WIN-55,212-2 chronically implanted into the CA3 region of the dorsal hippocampus impairs learning: a novel method for studying chronic, brain-area-specific effects of cannabinoids.
We report here that local hippocampal WIN-55,212-2 implants release this cannabinoid agonist for extended periods, the release is restricted to the implanted brain region and is behaviorally active. Radiolabeled WIN-55,212-2 was implanted bilaterally into the CA3 region of the dorsal hippocampus by means of fused silica capillaries. Significant amounts of the compound were released from the implants for at least 10 days. No labeled WIN-55,212-2 was detected in other brain regions, for example, the cortex, amygdala, thalamus, hypothalamus, and pons. In a separate experiment, radiolabeled WIN-55,212-2 was implanted chronically into the same hippocampal region, and rats were assessed 8 days later in the object-recognition test. In contrast to controls, rats implanted with WIN-55,212-2 were unable to differentiate familiar and unfamiliar objects. Object recognition was reinstated by the cannabinoid antagonist SR141716A, as rats implanted with both WIN-55,212-2 and SR141716A did not differ from controls. Thus, chronic hippocampal WIN-55,212-2 implants impaired recognition memory via the CB1 receptor. The memory-impairing effects of acute cannabinoid treatments are well known, but the effects of chronic treatments are controversial. The rate and magnitude of tolerance, however, have been shown to be brain-area specific and cell-type specific. Here we show that chronic hippocampal treatments impair memory, suggesting that no tolerance develops in the hippocampus towards the memory-impairing effects of cannabinoids. The data also suggest that chronic, brain-area-specific effects of cannabinoids can be studied by the novel method described here.
Barna
István
I
Institute of Experimental Medicine, Budapest, Hungary. barna@koki.hu
Soproni
Krisztina
K
Arszovszki
Antónia
A
Csabai
Katalin
K
Haller
József
J
D000818:Animals; D048588:Benzoxazines / Q000009:adverse effects* / Q000493:pharmacokinetics; D002186:Cannabinoids / Q000009:adverse effects; D003216:Conditioning, Operant / Q000187:drug effects; D003692:Delayed-Action Preparations; D004193:Discrimination Learning / Q000187:drug effects; D004334:Drug Administration Schedule; D004343:Drug Implants; D004361:Drug Tolerance; D006624:Hippocampus; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced*; D009025:Morpholines / Q000009:adverse effects* / Q000493:pharmacokinetics; D009281:Naphthalenes / Q000009:adverse effects* / Q000493:pharmacokinetics; D010880:Piperidines; D011720:Pyrazoles; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists*; D021641:Recognition, Psychology / Q000187:drug effects; D000077285:Rimonabant; D014018:Tissue Distribution
D048588:Benzoxazines; D002186:Cannabinoids; D003692:Delayed-Action Preparations; D004343:Drug Implants; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D000077285:Rimonabant