β-Carbolines with agonistic and inverse agonistic properties at benzodiazepine receptors of the rat

The anxiogenic or anxiolytic properties of five β-carbolines were assessed in rats trained in two-lever operant chambers to operate one lever to obtain food reward when treated with a training drug, and the other when treated with saline. Two such drug-discrimination tests were used, employing either chlordiazepoxide (CDP) or pentylenetetrazol (PTZ) as training drugs. The benzodiazepine (BZ) agonist, ZK 93 423, substituted for the CDP cue and antagonized the PTZ cue. The inverse agonists DMCM and FG 7142 showed the opposite effects. An antagonist, ZK 93 426, antagonized the CDP cue but did not substitute for PTZ, while a partial agonist was identified as CDP-like but only partially antagonized the PTZ cue. An anxiolytic profile (substitution for CDP and antagonism of PTZ) was associated with GABA ratios of about 2, and an anxiogenic profile with GABA ratios less than 1. The antagonist and partial agonist displayed intermediate values. These observations are generally consistent with the β-carbolines modulating anxiety through their activity at BZ receptors influencing GABAergic neurotransmission.