Ellen A. Walker - US grants

A significant health problem for patients receiving chronic opioids for the relief of severe pain is the development of tolerance to the opioid's actions so that escalating doses of the opioid are required to maintain corresponding levels of analgesia. However, some opioids produce more pronounced tolerance than others and this difference has been suggested to be due to the opioid's ability to activate the receptor, or intrinsic efficacy. One strategy to clinically hinder tolerance might be to give opioids with varying efficacies in different sequences of chronic opioid treatment. Preclinical studies of repeated opioid treatment with various mu agonists may be useful in predicting the role of agonist intrinsic efficacy in tolerance and cross-tolerance development. A rat tail- withdrawal assay will be employed as a measure of antinociception. Briefly, the rats will be loosely restrained in rodent restrainers and 5-10 cm of the tail will be placed into 40 degrees and 55 degrees C water. The latency to tail-withdrawal is measured as the dependent variable and a 15 sec cut-off latency is imposed. Using this assay, the proposed experiments will examine the pattern of tolerance development to the antinociceptive effects of etorphine, etonitazene, morphine, buprenorphine, and GPA 1657 when subjects are treated chronically with etonitazene, morphine, buprenorphine, and GPA 1657, respectively. The pattern of tolerance development will be compared across agonists to determine if the degree of tolerance varies with relative intrinsic efficacy. Receptor theory would predict that the greatest degree of tolerance will be observed for the purported lower efficacy agonists, buprenorphine and GPA 1657, since these agonists typically require a greater fraction of the receptor population to produce a maximum effect. A smaller degree of tolerance may be observed for the purported higher efficacy agonists etorphine, etonitazene, and morphine since these agonists typically require a smaller fraction of the receptor population to produce a maximum effect. All five agonists will be studied in cross-tolerance experiments with the other four agonists in order to assess the possibility that chronic treatment with a lower efficacy agonist, such as buprenorphine or GPA 1657, will produce a greater degree of tolerance to all agonists than will chronic treatment with a higher efficacy agonist such as morphine, etorphine, or etonitazene. Experiments will study the effects of increasing maintenance doses of all five agonists on patterns of tolerance and cross-tolerance in order to characterize the relationship of agonist intrinsic efficacy to maintenance dose. Experiments will also characterize the pattern of recover for high efficacy agonists such as morphine, etorphine, and etonitazene and for low efficacy agonists such as buprenorphine and CPA 1657.

DESCRIPTION (Adapted from the Applicant's Abstract): Excitatory amino acid (EAA) receptors, and particularly the N-methyl-D-aspartate (NMDA) receptor, have been shown to play a critical role in learning and memory and to attenuate the development of tolerance to the prototypic opioid morphine. Tolerance to the behavioral effects of morphine has been shown to be influenced by both pharmacological (non-associative) and learning (associative) processes. The proposed experiments investigate the pharmacological and behavioral influence of the prototypic competitive NMDA antagonist, CGS 19755, and the prototypic noncompetitive NMDA antagonist, dizocilpine, on the development of tolerance to the behavioral effects of morphine. The pharmacological effects of chronic administration of NMDA antagonists on the development of tolerance to the antinociceptive effects of morphine will be determined in a rat tail-withdrawal procedure. These experiments will determine pharmacological endpoints such as potency, time-course, and effectiveness of NMDA antagonists on morphine-induced antinociception and tolerance. The influence of NMDA antagonists on the development of environmentally associated (i.e., associatively learned) tolerance to morphine will also be studied using the tail-withdrawal assay. The effects of dizocilpine on the retention or extinction of associative tolerance will also be examined. Finally, the effect of acute and chronic administration of NMDA antagonists on the development of tolerance to morphine in an instrumental conditioning procedure will be investigated. Rats will be trained to discriminate 3.2 mg/kg morphine from saline under a fixed-ratio schedule of food delivery. NMDA antagonists will be administered either alone or in conjunction with morphine to determine if tolerance to the stimulus and rate-decreasing effects of morphine are altered.

DESCRIPTION: (Applicant's Abstract) The neuronal mechanisms underlying the development of opioid tolerance and dependence have eluded researchers for decades. Recent investigations of a novel pharmacological class of compounds, called neutral antagonists, indicate that these compounds may attenuate effects produced by agonists but fail to produce effects of their own. In addition, neutral antagonists appear to reverse the effects produced by traditional antagonists in vivo and in vitro. A class of somatostatin analogues has been synthesized that includes selective high-affinity opioid ligands that may be candidates as neutral antagonists for the mu-opioid receptor. A few current reports have indicated that these purported neutral antagonists reverse opiate withdrawal produced by traditional mu-opiate receptor antagonists. The goal of the proposed experiments is to evaluate the behavioral and pharmacological properties of the putative neutral antagonists in nondependent and morphine-dependent rats using a variety of analgesia and drug discrimination procedures. By providing the first systematic evaluation of the behavioral effects of neutral antagonists, these studies could radically alter the manner in which we think about opioid receptor pharmacology. Furthermore, because these drugs block the effects of mu opioids, but do not precipitate withdrawal, the findings of these experiments will be highly relevant to the treatment of opioid dependence.

