of venlafaxine on alprazolam, a substrate of the cytochrome pigment 450 (CYP) isoenzyme CYP3A4, were investigated in 16 healthy volunteers. A single 2-mg oral dose of alprazolam was combined with steady-state levels of venlafaxine administered orally at 75 mg twice daily. The levels of alprazolam in plasma and of alprazolam, alpha-hydroxyalprazolam, and 4-hydroxyalprazolam in urine were determined. Steady-state venlafaxine and O-desmethylvenlafaxine concentrations in plasma were reached before venlafaxine was coadministered with alprazolam. Coadministering venlafaxine increased the apparent oral clearance and volume of distribution of alprazolam by 36 percent and 9 percent, respectively, and decreased the alprazolam area under the concentration-time curve and half-life by 29 percent and 21 percent, respectively. There were small but statistically significant increases in mean baseline scores for the digit-symbol substitution and symbol copying tests, probably reflecting a time-dependent learning effect. The maximum score decrease from baseline for these two tests also increased, possibly representing an additive effect of alprazolam and venlafaxine. Overall, venlafaxine did not inhibit the CYP3A4-mediated metabolism of alprazolam in vivo, which corroborates other in vitro and in vivo data showing a lack of CYP3A4 inhibition with venlafaxine.

Adolescent↗
PubMed1988

Alprazolam in panic disorder and agoraphobia: results from a multicenter trial. III. Discontinuation effects.

Preliminary reports of discontinuation of alprazolam therapy in patients with panic disorder have revealed worsening of symptoms despite gradual withdrawal of medication. In this study, 126 patients with panic disorder and phobic avoidance received either alprazolam or placebo in doses of 2 to 10 mg daily for eight weeks. The medication was tapered over a period of four weeks, and patients were observed for another two weeks after all medication was discontinued. Sixty of the 63 alprazolam-treated patients and 49 of the 63 placebo-treated patients entered the taper and discontinuation study. After improvement in the active treatment period, the alprazolam-treated group had significant relapse between the first and last week of taper. However, during the second postdiscontinuation week, outcome scores were not significantly different from those of the placebo-treated group who did not deteriorate during taper. Twenty-seven percent of the alprazolam-treated group reported a rebound of panic attacks during taper and 13% reported a rebound of anxiety on the Hamilton Anxiety Scale. No serious or life-threatening withdrawal symptoms were reported, but distinct, transient, mild to moderate withdrawal syndrome occurred in 35% of the alprazolam-treated group and in none of the placebo-treated group. The coexistence of symptom rebound and a withdrawal syndrome occurred in 10% of the alprazolam-treated group, but both subsided by the end of the second week without alprazolam. We recommend that patients with panic disorder be treated for a longer period, at least six months, and that medication be tapered over a more prolonged period, at least eight weeks, especially where high doses are employed.

Adult↗
PubMed1989

Clinical and medication outcome after short-term alprazolam and behavioral group treatment in panic disorder. 2.5 year naturalistic follow-up study.

Sixty patients with agoraphobia with panic attacks or panic disorder who completed a 4-month combined drug and behavioral group treatment program and were discharged on a regimen of alprazolam were interviewed 1.7 to 4 years (mean, 2.5 years) after discharge. At follow-up (FU), 18 (30%) of the patients had discontinued alprazolam treatment, 36 (60%) continued with a lower dose, 3 (5%) received the same dose, and 3 (5%) received an increased dose compared with discharge. A lower frequency of panic attacks at admission was associated with an increased ability to discontinue alprazolam treatment. There was little evidence of tolerance to the antipanic effects of alprazolam. Panic attack frequency dropped from a mean of 4.4 attacks per week at admission to 1.2 attacks per week at discharge and remained decreased at 1.6 attacks per week at FU. Treatment gains in the program were maintained or enhanced on 11 of 14 behavioral measures at FU and were similar in the groups that were receiving and not receiving alprazolam. Patients receiving nonpharmacologic therapy in the FU period tended to have greater symptom severity, possibly due to self-selection. A lifetime diagnosis of major depression at admission was associated with higher levels of depressive and anxiety symptoms and higher alprazolam doses at FU. Episodes of major depression were common in the FU period and did not appear to be prevented by initial alprazolam and behavioral therapy or by low-dose alprazolam maintenance.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Acute effects of the anxiolytics suriclone and alprazolam on cognitive information processing utilizing topographic mapping of event-related brain potentials (P300) in healthy subjects.

