D-cycloserine--naloxone interactions in opioid-dependent humans under a novel-response naloxone discrimination procedure.

Six participants currently in opioid maintenance treatment were trained to distinguish between naloxone (0.15 mg/70 kg, intramuscularly [i.mj) and placebo under an instructed novel-response drug-discrimination procedure. Doses of the partial glycine agonist D-cyclostrine (0-500 mg/70 kg, per os [P.O.]) alone and combined with naloxone (0.15 mg/70 kg) were then tested. D-cycloserine alone produced minimal drug-appropriate responding, no significant changes in self-reported effects, and increases only in systolic blood pressure. When combined with the naloxone, D-cycloserine partially attenuated naloxone-appropriate responding. D-cycloserine attenuated naloxone-induced increases in visual analog scale ratings of "like naloxone" and scores on the Lysergic Acid Diethyl Amide subscale of the Addiction Research Center Inventory (D. R. Jasinski, 1977; W. R. Martin, J. W. Sloan, J. D. Sapiro, & D. R. Jasinski, 1971). Naloxone attenuated D-cycloserine-induced increases in systolic blood pressure. These results suggest that D-cycloserine at doses up to 500 mg/70 kg may have some limited usefulness in relieving symptoms of opioid withdrawal. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Hydromorphone-naloxone combinations in opioid-dependent humans under naloxone novel-response discrimination procedure.

Naloxone-hydromorphone combinations were tested in participants trained to discriminate naloxone from placebo under a novel-response drug discrimination procedure while maintained on methadone. Naloxone alone produced dose-related increases in naloxone appropriate responding, little or no "novel"-appropriate responding, and increases in opioid antagonist adjective ratings (n?=?5). Hydromorphone alone produced dose-related increases in novel-appropriate responding, little or no naloxone-appropriate responding, and increases in opioid agonist adjective ratings (n?=?6). When combined with naloxone, hydromorphone produced dose-related decreases in naloxone-appropriate responding and antagonist adjective ratings (n?=?6). These findings are consistent with nonhuman data and suggest that this procedure may be useful as a human laboratory model of opioid withdrawal. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Individual differences in humans responding under a cocaine discrimination procedure: Discriminators versus nondiscriminators.

Twenty-six cocaine-abusing volunteers were trained to discriminate cocaine (80 mg/70 kg, p.o.) from placebo. On the basis of a discrimination acquisition criterion (i.e., >80% drug-appropriate responding for 4 consecutive sessions within 8–10 sessions), 18 participants were classified as discriminators (Ds) and 8 as nondiscriminators (NDs). Relative to Ds, NDs reported a greater amount of cocaine use per time. During the training phase, NDs showed significantly lower ratings than Ds on a stimulant ratings scale, regardless of the training drug condition. During the test-of-acquisition phase, cocaine-induced increases in scores on ratings of drug strength, anxious-nervous and cocaine high, as well as on a euphoria ratings scale, were significantly greater in Ds than NDs, relative to placebo. These results suggest that drug use history, general arousal level, and drug sensitivity may be important variables influencing the acquisition of cocaine versus placebo discrimination in cocaine abusers. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Validation of the multiple-choice procedure for investigating drug reinforcement in humans.

Three experiments demonstrated the validity of studying drug reinforcement in humans by using a novel Multiple-Choice Procedure. The distinguishing characteristic of the procedure is that it arranges intermittent reinforcement for choices between pairs of potential reinforcers (e.g., drug vs. money). A series of manipulations was conducted. the outcomes of which were predicted on the basis of a well-established literature on operant behavior maintained by food and drug. Specifically, the experiments manipulated reinforcer availability (i.e., extinction), deprivation versus satiation, and reinforcer magnitude in cigarette smokers and demonstrated the predicted changes in cigarette reinforcement as measured by the Multiple-Choice Procedure. Finally, the reinforcer magnitude manipulation was concurrently studied using a conventional two-option choice procedure and the results were shown to be virtually identical to those with the Multiple-Choice Procedure. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Secobarbital in humans discriminating triazolam under two-response and novel-response procedures

