this proposal seeks to study time-dependent sensitization (TDS) after benzodiazepines (BZDs). TDS refers to the ability of many drugs to induce effects which grow or sensitize with time after acute treatment such that re-administration weeks later results in a significant enhancement of those actions: The present application is based on preliminary findings indicating that: 1) a single pretreatment with a low dose of diazepam significantly enhances the anticonvulsant effect of the same dose readministered two weeks later; 2) one injection of diazepam significantly sensitizes both haloperidol catalepsy and ptosis two weeks but not two hours later; 3) a single injection of saline 1 month earlier completely counteracts the antipentylenetetrazol (PTZ) action of diazepam (administered 1 hour before PTZ) on dopamine levels and turnover in the nucleus accumbens and frontal cortex and 4) TDS might occur to some of the antistress effects of diazepam. Our principal goals in this application are to determine whether the preliminary findings are likely to be generalizable to other BZD's, whether they could be due to pharmacokinetic factors and whether they are likely to be mediated by BZD receptors. These questions will be addressed using behavioral and biochemical procedures. If borne out, our findings would be of considerable significance. Specifically, they would suggest that: 1) The influence of a single modest exposure to a BZD can grow for extraordinary periods of time, possibly indicating that the progressive effect of anxiolytics during the first week or two of therapy may reflect a time-dependent sensitization process triggered by initial treatment and independent of repeated drug administration. In turn, this would suggest a new therapeutic regime, likely to avoid tolerance and consequent physical dependence, and 2) A single exposure to a BZD triggers an antidopaminergic influence which grows with time, possibly indicating that individuals earlier exposed to BZD's might be more sensitive to the actions of neuroleptics.
| Caggiula, A R; Epstein, L H; Antelman, S M et al. (1991) Conditioned tolerance to the anorectic and corticosterone-elevating effects of nicotine. Pharmacol Biochem Behav 40:53-9 |
| Antelman, S M; Cunnick, J E; Lysle, D T et al. (1990) Immobilization 12 days (but not one hour) earlier enhanced 2-deoxy-D-glucose-induced immunosuppression: evidence for stressor-induced time-dependent sensitization of the immune system. Prog Neuropsychopharmacol Biol Psychiatry 14:579-90 |
| Antelman, S M; Kocan, D; Edwards, D J et al. (1989) Anticonvulsant and other effects of diazepam grow with time after a single treatment. Pharmacol Biochem Behav 33:31-9 |
| Caggiula, A R; Antelman, S M; Aul, E et al. (1989) Prior stress attenuates the analgesic response but sensitizes the corticosterone and cortical dopamine responses to stress 10 days later. Psychopharmacology (Berl) 99:233-7 |
