Learnt tolerance to sedative effects of chlordiazepoxide on self-stimulation performance, but no tolerance to facilitatory effects after 80 days.

Sedative and facilitatory effects on variable-interval hypothalamic self-stimulation were monitored during chronic treatment with chlordiazepoxide (CDP; 7.5 mg/kg IP), given at 48-h intervals in two groups of rats. Group 1 was injected immediately before each of 40 1-h self-stimulation sessions ("drugged responding"); Group 2 was injected after self-stimulation for the first 20 sessions ("undrugged responding"), and before self-stimulation for a further 20 sessions ("drugged responding"). Significant sedation occurred in both groups in initial sessions of drugged responding, even though Group 2 had already received 20 injections of CDP (after undrugged sessions). Sedative effects showed very rapid tolerance, and disappeared after 1-3 sessions, but only in rats which had been responding while drugged (and which thus had had opportunities to develop coping strategies against the sedative effects). After further sessions of drugged responding, sedation was replaced by apparently stimulant effects. Stimulant effects showed no tolerance at all in either group even after 40 injections, thus differing from anti-conflict (and other) effects of BZDs, which generally show gradual tolerance. These results show that coping strategies acquired by instrumental learning can account for rapid and selective tolerance to sedative effects. Coping strategies do not account for the differing rates of tolerance to stimulant and to other effects of BZDs; these differences may indicate pharmacologically distinct brain systems downstream from the BZD receptor.