The percentage of long-term survivors after intensive chemotherapy and the outcome of MDS patients who achieve partial remission (PR) with intensive chemotherapy (IC) are not known. Between 1981 and 1996 we treated 99 patients with de novo MDS who had high-risk MDS or progression to AML, with IC. 41 (41%) achieved CR, 16 (16%) achieved partial remission (PR), 26 (26%) had failure, and 16 (16%) died in aplasia. Eight of the patients who achieved CR were autografted, three were allografted and the remaining cases received moderate consolidation chemotherapy. After IC, the 16 PR patients fulfilled the criteria for RA in 15 cases and CMML in one case. Median PR duration was 17 months, and three PR were > 3 years (39, 50+, 82+ months). Median actuarial survival of patients who achieved PR and CR was 18 months and 20 months from the onset of IC, respectively (difference not significant). Of the 71 patients treated before 1993, with sufficient follow-up, 10 (14%) had survived > 4 years (long-term survivors). Four of them were alive in first CR after 49+ to 110+ months and probably cured, two were alive in PR after 50+ and 82+ months and four had died after 49-78 months. Long-term survivors were characterized by a significantly higher incidence of RAEB-T at diagnosis, and with normal or favourable cytogenetic findings. In patients with RAEB-T at diagnosis included before 1993, 8/23 (35%) cases who had no unfavourable karyotype had survived > 4 years. Our findings suggest that MDS patients who achieve PR with IC, and not only those who achieve CR, can benefit from this type of treatment. The percentage of long-term survivors remains low, however, and is almost restricted to patients with RAEB-T at diagnosis and no unfavourable karyotype.     

Intravenous cocaine discrimination in humans.

Ten cocaine-dependent participants were trained to discriminate between intravenous saline and 20 mg/70 kg cocaine. During the first session, saline and cocaine injections were alternated twice, with each separated by 1 hr. The injections were identified by letter codes. During the next 3 sessions, 12 trials were conducted, with saline and cocaine administered 6 times each in pseudorandom order. Thirty minutes following each injection, participants were asked to identify the injection by letter code. Seven of the 10 learned the discrimination (at least 10 trials correct). To evaluate sensitivity, the investigators tested participants with different doses of cocaine in test sessions. In the next phase, methamphetamine (5 and 10 mg/70 kg) and pentobarbital (50 and 100 mg/70 kg) were given intravenously during test sessions to determine whether the discrimination exhibited pharmacological class selectivity. During the evaluation of sensitivity and selectivity, training sessions were interspersed. As dose of cocaine increased, the number of participants identifying the test dose as cocaine increased, demonstrating sensitivity. The higher doses of methamphetamine and pentobarbital substituted for cocaine. The physiological and subjective effects of cocaine and methamphetamine were stimulant-like and dose related. Pentobarbital produced no physiological changes but increased Visual Analog Scale ratings of Sedation, Good Drug Effect, and High. This failure to demonstrate pharmacological selectivity may be related to participants' learning a drug-vs.-no-drug discrimination, and thus it may be necessary to alter training procedures in future studies. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Discriminative-stimulus effects of zolpidem, triazolam, pentobarbital, and caffeine in zolpidem-trained humans.

Six non-drug-abusing humans were trained to discriminate 15 mg zolpidem in the present experiment. After participants acquired discrimination, a range of doses of zolpidem (2.5–15.0 mg), triazolam (0.0625–0.3750 mg), pentobarbital (25–150 mg), caffeine (100–600 mg), and placebo were tested to determine whether they shared discriminative-stimulus effects with 15 mg zolpidem. The participant-rated and performance-impairing effects of zolpidem, triazolam, pentobarbital, and caffeine were assessed concurrently. Triazolam and pentobarbital dose dependently increased zolpidem-appropriate responding. Caffeine occasioned low levels of zolpidem-appropriate responding. Zolpidem, triazolam, and pentobarbital, but not caffeine, generally produced a similar constellation of participant-rated drug effects (e.g., increased scores for the Pentobarbital, Chlorpromazine, and Alcohol Group subscale on the Addiction Research Center Inventory) and dose dependently impaired performance. These results suggest that humans can reliably discriminate zolpidem. Despite its unique benzodiazepine-receptor binding profile, the discriminative-stimulus, participant-rated, and performance-impairing effects of zolpidem are similar to those of the barbiturates and benzodiazepines. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Acute behavioral effects of triazolam and caffeine, alone and in combination, in humans.

