Spontaneous activity as a contingency-controlled behavior within an operant context: alprazolam concentration-effect relations after subcutaneous administration in rats

RATIONALE: Environmental factors affect serum drug concentration-effect relations. For example, after midazolam administration, longer pre-session delays imposed in experimental chambers produced differential concentration-effect relations compared to those of shorter delays. OBJECTIVES: To evaluate the extent to which serum concentrations determine alprazolam's effects on spontaneous activity in the presence and absence of a differential reinforcement of low rate (DRL 45-s) contingency using pharmacokinetic-pharmacodynamic analysis. Serum concentrations reported here were simulated from our published pharmacokinetic parameters for alprazolam. METHODS: One group (n=8) was used to investigate alprazolam's effects on spontaneous activity within the DRL contingency by placing an activity platform beneath each operant chamber to monitor concurrently both spontaneous activity (large and small movements) and DRL performance (shorter-response and reinforcement rates) in 3-h sessions; a parallel group (n=7) was used without the operant context. The concentration-effect relation of the reinforcement rate was compared and contrasted with those of spontaneous activity. RESULTS: Alprazolam decreased large and small movements within the DRL contingency, which corresponded to that of reinforcement rates under the DRL 45-s schedule. In contrast, without the DRL contingency, alprazolam's effects on small movements were short-lived (i.e., 30 min) and no effects on large movements were detected. Hence, the predicted concentration-effect relations for the reinforcement rate function described those of spontaneous activity well within the operant context, but not those without the operant context. Furthermore, the latter showed no correlation between serum alprazolam concentration and large movements; a significant, but low negative correlation for small movements was observed. CONCLUSIONS: The duration of alprazolam's action was dependent on not only dose size but also the behavioral measure examined. By imposing the DRL contingency, spontaneous activity behaves as an ideal pharmacodynamic measure (i.e., continuous, sensitive, and objective).     

Effects of alprazolam and imipramine on parasympathetic cardiac control in patients with generalized anxiety disorder

A noninvasive measure was used to assess the effects of alprazolam, imipramine and placebo on parasympathetic (vagal) cardiac control following 6-weeks of medication in patients with generalized anxiety disorder. Flexible dosage at therapeutic levels resulted in increased heart rate and blood pressure and in decreased cardiac vagal control in patients receiving imipramine but not alprazolam or placebo. About 50% of the variance in heart rate changes and changes in mean arterial blood pressure following treatment with imipramine could be accounted for by changes in cardiac vagal control. Decreased cardiac vagal control can now be added to the list of cardiovascular changes seen following several weeks of treatment with imipramine.     

Precipitated withdrawal in squirrel monkeys after repeated daily oral administration of alprazolam,diazepam, flunitrazepam or oxazepam

The lowest dose of alprazolam, diazepam, flunitrazepam and oxazepam consistently to induce loss of righting reflex in squirrel monkeys or vehicle was orally administered to monkeys on 18 consecutive days: 2 mg/kg alprazolam (n=4), 30 mg/kg diazepam (n=4), 1 mg/kg flunitrazepam (n=4), 280 mg/kg oxazepam (n=5), or vehicle (n=4). Tolerance developed rapidly for loss of righting reflex, more slowly for sleep and only minimally for muscle relaxation observed during the period immediately following daily oral administration. Injection of the specific benzodiazepine receptor antagonist flumazenil (10 mg/kg IV) 5 h after the ninth daily oral treatment produced signs of precipitated withdrawal (tremor, vomiting and/or convulsions) in one alprazolam-, four diazepam-, one flunitrazepam- and four oxazepam-treated monkeys, but not in the vehicle-treated monkeys. Physiological saline injected intravenously several days later under these same experimental conditions failed to provoke a precipitated withdrawal reaction. When flumazenil-induced precipitated withdrawal was again evaluated after the 18th daily oral treatment, withdrawal signs were observed in all alprazolam- and all diazepam-treated monkeys, as well as in three flunitrazepam- and three oxazepam-treated monkeys, but not in the vehicle-treated monkeys (convulsions were observed in one alprazolam-, two diazepam-, one flunitrazepam- and two oxazepam-treated monkeys). No signs of spontaneous withdrawal were observed in any of the monkeys during a subsequent 3-week drug-free period. Thus, repeated administration of approximately equieffective doses of these four benzodiazepines resulted in a similar development of tolerance and physical dependence (indicated by the occurrence of a precipitated withdrawal reaction).     

