Many drugs produce a pattern of dependence characterized by subjective signs such as anxiety arising during withdrawal. Typically these signs occur earlier and last much longer than more overt physical signs of withdrawal. Because they are subjective aspects of withdrawal, they have been difficult to study in animal models of drug dependence. The proposed research will determine the usefulness of a drug discrimination technique in detecting subjective signs arising during withdrawal from benzodiazepines. 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 PTZ stimuli share a corresponding pattern of provoking or diminishing human anxiety. This observation suggests that the discrimination of PTZ stimuli may be suitable for investigating subjective events related to drug dependence/withdrawal phenomena. These experiments will use trained rats to discriminate PTZ to determine if withdrawal from dependence on benzodiazepines generates internal stimuli that mimic those of PTZ. Further objectives include establishing that a benzodiazepine receptor antagonist precipitates withdrawal; comparison of overt physical signs of withdrawal that may occur under a dosing regimen necessary to produce withdrawal signs detected by the PTZ discrimination; characterization of withdrawal from a benzodiazepine with a short elimination half-life; and determination of the extent to which withdrawal signs can be modified by administration of drugs known to either share features of sedative-hypnotic cross-dependence or provide relief of sedative-hypnotic withdrawal signs in humans. Experiments use rats trained using drug discrimination methodology to perform one task in the presence of PTZ, and a second task in the absence of PTZ. They will be made dependent on benzodiazepines by repeated injection, and subsequently they will be withdrawn (spontaneous or precipitated) and tested for generalization of the withdrawal state to the PTZ stimulus and correlation of PTZ withdrawal signs in humans. Experiments use rats trained using drug discrimination methodology to perform one task in the presence of PTZ, and a second task in the absence of PTZ. They will be made dependent on benzodiazepines by repeated injection, and subsequently they will be withdrawn (spontaneous or precipitated) and tested for generalization of the withdrawal state to the PTZ stimulus and correlation of PTZ withdrawal signs to overt signs of withdrawal. Additional experiments will determine the degree to which other anxiolytic drugs, alcohol and clonidine modify the PTZ-like stimuli arising during withdrawal. Positive results will be significant because they will provide a useful model for objectively quantifying a subjective feature of drug dependence/withdrawal in animals, and they will provide a general procedure that may be useful for investigating subjective aspects of withdrawal from other drug classes.
| 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 |
| Emmett-Oglesby, M W; Mathis, D A (1989) Withdrawal from benzodiazepine dependence as a discriminative stimulus. NIDA Res Monogr 95:284 |
| 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; 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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