The acute behavioral effects of triazolam (0, 0.375, and 0.75 mg/70 kg) and caffeine (0, 250, and 500 mg/70 kg), alone and in combination, were assessed in 9 male volunteers. Ss received all possible dose combinations according to a Latin square design. Triazolam administered alone dose dependently disrupted learning and performance on the Repeated Acquisition and Performance procedure and the Digit Symbol Substitution Test and increased S ratings of sedation. Caffeine administered alone did not significantly affect learning or performance measures, but it did dose dependently increase S ratings of drug strength. Caffeine significantly attenuated triazolam-induced decrements in learning and performance. Consistent with effects on learning and performance, caffeine offset triazolam-induced increases in S ratings of sedation. Combining caffeine and triazolam did not significantly alter increases in S ratings of drug strength observed with caffeine alone. These effects are qualitatively similar to those observed with other benzodiazepines (e.g., lorazepam) and document a high degree of consistency in the behavioral pharmacology of benzodiazepine-caffeine combinations in humans. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Auditory evoked-response differentiation with discrimination learning in humans.

To examine the possible functional significance of the registration of the salience of stimulus events in the vertex potential, 40 college students were given a discrimination-learning paradigm involving stimuli that were equally informational but of different value. Wave forms were obtained over the entire course of acquistion. Level of discriminative accuracy and extent of evoked-response differentiation were found to be closely related, indicating that differentiation predominantly reflected improvement in the perceptual-cognitive "labeling" of the stimuli. When the identical stimuli served a feedback rather than a cueing role, evoked responses were markedly different, and there was no apparent relationship to accuracy or learning. (26 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cholinergic drug effects on a delayed conditional discrimination task in the rat

The centrally acting cholinergic antagonist scopolamine (0.025-0.10 mg/kg ip) and the peripherally acting cholinergic antagonist methyl-scopolamine (0.01-0.10 mg/kg) dose dependently impaired discriminability independent of delay in a delayed conditional discrimination task that precludes use of mediating behavior. This indicates that scopolamine does not specifically affect working memory. Drugs that enhance cholinergic transmission neither improved discriminability nor attenuated scopolamine-induced impairments. In a post hoc analysis scopolamine was found to impair discriminability in a delay-dependent manner in rats that performed at a high level in pretest sessions. Methyl-scopolamine impaired performance independently of delay in these rats. The authors suggest that a ceiling effect at short delays produced this Drug x Delay interaction of scopolamine in the best performing rats.     

Discriminative-stimulus and participant-rated effects of methylphenidate, bupropion, and triazolam in d-amphetamine-trained humans.

The discriminative-stimulus and participant-rated effects of a range of doses of d-amphetamine (2.5–20 mg), methylphenidate (5–40 mg), bupropion (50–400 mg), and triazolam (0.0625–0.5 mg) were tested in 5 humans trained to discriminate between oral d-amphetamine (20 mg) and placebo. d-Amphetamine and methylphenidate generally dose dependently increased drug-appropriate responding. Bupropion and triazolam on average occasioned less than or equal to 40% drug-appropriate responding. d-Amphetamine, methylphenidate, and bupropion produced stimulant-like participant-rated effects, while triazolam produced sedative-like effects. These results further demonstrate that the acute behavioral effects of d-amphetamine and methylphenidate overlap extensively in humans, which is concordant with preclinical studies. Bupropion produced some d-amphetamine-like, participant-rated drug effects but did not occasion significant levels of d-amphetamine-appropriate responding. These findings are concordant with previous findings of a dissociation between the discriminative-stimulus and participant-rated effects of drugs. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Negative patterning is easier than a biconditional discrimination.

