Associative control of tolerance to the sedative and hypothermic effects of chlordiazepoxide.

Pavlovian control of tolerance to the sedative and hypothermic effects of chlordiazepoxide (CDP) was demonstrated in two experiments. In Experiment I, drug-experienced rats were repeatedly treated with CDP (30 mg/kg) in one environment (CS+); on alternate days, they were given saline injections in a different environment (CS-). Duration of sleeping and inactivity were used as measures of sedation. A comparable conditioning procedure was used in Experiment II, but tolerance to the hypothermic effect of CDP was the dependent measure. During tolerance testing, rats from both Experiments I and II were given CDP in one of three environments, CS+, CS-, or a novel environment (CSnov). In Experiment I, rats were equally tolerant in all three test environments when duration of sleep was assessed. However, when inactivity was used as the measure of tolerance, rats showed tolerance in CS+ and CS-, and significantly less tolerance in CSnov. Drug-naive controls showed similar nontolerant responses to CDP in all environments, thus ruling out the possibility that the effect of sedation was mediated nonassociatively. In Experiment II, drug-experienced rats showed tolerance to CDP-induced hypothermia in CS+ and CS- but less tolerance in CSnov. A compensatory hyperthermia was observed when these rats were given saline in CS+. There was some evidence for a generalization gradient in the conditional control of tolerance in both experiments.

"Paradoxical" analgesia induced by naloxone and naltrexone.

Analgesic effects of pellet implantation of the opiate antagonists naloxone and naltrexone and of chronic administration of naloxone by subcutaneous injection were examined. Rats were implanted with a slow-release pellet containing 10 mg naloxone or 10 mg naltrexone and tested for paw-lick latency on a hotplate apparatus. Controls were implanted with placebo pellets or given saline injections as appropriate. There were five test trials at intervals up to 72 h after implantation of naloxone and up to 120 h after the implantation of naltrexone. In a separate experiment, 5 mg/kg naloxone was injected; there were single trials on 5 consecutive days. All drug-treated animals displayed clear and substantial analgesia by their second test trial. This "paradoxical" analgesia was gradually reversed in the pellet-implant groups as tissue levels of the antagonists declined, but increased progressively with each trial involving injections. It was hypothesized that blockade of endogenous opiates by antagonists resulted in a form of "super-pain" on the hotplate, which in turn activated a normally redundant "backup" analgesic system. The results with naloxone injections show that unlike opiate-mediated analgesia, this hypothetical system is resistant to tolerance.

Alcohol is an effective cue in the conditional control of tolerance to alcohol.

To assess the effectiveness of a pharmacological cue as a conditional stimulus in the Pavlovian model of drug tolerance, two groups of Wistar rats received equal numbers of IP injections of a low and a high dose of alcohol. One group (Paired) received a low dose (0.8 g/kg) of alcohol followed 60 min later by the high dose (2.5 g/kg). Another group (Unpaired) received the low and high doses on an unpaired basis. When tested for tolerance to the hypothermic effect of the high dose of alcohol, only the Paired group showed tolerance, and only if the low dose preceded the high. When a saline injection preceded the high dose injection, the Paired group showed a loss of tolerance. The Paired group also showed a compensatory hyperthermia following the low dose injection. Animals from the Paired group that received repeated administrations of the low dose followed by saline, showed a significant extinction effect as compared with animals that received repeated saline injections only. These findings support the Pavlovian model of conditional tolerance, extending the realm of effective conditional stimuli to include a low dose of a drug.

Aversive conditioning in the rat: effects of a benzodiazepine and of an opioid agonist and antagonist on conditioned hypoalgesia and fear.

Hypoalgesia and fear co-occurred in rats trained on a heated floor and tested for their latencies to paw lick on that floor and to step down onto a nonheated floor. These responses were extinguished, suggesting a mediation by aversive conditioning processes. A benzodiazepine impaired the acquisition of aversive conditioning, but it did not attenuate the expression of conditioned hypoalgesia. The opioid agonist morphine also impaired acquisition across a range of drug doses and variations in hypoalgesic tolerance, whereas the opioid antagonist naloxone facilitated acquisition. The results are discussed in terms of the perceptual-defensive-recuperative (Fanselow, 1986) and working memory (Grau, 1987) models of the mechanisms for the co-occurrence of conditioned hypoalgesia and fear.

