The effects of intracranial administration of hallucinogens on operant behavior in the rat I. lysergic acid diethylamide

Abstract

Lysergic acid diethylamide (LSD) was infused in one μl volumes into discrete brain regions of rats trained to press a bar for food reinforcement. The sites were chosen as major areas of the brain 5-hydroxytryptamine (5HT) system: the dorsal and median raphe nuclei, dorsal hippocampus, lateral habenular nuclei, and the prefrontal cortex. Following training in a fixed ratio-40 (FR-40) operant behavior rats were implanted with stainless steel cannulae aimed at the brain area to be examined. Bilateral cannulae were implanted for the lateral habenular nuclei, dorsal hippocampus and the prefrontal cortex. Following recovery from surbery, LSD (8.6 to 86 μg) or vehicle was infused immediately before a daily operant session. Infusion of vehicle was inactive. LSD produced a dose-dependent decrease in reinforcements and an increase in 10-sec periods of non-responding (pause intervals). LSD was significantly more potent when infused into the dorsal raphe nucleus than following intracerebroventricular (ICV) administration, whereas LSD was less potent when infused into the median raphe, lateral habenula or dorsal hippocampus. ED50s for increases in pause intervals were 9, 13, 23, 25, and 54 μg for infusion into the dorsal raphe, prefrontal cortex, dorsal hippocampus, median raphe, and lateral habenular nuclei, respectively. The ED50 for ICV administration in a previous study was 15 μg. The ED50 of LSD placed into the prefrontal cortex did not differ significantly from that of the ICV infusion. The time-course of effects of equivalent doses of LSD was shorter than the 40-min operant session for IP, ICV, dorsal raphe, lateral habenula, and dorsal hippocampus administrations. However, median raphe and prefrontal cortex infusions of comparable doses increased pausing throughout the 40-min session. The dose-response curve for IP administration of LSD was shifted to the left in animals with cannulae in dorsal raphe or prefrontal cortex, whereas no changes were seen in the response to IP administration of LSD in animals cannulated in the other sites. These data suggest that the disruption of operant behavior by LSD may have important components of activity in the dorsal raphe, median raphe and the prefrontal cortex. Nevertheless, it seems likely that LSD acts at multiple brain sites simultaneously in order to induce these behavioral effects.