Many drugs produce a pattern of withdrawal from dependence characterized by subjective symptoms such as anxiety. Research on the importance of withdrawal signs and symptoms in maintaining drug dependence has frequently focused on the more vivid physical signs. However, the symptoms of withdrawal occur earlier and last much longer than the more overt physical signs, and its is plausible that these events are critical in the maintenance of drug taking. Because they are subjective aspects of withdrawal, they have been difficult to study in animal models of drug dependence. The proposed research will continue our investigation of the usefulness of a drug discrimination technique for detecting interoceptive stimulus events that are associated with benzodiazepine withdrawal. These experiments are based on the observation that rats can be trained to discriminate the stimulus properties of pentylenetetrazol (PTZ). In general, the pattern of drugs that mimic or block the PTZ stimulus share a corresponding pattern of provoking or diminishing human anxiety. Based on this observation we have established that eh discrimination of PTZ stimuli is a suitable procedure for investigating subjective events related to drug dependence/withdrawal. The proposed experiments will use rats trained to discriminate PTZ to expand our study of withdrawal from benzodiazepine dependence. In this grant period, we will continue these investigations in three different areas. First, we propose to investigate a novel mechanism that may mediate benzodiazepine tolerance and dependence, and these studies will include both behavior and receptor-binding components. Both our laboratory and other groups have obtained data showing that following chronic administration of a benzodiazepine agonist, the benzodiazepine- receptor antagonist Ro 15-1788 produces withdrawal phenomena that occur both at a time when the agonist is present in the subject and at a time when no agonist or metabolites are present in the subject. These observations are intriguing because they provide a new mechanism to account for benzodiazepine dependence/withdrawal phenomena. In this model, withdrawal does not occur just because the receptor-antagonist displaces the dependence-producing drug from the receptor; rather withdrawal occurs because the intrinsic properties of the receptor have been altered such that agonists are less potent in their effects, inverse agonists are more potent in their effects and previously neutral antagonists such as Ro 15-1788 show the properties of inverse agonists. We will test this hypothesis at both the behavioral and receptor-binding level, using detection of a PTZ-like stimulus as the behavioral assay. A second portion of the proposed experiments will test for tolerance to the discriminative stimulus properties of diazepam. There is surprisingly little information available about this type of tolerance, and the proposes studies will determine fundamental parameters of induction and recovery from tolerance as a function of the dose of diazepam given chronically. These studies are potentially important for understanding benzodiazepine dependence because tolerance to the subjective effects of a drug may be directly linked to an increased probability that the drug will be taken in higher doses. A third portion of the proposed experiments will test for brain sites mediating the detection and blockade of the PTZ stimulus. These experiments are important to the overall aims os the grant because they will provide information for future tests of brain sites that mediate benzodiazepine withdrawal. In addition, this set of experiments may provide insight into brain areas involved in the modulation of anxiogenic/anxiolytic actions of drugs.
| Lytle, D A; Emmett-Oglesby, M W; Stephens, D N (1995) Discriminative stimulus effects of midazolam and abecarnil in rats treated chronically with diazepam or abecarnil. Psychopharmacology (Berl) 121:339-46 |
| Emmett-Oglesby, M W; Lytle, D A; English, S A (1993) Abecarnil used to treat benzodiazepine withdrawal. Psychopharmacol Ser 11:121-31 |
| Pugh, S L; Boone, M S; Emmett-Oglesby, M W (1992) Tolerance, cross-tolerance and withdrawal in rats made dependent on diazepam. J Pharmacol Exp Ther 262:751-8 |
| Emmett-Oglesby, M W; Rowan, G A (1991) Drug discrimination used to study drug withdrawal. NIDA Res Monogr :337-57 |
| Emmett-Oglesby, M W; Mathis, D A; Moon, R T et al. (1990) Animal models of drug withdrawal symptoms. Psychopharmacology (Berl) 101:292-309 |
| Mathis, D A; Emmett-Oglesby, M W (1990) Quantal vs. graded generalization in drug discrimination: measuring a graded response. J Neurosci Methods 31:23-33 |
| Harris, C M; Emmett-Oglesby, M W; Lal, H (1989) Sensitivity of pentylenetetrazol discrimination increased by a stimulus fading technique. Psychopharmacology (Berl) 98:460-4 |
| Emmett-Oglesby, M W (1989) Anxiogenic effects of drug withdrawal. NIDA Res Monogr 95:127-8 |
| Emmett-Oglesby, M W; Mathis, D A (1989) Withdrawal from benzodiazepine dependence as a discriminative stimulus. NIDA Res Monogr 95:284 |
| Emmett-Oglesby, M W; Mathis, D A; Harris, C M et al. (1988) Withdrawal from diazepam substitutes for the discriminative stimulus properties of pentylenetetrazol. J Pharmacol Exp Ther 244:892-7 |
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