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Biomedical subjects

D A Ciraulo

Publications and source records attributed to D A Ciraulo.

At least 19 recordsLinked to original sources
PubMed2001

Additive effects of intra-accumbens infusion of the cAMP-specific phosphodiesterase inhibitor, rolipram and cocaine on brain stimulation reward.

Evidence from cocaine self-administration studies suggests that increasing the activity of cyclic AMP (cAMP) pathways within the nucleus accumbens may produce a reduction in cocaine's reinforcing effects. Rolipram may increase intra-cellular levels of cAMP by selectively inhibiting Type IV phosphodiesterases, enzymes that catalyze cAMP breakdown. The present study was undertaken to test the hypothesis that infusion of rolipram into the nucleus accumbens would decrease cocaine-induced enhancement of the sensitivity of brain stimulation reward (BSR) pathways. BSR thresholds were determined in rats after the systemic administration of cocaine (4 mg/kg IP) and the infusion of rolipram (0.2 microg/side) into the nucleus accumbens both alone and in combination. Thresholds also were determined after the systemic administration of rolipram alone and, as a positive control, for amphetamine (10 microg/side) infused into the nucleus accumbens. BSR thresholds were significantly lowered below baseline levels following d-amphetamine administration suggesting that cannulae were in place to allow perfusion of reward pathways. Compared to values for saline alone, thresholds were lower after the injection of cocaine (4 mg/kg IP) or the infusion of rolipram (0.2 microg/side) into the nucleus accumbens. Treatment with the combination of cocaine and intra-nucleus accumbens rolipram produced a greater lowering of the BSR threshold than did administration of either rolipram or cocaine alone. Systemic administration of rolipram (0.5 mg/kg IP) either blocked the effects of BSR or raised BSR thresholds and produced stimulation-induced head jerking in most of the test animals. These results suggest that infusion into the nucleus accumbens of rolipram, an agent that putatively elevates cAMP levels in this structure, can enhance the sensitivity of reward pathways to BSR and can augment cocaine's actions on these pathways.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2001

Adenosine agonists CGS 21680 and NECA inhibit the initiation of cocaine self-administration.

Administration of the adenosine antagonist caffeine will facilitate the reinstatement of cocaine self-administration responding. This suggests that adenosine receptors may play a role in the motivational systems that regulate cocaine-seeking behaviors. If so then adenosine agonists may act to block cocaine self-administration. To test this hypothesis, the effects of the nonselective adenosine agonist NECA and of the A2A selective agonist, CGS 21680 on the self-administration of cocaine were determined. In these experiments, rats were allowed to obtain intravenous cocaine infusions (0.6 mg/kg/infusion) delivered under a Fixed Ratio 5 schedule. Treatment with either NECA or CGS 21680 in comparison to vehicle administration reduced the number of infusions received per session. This, primarily, was due to a marked increase in the latency for delivery of the first cocaine infusion. Responding after drug-induced delays tended to be at control levels. Adenosine agonists are known to have sedative effects and these actions might play a role in NECA and CGS 21680-induced increases in latencies for cocaine delivery. These results indicate that the administration of adenosine agonists may inhibit cocaine-seeking behaviors. The degree to which these actions are on motivational systems as opposed to involving less specific effects remains to be fully elucidated.

Adenosine↗
PubMed2001

A benzodiazepine mood effect scale: reliability and validity determined for alcohol-dependent subjects and adults with a parental history of alcoholism.

The Tufts Addiction Research Center Inventory--Morphine Benzedrine Group (ARCI-MBG) scale was designed to measure benzodiazepine-induced mood elevation. The reliability and validity of the Tufts ARCI-MBG scale were determined in 64 subjects with a history of alcoholism (HA), a positive history of parental alcoholism, defined as one or both parents meeting DSM-III-R criteria for alcohol dependence (PHP), and matched control subjects. Significant correlations were found for within-day Tufts ARCI-MBG scale scores for all groups and for between-day scores for PHP and matched control subjects. Interitem reliability was significant for pooled baseline scores. For HA subjects, correlations between mean Tufts ARCI-MBG scale and Drug Liking scores that were obtained after either alprazolam or diazepam administration were significant. These results suggest that the Tufts ARCI-MBG scale is a reliable test that is a valid measure of benzodiazepine-induced mood elevation.

Adult↗
PubMed2000

Decreased EEG sensitivity to alprazolam in subjects with a parental history of alcoholism.