DESCRIPTION (provided by applicant): Psychoactive drugs can influence behavior by acting as rewarding and cuing stimuli in drug dependence. When drugs serve as rewards and motivate new behavior, drug-taking behavior develops. When drugs serve as cues (called discriminative stimuli), people learn to identify their characteristic effects in the body, such as changes in mood and emotion. These cues may reinstate drug-taking behavior and certainly play a role in the relapse of drug addiction. Using the drug discrimination method in the laboratory, subjects are specifically trained to recognize these drug effects. Investigators can then measure drug effects in a precise, quantitative, and reliable manner using drug discrimination methods and related approaches. One of the main goals of SSPD is the acquisition, exchange and distribution of information concerning recent research in the field of stimulus properties of drugs. In this application, the SSPD is requesting support from the National Institute on Drug Abuse (NIDA) to support our satellite symposium to the European Behavioral Pharmacology Society Conference in Barcelona, Spain on September 9, 2005. Our organization is uniquely qualified to address three important issues in drug abuse and addiction in our satellite symposium: 1) the role of discriminative stimulus and conditioned drug effects in the reinstatement and relapse of drug abuse; 2) the training and development of graduate students and junior colleagues interested in the advancement of drug abuse research, especially in regards to stimulus effects and drug cues; and finally 3) the open dialogue and exchange between senior NIDA-funded researchers and our European colleagues on the contribution of various drug cues to the acquisition, maintenance and treatment of drug addiction. For this day-long satellite session, papers will be solicited from all members and interested scientists from SSPD, EBPS, or the scientific community at large by announcing the meeting and presentations on our website, the EBPS website, our own electronic newsletter (February 2005), as well as a series of relevant listserves. Finally, as in previous years (1978-1998), the proceeding of our international satellite will be submitted for review for publication. The SSPD Satellite to the EBPS 2005 Conference promises to coordinate, exchange, and disseminate information to further our understanding of drug abuse.

DESCRIPTION (provided by applicant): The belief that cancer chemotherapy causes impairment of cognitive ability (termed 'chemo-fog', 'chemo- brain', or 'chemotherapy-related cognitive dysfunction') in a significant number of patients is widely accepted by patients and healthcare providers. A host of other factors are involved, such as the underlying pathology, the presence of a chronic disease, and psychological factors that are difficult to eliminate in human trials. In addition, during the course of treatment many, if not the majority, of patients receive a 'cocktail'combination of several drugs, providing abundant opportunity for drug interactions. Therefore, to accurately assess the possible cognitive effects of chemotherapeutic agents independent of the complications associated with clinical studies, we propose to directly test chemotherapeutic agents in a mouse model of learning and memory called autoshaping. The autoshaping procedure is a rapid, objective, and reliable measure of whether a drug will affect acquisition, consolidation, retrieval, extinction, spontaneous recovery, and reacquisition of a learned response. Specifically, we will treat male and female mice with multiple doses of cyclophosphamide, doxorubicin, 5-fluorouracil, methotrexate, tamoxifen, and docetaxel at various time points to measure effects on acquisition, consolidation, retrieval, extinction, spontaneous recovery, reacquisition, and state-dependent learning in the autoshaping procedure and on motivation in the progressive ratio procedure. The drugs will be tested individually and, importantly, in varying combinations using the mathematically rigorous 'joint-action analysis.'In addition, the chemotherapeutic agents and their combinations will be administered both acutely and repeatedly in male and female mice. We hypothesize that acute or repeated exposure to single or combined chemotherapeutic agents will produce greater decrements in the learning processes more heavily reliant on hippocampal functioning (consolidation, retrieval, and reacquisition) than those less reliant on hippocampal functioning (acquisition and extinction) at doses that do not alter the motivational aspects of the liquid reinforcer. Similarly, we predict that the retrieval of extinction learning (spontaneous recovery) will be affected to a greater degree by the chemotherapeutic agents than the acquisition of extinction learning. We also predict synergistic deficits with the antiestrogen tamoxifen and the other chemotherapeutic agents especially on consolidation and retrieval in female mice. Taken together, these experiments will provide the first comprehensive examination of the behavioral effects of a range of chemotherapeutic agents and their combinations in a simple, cognitive model in mice. PUBLIC HEALTH RELEVANCE: The studies proposed in the present application will assess the effects of six commonly used chemotherapy agents alone and in combination for the capacity to disrupt learning and memory in a preclinical mouse model. If certain drugs/combinations produce more adverse effects than others do, clinicians can make informed choices about their patients'therapy and improve the quality of life for cancer survivors and their families.