Antipruritic effects of transient heat stimulation on histaminergic and nonhistaminergic itch.

BACKGROUND: Chronic itch is notoriously difficult to treat. Counterstimuli are able to inhibit itch, but this principle is difficult to apply in clinical practice, and the mechanisms behind counterstimulation-induced itch suppression in humans are unclear. OBJECTIVES: Firstly, to analyse the stimulus-response effects of transient heat stimuli on histaminergic and nonhistaminergic itch, and secondly, to investigate whether the antipruritic effect depends on homotopic (peripheral mediation) or heterotopic (central mediation) counterstimulation relative to the itch provocation site. METHODS: Eighteen healthy volunteers participated (eight female, mean age 25·7 ± 0·8 years). Itch was evoked on premarked areas of the volar forearms, by either histamine (1% solution) or cowhage (35-40 spicules). In addition to the itch provocations (experiment 1), 5-s homotopic heat stimuli at 32, 40, 45 or 50 °C were applied. In experiment 2, heat stimuli were applied either homotopically, intrasegmentally (next to the provocation site) or extrasegmentally (dorsal forearm). Itch intensity was evaluated throughout the procedures using a digital visual analogue scale. RESULTS: Homotopic counterstimuli inhibited histaminergic itch by 41·3% at 45 °C (P < 0·01) and by 76·7% at 50 °C (P < 0·001). Cowhage-induced itch was less prone to counterstimulation and was significantly diminished only at 50 °C, by 43·6% (P = 0·009). Counterstimulations applied heterotopically were not able to inhibit itch significantly. CONCLUSIONS: Itch pathway-specific effects of counterstimuli were observed between homo- and heterotopic stimulation. Histaminergic itch was robustly inhibited by short-term homotopic noxious heat stimuli for up to 10 min. Nonhistaminergic itch was only weakly inhibited. The inhibitory effects exerted by the short-term heat stimuli only occurred following homotopic counterstimulation.

Stimulus control in pigeons based on proprioceptive stimuli from floor inclination.

Two groups of pigeons trained to peck a dimly illuminated disc in an otherwise dark experimental chamber with the floor horizontal (0 degrees tilt) or inclined 30 degrees to the left, respectively, show decremental generalization gradients of response rate when the floor inclination is varied from its training position. Discrimination training in which food reinforcement is available under one floor tilt condition but not under another steepens the slope of such gradients. In a secondv experiment, pigeons reinforced for pecking when the floor was tilted 10 degrees or 20 degrees and not reinforced under the alternative condition showed steep gradients with maximal responding displaced from the reinforced stimulus.

Retrograde amnesia for old (reactivated) memory: some anomalous characteristics.

Old memory, when reactivated by cue exposure, was disrupted by mild or deep hypothermia treatments. New memory was impaired only by deep cooling. Moreover, old but not new learning showed spontaneous recovery. Old reactivated memory may be qualitatively different from newly acquired memory.

Comprehensive geriatric assessment in female elderly patients with Alzheimer disease and other types of dementia.