To drink or not to drink? Assessing conflicting desires in dependent drinkers in treatment.

Reactivity to Alcohol and Neutral Cues was compared in male, inpatient problem drinkers (N = 30). Subjects reported an overall desire not to drink alcohol which decreased in the presence of the Alcohol Cue. There were no cue-specific changes in heart rate, blood pressure and arousal level and a non-significant trend for increased stress in the Alcohol Cue condition. Subgroups of subjects reporting positive and negative desire for alcohol were identified. Subjects who reported negative desire for alcohol in the Alcohol Cue condition also reported greater self-efficacy to resist drinking in the future. These findings have implications for understanding the nature of self-reported desire for alcohol and its potential role in the treatment of alcohol dependence.

Alcohol exposure therapy: generalisation and changes in responsivity.

Fifty male alcohol-dependent individuals presenting for treatment were randomly assigned to either a cue exposure (CE) or control group. The experimental group were presented with 10 exposure trials to the sight and smell of alcohol, whilst the control group were presented with a neutral beverage. Following this, subjects received exposure to alcohol in a different room to examine whether extinguished responses generalised to a different environment. Results showed that only those subjects presented with the alcohol cue showed a significant reduction in cue-elicited swallowing, subjective withdrawal symptoms, arousal and urge to drink alcohol and that these extinguished responses remained diminished in magnitude in a different environment. These results provide additional support for the effectiveness of CE in reducing responsivity to alcohol cues.

Infrared Study of H(10)Si(10)O(15) Chemisorbed on a Si(100)-2x1 Surface.

Reflection-absorption infrared spectroscopy of the model interface derived from H(10)Si(10)O(15) on Si(100)-2x1 is presented. The spectra obtained are compared to the H(8)Si(8)O(12)-derived model interface and discussed in terms of the soft X-ray photoemission spectroscopy obtained for cluster-derived interfaces.

Testing the global-slowing hypothesis: are alcohol's effects on human performance process-specific or task-general?

In an interesting recent meta-analysis, Maylor and Rabbitt (1993) suggested that alcohol's effects on human performance may not be process- or stage-specific, but reflect a general, undifferentiated, cognitive slowing. According to this view, performance is globally slowed by a constant multiplicative fraction (b), such that the longer a process takes without alcohol on board (a -), the more it will be slowed by alcohol (a +). In summary: RTa+ = b b (RTa-). In this sense, the effects of alcohol are determined simply by the duration of a process or stage--not by its function or content--and attempts to map the effects of alcohol to specific cognitive operations are essentially futile. This global-slowing hypothesis entails, then, (i) that the function relating RTa+ to RTa- will be linear and increasing; (ii) that the value of b will be significantly greater than 1.0; and (iii) that all experimental factors which increase the complexity (hence, duration) of a task or stage will interact with alcohol. In this study we tested the global-slowing hypothesis directly using fixed set, varied set and concurrent sets item-recognition paradigms. All three tasks showed convincing additivity between alcohol and other key experimental factors which affect response latency (e.g., setsize, response type); there was no hint of any of the spectrum of significant interactions predicted by the global-slowing hypothesis. A meta-analysis of varied set latencies, analogous to Maylor and Rabbitt's, yielded a reasonably linear alcohol/no-alcohol function, but with a slope constant (b) less than 1.0. In all, the data provided little support for the global-slowing hypothesis.

Reactivity to alcohol-related cues in heavy and light drinkers.

Physiological responses and self-reported desire for alcohol were compared in heavy (n = 21) and light (n = 29) drinkers under each of two cue conditions. The cues were presented in a counterbalanced order and consisted of the sight, smell and taste of the subject's preferred alcoholic beverage (alcohol cue) and of a nonalcoholic lemon-flavored drink (neutral cue). Heavy drinkers showed a significant linear increase in reported desire for alcohol over time in the presence of the alcohol cue. This persistent increase in desire for alcohol seen in heavy drinkers contrasted with the initial increase shown by light drinkers which dissipated over time. Neither group showed any significant change in desire for alcohol when presented with the neutral cue. Heavy drinkers showed lower levels of skin conductance than light drinkers and all subjects showed changes in heart rate during exposure to both cues. Heart rate was affected differentially in the two groups of drinkers but only when the alcohol cue was presented first. Neither blood pressure nor stress and arousal levels changed significantly from pre- to post-cue presentations. The findings of this study have implications for understanding the nature and time course of cue-elicited desire for alcohol and its potential role in the development and treatment of alcohol dependence.

A time series investigation of three nicotine regulation models.

Time series data were collected twice daily for 62 days from 10 individuals on three variables related to smoking habit strength: number of cigarettes smoked, salivary cotinine, and carbon monoxide. The two purposes of this study were: (a) to evaluate which time series model(s) best fits each of the measures; and (b) to determine which model of nicotine regulation is consistent with the data. Three models of nicotine regulation were considered: (a) nicotine fixed effect; (b) nicotine regulation; and (c) multiple regulation. These models provide different predictions about the size and direction of the lag-one autocorrelation. Each measure was described in terms of one of a family of time series models represented mathematically as ARIMA (p, d, q). Models varied by individual, but a single model described the majority of subjects for all three variables. The clearest model identification was for the number of cigarettes smoked where an ARIMA (1, 0, 0) model with a moderate to strong negative dependency fit the majority of the subjects. This provided strong support for the multiple regulation model. An appendix provides a brief review of time series methodology.

Cue exposure in the treatment of drug dependence: the potential of a new method for preventing relapse.

Cue exposure has been used successfully in the treatment of neurotic disorders. Its application to the treatment of drug dependence is founded on the premise that craving for drugs can become classically conditioned to internal and external drug-related cues and that such conditioned craving responses play an important part in relapse to drug use. This article reviews the theoretical background for the use of cue exposure, research on cue reactivity in samples of drug-dependent persons and the role of cue reactivity in relapse. What evidence exists on the clinical effectiveness of cue exposure is reviewed in some detail and a number of clinical issues relating to its practical application are discussed. It is concluded that controlled trials of the effectiveness of cue exposure treatment for drug dependence should be implemented without further delay.

Alcohol cue exposure directed at a goal of moderate drinking.

A novel form of moderation-oriented cue exposure treatment for alcohol dependence is illustrated in a single case study. Formal clinic-based cue exposure following a priming dose of the client's preferred beverage is succeeded by supervised and then unsupervised in vivo practice at resisting continued drinking in tempting situations. Improvements on a range of outcome measures seen up to 12-month follow-up were supported by the results of an analogue measure of desire to drink. The potential place of this form of treatment in the range of services offered to problem drinkers is discussed.

Comparative density functional study of methanol decomposition on Cu4 and Co4 clusters.

A density functional theory study of the decomposition of methanol on Cu(4) and Co(4) clusters is presented. The reaction intermediates and activation barriers have been determined for reaction steps to form H(2) and CO. For both clusters, methanol decomposition initiated by C-H and O-H bond breaking was investigated. In the case of a Cu(4) cluster, methanol dehydrogenation through hydroxymethyl (CH(2)OH), hydroxymethylene (CHOH), formyl (CHO), and carbon monoxide (CO) is found to be slightly more favorable. For a Co(4) cluster, the dehydrogenation pathway through methoxy (CH(3)O) and formaldehyde (CH(2)O) is slightly more favorable. Each of these pathways results in formation of CO and H(2). The Co cluster pathway is very favorable thermodynamically and kinetically for dehydrogenation. However, since CO binds strongly, it is likely to poison methanol decomposition to H(2) and CO at low temperatures. In contrast, for the Cu cluster, CO poisoning is not likely to be a problem since it does not bind strongly, but the dehydrogenation steps are not energetically favorable. Pathways involving C-O bond cleavage are even less energetically favorable. The results are compared to our previous study of methanol decomposition on Pd(4) and Pd(8) clusters. Finally, all reaction energy changes and transition state energies, including those for the Pd clusters, are related in a linear, Brønsted-Evans-Polanyi plot.

Increased silver activity for direct propylene epoxidation via subnanometer size effects.

Production of the industrial chemical propylene oxide is energy-intensive and environmentally unfriendly. Catalysts based on bulk silver surfaces with direct propylene epoxidation by molecular oxygen have not resolved these problems because of substantial formation of carbon dioxide. We found that unpromoted, size-selected Ag3 clusters and approximately 3.5-nanometer Ag nanoparticles on alumina supports can catalyze this reaction with only a negligible amount of carbon dioxide formation and with high activity at low temperatures. Density functional calculations show that, relative to extended silver surfaces, oxidized silver trimers are more active and selective for epoxidation because of the open-shell nature of their electronic structure. The results suggest that new architectures based on ultrasmall silver particles may provide highly efficient catalysts for propylene epoxidation.

The role of non-covalent interactions in electrocatalytic fuel-cell reactions on platinum.

The classic models of metal electrode-electrolyte interfaces generally focus on either covalent interactions between adsorbates and solid surfaces or on long-range electrolyte-metal electrostatic interactions. Here we demonstrate that these traditional models are insufficient. To understand electrocatalytic trends in the oxygen reduction reaction (ORR), the hydrogen oxidation reaction (HOR) and the oxidation of methanol on platinum surfaces in alkaline electrolytes, non-covalent interactions must be considered. We find that non-covalent interactions between hydrated alkali metal cations M(+)(H(2)O)(x) and adsorbed OH (OH(ad)) species increase in the same order as the hydration energies of the corresponding cations (Li(+) >> Na(+) > K(+) > Cs(+)) and also correspond to an increase in the concentration of OH(ad)-M(+)(H(2)O)(x) clusters at the interface. These trends are inversely proportional to the activities of the ORR, the HOR and the oxidation of methanol on platinum (Cs(+) > K(+) > Na(+) >> Li(+)), which suggests that the clusters block the platinum active sites for electrocatalytic reactions.

Alloys of platinum and early transition metals as oxygen reduction electrocatalysts.

The widespread use of low-temperature polymer electrolyte membrane fuel cells for mobile applications will require significant reductions in the amount of expensive Pt contained within their cathodes, which drive the oxygen reduction reaction (ORR). Although progress has been made in this respect, further reductions through the development of more active and stable electrocatalysts are still necessary. Here we describe a new set of ORR electrocatalysts consisting of Pd or Pt alloyed with early transition metals such as Sc or Y. They were identified using density functional theory calculations as being the most stable Pt- and Pd-based binary alloys with ORR activity likely to be better than Pt. Electrochemical measurements show that the activity of polycrystalline Pt(3)Sc and Pt(3)Y electrodes is enhanced relative to pure Pt by a factor of 1.5-1.8 and 6-10, respectively, in the range 0.9-0.87 V.

Scaling properties of adsorption energies for hydrogen-containing molecules on transition-metal surfaces.

Density functional theory calculations are presented for CHx, x=0,1,2,3, NHx, x=0,1,2, OHx, x=0,1, and SHx, x=0,1 adsorption on a range of close-packed and stepped transition-metal surfaces. We find that the adsorption energy of any of the molecules considered scales approximately with the adsorption energy of the central, C, N, O, or S atom, the scaling constant depending only on x. A model is proposed to understand this behavior. The scaling model is developed into a general framework for estimating the reaction energies for hydrogenation and dehydrogenation reactions.

Some effects of exposure to a heat stressor upon the rat's subsequent reactions to that stressor.

In six experiments, rats were placed on a heated plate on two occasions (test and retest), and the latencies with which they licked their paws were taken as an index of their sensitivity to nociceptive stimulation. Experiment 1 provided evidence that rats were selectively analgesic on retest depending upon the intensity of the heat experienced on the initial test. Experiment 2 showed that this analgesia was recruited rapidly and was long-lasting, as it was observed when retest was scheduled as early as 0.2 and as late as 48 h after the initial exposure to the hot-plate. Experiment 3 documented a role for conditioning processes, as this analgesia was removed by an extinction-like procedure conducted between test and retest. Experiments 4 and 5 provided evidence for a non-opioid mechanism of pain control, because the analgesia was not diminished by the opioid antagonist, naloxone, nor by a history of morphine injections. These experiments also revealed that the analgesia observed on retest was enhanced and reduced when rats were given naloxone and morphine, respectively, on the initial test. Finally, Experiment 6 showed that the analgesia on retest summated with that produced by morphine. The results were taken to mean that the hot-plate assay for analgesia can itself activate endogenous mechanisms of pain control, and some speculations were offered as to how this occurred.