Elsevier

Neuropharmacology

Volume 42, Issue 8, June 2002, Pages 993-1007
Neuropharmacology

Review
Functions of cannabinoid receptors in the hippocampus

https://doi.org/10.1016/S0028-3908(02)00060-6Get rights and content

Abstract

Marijuana smoking is recognised to impair human cognition and learning, but the mechanisms by which this occurs are not well characterised. This article focuses exclusively on the hippocampus to review the effects of cannabinoids on hippocampal function and evaluate the evidence that hippocampal cannabinoid receptors play a role in learning and formation of memory. Activation of cannabinoid receptors inhibits release of a variety of neurotransmitters, and modulates a number of intrinsic membrane conductances. Suppression of inhibitory GABAergic synaptic transmission has been repeatedly described, but whether there is also control of excitatory glutamatergic transmission is more controversial. The recognition that the commonly used WIN55,212-2 also acts via non-cannabinoid receptors may help resolve this issue. The involvement of endocannabinoids in depolarisation induced suppression of inhibition (DSI) and the demonstration that activation of metabotropic glutamate receptors can stimulate endocannabinoid release have provided the first insights into the physiological roles of the cannabinoids. Cannabinoids have consistently been reported to inhibit high frequency stimulation induced synaptic long-term potentiation but the experimental design of most behavioural experiments have meant it is not possible to categorically demonstrate a role for hippocampal cannabinoid receptors in learning and memory.

Section snippets

Background to the cannabinoids

Mammalian tissues contain at least two types of cannabinoid receptors, CB1 and CB2, both of which have been cloned (for reviews see Pertwee, 1997, Pertwee and Ross, 2002). CB1 receptors are present in the central nervous system and also in certain peripheral tissues (Pertwee, 1997). Within the brain, the distribution of CB1 receptors is heterogeneous, areas expressing this receptor type in particularly high concentrations include the cerebral cortex, hippocampus, lateral caudate-putamen,

Anatomical localisation of cannabinoid receptors in the hippocampus

The anatomical localisation of CB receptors in the brain has been visualised using in situ hybridisation to detect mRNA, and autoradiographic or immunohistochemical labelling of CB receptors themselves. Since it is thought that CB2 receptors are only present in peripheral tissues (Munro et al., 1993, Pertwee, 1997), these studies have focused on the distribution of CB1 receptors. The use of various antibody labels have consistently found the CB1 receptor immunoreactivity to be localised to the

Effects of cannabinoids on release of neurotransmitters

There is abundant evidence that cannabinoids can inhibit the release of several neurotransmitters throughout the brain (see Schlicker and Kathmann, 2001), but in the hippocampus this has focused on GABA and acetylcholine (ACh). Δ9-THC, CP55940, R-(+)-WIN55,212-2 and anandamide all inhibit release of ACh from the hippocampus in vivo (Carta et al., 1998, Gessa et al., 1997, Gessa et al., 1998) or in vitro (Gifford and Ashby, 1996, Gifford et al., 1997a, Gifford et al., 1999, Gifford et al., 2000

Behavioural function of hippocampal cannabinoid receptors

The hippocampus forms part of the medial temporal lobe, a brain structure strongly implicated in learning and formation of ‘declarative’ (Squire, 1987, Squire, 1992) or ‘episodic’ (Tulving, 1983) memory. It is therefore reasonable to assume that CB1 receptor-mediated effects on electrophysiological and cellular responses also translate into behaviourally relevant events. The corollary is that hippocampal CB1 receptors may participate in mechanisms of encoding, consolidation and/or retrieval in

Future directions

The investigation of the effects of cannabinoids on the hippocampus is at an intriguing stage because there is now real cause for optimism that many of the apparent inconsistencies and contradictions in the literature may soon be explained. Just some of the possible points of clarification that are prompted by this review include the following. It will be important to characterise the receptors mediating the effects of R-(+)-WIN55,212-2 on GTPγS binding and excitatory synaptic transmission in

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