In a double-blind, placebo-controlled, cross-over study, acute effects of suriclone--a cyclopyrrolone derivative--were investigated by means of topographic mapping of event-related potentials (ERPs). Fifteen normal volunteers, aged 22-35 years, received randomized, oral single doses of placebo, 0.1 mg, 0.2 mg and 0.4 mg suriclone and 1 mg alprazolam as a reference compound. ERPs were investigated in an auditory oddball paradigm before and 3 h after intake of each drug. In addition to 17 EEG leads, vertical and horizontal electro-oculograms (EOGs) were recorded. After EOG minimization and artifact identification, the peak latencies of the spatial average were determined by an automatic procedure. Compared to placebo, no significant effects of the low and middle doses of suriclone on N1 amplitude were observed; the highest dosage reduced N1 amplitude, as did 1 mg alprazolam to an even greater extent. While no consistent effects on P2 amplitude were observed after suriclone, alprazolam reduced P2 amplitude. P300 amplitude was reduced only after the highest dosage of suriclone, but much more so after alprazolam. P300 latency was not affected significantly by suriclone, but a marked prolongation of P300 latency was observed after 1 mg alprazolam. Concerning N1 and P2 effects, alprazolam, but not suriclone, may have an inhibitory influence on stimulus-induced cortical arousal. Concerning P300 effects, the used doses of suriclone were superior to 1 mg alprazolam, which seemed to have reduced cognitive information processing capacity and prolonged stimulus evaluation time. Self-rated well-being (adjective checklist) showed subtle beneficial effects after 0.1 mg and 0.2 mg, but marked sedative effects after both 0.4 mg suriclone and 1 mg alprazolam.

Adult↗
PubMed1994

A pharmacokinetic and pharmacodynamic evaluation of the combined administration of alprazolam and fluvoxamine.

We have assessed the pharmacokinetic and pharmacodynamic interaction between fluvoxamine, a serotonin reuptake inhibitor, and alprazolam, a triazolobenzo-diazepine. Healthy men took fluvoxamine maleate daily for 10 days (50 mg on days 1-3, 100 mg on days 4-10) (n = 20), 1 mg of alprazolam four times daily for four days (days 7-10 of the study period) (n = 20), or a combination of the two (n = 20), according to a parallel study design. Alprazolam and fluvoxamine concentrations were measured in serial plasma samples by HPLC and gas chromatography respectively, and psychomotor performance and memory were assessed on days 1, 7, and 10. Fluvoxamine increased plasma alprazolam concentrations by 100%. The mean apparent half-life of alprazolam was increased from 20 h to 34 h after fluvoxamine co-administration. The increased plasma concentrations of alprazolam resulted in significantly greater reductions in psychomotor performance evident on day 10. Mean fluvoxamine plasma concentrations were about 25% lower in those who took the combination than in those who took only fluvoxamine; this was more likely due to heterogeneity between the treatment groups than to an effect of alprazolam. The dosage of alprazolam should be reduced during co-administration with fluvoxamine.

Adult↗
PubMed2000

Increased sensitivity to alprazolam in females with a paternal history of alcoholism.