Two groups of rats were trained for 50 days on different discriminations in a magazine approach paradigm. One group was trained with a negative patterning schedule and a positive patterning schedule concurrently: they received intermixed trials of A+, B+, AB-, C-, D-, CD+ (A, B, C, and D are four distinct stimuli; the plus sign denotes reinforcement with food, and the minus sign denotes nonreinforcement). The second group of rats was trained with the same four stimuli arranged as compounds and reinforced according to the biconditional schedule AB+, CD+, AC-, and BD-. The first group learned the positive patterning schedule much more quickly than the negative patterning schedule, but they learned the negative patterning schedule more effectively than the second group learned the biconditional schedule. The authors discuss the implications of these findings for models of stimulus representation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A multidimensional scaling analysis of vowel discrimination in humans and monkeys

Multidimensional scaling (MDS) was used to compare perceptual maps for 10 synthetic English vowels in humans and Old World monkeys (Macaca fuscata and Cercopithecus albogularis). Subjects discriminated among the vowels using a repeating background procedure, and reaction times were submitted to an MDS analysis to derive measures of perceive similarity. The dimensions that emerged related to the frequencies of the first (F1), second (F2), and third (F3) formants. Human data indicated a good match to previous MDS studies using rating procedures or confusion matrices: The dominant dimension mapped onto vowel F2, the phonetically most important formant, and the second and third dimensions mapped onto F1 and F3, respectively. For monkeys, equal weightings occurred for F1 and F2, and F3 was not clearly represented. Monkey sensitivity to the formants appeared to relate to formant amplitudes. If monkeys are giving an accurate representation of the psychoacoustic relations among the formants, then our human results suggest that species-specific mechanisms, reflecting the salience of the phonetic feature of advancement, may contribute to vowel coding in humans.     

Effects of oral cocaine on intravenous cocaine discrimination in humans.

This study was designed to evaluate the drug discrimination paradigm as a model for assessing the ability of potential agonist medications to block the effects of intravenous cocaine. Previous research has demonstrated that oral cocaine attenuated the subjective and physiological effects of intravenous cocaine injections, and in the absence of a known efficacious medication for cocaine use disorders, a proof-of-concept approach was used in which cocaine was acutely administered orally to block intravenous cocaine's discriminative-stimulus effects. During training, 11 cocaine-dependent participants were able to discriminate between intravenous saline and 20 mg/70 kg iv cocaine, and 8 of these participants completed the study. After training, participants ingested capsules containing either placebo or 300 mg/70 kg cocaine 60 min prior to the intravenous injection of different doses of cocaine during test sessions with no contingencies in place. Each cocaine dose was administered twice, once under each oral pretreatment condition. Training sessions were interspersed among the test sessions. Physiological and subjective effects were measured throughout each session. Oral cocaine moderately increased some of the subjective and physiological effects of the lower doses of intravenous cocaine, whereas effects at the higher doses were unaltered. Similar changes were seen for the discrimination results. Thus, although oral cocaine given acutely likely is not a viable treatment medication for cocaine dependence, the usefulness of the drug discrimination model in the evaluation of agonist treatment medications remains unclear. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Viscosity discrimination: a comparison of an adaptive two-alternative forced-choice and an adjustment procedure

Differential thresholds for viscosity were measured in ten subjects with the use of an adaptive two-alternative forced-choice procedure. An electromagnetic linear motor was connected to each wrist and the viscosity of the motors was under computer servo control. For each block of 50 trials the viscosity of one motor was fixed at a reference value which ranged from 4 to 512 N s m-1, and the viscosity of the other motor varied according to the subject's responses. On each trial subjects were required to indicate which motor had the greater viscosity and were given feedback of the correct response. By this procedure the Weber fraction for viscosity was calculated to be 19%, which is lower than the Weber fraction of 34% estimated by using the method of adjustment. The criterion used for determining the threshold differs in the two procedures (71% and 84% correct, respectively), and the results from the two studies were found to be consistent. They suggest that the Weber fraction for viscosity remains remarkably stable despite differences in the methods of measurement.     

Receptive musical aptitude using a binaural frequency discrimination test

Musical aptitude is the most important precondition for any applicant taking up studies at a music conservatory. Thus, the applicants are tested and assessed very thoroughly by experienced music teachers. To support these subjective results by objective data a procedure was developed allowing to test both the examinee's frequency and octave discrimination capacity in a simple way. In a 1-Hz cycle the frequencies f1 and f2 are directed mutually to the right and left ear, respectively, at a defined sound level. Then the examinee is asked to syntonize e.g. frequency equality f1 = f2 (or f1 = 2 x f2). It can be shown that there is a direct correlation between the amount of deviation from nominal frequency and subjective assessment of musicality.     

