There is substantial evidence in clinical therapy that psychic dependence occurs to the benzodiazepine tranquilizers as it does to other sedative/hypnotics. The problem of physical dependence has been more difficult to demonstrate. Often, in the clinical setting the spontaneous withdrawal associated with the cessation of therapy is confused with the original symptoms for which anxiolytic medication was first prescribed. With the availability of specific benzodiazepine antagonists, drug-precipitated withdrawal has been reported. Our objective is to examine several aspects of benzodiazepine dependence--pharmacological, anatomical and physiological. A model system which shows dependence in rats to this class of drugs is described. Dependence is induced by pretreating with diazepam HC1 (5 mg/kg, IP) for 8 days. Approximately 3 hours after the final dosing, either of the benzodiazepine antagonists, CGS-8216 or Ro 15-1788, is given to precipitate a withdrawal response as demonstrated by a significant increase in plasma corticosterone. This model will be substantiated by correlating changes in hormone response with behavioral activity. The use of plasma corticosterone to indicate the stress of withdrawal is made possible through the use of enclosed experimental chambers and appropriate surgical procedures. Blood samples are obtained and injections made through a chronic indwelling catheter inserted via the external jugular vein to the entrance of the right atrium. With the stereotaxic implantation of intracerebroventricular cannula guides, injections or pellet implants will be made into the cerebrospinal fluid or tissue sites in the hippocampus to examine benzodiazepine dependence and withdrawal precipitation. Further, electrolytic and neurocytotoxic lesion studies are proposed to confirm the involvement of specific neurotransmitters and anatomical sites in this process. These experiments will be amplified with evaluations of the neurotransmitter profile: serotonin, GABA, norepinephrine, dopamine, and acetylcholine in various areas of the brain as well as an autoradiographic analysis of benzodiazepine receptor density and affinity. It is anticipated that the results of these experiments will lend greater insight into the process of benzodiazepine dependence, the mechanisms and processes involved, and the influence of specific sites and neurotransmitters in the central nervous system.
| Eisenberg, R M (1993) Sound vibration, a non-invasive stress: antagonism by diazepam. Psychopharmacology (Berl) 110:467-70 |
| Eisenberg, R M; Johnson, C (1989) Effects of beta-carboline-ethyl ester on plasma corticosterone--a parallel with antagonist-precipitated diazepam withdrawal. Life Sci 44:1457-66 |