RATIONALE: Few studies have directly examined the effects of benzodiazepines in individuals with a family history of alcoholism, particularly women, to determine whether they are differentially sensitive to their effects. OBJECTIVES: To determine whether females with a confirmed paternal history of alcoholism (FHP; n=14) were differentially sensitive to the mood and performance effects of alprazolam and buspirone compared with females without a first-degree family history of alcoholism (FHN; n=14). METHODS: The acute effects of placebo, alprazolam (0.25, 0.50, 0.75 mg), and buspirone (5, 10, 15 mg) were evaluated using a double-blind, placebo-controlled outpatient design. Drug effects were assessed using performance tasks, observer ratings of drug effect, and subjective ratings of mood, drug strength, and drug liking. RESULTS: Alprazolam impaired performance in a dose-related manner on all performance tasks for both groups of females, whereas buspirone had minimal effects on performance. The highest dose of alprazolam impaired the response to the digit symbol substitution test (DSST), digit recall, and word memory more in FHP females than in FHN females. Further, performance on the DSST and immediate word recall was able to accurately predict family history status. Correspondingly, FHP women reported greater increases in "difficulty concentrating" and "unmotivated" and greater decreases in items such as positive mood following alprazolam than FHN women. In contrast, alprazolam produced similar dose-related increases in subject-rated and observer-rated drug strength ratings in both groups of females. Lastly, there was no evidence of an increase in ratings of drug liking in either group following alprazolam. CONCLUSIONS: In contrast to many previous findings with FHP males, these results suggest that FHP females may be more sensitive to the performance-impairing effects and negative subjective effects of alprazolam.

Affect↗
PubMed2000

A comparison of plasma alprazolam concentrations following different routes of chronic administration in the Sprague-Dawley rat: implications for psychotropic drug research.

RATIONALE: Benzodiazepines are effective in the treatment of anxiety disorders over a prolonged period of time. This results in relatively stable plasma concentrations over the course of a day. However, due to differences in drug clearance in rats, which generally metabolize and clear drugs much more rapidly than humans, it is difficult to model this steady level in rats. OBJECTIVES: Several methods of chronic alprazolam administration were compared to determine which would best result in reproducible, therapeutically relevant levels of the drug. METHODS: Male Sprague-Dawley rats were administered alprazolam via two subcutaneous routes, Alzet 2ML2 osmotic minipumps and commercially produced slow-release pellets, for 1 week and 2 weeks, respectively. Additionally, alprazolam was orally administered for 2 weeks by mixing the compound into a commercially available liquid, fat emulsion-based diet. The use of silastic implants to deliver several different benzodiazepines was also evaluated in vitro. RESULTS: Following 7 days of alprazolam administration at 2 mg/kg per day via osmotic minipump, plasma concentrations in ten identically treated rats ranged from <1 ng/ml to 97 ng/ml. Slow-release pellets produced more consistent plasma concentrations, but were only minimally effective at raising plasma concentrations. In vitro studies utilizing silastic implants containing 90 mg drug in 6 cm of tubing revealed stable release of only 45-55 microg/day alprazolam versus 625-650 microg/day diazepam. In contrast to these methodologies, incorporation of alprazolam into a commercially available liquid diet (approximately 25-150 mg/kg per day) provided consistent, dose-dependent increases in plasma concentrations of alprazolam and its metabolites in a range appropriate for mimicking clinical exposure. CONCLUSIONS: These findings indicate that the most effective technique to produce plasma concentrations of alprazolam that are reproducible, clinically pertinent, and consistent between rats is to incorporate the drug into a liquid diet. These findings may also be of value in determining dosing routes for other benzodiazepines or psychotropic drugs.

Alprazolam↗
PubMed2001

Alprazolam withdrawal and tolerance measured in the social conflict test in mice.

