BEHAVIORAL-EFFECTS OF NOVEL BENZODIAZEPINE (OMEGA) RECEPTOR AGONISTS AND PARTIAL AGONISTS - INCREASES IN PUNISHED RESPONDING AND ANTAGONISMOF THE PENTYLENETETRAZOLE CUE

In recent years a number of novel compounds have been described with a ffinity and specificity for BZ (omega) receptors. While some of these agents appear to act, like benzodiazepines themselves, as full agonist s at different receptor subtypes (e.g. suriclone), several non-selecti ve partial agonists (e.g. bretazenil) have been described, as have a n umber of BZ(1) (omega(1)) selective drugs (e.g. zolpidem). Previous wo rk has reported a number of differences between the behavioural effect s of some of these drugs and those of benzodiazepines; however, very f ew studies have attempted systematic comparisons of a large number of drugs in different procedures. In the present study a wide range of BZ (omega) receptor ligands was studied using two behavioural methods in rats: unpunished and punished food-reinforced operant responding and the discriminative stimulus effects of pentylenetetrazole. Punished op erant responding showed increases with the benzodiazepines, chlordiaze poxide and clorazepate, the non-benzodiazepines, saripidem, CL 273,547 and F 2692 (limited effect at a single dose) and the partial agonists bretazenil and Ro 19-8022, but the BZ(1) selective agents, alpidem, a becarnil and CL 284,846, did not increase rates of punished operant re sponding. Rates of unpunished responding were decreased by higher dose s of all drugs except bretazenil and Ro 19-8022. Dose-related antagoni sm of the pentylenetetrazole (18 mg/kg) discriminative stimulus was pr oduced by several benzodiazepines, by the partial agonists bretazenil, Ro 19-8022 and divaplon, and by suriclone, saripidem and CL 273,547. The BZ(1) (omega(1)) selective drugs abecarnil, CL 284,846, zolpidem, CL 218,872 and alpidem were also active in blocking pentylenetetrazole but produced only partial antagonism which was not clearly dose-relat ed. The results show that novel BZ (omega) receptor ligands do not alw ays produce a behavioural profile identical to that shown by benzodiaz epines. In particular, BZ(1) (omega(1)) selective drugs do not give ri se to clear increases in punished operant responding and have only lim ited efficacy in blocking the pentylenetetrazole cue. These effects ma y be due to the marked propensity of BZ(1) (omega(1)) selective drugs to decrease operant response rates.