Modulation of the discriminative stimulus produced by pentylenetetrazol by centrally administered drugs

Pentylenetetrazol is anxiogenic in humans and produces an interoceptive discriminative stimulus in rats which is mimicked by anxiogenic drugs and other treatments and antagonized by anxiolytic drugs. It was proposed that the discriminative stimulus of pentylenetetrazol originates centrally. This hypothesis was tested by injecting small amounts of anxiogenic or anxiolytic drugs into the brain and comparing their ability to mimic or block, respectively, the response to pentylenetetrazol, observed after systemic injection. Food-restricted rats were trained in a two-lever operant task to discriminate the interoceptive discriminative stimulus produced by pentylenetetrazol. Intraperitoneal or intracerebroventricular injection of Ro 5-3663 was substituted in a dose-dependent manner for the stimulus produced by systemically administered pentylenetetrazol. Diazepam injected systemically, blocked the pentylenetetrazol-like stimulus associated with Ro 5-3663 administered systemically or centrally. Midazolam injected intracerebroventricularly and in a dose-dependent manner, antagonized the discriminative stimulus produced by systemic injection of pentylenetetrazol. When injected into the amygdala, midazolam also antagonized in a dose-dependent manner the pentylenetetrazol-induced stimulus. Thus, these data suggest that there are sites in the CNS for both the initiation of a pentylenetetrazol-like stimulus by Ro 5-3663 and the antagonism of the stimulus produced by pentylenetetrazol by midazolam.