RATIONALE: It is difficult to assess withdrawal from benzodiazepines, and preclinical assessment of behaviour during social conflict offers the opportunity to quantify tolerance and withdrawal by measuring aggressive, defensive and social behaviour. The relationship between benzodiazepine withdrawal symptoms and the development of tolerance is not well understood. Are withdrawal symptoms dependent on the development of tolerance? OBJECTIVE: The aim of the present study was to compare the development of tolerance to alprazolam effects on the behavioural repertoire during the social conflict test in mice, and to determine whether or not behavioural changes during alprazolam withdrawal are correlated with the development of tolerance. METHODS: An experimental model consisting of interactions of pairs of singly housed male mice with non-aggressive group-housed male mice was used. Alprazolam (1 mg/kg) was given orally once or repeatedly (twice daily) for 8 or 21 days. Behaviour was measured, based on videoanalysis, in aggressive mice before treatment, 30 min or 3 days after the last dose, respectively. RESULTS: A single administration of alprazolam significantly reduced aggressive activities and increased social investigation without changing locomotion or other behaviour. Tolerance developed to the inhibitory effects of alprazolam on aggressive behaviour but not to the effects of alprazolam to increase social investigation. When withdrawn from alprazolam, mice exhibited less social investigation and locomotion while aggression tended to be increased. CONCLUSIONS: Tolerance to the alprazolam effects on aggressive and social behaviour developed at different rates suggesting that they are differentially regulated. Furthermore, the evidence of withdrawal responses appearing in a behaviour to which tolerance had not developed does suggest that tolerance and withdrawal phenomena are dissociated in benzodiazepines.

Alprazolam↗
PubMed1993

The effects of alprazolam on corticotropin-releasing factor neurons in the rat brain: implications for a role for CRF in the pathogenesis of anxiety disorders.

Considerable evidence indicates that corticotropin-releasing factor (CRF) is responsible for integrating not only the endocrine, but the autonomic and behavioral responses of an organism to stress. We have investigated the effects of the anxiolytic triazolobenzodiazepine, alprazolam, on the activity of the hypothalamic-pituitary-adrenal (HPA) axis and of CRF neurons following acute and chronic administration. In addition, because many of the signs and symptoms observed in animals and humans following abrupt discontinuation of benzodiazepines resemble those of the stress response, we examined the effect of alprazolam withdrawal on CRF neurons and HPA axis activity. Alprazolam decreases CRF concentrations in the locus coeruleus 0.5-3.0 hours following acute injection. Similarly, chronic (14 days) alprazolam administration also results in decreased CRF concentrations in the locus coeruleus. CRF concentrations return to control values 24 hours following abrupt alprazolam withdrawal. Moreover, abrupt alprazolam withdrawal results in increased plasma ACTH and corticosterone concentrations and decreased anterior pituitary CRF receptor concentrations 24 hours following drug discontinuation. Thus, abrupt alprazolam withdrawal profoundly activates the HPA axis. These indices of HPA axis activity return to control values by 48 hours post-withdrawal. These actions of alprazolam on CRF neurons are opposite to those observed following acute or chronic stress. These results support the hypothesis that CRF-containing neurons innervating the locus coeruleus may be involved in the pathogenesis of anxiety, and in the actions of clinically efficacious anxiolytics.

Alprazolam↗
PubMed1990

Chronic administration of benzodiazepines--V. Rapid onset of behavioral and neurochemical alterations after discontinuation of alprazolam.

Discontinuation of chronic treatment with alprazolam may cause a characteristic clinical syndrome. To assess the basis of this syndrome, mice were treated with alprazolam, 2 mg/kg, for 7 days, a regimen associated with the development of tolerance and downregulation of receptors. Effects on motor activity and the binding and function of GABA receptors were evaluated 1, 2, 4 and 7 days after discontinuation. Motor activity was similar to controls 1 day after cessation of alprazolam, increased from days 2 to 4 after-alprazolam, and returned to control values by 7 days. The binding of benzodiazepines in vivo and in vitro was increased in the cortex 2 and 4 days after alprazolam and in the hypothalamus at 4 days after alprazolam. Binding returned to control values in all areas by 7 days. Binding at the chloride channel, using [35S]t-butylbicyclophosphorothionate, was not significantly altered after discontinuation. Muscimol-stimulated uptake of [36Cl-] in cortical synaptoneurosomes was increased at 4 days after alprazolam, compared to days 1, 2 and 7. Thus, behavioral and neurochemical alterations was associated with the discontinuation of alprazolam. These alterations were qualitatively similar to those observed following discontinuation of lorazepam but occurred more rapidly and with differing regional specificity.

Alprazolam↗
PubMed1988

Low-dose alprazolam augments motor activity in mice.