Zolpidem 10 mg given at daytime is not antagonized by 300 mg caffeine in man

We hypothesized, on the basis of in vitro observations, that a higher oxygen partial pressure within perfluorocarbon-containing microbubbles (PCMB) would enhance inward nitrogen diffusion after venous injection, leading to improved myocardial contrast. The in vitro studies measured PCMB size and concentration after injection into arterial blood that was obtained during inhalation of either room air or 100% oxygen. We then compared the myocardial contrast produced from PCMB sonicated in the presence of either a nitrogen-free environment (100% oxygen) or room air in three closed chest dogs. PCMB exposed to oxygenated blood in vitro were significantly smaller after insonation than PCMB exposed to arterial blood obtained during room air inhalation, confirming the important role of dissolved nitrogen in stabilizing PCMB size. In vivo studies demonstrated that intravenous PCMB sonicated with 100% oxygen produced significantly greater anterior and posterior myocardial contrast than PCMB sonicated in the presence of room air.     

Fos protein expression in the circadian clock is not associated with phase shifts induced by a nonphotic stimulus, triazolam

A mutant human lysozyme, designated as C77A-a, in which glutathione is bound to Cys95, has been shown to mimic an intermediate in the formation of a disulfide bond during folding of human (h)-lysozyme. Protein disulfide isomerase (PDI), which is believed to catalyze disulfide bond formation and associated protein folding in the endoplasmic reticulum, attacked the glutathionylated h-lysozyme C77A-a to dissociate the glutathione molecule. Structural analyses showed that the protein is folded and that the structure around the disulfide bond, buried in a hydrophobic core, between the protein and the bound glutathione is fairly rigid. Thioredoxin, which has higher reducing activity of protein disulfides than PDI, catalyzed the reduction with lower efficiency. These results strongly suggest that PDI can catalyze the disulfide formation in intermediates with compact structure like the native states in the later step of in vivo protein folding.     

Assessment of perinatal pathologies in premature neonates using a syllable discrimination task

OBJECTIVE: To determine the preferred treatment of clinically localized prostate cancer. DESIGN: Cancer grade, patient age, and comorbidities are considered in a Markov model with Monte Carlo sensitivity analyses. Large and recent pooled analyses and patient-derived utilities are included. RESULTS: Principal findings suggest benefit for radical prostatectomy relative to watchful waiting for men under 70 years of age with low to moderate comorbidity. Men older than 70 with high comorbidity and disease of low to moderate grade do better with watchful waiting. CONCLUSIONS: Cohort-level sensitivity analyses suggest a quality-based treatment benefit for radical prostatectomy for younger men and treatment harm for older men. Tailored patient and clinician decisions remain necessary, especially for men older than 70 in good health but with aggressive cancers.     

A follow-up study of the acute behavioral effects of benzodiazepine-receptor ligands in humans: Comparison of quazepam and triazolam.

Quazepam, a trifluoroethylbenzodiazepine hypnotic, and triazolam, a triazolobenzodiazepine hypnotic, differ in terms of their benzodiazepine-receptor binding profile. Previous studies have suggested that quazepam produces less performance impairment than triazolam. Whether these effects are due to differences between quazepam and triazolam in terms of their benzodiazepine-receptor binding profile or to the testing of insufficient doses is unknown. The present study compared the acute behavioral effects of triazolam, quazepam, and placebo in 12 healthy humans using a within-subjects, placebo-controlled, crossover design. Quazepam and triazolam produced comparable dose-dependent performance impairment and increased ratings of drug effect and drowsy. Quazepam increased ratings of dizzy/light-headed, performance impaired, and sleepy. Triazolam increased ratings of high. Thus, across a sufficient range of doses, the performance-impairing effects of quazepam were similar to those of triazolam. By contrast, quazepam and triazolam produced somewhat different constellations of participant-rated drug effects. These differential drug effects may be attributable to differences between quazepam and triazolam in terms of their benzodiazepine-receptor binding profile. (PsycINFO Database Record (c) 2010 APA, all rights reserved)