Altered benzodiazepine sensitivity in subjects with a history of parental alcoholism (PHP) compared to control subjects (NC) has been reported for regional brain blood volume, eye movement tasks, and subjective effects. This study tests the hypothesis that PHP subjects are less sensitive to benzodiazepine effects on EEG activity than are NC subjects. Frontal EEG activity was recorded in PHP and NC subjects after administration of the benzodiazepine, alprazolam (1 mg), or placebo. PHP subjects had decreased sensitivity to the EEG effects of alprazolam compared to NC subjects. Significant differences were detected for change in percent relative beta activity and alpha and theta band power. Pharmacokinetic parameters did not differ significantly between groups. These results suggest that PHP subjects are less sensitive to the effects of alprazolam on central electrophysiological activity than are NC subjects.

Adolescent↗
PubMed1999

The type IV phosphodiesterase inhibitors, Ro 20-1724 and rolipram, block the initiation of cocaine self-administration.

The hypothesis that the selective activation of cyclic AMP (cAMP) signal transduction pathways will suppress the initiation of cocaine self-administration was examined in this investigation. To test this hypothesis, the effects of the administration of the cAMP-specific (type IV) phosphodiesterase inhibitors, rolipram and Ro 20-1724, on cocaine self-administration were determined. The effects of Ro 20-1724 treatment on operant responding for food also were examined. Both cocaine and food were delivered following a fixed-ratio 5 schedule. A significant increase in the latency for the delivery of the first cocaine infusion and a reduction in the number of infusions obtained per session were produced by treatment with either rolipram or Ro 20-1724. Similar effects on responding for food were seen with Ro 20-1724 administration. Responding after drug-induced delays tended to be at control levels. These results suggest that cAMP-specific phosphodiesterase inhibitors may inhibit the initiation of operant responding for either cocaine or food. However, the extent to which these actions involve specific effects on central motivational systems as opposed to other mechanisms remains to be determined.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1998

Functional magnetic resonance imaging of alprazolam-induced changes in humans with familial alcoholism.

This study sought to identify whether subjects with a family history (FH + ) of alcoholism had changes in regional cerebral blood volume (rCBV) after an alprazolam challenge which distinguished them from subjects without a family history (FH -) of alcoholism using functional MRI (fMRI). Twelve FH + and eight FH - subjects were challenged with 1 mg of alprazolam or placebo in a double-blind crossover design. FMRI scans were obtained at baseline, 1 and 2 h after the challenge using the dynamic susceptibility contrast method with gadolinium. Mood scales, the Tufts Addiction Research Center Inventory-Morphine Benzedrine Group Scale and the drug liking scale, were administered every 30 min to assess drug effects. Global analysis of CBV showed a treatment by time decrease on alprazolam relative to placebo, but no effect by family history. The FH + group showed rCBV decreases at 1 h in the left caudate and left inferior prefrontal region, while the FH - group showed rCBV decreases at 2 h in the right inferior prefrontal region and anterior cingulate in response to alprazolam relative to placebo. FH + subjects reported more mood enhancement with alprazolam. This fMRI technique detected global and regional CBV changes induced by alprazolam. The location and rate of alprazolam-induced rCBV changes differed between FH + and FH - subjects. These changes may be related to the increased mood enhancement found in subjects genetically predisposed to alcoholism.

Adult↗
PubMed1998

Appetite suppressant drugs as inhibitors of human cytochromes P450: in vitro inhibition of P450-2D6 by D- and L-fenfluramine, but not phentermine.

The activity of D-fenfluramine, L-fenfluramine, and phentermine as inhibitors of five human cytochromes P450 was evaluated using human liver microsomes in vitro. All three compounds produced negligible inhibition of P450-1A2, -2C9, -2E1, and -3A. Phentermine also did not inhibit P450-2D6. However, D- and L-fenfluramine significantly inhibited P450-2D6 activity as measured by dextromethorphan O-demethylation, with mean 50% inhibitory concentrations (15.1 microM) within one order of magnitude of that for fluoxetine (2.7 microM). Findings from the in vitro assay are consistent with clinical studies showing significant inhibition of desipramine clearance by coadministration of fenfluramine.

Appetite Depressants↗
PubMed1997

Alterations in pharmacodynamics of anxiolytics in abstinent alcoholic men: subjective responses, abuse liability, and electroencephalographic effects of alprazolam, diazepam, and buspirone.

