Wolfgang Klosterhalfen

Pavlovian conditioning of immunosuppression modifies adjuvant arthritis in rats.

Ten days prior to induction of adjuvant arthritis (by injection of complete Freunds adjuvant into a rats hind paw), three groups of rats were dosed with cyclophosphamide (CY), an immunosuppressive drug. A saccharin/vanilla solution (SV) was presented either 2 days (Group NC) or immediately before CY treatment (Groups C and C2). Three further SV presentations started either 30 min (Groups C and NC) or 2 days after antigenic stimulation (Group C2). The groups did not differ with respect to the degree of swelling in the injected paws. In contrast, Group C differed significantly from Groups NC and C2 with respect to the uninjected hind paws: Group C showed no external signs of a proliferation of inflammation, whereas approximately half of the animals in the other two groups developed small lesions. A second experiment, similar to the first, yielded the same results. These results essentially confirm previous findings on conditioned immunosuppression and extend them to an inflammatory joint disease.

Effects of overshadowing on conditioned nausea in cancer patients: an experimental study

The infusion of cytotoxic drugs in cancer patients is often accompanied by posttreatment nausea (PN). In addition, patients complain about nausea prior to an infusion [i.e., anticipatory nausea (AN)]. AN is mainly explained by classical conditioning, with the infusion as the unconditioned stimulus (US) and with the stimuli signaling the infusion as conditioned stimuli (CS). Despite this conditioning etiology, a specifically derived therapy to attenuate the CS-US contingency is missing. The purpose of this study is to develop and to test an overshadowing procedure for prevention of AN, and also for the modification of PN intensity. Sixteen cancer patients were assigned to one of two groups: Overshadowing+ (OV+) and Overshadowing- (OV-). At the start of all infusions of two consecutive chemotherapy cycles A and B (acquisition), OV+ subjects drank a saliently tasting beverage (the overshadowing CS), whereas group OV- drank water. All patients received water in cycle C (test). Self-reported symptoms and heart rates were recorded. As expected, in cycle C (test), no patient of group OV+ showed AN, whereas two patients of group OV- developed AN. There was a tendency for a reduction of the intensity of PN, in terms of duration and latency after overshadowing, in cycle C: OV+ patients tended to show a shorter duration and a longer latency between end of infusion and PN onset. In OV-, there was a significantly larger heart rate deceleration in both measurement periods, in the anticipatory and the posttreatment measurement period. Data suggest to apply overshadowing for prevention of AN and modification of PN. Physiological markers of conditioned nausea are revealed. After its procedural implementation, the technique can be used in larger samples now.

Conditioned cyclosporine effects but not conditioned taste aversion in immunized rats.

In 2 experiments, the development of adjuvant arthritis (an experimental autoimmune disease) was inhibited by exposing rats to a flavored solution that had previously been paired with injections of cyclosporine (an immunodepressive drug) compared with rats with the same history but exposed to a flavored solution that had previously not been paired with drug injections. In contrast to earlier experiments on conditioned cyclophosphamide effects, rats did not avoid the taste that had previously been paired with drug administration. Thus, conditioned immunopharmacologic effects were not confounded with taste aversion. These observations are interpreted as reflecting an associative learning process that affected the development of an autoimmune disease.

Anticipatory nausea in cancer patients receiving chemotherapy: Classical conditioning etiology and therapeutical implications

The delivery of cytotoxic drugs in cancer treatment is often accompanied by posttreatment side effects (e.g., nausea). Moreover, there is evidence that cancer patients are at risk to develop these side effects in anticipation of chemotherapy (i.e., anticipatory nausea [AN]). AN can be explained as the result of a classical conditioning process with the cytotoxic drug as the unconditioned stimulus (US). Stimuli paired with the US (e.g., smells, tastes) can become conditioned stimuli (CSs) eliciting AN as the conditioned response (CR). The present study was conducted to test whether AN shows characteristics of a CR. Fifty-five ambulatory cancer patients were asked to record nine kinds of physical symptoms (e.g., nausea, vomiting, sweating) on time-scheduled symptom lists: after an infusion (indicating posttreatment symptoms) and prior to their next infusion (indicating anticipatory symptoms). Each measurement period covered a maximum of 48 hours. AN was reported by ten patients (18.08%). Data revealed (a) a statistically significant association between posttreatment nausea and vomiting, respectively, and AN; (b) the occurrence of AN increased with drug emetogenity (i.e., US-intensity); and (c) the duration of AN increased with temporal proximity to the infusion. The results support the conditioning model. Thus, it is proposed to prevent AN by classical conditioning techniques (e.g., overshadowing).