Pharmacokinetics and pharmacodynamics of alprazolam after oral and IV administration

Six fasting male subjects (20–32 years of age) received an oral tablet and an IV 1.0-mg dose of alprazolam in a crossover-design study. Alprazolam plasma concentration in multiple samples during 36 h after dosing was determined by electron-capture gas-liquid chromatography. Psychomotor performance tests, digit-symbol substitution (DSS), and perceptual speed (PS) were administered at 0, 1.25, 2.25, 5.0, and 12.5 h. Sedation was assessed by the subjects and by an observer using the Stanford Sleepiness Scale and a Nurse Rating Sedation Scale (NRSS), respectively. Mean kinetic parameters after IV and oral alprazolam wre as follows: volume of distribution (V _d) 0.72 and 0.84 l/kg; elimination half-life (t _1/2) 11.7 and 11.8 h; clearance (Cl) 0.74 and 0.89 ml/min/kg. There were no significant differences between IV and oral alprazolam in V _d, t _1/2, or area under the curve. The mean fraction absorbed after oral administration was 0.92. Performance on PS and DSS tests was impaired at 1.25 and 2.5 h, but had returned to baseline at 5.0 h for both treatments. Onset of sedation was rapid after IV administration and the average time of peak sedation was 0.48 h. Sedation scores were significantly lower during hour 1 after oral administration than after IV, but were not significantly different at later times. Alprazolam is fully available after oral administration and kinetic parameters are not affected by route of administration. With the exception of rapidity of onset, the pharmacodynamic profiles of IV and oral alprazolam are very similar after a 1.0-mg dose.     

Influence of alprazolam on opioid analgesia and side effects during steady-state morphine infusions

The primary purpose of this study was to examine whether alprazolam pretreatment can increase the analgesic potency of morphine without increasing opioid side-effect intensities. We employed computer-controlled, variable-rate morphine infusions based on each subject's pharmacokinetic profile for morphine derived from a tailoring bolus dose of the drug administered 1 or 2 weeks before the infusion test sessions. On each of 2 test days, we used dental electrical stimulation to determine stimulus intensity that produced consistent reports of strong (but tolerable) pain; this intensity was used for the rest of that session. Then, we measured baseline (no drug) pain intensity reports, pain-related evoked potentials recorded from vertex, and other parameters typically affected by opioids (subjective side effects). We administered alprazolam (1 mg) or placebo (lactose) orally to the subject and then repeated the test battery 30 min later. One hour after the alprazolam or placebo dose, we initiated the tailored morphine infusion to reach target plasma morphine concentration plateaus of 16, 32 and 64 ng/ml (45-min duration each) on both test days. The test battery used during baseline was then repeated at each target concentration plateau. The order of alprazolam versus placebo pretreatments was counterbalanced across subjects and known only to the investigator operating the infusion system. Results suggest that alprazolam at the dose studied did not alter analgesic potency of morphine. However, alprazolam did clearly decrease the intensity of nausea reported by subjects during and after termination of the morphine infusions. Of special interest, alprazolam alone (30 min after oral dosing) decreased evoked potential amplitude consistently without affecting pain intensity reports. This unexpected finding suggests that stimulated-related evoked potential amplitude is not an obligatory correlate of experimental pain perception.     

Dose-dependent effects of intravenous alprazolam on neuroendocrine,biochemical, cardiovascular,and behavioral parameters in humans

Neuroendocrine, biochemical, cardiovascular, and behavioral parameters were assessed in seven normal volunteers for 2 h after intravenous administration of alprazolam (APZ). Three doses of APZ (0.003, 0.007, and 0.02 mg/kg) were administered to each subject in a random order with at least 4 days between infusions. Plasma growth hormone and sedation increased in a dose dependent manner after APZ, and there was a dose dependent change in the shape of the cortisol response to APZ. No dose-response relationships were evident for plasma ACTH and norepinephrine. These differences in dose-response relationships may reflect the involvement of multiple systems in controlling neuroendocrine, biochemical, and subjective responses to APZ infusion. The optimal dose of APZ needed to produce a neuroendocrine or behavioral change appears to differ depending on the parameter of interest.     

Attenuation of the hypothalamic-pituitary-adrenal axis responsivity to the Trier Social Stress Test by the benzodiazepine alprazolam

Little is known about effects of commonly used anxiolytic drugs on psychologically evoked responses of two major stress systems, the hypothalamic–pituitary–adrenal (HPA) and the sympathetic–adrenal–medullary (SAM) axis. The purpose of the present study was to assess effects of the anxiolytic alprazolam on responses of the HPA and the SAM axes to a standardized psychosocial stress protocol, the Trier Social Stress Test (TSST). Forty-six healthy, non-smoking, non-medicated males, aged between 18 and 45 years, were invited once to the laboratory and received a single oral dose of 1 mg alprazolam or placebo, respectively, 1 h prior to the TSST. The secretion of ACTH, cortisol, epinephrine, norepinephrine as well as changes in heart rate, blood pressure, and psychological states (anxiety, wakefulness, good mood, calmness) in response to the TSST were measured. Subjects pre-treated with alprazolam showed a strongly blunted response of ACTH as well as total and free cortisol to the TSST. Whereas alprazolam-treated subjects displayed significantly lower systolic blood pressure immediately before the TSST, neither the secretion of epinephrine, norepinephrine nor changes of heart rate in response to the stress test differed from placebo-treated subjects. Regarding psychological parameters, alprazolam clearly decreased subjective ratings on the questionnaire scale “wakefulness” and increased ratings on the scale “good mood”, whereas ratings on scales assessing “state anxiety” or “agitation” were not affected.

