Behavioral measures of opioid dependence and withdrawal

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28004/1/0000440.pd

On the Significance of Absorption Features in HST/COS Data

We present empirical scaling relations for the significance of absorption features detected in medium resolution, far-UV spectra obtained with the Cosmic Origins Spectrograph (COS). These relations properly account for both the extended wings of the COS line spread function and the non-Poissonian noise properties of the data, which we characterize for the first time, and predict limiting equivalent widths that deviate from the empirical behavior by \leq 5% when the wavelength and Doppler parameter are in the ranges \lambda = 1150-1750 A and b > 10 km/s. We have tested a number of coaddition algorithms and find the noise properties of individual exposures to be closer to the Poissonian ideal than coadded data in all cases. For unresolved absorption lines, limiting equivalent widths for coadded data are 6% larger than limiting equivalent widths derived from individual exposures with the same signal-to-noise. This ratio scales with b-value for resolved absorption lines, with coadded data having a limiting equivalent width that is 25% larger than individual exposures when b \approx 150 km/s.Comment: 25 pages, 3 tables, 7 figures, accepted for publication in PAS

Chronic l-Alpha Acetylmethadol in Rhesus Monkeys: Discriminative Stimulus and Other Behavioral Measures of Dependence and Withdrawal 1

ABSTRACT This study characterized discriminative stimulus and other effects of naltrexone in rhesus monkeys treated daily with the long-acting opioid l-alpha acetylmethadol (LAAM). An initial dose-finding study assessed the rate-decreasing effects of naltrexone in three monkeys receiving LAAM daily (0.32-1.78 mg/ kg); subsequently, these monkeys and a fourth received 1.0 mg/kg/12 hr of LAAM although discriminating between naltrexone and saline. Responding occurred on the saline lever after the administration of LAAM, whereas Ͼ90% drug-lever responding occurred after the administration of 0.1 mg/kg of naltrexone that also elicited signs of withdrawal. Naloxone and quadazocine, but not morphine, nalbuphine or ketamine, substituted for naltrexone. Morphine and nalbuphine shifted the naltrexone dose-effect curve to the right. Compared to precipitated withdrawal, deprivation-induced withdrawal occasioned less naltrexone-lever responding and fewer observable signs of withdrawal. Maximal naltrexone-level responding occurred 24 to 48 hr after the discontinuation of LAAM treatment; the frequency of other withdrawal signs also peaked 24 to 48 hr after the discontinuation of LAAM. Partial naltrexone-lever responding occurred for up to 10 days after discontinuation of LAAM treatment; 4 and 8 days after the discontinuation of LAAM treatment, 0.1 mg/kg of naltrexone did no further increase naltrexone-lever responding or withdrawal signs suggesting that less-then-maximal naltrexone-lever responding was not due to long-lasting effects of LAAM or its metabolites. The discriminative stimuli that are associated with LAAM deprivation might be different from the stimuli associated with either training condition. This study is the first antagonist discrimination in non-humans primates treated chronically with LAAM and the results indicate that the naltrexone stimulus is related to opioid withdrawal. The frequent administration of some drugs often results in the development of dependence that can be quantified by the severity of withdrawal that occurs after either the discontinuation of drug treatment or the administration of a pharmacologic antagonist. Of particular clinical relevance are the adverse signs and symptoms (i.e., withdrawal) that often emerge on the discontinuation of drug use and that can contribute to the continued drug use. Moreover, individuals often report an increased motivation to obtain and use drugs during periods of withdrawal LAAM is a mu opioid agonist that is used as a maintenance therapy in opioid-dependent patients. In huma

Leaf phenology amplitude derived from MODIS NDVI and EVI: maps of leaf phenology synchrony for Meso‐ and South America

The leaf phenology (i.e. the seasonality of leaf amount and leaf demography) of ecosystems can be characterized through the use of Earth observation data using a variety of different approaches. The most common approach is to derive time series of vegetation indices (VIs) which are related to the temporal evolution of FPAR, LAI and GPP or alternatively used to derive phenology metrics that quantify the growing season. The product presented here shows a map of average ‘amplitude’ (i.e. maximum minus minimum) of annual cycles observed in MODIS‐derived NDVI and EVI from 2000 to 2013 for Meso‐ and South America. It is a robust determination of the amplitude of annual cycles of vegetation greenness derived from a Lomb–Scargle spectral analysis of unevenly spaced data. VI time series pre‐processing was used to eliminate measurement outliers, and the outputs of the spectral analysis were screened for statistically significant annual signals. Amplitude maps provide an indication of net ecosystem phenology since the satellite observations integrate the greenness variations across the plant individuals within each pixel. The average amplitude values can be interpreted as indicating the degree to which the leaf life cycles of individual plants and species are synchronized. Areas without statistically significant annual variations in greenness may still consist of individuals that show a well‐defined annual leaf phenology. In such cases, the timing of the phenology events will vary strongly within the year between individuals. Alternatively, such areas may consist mainly of plants with leaf turnover strategies that maintain a constant canopy of leaves of different ages. Comparison with in situ observations confirms our interpretation of the average amplitude measure. VI amplitude interpreted as leaf life cycle synchrony can support model evaluation by informing on the likely leaf turn over rates and seasonal variation in ecosystem leaf age distribution

Comparison of naltrexone and quaternary naltrexone after systemic and intracerebroventricular administration in pigeons

