AbstractPharmacological, electrophysiological, and biochemical studies have been conducted with rats in an attempt to demonstrate that some of the behavioral effects of nicotine may involve non‐cholinergic brain sites. The behavioral response consisted of a prostration‐immobilization syndrome following the injection of 1−10 μg of nicotine into the region of the lateral or third transmitters and their antagonists, and a number of other psychotropic drugs were ineffective in either enhancing or antagonizing the action of nicotine. Associated with the behavioral response were distinct electrophysiological patterns recorded from electrodes implanted in the dorsal hippocampus in freely moving rats. The characteristic electrical changes consisted of shifts in the frequency from 6 to 8 per second to 2 to 4 per second, and shifts in the amplitude from 300 to 400 μV to 100 to 200 μV. A number of derivatives of nicotine and piperidine were synthesized which were found to be antagonistic to the psychopharmacological and electrical effects of nictotine. The natural (−)‐nicotine isomer was found to be at least 100 times as effective as the (+)‐nicotine on the brain. It was not possible to demonstrate3H nicotine bending to neural membrane preparations; however, the sereospecific nicotine binding was demonstrable in fresh brain slices and to glass filters. The Kbwas 2.0 ×