The most visible manifestation of dementia is the progressive inability to activities of daily living (ADL) and to instrumental activities of daily living (IADL). The comprehensive geriatric assessment (CGA) is the validated and recommended instrument to a correct evaluation and decision making in elderly patients. To judge if the decline in cognitive functions is associated with a worsening in functional, emotional and clinical status measured by CGA, we also compared CGA in the same patients stratified for mild, moderate and severe dementia. From September 2004 to November 2005 we studied 47 institutionalized female patients with Alzheimer's disease (AD) and other types of dementia. Mean age was 83.70+/-0.88 years (range 70-101). Their multidimensional evaluation was performed by the CGA. We evaluated geriatric syndromes (AGS, 2004), polypharmacy, frailty, hemoglobin (Hb), serum creatinine (CR) and white blood cells (WBC). We stratified the population in 3 groups for the mini mental state examination (MMSE): severe (MMSE 0-9; 5 patients), moderate (MMSE 10-29; 23 patients) and mild dementia group (MMSE 20-30; 19 patients), and searched for statistical differences in the parameters of CGA. MMSE was significantly related to dependence in ADL (mean=x=1.85), IADL (x=0.57), cumulative illness rating scale-geriatrics (CIRS-G) (x=9.55), geriatric depression scale (GDS) (x=8.71), geriatric syndromes (x=2.49), Hb, CR, WBC and number of drugs (x=6.51, range 2-15) (p=0.001). MMSE low score was also correlated with a worse mini nutritional assessment (MNA) (x=19.5; p=0.003). Frail patients were 61.7%. We found a statistically significant difference in the prevalence of geriatric syndromes between mild vs. moderate dementia group (p=0.02). Mild vs. moderate group, and moderate vs severe group were significantly different concerning Hb levels (p=0.009 and 0.002, respectively). Patients with severe cognitive impairment are more likely to be dependent at ADL and IADL; to present a larger number of comorbidity and geriatric syndromes; to have lower !evels of Hb and higher levels of CR; to be in a worse nutritional status and to take a larger number of drugs. Polypharmacy maybe related to high comorbidity but the risk of irrational drug use should be evaluated. We suggest single testing with CGA as an effective tool providing a comprehensive assessment of elderly, and able to detect unaddressed corrigible problems.

Forgetting of stimulus attributes: methodological implications for assessing associative phenomena.

Differential responding to changes in the stimulus situation, long central to the concept of stimulus control, also provides the implicit conceptual basis for assessing the nature of a variety of associative relationships. However, there is substantial evidence that the perception of stimulus similarity is not a static property. Generalization gradients to contextual as well as discriminative stimuli flatten over time, and this increase in perceived similarity presumably reflects forgetting of the detailed characteristics or attributes of stimuli. Methodologically, the flattening of the gradient imposes an important constraint: The effect of a stimulus shift will be highly sensitive to the length of the delay interval between training and testing. Conceptually, the loss of memory for stimulus attributes also implies that the sources of interference in retention can increase over time.

The contextual change paradox is still unresolved: comment on Bouton, Nelson, and Rosas (1999)

According to the contextual change theory of memory loss, spontaneous forgetting reflects a retrieval impairment due to subtle and unprogrammed shifts in environmental cues over a retention interval. However, Riccio, Richardson, and Ebner (1984) noted an apparent paradox in this model; specifically, laboratory studies inducing explicit shifts in contextual cues found less disruption of performance as retention intervals increased. Bouton, Nelson, and Rosas (1999) critiqued several of the claims made by Riccio et al. and concluded that the contextual cue theory is still a valid account of spontaneous forgetting. In this comment, the authors address the 3 major criticisms offered by Bouton et al., point out an inconsistency in their argument, and conclude that the original paradox still poses problems for the contextual change theory of forgetting.

Differential susceptibility to anterograde and retrograde amnesia treatments in preweanling rats.

Although there have been several reports that preweanling rats and mice are relatively resistant to experimentally induced retrograde amnesia, there is virtually no information concerning susceptibility to anterograde amnesia in subjects of this age. Therefore, in the present experiment, 23-day-old rats received hypothermia either prior to, or immediately after, punishment training in an attempt to induce anterograde and retrograde amnesia, respectively. When tested 24 hr later, only those subjects given hypothermia prior to training exhibited any loss of retention. Thus these results confirmed previous evidence of resistance to retrograde amnesia in preweanling rats and further demonstrated that substantial anterograde amnesia could be obtained in these subjects. Performance of subjects tested after a 5-min retention interval revealed that the poor retention performance in subjects cooled prior to training and tested 24 hr later was not due to a learning deficit. These results are also discussed with respect to the issue of the independence of anterograde and retrograde amnesia.

Anterograde amnesia induced by hyperthermia in rats.

Anterograde amnesia (AA), forgetting of events that occur following a traumatic episode, has recently been demonstrated by using a mild decrease in temperature (hypothermia) as the amnestic agent. However, no data currently exist to indicate if an increase in body temperature (hyperthermia) might affect memory processing in a similar manner. Experiments 1 and 2 demonstrated that increasing the colonic body temperature of the rat to 3-4 degrees C or more above normal during avoidance training produced a significant retention loss when the test occurred 24 hr after training. Slight hyperthermia to 1-2 degrees C above normal did not impair retention. In Experiment 3, AA resulting from an elevation in temperature was reversed by reheating "amnestic" subjects just prior to the 24-hr test. By rapidly reversing hyperthermia immediately after the training trial with a cooling procedure, Experiment 4 demonstrated that hyperthermia-induced AA was not the result of retrograde influences of the heating treatment. Implications of these results are discussed in terms of possible retention deficits which could conceivably follow environmental heat stress or fever hyperthermia resulting from bacterial infection.

Overshadowing effects in the stimulus control of morphine analgesic tolerance.

This study attempted to replicate previous demonstrations of classical conditioning of morphine analgesic tolerance, with the additional aim of determining whether stimulus overshadowing effects might explain previous conflicting findings. Eight groups of rats received a series of 10 morphine (5 mg/kg) and/or saline injections, differing only with respect to the contingency between a compound visual-auditory conditioned stimulus (CS) and the substance injected. When tested for analgesic responding to morphine in the presence of the compound CS, only those groups for which the CS and morphine injections were paired during the acquisition sequence evidenced tolerance. In a second experiment, tolerant animals were tested in the presence of one component of the compound CS. When a loud (85 dB) tone was used in the compound, less analgesic tolerance was elicited later by the weaker visual stimulus alone. This differential stimulus control of the analgesic response suggests that overshadowing may contribute to failures to replicate conditioned morphine tolerance. That internal morphine-produced stimuli might overshadow external cues is considered.

Is anterograde amnesia a special case of retrograde amnesia?

In anterograde amnesia, memory loss is obtained for events that occur subsequent to the traumatic insult. But because the effects of an anterograde agent or treatment usually last for minutes, or even hours, after the nominal training event, processing of information may be altered during the postacquisition period as well as during acquisition. Since posttraining manipulations are themselves capable of modulating memory, or inducing retrograde amnesia, the memory loss due to a putative anterograde treatment may instead represent retrograde processes. The present experiment examined this potential source of confounding by using an amnestic treatment that can be quickly reversed after training in order to remove postacquisition effects. Thus, the presence of amnesia would isolate anterograde contributions as the source of loss. For induction of anterograde amnesia, rats were trained while at reduced body temperature (29 degrees C). A rapid rewarming procedure was introduced for some animals immediately after training to ensure that the hypothermic state did not extend into the postacquisition period. Other subjects were rapidly rewarmed 1 hr after training to control for any effects of the rewarming manipulation. Both groups showed severe anterograde amnesia that was indistinguishable from that obtained in the gradually rewarmed controls. These data provide an empirical example of an anterograde-induced memory deficit that is independent of retrograde influences.

Role of ACTH in recovery from retrograde amnesia induced by hypothermia in rats.

The present investigation assessed whether increased congruency between ACTH state present shortly after training and that at testing contributed to memory recovery. If recovery were related to an increased correspondence between internal state present after training and that at testing, then suppressing ACTH release should block memory recovery. This was the hypothesis that was examined in the present investigation. Specifically, animals were trained on a passive avoidance task, administered hypothermia (the amnestic agent) and, shortly prior to testing, given treatments known to be effective in reversing memory loss induced by hypothermia. Before training (Experiment 1) or testing (Experiment 2) animals were injected with either dexamethasone (an agent that suppresses ACTH release) or saline. Results, in general, indicated that when ACTH release was suppressed, a blunted recovery effect was obtained. This reduction in the extent of memory recovery was observed when ACTH was suppressed either at training or at testing. These data are interpreted as providing support for an ACTH-related, state-dependent retention mechanism contributing to recovery from hypothermia-induced retrograde amnesia in rats.

Associative processes in adaptation to repeated cold exposure in rats.

Learning processes have been implicated in drug tolerance, but the role of associative mechanisms in adaptation to stressors has not previously been determined. Rats that received daily brief cold exposures demonstrated adaptation to the cold as measured by an attenuation of hypothermia. Tolerance to the cold was disrupted by changing the context in which the subject experienced the cold. These findings provide evidence of associative processes in adaptation to cold exposure and illustrate that these processes are not limited to drug tolerance.

Modulation of aversively motivated learning in rats adapted to a cold stressor.

Two experiments studied effects of adaptation to cold water stress upon learning in two aversively motivated (shock) tasks. Experiment 1 found animals previously experiencing cold water stress exhibited more tolerance to shock, having shorter latencies, in an approach-avoidance conflict situation than non-treated controls. In Experiment 2, animals with previous cold water stress experience exhibited longer response latencies than controls in an active-avoidance task. These findings provide evidence that adaptation to a noncontingent stressor can modulate behavioral responses which suggest increased tolerance.

Hypothermia-induced anterograde amnesia and its reversal in rats trained on a T-maze escape task.

Previous studies have demonstrated anterograde amnesia (AA) and its reversal in rats trained on passive avoidance tasks. The present investigation was conducted to determine whether induction and/or reversal of AA is limited to inhibitory learning tasks or whether these phenomena can be illustrated in behavioral situations involving choice. Accordingly, in Experiment 1, rats were trained on a T-maze escape task as either hypothermic (28 degrees C) or normothermic. Twenty-four hours later half of each acquisition group was tested as either hypothermic or normothermic. Results indicated a stern retention decrement for animals trained at a lower body temperature and tested as normothermic. However, this prograde memory deficit was attenuated when animals were recooled shortly prior to testing. In an attempt to extend the phenomenon of memory recovery observed in Experiment 1, Experiment 2 examined whether pretest injections of d-amphetamine (0.5 mg/kg), a purported amnesia-attenuating agent, could lessen the AA induced by hypothermia. Amphetamine, at least at the dose used, did not reduce the memory impairment. Results are interpreted in terms of the state dependent nature of memory.

Concussion-induced retrograde amnesia in rats.

Three experiments were conducted to investigate the characteristics of retrograde amnesia (RA) induced by concussion in rats. In Experiment 1, rats receiving experimental concussion shortly after training in a single punishment trial exhibited severe forgetting on a retention test 48 h later. In the second experiment, rats receiving a concussion within 6 h after training showed severe RA, while those receiving concussion one day to five days after training exhibited progressively weaker amnesia. In Experiment 3, amnesic animals in one group received pretest noncontingent foot shock as a reminder treatment. This pretest cue significantly increased the cross-through latency, thus indicating a reduction in the memory deficit resulting from concussion. These results suggest that experimental concussion can be an effective method to induce retrograde memory loss in rats; that the RA caused by concussion is time-dependent; and that concussion-induced RA can be alleviated by a pretest cue indicating that the underlying mechanism of concussion-induced RA is more likely to be a retrieval deficit than a consolidation failure.

Ketaset-Rompun extends the temporal gradient for hypothermia-induced retrograde amnesia.

In studies of experimentally induced retrograde amnesia (RA), as the interval between training and the amnestic treatment is lengthened, amnesia decreases (4). This temporal gradient for RA has been reported with a wide variety of amnestic agents, including RA produced by thermoregulatory disturbances (8). This temporal gradient for RA is not unlike certain characteristics of classical conditioning, where weaker conditioned responding occurs when the interval between the conditioned stimulus (CS) and unconditioned stimulus (US) is lengthened. Furthermore, there is evidence that administration of anesthetics can lengthen the "effective conditioning" interval between the CS and US, as demonstrated in a conditioned taste-aversion (CTA) procedure (10). In that study, little conditioning was observed when a 3-h delay (or more) was incorporated between presentations of the CS (flavor) and the US (toxin). However, if subjects were anesthetized immediately after the CS was delivered and remained anesthetized during the CS-US interval, strong conditioning was observed with CS-US intervals of up to 9 h. The aim of the present experiment was to determine if the temporal gradient for hypothermia-induced RA could also be lengthened. That is, we tested whether the interval between training and hypothermia treatment could be lengthened by anesthetizing subjects with Ketaset-Rompun. The results indicate that the training-to-amnestic agent interval could be lengthened within moderate limits. The implications for hypothermia-induced RA is further discussed.