Subjective responses, including those associated with abuse liability and changes in frontal electroencephalographic activity, were assessed in abstinent alcoholic men and control subjects after administration of alprazolam, diazepam, buspirone, and placebo. Plasma concentrations of alprazolam, diazepam, and desmethyldiazepam also were determined. Abuse liability scales were elevated for alcoholic participants above control levels after alprazolam and diazepam. Areas under the concentration-time curve differed only for desmethyldiazepam, which was lower for the alcoholic participants. Compared with control subjects, alcoholic participants had greater declines in the absolute power of the alpha band after diazepam challenge. Alcoholic participants, unlike control subjects, had areas under the effect-time curve for alpha and theta bands that were lower after administration of alprazolam or diazepam than they were after receiving placebo. These results suggest that alprazolam and diazepam are more likely to be abused by alcoholic men than by nonalcoholic men and that alcoholic men have enhanced sensitivity to the effects of benzodiazepines on alpha and theta activity.

Adult↗
PubMed1996

Liability to alprazolam abuse in daughters of alcoholics.

OBJECTIVE: The purpose of this study was to determine mood changes in women with a parental history of alcohol dependence (daughters of alcoholics) after challenge does of alprazolam and placebo in comparison with responses in women without a history of parental alcohol dependence. METHOD: Visual analog scales that assess liability to benzodiazepine abuse were administered to 12 adult daughters of alcoholics and 11 comparison subjects after alprazolam challenge. RESULTS: The daughters of alcoholics had greater pleasant mood responses after a single dose of alprazolam than did the comparison subjects despite having similar plasma alprazolam levels. CONCLUSIONS: The findings of this study suggest that the mood-enhancing effects of alprazolam are greater in daughters of alcoholics than in subjects without a history of parental alcohol dependence.

Adult↗
PubMed1993

A placebo-controlled trial of selegiline (L-deprenyl) in the treatment of tardive dyskinesia.

The goal of this study was to determine whether selegiline (L-deprenyl), a selective monoamine oxidase B inhibitor and antioxidant, would improve neuroleptic-induced tardive dyskinesia (TD). Thirty-three patients with TD were randomly assigned to selegiline 10 mg/day or placebo for 6 weeks and were assessed at baseline and at weeks 1, 2, 4, and 6 for TD, parkinsonism, akathisia, depression, and positive and negative symptoms. Examinations for TD were videotaped and scored by a rater unaware of the temporal sequence of examination. Twenty-eight subjects completed at least 1 week of treatment; all five dropouts were receiving selegiline. When baseline score and gender were controlled, the group receiving selegiline displayed significantly less improvement of TD compared with the placebo group. The two treatment groups did not differ in any other outcome measure. Selegiline was less effective than placebo in reducing symptoms of TD over a 6-week trial. This may be the result of the dopamine agonist effects associated with selegiline.

Adult↗
PubMed1993

Alprazolam pharmacokinetics, metabolism, and plasma levels: clinical implications.

The triazolobenzodiazepine alprazolam is biotransformed by hepatic microsomal oxidation, yielding two hydroxylated metabolites (4-hydroxy- and a-hydroxy-alprazolam) as the principal metabolic products. Both metabolites have lower benzodiazepine receptor affinity than the parent compound and at steady state appear in plasma at concentrations considerably lower than intact alprazolam. Thus, clinical activity during treatment with alprazolam is essentially entirely attributable to intact alprazolam. The cytochrome P450 IIIA subfamily appears to mediate alprazolam metabolism in humans. This cytochrome subfamily is not subject to variation due to genetic polymorphism. Ketoconazole, cimetidine, macrolide antibiotics, and serotonin-reuptake-inhibitor antidepressants impair alprazolam biotransformation in vitro. Reduced clearance of alprazolam in vivo has been demonstrated for drugs in this group that have been studied in humans; for those not yet studied, impaired alprazolam clearance should be anticipated during coadministration. Studies of plasma alprazolam concentration versus clinical response during short-term treatment of panic disorder indicate that therapeutic response at steady-state plasma levels of 20 to 40 ng/mL is significantly greater than at levels less than 20 ng/mL. Substantial additional benefit from plasma levels greater than 40 ng/mL is not consistently demonstrated. However, side effects attributable to benzodiazepine agonist activity (e.g., drowsiness, sedation) increase in frequency with increasing steady-state plasma levels. Concentration-response data indicate that monitoring of alprazolam plasma levels can be of considerable clinical value during treatment of panic disorder.

Alprazolam↗
PubMed1993

Alprazolam and benzodiazepine dependence.