Classically Conditioned Effects of Cyclophosphamide on White Blood Cell Counts in Rats

High doses of cyclophosphamide (CY) are toxic to bone marrow and lead to leukopenia. ’ In rats white blood cell counts are reduced to about 20% three to four days after drug administration and return to normal after about ten days. In the experiments to be presented here we asked whether the CY-induced leukopenia is subject to Pavlovian conditioning. In view of recent conditioning experiments with CY, this question may not be surprising. The drug has a variety of effects in the body, and some of these effects have already been shown to be conditionable. Cyclophosphamide has hormonal effects, such as increasing plasma corticosterone (PC), which can be conditioned.’ In addition, the drug may cause severe nausea and vomiting. This is perhaps a reason why CY acts as a powerful unconditioned stimulus (US) to produce conditioned taste aversion (CTA) in animals and humans.’ Furthermore, CY is an alkylating agent which is highly immunosuppressive. That the immunosuppressive properties of CY are also subject to conditioning was suggested by a study of CTA with CY: Ader4 discovered that rats that were reexposed to a saccharin drinking solution (conditioned stimulus, CS) after it had been paired with CY displayed not only marked aversion to saccharin, but also increased mortality. Ader hypothesized that the mortality was a result of conditioned immunosuppression. This hypothesis has gained support from an impressive amount of data summarized by Ader and Cohen.’ In brief: the presentation of saccharin, previously paired with CY, was shown to result in a depression of humoral and cell-mediated immune responses assessed after appropriate antigenic stimulation. Clinical relevance of the phenomenon is suggested by the fact that the development of autoimmune diseases such as murine systemic lupus erythematosus and adjuvant arthritis in rats can be inhibited using similar conditioning procedures.”8 In the experiments on conditioned PC elevation2 and on conditioned immunosuppression, ’3 the CS that was paired with CY had virtually always come to function as a substitute for the drug in eliciting immediately observable effects similar to those of the drug. On the basis of these experiments we predicted that if the CY-produced reduction in white blood cells is indeed subject to conditioning, CS presentation will result in an exacerbation rather than alleviation of leukopenia. The aim of the present experiments was to assess whether exposure to a CS that was paired with CY exacerbates the CY-produced leukopenia. Moreover, the exper-

Classically conditioned changes of blood glucose level in humans

Procedures of classical conditioning in animals and man have provided evidence that most psychophysiological responses can be acquired by repeated association with previous neutral stimuli. Many animal studies reported on conditioned changes in the blood glucose level; the nature of the conditioned response (CR), hypo- or hyperglycemia, however, seems to vary with experimental procedures. The present study aimed to elicit conditioned blood glucose changes in human subjects. Thirty male volunteers participated in five sessions each. The sessions were separated by 3 days, with identical time course and procedure. The subjects were informed that we wanted to test the effects of insulin or placebo injections on cognitive functioning, and were kept busy with pseudotests. In four sessions, subjects were injected with 0.035 IU/kg body weight of human insulin as the unconditioned stimulus (US), which induced the expected fall in blood glucose level below 50 mg/dl (UR). Injections were accompanied by a specific stimulus compound (conditioned stimulus, CS) in half of the subjects. In the fifth session, the CS was associated with a placebo injection. About half of the subjects showed a change from the baseline level of blood glucose of more than 10 mg/dl, which we would interpret as a conditioned response. Conditioning occurred more often in those subjects who were given a CS compound in addition to the injection, which itself together with the experimental environment may have been a sufficient CS.

Habituation of heart rate in functionally decorticate rats

Habituation of acoustically evoked heart rate responses and retention of this habituation was studied in functionally decorticate rats. An improved technique to induce cortical spreading depression (CSD) resulted in a pronounced and continuous depression of electroencephalographic activity. In Experiment 1, short-term habituation (STH) was demonstrated in decorticate rats and surgical controls; long-term habituation (LTH, 24 hr) occurred only in intact animals. In Experiment 2, only CSD groups were used. As in the first experiment, STH but not LTH was obtained under CSD. However, there was clear evidence that habituation could be retained subcortically for 30 min. It is concluded that the rats cortex is not necessary for habituation of acoustically evoked heart rate responses and retention of this habituation over a moderately long interval. However, the results suggest that the cortex is involved in LTH and that the neuronal substrates of STH and LTH are, in significant part, different.