ACTH- and noncontingent footshock-induced recovery of an extinguished passive avoidance response.

The effectiveness of both exogenous adrenocorticotropic hormone and noncontingent footshock as agents for the recovery of an extinguished passive avoidance response was assessed. Six groups of male Holtzman rats were administered either adrenocorticotropic hormone (4IU), or a single noncontingent footshock, either 15 minutes, 24 hours, or 7 days prior to retention testing. Two control groups received an injection of the inactive gel vehicle either 15 minutes or 7 days prior to test. Adrenocorticotropic hormone administered either 15 minutes or 24 hours prior to test, as well as noncontingent footshock delivered 24 hours (but not 15 minutes) prior to test, served as effective reinstatement agents. Substantial "spontaneous recovery" of responding precluded evaluation of reinstatement effects at the 7 day retention interval. The persistence of the recovery for at least 24 hours is consistent with the notion that both adrenocorticotropic hormone and noncontingent footshock not only enhance memory retrieval of the original fear conditioning, but also cause the training memory to be further processed.

State-dependent retention produced with estrus in rats.

State-dependent retention (SDR) has frequently been demonstrated with drug-induced physiological changes which apparently serve as contextual cues for memory. These support the assumption that commonly occurring endogenous dispositions play a role in memory, yet there are few reports showing SDR with states that are likely to be part of an organism's natural experiences. To determine if behavioral estrus could produce SDR, ovariectomized female rats were rendered estrus via hormone injections or remained anestrus via placebo injections, trained with quinine-laced apple juice, and later tested while in the same or different state for reactions towards pure juice. SDR was not evident in the amount of juice consumed; however, those tested in the same state as the initial experience were slower to initiate drinking than those tested in a different state revealing a state-dependent influence on memory related to phases of the ovarian cycle.

Effects of prior aversive experience upon retrograde amnesia induced by hypothermia.

Two experiments examined the extent to which retrograde amnesia (RA) is attenuated by prior learning experiences. In Experiment 1, rats initially received either passive avoidance training in a step-through apparatus, exposure to the apparatus, or noncontingent footshock. When training on a second but different passive avoidance task was followed by hypothermia treatment, RA was obtained only in the latter two groups. In Experiment 2, one-way active avoidance training, yoked noncontingent shocks, or apparatus exposure constituted the initial experience. Subsequent step-down passive avoidance training and amnestic treatment resulted in memory loss for the prior apparatus exposure group, but not for either of the preshocked conditions. These experiments demonstrate that certain types of prior aversive experience can substantially modify the magnitude of RA, and, in conjunction with other familiarization studies, emphasize a paradox for interpretations of RA based solely upon CNS disruption. The possibility that hypothermia treatment serves as an important contextual or encoding cue necessary for memory retrieval was considered. It was suggested that prior experience may block RA by enabling rats to differentiate training and treatment conditions.

The effect of CS-preexposure on conditioned taste aversion in young and adult rats.

Young and adult rats were given nonreinforced exposures to the flavor-CS prior to a taste aversion conditioning session. CS-preexposure prevented the conditioning of a taste aversion in young rats but only attenuated conditioning in adults. These results suggest that an enhanced CS-preexposure effect may account for the previously reported weaker conditioned taste aversion observed in young rats, as compared to adults, when there is a protracted interstimulus interval.