Hippocampal endocannabinoids inhibit spatial learning and limit spatial memory in rats.
BACKGROUND
As exogenous cannabinoid agonists impair memory formation, could it be that antagonists have opposing effects and act as memory-enhancing drugs?


OBJECTIVE
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 CB(1) receptor in these actions.


METHODS
In the water maze, spatial reference memory was probed using different training protocols followed by assessment of behavioral flexibility. The CB(1) 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 CB(1) receptor blockade in multiple non-memory and memory-related brain regions and the possibility that selective inactivation of hippocampal CB(1) receptors may be memory enhancing.
School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK.
Lianne
L
Robinson
Susan
S
McKillop-Smith
Nicola L
NL
Ross
Roger G
RG
Pertwee
Robert E
RE
Hampson
Bettina
B
Platt
Gernot
G
Riedel
D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000037:antagonists & inhibitors*; D003627:Data Interpretation, Statistical; D063388:Endocannabinoids; D005108:Extinction, Psychological / Q000187:drug effects; D006624:Hippocampus / Q000502:physiology*; D007274:Injections, Intraperitoneal; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D008568:Memory / Q000187:drug effects*; D008845:Microinjections; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D004856:Postural Balance / Q000187:drug effects; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D000077285:Rimonabant; D013028:Space Perception / Q000187:drug effects*; D013550:Swimming / Q000502:physiology / Q000523:psychology
D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant