Measuring receptor/ligand interaction at the single-bond level: experimental and interpretative issues

There is increased interest in measuring kinetic rates, lifetimes, and rupture forces of single receptor/ligand bonds. Valuable insights have been obtained from previous experiments attempting such measurements. However, it remains difficult to know with sufficient certainty that single bonds were indeed measured. Using exemplifying data, evidence supporting single-bond observation is examined and caveats in the experimental design and data interpretation are identified. Critical issues preventing definitive proof and disproof of single-bond observation include complex binding schemes, multimeric interactions, clustering, and heterogeneous surfaces. It is concluded that no single criterion is sufficient to ensure that single bonds are actually observed. However, a cumulative body of evidence may provide reasonable confidence. © 2002 Biomedical Engineering Society. PAC2002: 8715Kg, 8715By, 8716-b     

Weighted linear cue combination with possibly correlated error

We test hypotheses concerning human cue combination in a slant estimation task. Observers repeatedly adjusted the slant of a plane to 75 degrees. Feedback was provided after each setting and the observers trained extensively until their setting error stabilized. The slant of the plane was defined by either linear perspective alone (a grid of lines) or texture gradient alone (diamond-shaped texture elements) or the two cues together. We chose a High and Low variance version of each cue type and measured setting variability in four single-cue conditions (Low, High for each cue) and in the four possible combined-cue conditions (Low-Low, Low-High, etc.). We compared performance in the combined-cue conditions to predictions based on single-cue performance. The results were consistent with a linear combination of estimates from cues. Six out of eight observers did better with combined cues than with either cue alone. For three observers, performance was consistent with optimal combination of uncorrelated cues. Three other observers' results were also consistent with optimal combination, but with the assumption that internal cue estimates were correlated. The remaining two observers were consistent with sub-optimal cue combination.     

Hypothalamic-pituitary-adrenal axis and sympatho-adreno-medullary responses during stress-induced and drug cue-induced cocaine craving states

Rationale Environmental stimuli associated with cocaine are known to elicit drug craving and increase the likelihood of relapse. However, the psychobiological changes that occur with exposure to these stimuli and in episodes of drug craving are not well understood. This study examined the response of brain stress circuits to environmental stimuli that are known to increase cocaine craving in cocaine dependent individuals.Methods Fifty-four treatment seeking cocaine dependent individuals, who were admitted to an inpatient treatment research unit for 2–4 weeks, participated in three laboratory sessions. Subjects were exposed to a brief 5-min guided imagery procedure that involved imagining a recent personal stressful situation, a drug-related situation and a neutral-relaxing situation, one imagery per session presented in random order. Subjective ratings of craving and anxiety, cardiovascular measures, and plasma levels of adrenocorticotrophic hormone (ACTH), cortisol, prolactin, norepinephrine (NE) and epinephrine (EPI) were assessed.Results Exposure to stress and to drug cues each resulted in significant increases in cocaine craving and subjective anxiety, pulse rate, systolic blood pressure, ACTH, cortisol, prolactin and NE as compared to the response to neutral imagery. In addition, stress imagery also increased diastolic blood pressure and plasma EPI as compared to responses to the drug cue imagery and neutral-relaxing imagery.Conclusions The findings indicate a significant activation of the CRF-HPA axis and noradrenergic/sympatho-adreno-medullary (SAM) system response during stress-induced and drug cue induced cocaine craving states in cocaine dependent individuals. The role of stress system activation in cocaine craving and in cocaine use is discussed.     

The reinstatement model of drug relapse: history,methodology and major findings

Rational and objectives. The reinstatement model is currently used in many laboratories to investigate mechanisms underlying relapse to drug seeking. Here, we review briefly the history of the model and describe the different procedures that have been used to study the phenomenon of reinstatement of drug seeking. The results from studies using pharmacological and neuroanatomical techniques to determine the neuronal events that mediate reinstatement of heroin, cocaine and alcohol seeking by acute priming injections of drugs, drug-associated cues and environmental stressors are summarized. In addition, several issues are discussed, including (1) the concordance between the neuronal mechanisms involved in drug-induced reinstatement and those involved in drug reward and discrimination, (2) the role of drug withdrawal states and periods in reinstatement of drug seeking, (3) the role of neuronal adaptations induced by exposure to drugs in relapse, and (4) the degree to which the rat reinstatement model provides a suitable preclinical model of relapse to drug taking. Conclusions. The data derived from studies using the reinstatement model suggest that the neuronal events that mediate drug-, cue- and stress-induced reinstatement of drug seeking are not identical, that the mechanisms underlying drug-induced reinstatement are to some degree different from those mediating drug discrimination or reward, and that the duration of the withdrawal period following cocaine and heroin self-administration has a profound effect on reinstatement induced by drug cues and stress. Finally, there appears to be a good correspondence between the events that induce reinstatement in laboratory animals and those that provoke relapse in humans.     

Vertical gaze angle: absolute height-in-scene information for the programming of prehension

One possible source of information regarding the distance of a fixated target is provided by the height of the object within the visual scene. It is accepted that this cue can provide ordinal information, but generally it has been assumed that the nervous system cannot extract "absolute" information from height-in-scene. In order to use height-in-scene, the nervous system would need to be sensitive to ocular position with respect to the head and to head orientation with respect to the shoulders (i.e. vertical gaze angle or VGA). We used a perturbation technique to establish whether the nervous system uses vertical gaze angle as a distance cue. Vertical gaze angle was perturbed using ophthalmic prisms with the base oriented either up or down. In experiment 1, participants were required to carry out an open-loop pointing task whilst wearing: (1) no prisms; (2) a base-up prism; or (3) a base-down prism. In experiment 2, the participants reached to grasp an object under closed-loop viewing conditions whilst wearing: (1) no prisms; (2) a base-up prism; or (3) a base-down prism. Experiment 1 and 2 provided clear evidence that the human nervous system uses vertical gaze angle as a distance cue. It was found that the weighting attached to VGA decreased with increasing target distance. The weighting attached to VGA was also affected by the discrepancy between the height of the target, as specified by all other distance cues, and the height indicated by the initial estimate of the position of the supporting surface. We conclude by considering the use of height-in-scene information in the perception of surface slant and highlight some of the complexities that must be involved in the computation of environmental layout.     

Suppression or facilitation of operant behaviour by raclopride dependent on concentration of sucrose reward

Rats responded under continuous reinforcement for 1%, 10% or 95% sucrose pellets, under food deprived or ad libitum access conditions. In both cases responding was highest for 10% sucrose reinforcement, and a small proportion of 95% sucrose was not consumed. Ad libitum food access reduced response rates for all sucrose concentrations. Responding for 10% and 95% sucrose pellets followed a parallel time-course; and accumulation of 95% sucrose pellets was immediate and nonprogressive. Extinction following availability of 95% sucrose pellets caused an increase in response rate, but removal of 10% sucrose led only to a decline in responding. Under both food deprived and non-deprived conditions, the dopamine D-2 antagonist raclopride dose-dependently decreased responding for 1% or 10% sucrose, but increased responding for, and consumption of, 95% sucrose reward. After eight sessions of responding under extinction conditions, the presentation of reward-associated cues increased response rate early in the session. Raclopride had no effect during this period, but decreased responding later in the session. We consider the implications of these results for theories of neuroleptic drug action.     

Does the reaction of abstaining smokers to the smell of other people's cigarettes predict relapse?

Aims Recent ex‐smokers report a range of reactions to other people's cigarette smoke. We examined the hypothesis that those who find the smell of smoke pleasant and tempting are more likely to relapse than those who have a neutral or even negative reaction to it. Design A total of 1110 consecutive patients who attended for smoking cessation treatment and achieved at least 1 week of validated abstinence provided weekly ratings of their reactions to other people's cigarette smoke together with routine baseline measures and weekly ratings of withdrawal discomfort [measured on the Mood and Physical Symptom Scale (MPPS)]. Findings Twenty‐three per cent of the sample found the smell of other people's cigarette smoke during their first week of abstinence pleasant, and 54% found it tempting. There was only a modest correlation between the two variables. Finding the smoke pleasant was not related to smoking status in the following week, but finding the smoke tempting predicted relapse. Ratings of temptation were related to the severity of withdrawal discomfort and to dependence. Entering MPPS ratings of urges to smoke in the given week into regression analysis resulted in the general urges to smoke, rather than urges elicited by other people's smoke, becoming a significant predictor of smoking status in the following week. In patients who maintained continuous abstinence throughout 4 weeks of treatment the pleasantness ratings remained stable, while the ratings of temptation steadily decreased. Conclusions In abstaining smokers, the like or dislike of other people's smoke is not related to relapse. The temptation to smoke elicited by other people's smoke is related to outcome, but only as an indicator of a general ‘temptation threshold’. Patients who find other people's smoke tempting can be reassured that this reaction will gradually decrease.     

Enhanced interpretation of nonverbal facial cues in male rapists—a preliminary study

Interpretation of nonverbal cues was tested in 12 white, male, self-admitting rapists. All rapists were being treated for depression and were between the ages of 20 and 31. All victims were female strangers who had been observed in a social setting. The rapists and 12 age- and class-matched male controls viewed 10 male and 10 female volunteers during a specific gambling trial. Rapists were found to be more accurate than controls in interpreting both female and male nonverbal cues. This enhanced ability was hypothesized to be due to pathological expressions of intimacy and sexuality in the rapists' families of origin.     

Verbal cues effectively orient children's auditory attention in a CV-syllable dichotic listening paradigm

ABSTRACT

In their groundbreaking work featuring verbal dichotic listening tasks, Mondor and Bryden showed that tone cues do not enhance children's attentional orienting, in contrast to adults. The magnitude of the children's right-ear advantage was not attenuated when their attention was directed to the left ear. Verbal cues did, however, appear to favour the orientation of attention at around 10 years, although stimulus-onset asynchronies (SOAs), which ranged between 450 and 750?ms, were not rigorously controlled. The aim of our study was therefore to investigate the role of both types of cues in a typical CV-syllable dichotic listening task administered to 8- to 10-year-olds, applying a protocol as similar as possible to that used by Mondor and Bryden, but controlling for SOA as well as for cued ear. Results confirmed that verbal cues are more effective than tone cues in orienting children's attention. However, in contrast to adults, no effect of SOA was observed. We discuss the relative difficulty young children have processing CV syllables, as well as the role of top-down processes in attentional orienting abilities.