The triazolobenzodiazepine alprazolam appears to have a unique clinical spectrum, and recent studies indicate unusual binding properties at the benzodiazepine receptor when assessed in vivo at low doses (0.02-0.05 mg/kg). To assess the behavioral activity of alprazolam at low doses, we examined open-field activity after one hour in mice treated with alprazolam, triazolam, and clonazepam. Following triazolam and clonazepam administration, open-field activity decreased in a dose-dependent fashion. In contrast, low doses of alprazolam resulted in an increase in open-field activity, whereas higher doses decreased activity. For all three drugs, activity was linearly related to receptor binding. Pretreatment with a dose of the benzodiazepine antagonist Ro15-1788 sufficient to fully occupy receptors had no effect on open-field activity, but when administered concurrently with alprazolam (0.05 mg/kg) prevented the increase in activity seen with alprazolam alone. Increased open-field motor activity represents a behavioral correlate to the increases in receptor binding seen with low-doses of alprazolam. Changes in activity appear to be mediated at the benzodiazepine receptor, since an antagonist prevents increased activity. These data suggest that the unique clinical effects of alprazolam may be due in part to unusual interactions with the benzodiazepine receptor.

Alprazolam↗
PubMed1995

Benzodiazepine sensitivity in panic disorder: effects of chronic alprazolam treatment.

The aim of the current study was to determine the degree to which patients with panic disorder develop tolerance to subjective and physiological effects of benzodiazepine after chronic treatment with alprazolam. Response to acute administration of diazepam was assessed in 19 panic disorder patients receiving chronic treatment with alprazolam and 23 untreated panic disorder patients. At baseline in the laboratory, the two groups did not differ in peak saccadic eye movement velocity, saccade latency, short-term memory, plasma cortisol and growth hormone concentrations, heart rate, and self-rated levels of sedation and anxiety. Compared with untreated patients, alprazolam-treated patients displayed significantly less diazepam-induced change in peak saccadic velocity, saccade latency, growth hormone secretion, memory, and self-rated levels of sedation. There was no difference between groups in diazepam effects on plasma cortisol concentrations or self-rated anxiety. Within alprazolam-treated patients, diazepam-induced slowing of peak saccade velocity was significantly inversely correlated with illness severity, as measured by reported panic attacks per week and severity of phobic avoidance, but not with alprazolam dose, blood level, or duration of treatment. Because the alprazolam-treated group reported more panic attacks per week than the untreated panic patients, treated patients were divided into those who were asymptomatic versus those with continuing panic attacks. The subgroup of nine alprazolam-treated subjects who were asymptomatic also showed significantly less diazepam effects than the group of untreated panic disorder patients, suggesting that overall group differences were at least partially attributable to the development of tolerance to selected benzodiazepine effects with chronic alprazolam treatment.

Adult↗
PubMed1999

Discriminative stimulus properties of mCPP and alprazolam are not mediated by anxiety.

We investigated whether the interoceptive cues mediated by the anxiolytic benzodiazepine receptor agonist alprazolam and the anxiogenic serotonin (5-HT)(1B/2C) receptor agonist 1-(3-chlorophenyl)piperazine (mCPP) in rats are related to anxiety. mCPP-induced anxiety in humans can be blocked with alprazolam, and if mCPP drug discrimination is to be used as a model of anxiety, mCPP's stimulus should be blocked by alprazolam. Therefore, two groups of rats were trained to discriminate either alprazolam (2 mg/kg, p.o.) or mCPP (2 mg/kg, p.o.) from vehicle in a two-level operant drug discrimination procedure. Cross antagonism tests were performed with alprazolam and mCPP. mCPP did not antagonize alprazolam's stimulus to any extent, but disrupted responding severely. Low and intermediate doses of alprazolam (1.0-4.0 mg/kg, p.o.) did not antagonize the mCPP discriminative stimulus; only a high dose of 8.0 mg/kg (p.o.) partially antagonized mCPP but disrupted responding in most of the animals. We conclude that, at best, there is only weak evidence to suggest that the interoceptive cues of alprazolam and mCPP are mediated by modulation of anxiety processes, and that the mCPP drug discrimination as a model for anxiety is unreliable.