In healthy subjects, we observed a dissociation of the effects of alprazolam on the endocrine and the autonomic response to psychosocial stress. The psychological responses seemed to be masked by sedative properties of alprazolam.     

Benzodiazepines medazepam and midazolam are activators of pregnane X receptor and weak inducers of CYP3A4: Investigation in primary cultures of human hepatocytes and hepatocarcinoma cell lines

Benzodiazepines have wide-spread used in pharmacotherapy for their anxiolytic, myorelaxant, hypnotic, amnesic and anticonvulsive properties. Despite benzodiazepines are used in clinics over 50 years, they have not been surprisingly tested for capability to induce major drug-metabolizing cytochromes P450. In the current study, we have examined the potency of Alprazolam, Bromazepam, Chlordiazepoxide, Clonazepam, Diazepam, Lorazepam, Medazepam, Midazolam, Nitrazepam, Oxazepam, Tetrazepam and Triazolam to induce CYP1A2 and CYP3A4 in primary cultures of human hepatocytes. Benzodiazepines were tested in therapeutic concentrations and in concentrations corresponding to their plasma levels in intoxicated patients. We found weak but significant induction of CYP3A4 mRNA by Midazolam and Medazepam, while other benzodiazepines did not induce CYP3A4 expression. None of the tested compounds induced CYP1A2 mRNA in three independent human hepatocytes cultures. In addition, employing gene reporter assays with transiently transfected hepatocarcinoma cells, we found that tested benzodiazepines did not activate aryl hydrocarbon receptor (AhR), whereas Midazolam and Medazepam slightly activated pregnane X receptor (PXR). Consistently, two-hybrid mammalian assay using hybrid fusion plasmids GAL4-PXR ligand-binding domain (LBD) and VP16-SRC-1-receptor-interacting domain (RID) confirmed PXR activation by Midazolam and Medazepam. In conclusion, Alprazolam, Bromazepam, Chlordiazepoxide, Clonazepam, Diazepam, Lorazepam, Nitrazepam, Oxazepam, Tetrazepam and Triazolam can be considered as safe drugs in term of their inability to induce PXR- and AhR-dependent cytochrome P450 enzymes CYP1A2 and CYP3A4. Medazepam and Midazolam slightly activated pregnane X receptor and displayed weak potency to induce CYP3A4 mRNA in human hepatocytes.     

Acute effects of alprazolam on risky decision making in humans

Rationale GABA-A receptor ligands, including benzodiapines, may induce disinhibitory effects that increase the probability of risky decision making. To date, few laboratory studies have examined the acute, dose-related effects of benzodiazepines on human risk-taking behavior. Recent data indicate that in the United States alprazolam is the benzodiazepine most frequently misused for recreational purposes. Objectives The present study was designed to demonstrate a dose–response relationship between acute alprazolam administration and human risk taking. Furthermore, this investigation sought to examine: (1) the behavioral mechanisms that may be involved in changes in the probability of risky decision making related to alprazolam administration and (2) risk seeking-related personality variables that may predict drug effects on risk taking. Methods Using a laboratory measure of risk taking designed to address acute drug effects, 16 adults were administered placebo, 0.5, 1.0, and 2.0 mg alprazolam in a within-subject repeated-measures design. The risk-taking task presented subjects with a choice between two response options operationally defined as risky and nonrisky. Data analyses examined subjective effects, response rates, distribution of choices between the risky and nonrisky option, trial-by-trial response probabilities, and personality correlates related to drug effects at the 2.0-mg dose. Results Alprazolam administration produced dose-related changes in subjective effects, response rates, and, most importantly, dose-dependently increased selection of the risky response option. The 2.0-mg dose increased the probability of making consecutive risky responses following a gain on the risky response option. Increases at 2.0 mg were related to a combination of personality scales that included high venturesomeness and novelty seeking and low harm avoidance. Conclusions Alprazolam administration produced increases in human risk taking under laboratory conditions. In union with previous studies, the observed shift in trial-by-trial response probabilities suggests that sensitivity to consequences (e.g., oversensitivity to recent rewards) may be an important mechanism in the psychopharmacology of risky decision making. Additionally, risk-seeking personality traits may be predictive of acute drug effects on risk-taking behavior.     

参松养心胶囊配电针治疗焦虑症35例临床分析

目的观察参松养心胶囊配电针治疗焦虑症的临床效果。方法选焦虑症患者75例,随机分为治疗组35例、对照组40例。治疗组口服参松养心胶囊（1.6g,3次/d）,配电针刺激穴位共6周。对照组口服阿普唑仑（0.4～1.6mg,1次/d）共6周。以焦虑自评量表标准分（SAS）为观察指标。结果治疗组治疗后SAS降至（53.54±11.22）;对照组治疗后SAS降至（55.28±12.01）。2组效果差异无统计学意义,但对照组药物依赖性达55%,治疗组无1例成瘾。结论参松养心胶囊配电针治疗焦虑症临床疗效与阿普唑仑相同,但无药物依赖性,值得临床推广。