The behavioral effects of naltrexone and quaternary naltrexone were evaluated in two groups of pigeons. One group responded under a fixed-ratio schedule of food reinforcement and was trained to discriminate between 3.2 mg/kg morphine (i.m.) and saline. Drug-appropriate responding occurred in a dose-related manner to morphine, given intramuscularly and intraventricularly. When administered intraventricularly morphine was 50 times more potent as a discriminative stimulus and 50-100 times more potent at suppressing responding. Naltrexone, given intraventricularly and intramuscularly, attenuated the discriminative stimulus effects of morphine. Quaternary naltrexone was more potent at suppressing responding when administered intraventricularly but it failed to attenuate the discriminative stimulus effects of morphine. A second group of pigeons, responding under a variable-interval schedule of food reinforcement, was treated with 100.0 mg/kg/day of morphine. Naltrexone and quaternary naltrexone suppressed responding by both routes of administration. Naltrexone was approximately equipotent when given intramuscularly or intraventricularly, and the doses that suppressed responding were 50-500 times smaller than doses required to suppress responding in untreated pigeons. Although quaternary naltrexone was 1800 times more potent when given intraventricularly, the doses necessary to suppress responding by each route were the same as doses required in untreated pigeons. These results extend the conditions under which a quaternary derivative of naltrexone failed to display antagonist activity in the pigeon. The utility of this compound for characterizing central and peripheral mechanisms of action has not been established in different species and testing conditions and, therefore, appears to be appropriate only under conditions in which it is evaluated after systemic, as well as central, administration.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26698/1/0000246.pd

The competitive N-methyl-D-aspartate (NMDA) antagonist CGS 19755 attenuates the rate-decreasing effects of NMDA in rhesus monkeys without producing ketamine-like discriminative stimulus effects

The purported competitive excitatory amino acid antagonist CGS 19755 was compared to the non-competitive antagonists ketamine and MK-801 in three rhesus monkeys discriminating between 1.78 mg/kg of ketamine and saline while responding under a fixed-ratio 100 schedule of food presentation. MK-801 substituted completely for the ketamine discriminative stimulus and was 32 times more potent than ketamine as a discriminative stimulus. CGS 19755 was studies using sinlge and cumulative dosing procedures up to a dose of 10.0 mg/kg; for all conditions, CGS 19755 produced responding exclusively on the saline lever and had only modest rate-decreasing effects. N-Methyl-D-aspartate administered alone also did not produce ketamine-appropriate responding but did decrease response rates in a dose-related manner. N-Methyl-D-aspartate eliminated responding in all monkeys at doses of 5.6-10.0 mg/kg. MK-801 and ketamine antagonized the rate-decreasing effects of N-methyl-D-asparate, however, ketamine was most effective as an antagonist at doses that decreased response effects of N-methyl-D-asparate, however, ketamine was most the rate-decreasing effects of N-methyl-D-aspartate and shifted the N-methyl-D-aspartate dose-effect curve more than 5-fold to the right. The magnitude of antagonism of N-methyl-D-aspartate appeared to be somewhat greater with CGS 19755 than with MK-801 or ketamine. Thus, a competitive (CGS 19755) and some non-competitive (MK-801 and ketamine) excitatory amino acid antagonists can attenuate the rate-decreasing effects of N-methyl-D-aspartate. Surprisingly, the results suggest that antagonism of N-methyl-D-aspartate is not sufficient to produce ketamine-like discriminative stimulus effects under these conditions in rhesus monkeys.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28089/1/0000536.pd

Intracerebroventricular drug administration in pigeons

For many procedures used in behavioral pharmacology, the intracerebroventricular (ICV) route of drug administration is infrequently used due, in part, to the lack of a reliable technique for determining cannula patency in vivo. This study describes an in vivo technique for assessing ICV cannula patency in pigeons. The technique was applied in an experiment designed to evaluate several drugs, which are presumed to differ in the extent to which they enter the central nervous system, for their rate-suppressing effects in pigeons trained to peck a key on a fixed-ratio 20 schedule of food reinforcement. The opioid agonist morphine and antagonist quaternary naltrexone were 100 and 280 times more potent, respectively, in suppressing responding when administered ICV, as compared to systemic administration. Tertiary naltrexone was approximately equipotent as an antagonist of morphine's rate-suppressing effects when administered ICV or systemically. Quaternary naltrexone did not antagonize morphine by either route of administration. The utility of this in vivo cannula verification technique is discussed, as well as the limitations of comparisons between systemically-administered tertiary and quaternary derivatives.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25518/1/0000059.pd

A Randomized Comparison of Alternative Formats for Clinical Simulations

Computer-based clinical simulations for medical education vary widely in structure and for mat, yet few studies have examined which formats are optimal for particular educational settings. This study is a randomized comparison of the same simulated case in three formats: a "pedagogic" format offering explicit educational support, a "high-fidelity" format attempting to model clinical reasoning in the real world, and a "problem-solving" format that requires students to express specific diagnostic hypotheses Data were collected from rising third- year medical students using a posttest, attitudinal questionnaire, students' writeups of the case, and log files of students' progress through the simulation. Student performances on all measures differed significantly by format. In general, students using the pedagogic format were more proficient but less efficient. They acquired more information but were able to do proportionately less with it. The results suggest that the format of computer-based simulations is an important educational variable. Key words. medical education, undergraduate; clinical reasoning; computer-assisted instruction. (Med Decis Making 1991;11:265-272