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Hippocampal endocannabinoids inhibit spatial learning and limit spatial memory in rats

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Abstract

Rationale

As exogenous cannabinoid agonists impair memory formation, could it be that antagonists have opposing effects and act as memory-enhancing drugs?

Objectives

Here, we studied the effects of the cannabinoid antagonist SR141716A (SR; Rimonabant) on spatial learning and memory formation and assessed the possible involvement of hippocampal CB1 receptor in these actions.

Materials and methods

In the water maze, spatial reference memory was probed using different training protocols followed by assessment of behavioral flexibility. The CB1 receptor antagonist SR (3 mg/kg) was intraperitoneally administered before or immediately after training in experiment 1, or via minipumps intrahippocampally (0.89 ng and 0.089 ng/day) either during or after spatial learning, or subcutaneously in experiment 2.

Results

In experiment 1, systemic SR impaired spatial learning when given intraperitoneally (ip) before training coincident with increasing swim speed and thigmotaxis. Pretraining before drug treatment eliminated these effects while post-training injections had no effect. In experiment 2, intrahippocampal infusion of 0.089 ng SR during training enhanced acquisition learning, but did not affect long-term consolidation of spatial memory. In contrast, subcutaneous infusion of SR via minipumps had no effect. Post-training infusion of SR did not affect reversal learning, but short-term memory (1 h post-training) was weaker, and long-term memory for the reversal platform location was enhanced.

Conclusions

Systemic Rimonabant-induced deficits are due to anxiogenic properties of the drug. The difference between administration regimes is discussed in terms of CB1 receptor blockade in multiple non-memory and memory-related brain regions and the possibility that selective inactivation of hippocampal CB1 receptors may be memory enhancing.

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Acknowledgement

This work was supported by a component grant from the MRC to GR and RGP, and NIH grant DA08549 to REH. There is no conflict of interest.

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Authors and Affiliations

  1. School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK

    Lianne Robinson, Susan McKillop-Smith, Nicola L. Ross, Roger G. Pertwee, Robert E. Hampson, Bettina Platt & Gernot Riedel

  2. Department of Physiology and Pharmacology, Wake Forest University Baptist Medical Center, Winston-Salem, NC, USA

    Robert E. Hampson

Authors
  1. Lianne Robinson
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  2. Susan McKillop-Smith
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  3. Nicola L. Ross
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  4. Roger G. Pertwee
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  5. Robert E. Hampson
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  6. Bettina Platt
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  7. Gernot Riedel
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Correspondence to Gernot Riedel.

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Robinson, L., McKillop-Smith, S., Ross, N.L. et al. Hippocampal endocannabinoids inhibit spatial learning and limit spatial memory in rats. Psychopharmacology 198, 551–563 (2008). https://doi.org/10.1007/s00213-007-1012-8

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  • DOI: https://doi.org/10.1007/s00213-007-1012-8

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