SYSTEMIC OR INTRAHIPPOCAMPAL CANNABINOID ADMINISTRATION IMPAIRS SPATIAL MEMORY IN RATS

The purpose of the present study was to investigate the disruptive eff ects of cannabinoids on working memory as assessed in the eight-arm ra dial-maze. Systemic administration of Delta(9)-THC, WIN-55,212-2, and CP-55,940 increased the number of errors committed in the radial-maze. CP-55,940 was the most potent cannabinoid in impairing memory (ED(50) = 0.13 mg/kg). Delta(9)-THC and WIN-55,212-2 disrupted maze-choice ac curacy at equipotent doses (ED(50) values = 2.1 and 2.2 mg/kg, respect ively). In addition, systemic administration of each of these agents r etarded completion time. Whereas the doses of Delta(9)-THC and CP-55,9 40 required to retard maze performance were higher than those needed t o increase error numbers, WIN-55,212-2 was equipotent in both of these measures. On the other hand, neither anandamide, the putative endogen ous cannabinoid ligand, nor cannabidiol, an inactive naturally occurri ng cannabinoid, had any apparent effects on memory. A second aim of th is study was to elucidate the neuroanatomical substrates mediating the disruptive effects of cannabinoids on memory. Intrahippocampal inject ions of CP-55,940 impaired maze performance in a dose-dependent manner (ED(50) = 8 mu g/rat), but did not retard the amount of time required to complete the maze. The effects of intrahippocampal CP-55,940 were apparently specific to cognition because no other cannabinoid pharmaco logical effects (e.g., antinociception, hypothermia, and catalepsy) we re detected. This dissociation between choice accuracy in the radial-m aze and other cannabinoid pharmacological effects suggests that the wo rking memory deficits produced by cannabinoids may be mediated by cann abinoid receptors in the hippocampus.