Alprazolam↗
PubMed1997

Alprazolam, diazepam, yohimbine, clonidine: in vivo CA1 hippocampal norepinephrine and serotonin release profiles under chloral hydrate anesthesia.

1. Although the GABA-A receptor complex has been the main focus of anti-anxiety therapy, the neural interaction in the septohippocampal circuit between GABA-A and the neurotransmitter, 5-HT, compels a study of the monoamine, 5-HT, in anxiety as well. 2. Neurochemistry for anxiety is also intimately involved with the neurotransmitter, NE. Indeed, 5-HT is a component of the dorsal ascending noradrenergic bundle and both neurotransmitters, NE and 5-HT, have been implicated in clinical depression. 3. In vivo microvoltammetric studies were performed using miniature carbon based sensors to detect NE release and concurrent 5-HT release, with 2 separate neural electrochemical signals, within CA1 region of hippocampus, in the chloral hydrate anesthetized rat. 4. Time course studies showed that both the triazolobenzodiazepine (TBZD), alprazolam, and the benzodiazepine (BZD), diazepam, decreased hippocampal NE release. 5. The in vivo and on line neurochemical profile of hippocampal 5-HT release for alprazolam differed from that of diazepam, i.e. alprazolam increased hippocampal 5-HT release, whereas diazepam decreased hippocampal 5-HT release. 6. Time course studies showed that the alpha 2-adrenergic antagonist, yohimbine, an anxiogenic agent, increased both NE and 5-HT release in CA1 region of hippocampus; the alpha 2-adrenergic agonist, clonidine, decreased NE release and increased 5-HT release in the same region. 7. Neither the profile for the TBZD, alprazolam, nor that of the BZD, diazepam, mimicked the neurochemical profile for the anxiogenic agent, yohimbine; the neurochemical profile for the TBZD, alprazolam, was similar to that of the alpha 2-adrenergic agonist, clonidine. 8. Interestingly, alprazolam's hippocampal 5-HT/NE interaction is similar to clonidine's 5-HT/NE action at alpha 2-adrenergic autoreceptors, resulting in enhanced 5-HT release. 9. Enhanced 5-HT release in hippocampus, exhibited by the atypical TBZD, alprazolam, and not by the typical BZD, diazepam, may be an underlying mechanism for the antidepressant activity exhibited by alprazolam.

Adrenergic alpha-Antagonists↗
PubMed1999

Biotransformation of alprazolam by members of the human cytochrome P4503A subfamily.

1. To aid in the prediction of drug interactions with alprazolam, the human CYP involved in the 1'- and 4-hydroxylation of alprazolam were characterized using human liver microsomes, expressed enzymes and selective chemical inhibitors. 2. The formation of 4-hydroxyalprazolam and 1'-hydroxyalprazolam at an alprazolam concentration of 62.5 microM were reduced by the prototypic CYP3A inhibitor, troleandomycin (50 microM), by 97 and 9900 respectively. Only microsomes from B-lymphoblastoid cells expressing CYP3A4 were capable of catalysing the 1'- and 4-hydroxylation of alprazolam. 3. The formation rates of 1'-hydroxyalprazolam and 4-hydroxyalprazolam at an alprazolam concentration of 1 mM were significantly correlated (n = 19, r = 0.95, p<0.01) indicating that the same enzyme(s) mediated these biotransformations. A significant (p<0.01) correlation was observed between alprazolam 4- and 1'-hydroxylase activity and CYP3A-mediated midazolam 4-hydroxylase, midazolam 1'-hydroxylase, dextromethorphan N-demethylase and erythromycin N-demethylase activities. 4. In conclusion, in adult human liver the CYP3A subfamily members are the principal enzymes involved in the 1'- and 4-hydroxylation of alprazolam. Thus, clinically significant drug drug interactions between alprazolam and other CYP3A substrates are to be expected.

Alprazolam↗