The incidence of nonmedical use of alprazolam is very low relative to its widespread legitimate medical use; in fact, given the millions of patients who have received this medication, the incidence is remarkably small. In particular, among patients with anxiety disorders, dependence does not appear to be a clinically important problem. Alprazolam abuse and dependence represent only a small fraction of the large and serious nonmedical use problem in the United States, and when they occur, are among individuals who abuse other drugs. For example, a serious problem of alprazolam abuse may exist among patients in methadone maintenance treatment. A similar problem exists with diazepam. Alcohol abusers and alcohol-dependent individuals are another group among whom concern about benzodiazepine and alprazolam abuse exists. However, more and better information about the extent and nature of this use is needed. Many patients with alcohol or drug abuse also have anxiety disorders for whom effective pharmacotherapy may be needed. In the interim, caution but not prohibition to use should prevail in prescribing alprazolam to such patients. To the extent that nonmedical alprazolam use exists, evidence suggests that the vast majority of such use is the consequence of the inappropriate prescribing of the medication by a small number of physicians. One way to reduce the inappropriate use of benzodiazepines in methadone programs is to drug test the methadone-maintenance patients and to link positive urine tests to contingency-management strategies. The available data provide some support to the idea that alprazolam and diazepam have more abuse liability than other benzodiazepines.

Adult↗
PubMed1991

Benzodiazepine receptor binding response to acute and chronic stress is increased in aging animals.

Benzodiazepine receptor binding in vivo, as determined by the uptake of the high-affinity specific benzodiazepine receptor ligand [3H]Ro15-1788, was examined following acute and chronic defeat stress in male mice aged 6 weeks, 7 months and 1 year. Specific uptake in 6-week-old mice was increased from control values only in the cerebellum following acute but not chronic stress. Specific uptake in the cortex and hypothalamus was unchanged from control values following both acute and chronic stress. Seven-month-old mice demonstrated an increased specific uptake in the cortex and cerebellum when measured immediately following both acute stress and the final session of chronic stress. This enhanced binding returned to baseline levels by 24 h after stress. One-year-old mice demonstrated no change in specific uptake when measured after acute stress, while binding was enhanced in all brain regions after the final session of chronic stress. This increased binding was still evident at 24 h after the cessation of chronic stress. Changes in benzodiazepine binding differ as a response to acute and chronic stress, and this response varies markedly with age.

Acute Disease↗
PubMed1991

Benzodiazepine response and receptor binding after chronic ethanol ingestion in a mouse model.

Benzodiazepine receptor binding and open-field response were examined in male CD-1 mice after 6 weeks on a liquid diet providing either 36% ethanol or maltose-dextrin derived calories. In vivo binding of [3H]Ro15-1788, open-field activity and cortex and plasma concentrations were measured over a range of clonazepam doses (0.05-2.0 mg/kg). Mean +/- S.D. of ethanol consumption was 19.3 +/- 1.1 g/kg/day. Clonazepam concentration in plasma and cortex was related linearly to dose in both groups. Cortex concentrations exceeded plasma concentrations at all doses. Ethanol-consuming mice showed considerably less decrease in measures of horizontal and stereotypic activity at each dose studied. Mean in vivo IC50 was 20.9 +/- 4.0 ng/g for the control mice and 40.2 +/- 7.6 ng/g (P less than .001) in the ethanol-consuming mice. In vitro binding studies found a marked decrease in maximum binding in cortex (37%) with an increase in Kd (66%). Chronic ethanol can influence the acute effects of single doses of clonazepam and both in vivo and in vitro measures of benzodiazepine receptor binding.

Alcoholism↗
PubMed1990

The relationship of alprazolam dose to steady-state plasma concentrations.

Alprazolam is a widely used antianxiety agent, yet relatively little is known about the relationship between chronic oral doses and steady-state plasma levels. This study examines the relationship over a wide range of therapeutic doses. We conducted a parallel, double-blind, placebo-controlled study in 36 patients with agoraphobia with panic attacks, or panic disorder with limited phobic avoidance based on DSM-III criteria. Patients received alprazolam (N = 25) or placebo (N = 11) beginning at 1 mg/day and increased weekly until either a maximum tolerated dose or 10 mg/day was achieved. Dosages were then gradually tapered according to a predetermined schedule. The entire study period lasted 14 weeks. Laboratory and clinical assessments were conducted weekly. Doses up to 6 mg/day were tolerated by 80% of patients on alprazolam and doses of 10 mg/day were tolerated by 40% of patients. Twenty-seven percent of the placebo patients reached 10 tablets/day. In the alprazolam group, the principal cause of intolerance was sedation. Throughout the study no significant changes in vital signs or laboratory parameters were observed. Steady state alprazolam, 4-hydroxy alprazolam, and alpha-hydroxy alprazolam plasma levels were linearly related to dose. A 1 mg dosage increment produced, on the average, a corresponding 10 ng/ml increase in steady state level of the parent drug. Significant response was observed in subjects who achieved concentrations greater than 20 ng/ml, with a maximum of 81% of the samples classified as responders within the 60 ng/ml and above group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