Continuous slow release of low levels of diazepam produces tolerance to its depressant and anxiolytic effects on the startle reflex.
Development of tolerance to the depressant effects of diazepam on the acoustic startle reflex and to the blockade of fear-potentiated startle, a measure of fear or anxiety in rodents, was evaluated after chronic administration via continuous release from implanted diazepam-filled silastic capsules or daily intraperitoneal (i.p.) injections. After continuous exposure to diazepam via capsule implants, complete tolerance occurred to the depressant effects of diazepam on startle and partial tolerance occurred to the antifear effects. In contrast, no tolerance was observed after daily i.p. injection with comparable amounts of diazepam (5 mg/kg) although tolerance could be produced by daily i.p. injections of a much higher dose of diazepam (20 mg/kg). These data suggest that tolerance to at least some behavioral effects may be much easier to produce with continuous rather than intermittent occupation of benzodiazepine receptors.
D000818:Animals; D014151:Anti-Anxiety Agents; D001921:Brain / Q000378:metabolism; D003216:Conditioning, Operant / Q000187:drug effects; D003864:Depression, Chemical; D003975:Diazepam / Q000008:administration & dosage / Q000494:pharmacology*; D004343:Drug Implants; D004361:Drug Tolerance; D005442:Flumazenil / Q000494:pharmacology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013216:Reflex, Startle / Q000187:drug effects*
D014151:Anti-Anxiety Agents; D004343:Drug Implants; D005442:Flumazenil; D003975:Diazepam