Cannabinoids Encoding for Short-Term Reveal the MemoryNecessity in of RatsHippocampal Neural
Robert E. Hampson and Sam A. Deadwyler
Department of Physiology and Pharmacology and Center for Neurobiological Investigation of Drug Abuse,Wake Forest University School of Medicine, Winston Salem, North Carolina 27157
The memory-disruptive effects of 9-tetrahydrocannabinol ( 9-THC) and the synthetic cannabinoid WIN 55,212-2 (WIN-2) wereassessed in rats exposed to varying doses of each drug ( 9-THC,0.5–2.0 mg/kg; WIN-2, 0.25–0.75 mg/kg) during performance of a delayed nonmatch to sample (DNMS) task. Cannabinoids af-fected performance in a dose delay-dependent manner, withWIN-2 showing a potency more than four times that of 9-THC.These effects on DNMS performance were eliminated if thecannabinoid CB1 receptor antagonist SR141617A (Sanoﬁ Re-search Inc.) was preadministered, but doses of the antagonistalone had no effect on performance. Simultaneous recordingfrom ensembles of hippocampal neurons revealed that bothWIN-2 and 9-THC produced dose-dependent reductions in thefrequency (i.e.,“strength”) of ensemble ﬁring during the samplephase of the task to the extent that performance was at risk for errors on 70% of trials as a function of delay. This decrease inensemble ﬁring in the Sample phase resulted from selectiveinterference with the activity of differentiated hippocampal func-tional cell types, which conjunctively encoded different combi-nations of task events. A reduction in ensemble ﬁring strength didnot occur in the nonmatch phase of the task. The ﬁndingsindicate that activation of CB1 receptors renders animals at riskfor retention of item-speciﬁc information in much the same man-ner as hippocampal removal.
Key words: cannabinoids; memory; hippocampus; neural en-sembles; encoding; dose dependence; agonists/antagonists
The precise role of the mammalian hippocampus in the processingof memory has evolved considerably since initial reports some 40years ago (Scoville and Milner, 1957) showing retention deﬁcits inhumans after damage to the medial temporal lobe and relatedstructures (Milner, 1972; Zola-Morgan et al., 1986; Warrington andDuchen, 1992; Mishkin et al., 1998). Early studies in animalsshowed that lesions of hippocampus impaired performance in delaytasks (Correll and Scoville, 1965; Olton and Feustle, 1981; Rawlins,1985; Parkinson et al., 1988; Raffaele and Olton, 1988). However,later studies demonstrated that many of these deﬁcits resulted fromretrohippocampal damage, and performance was not impaired byibotenate lesions conﬁned to the dentate gyrus and CA1 and CA3subﬁelds (Jarrard, 1993; Rawlins et al., 1993). In rodents, it is alsoclear that hippocampal lesions impair spatial short-term memory(Angeli et al., 1993; Cho and Jaffard, 1995). We have recentlyshown that selective hippocampal removal impairs performance of a spatial delayed nonmatch to sample (DNMS) task in rodents(Hampson et al., 1999a). Similar but completely reversible memory