Dysregulation of the endogenous cannabinoid system in adult rats prenatally treated with the cannabinoid agonist WIN 55,212-2.
Cannabis is widely abused by women at reproductive age and during pregnancy. Animal studies showed a particular vulnerability of the developing brain to prenatal chronic cannabinoid administration. We determined whether prenatal exposure to WIN 55,212-2, a potent cannabinoid receptor agonist, affected (1) density, affinity and/or function of cannabinoid CB(1) receptors, (2) endogenous levels of the endocannabinoid anandamide, (3) activities of the major anandamide synthesising and hydrolysing enzymes, N-acyl-phosphatidylethanolamine-specific phospholipase D (NAPE-PLD) and fatty acid amide hydrolase (FAAH), respectively, in brain areas of adult male offspring rats. Furthermore, the effect of prenatal WIN 55,212-2 on spontaneous motility was analyzed. Pregnant rats were treated daily with WIN 55,212-2 (0.5 mg/kg, gestation day 5-20) or vehicle. [(3)H]CP 55,940 and WIN 55,212-2-stimulated [(35)S] GTPgammaS binding were carried out in cerebellum, cerebral cortex, hippocampus, striatum and limbic areas of male adult offspring. Levels of anandamide, FAAH and NAPE-PLD activity were also determined. EC(50) values for WIN 55,212-2-stimulated [(35)S]GTPgammaS binding were significantly different in hippocampus (-26%) and striatum (+27%) in WIN 55,212-2-treated rats. Cannabinoid CB(1) receptor density and affinity were not affected in any analyzed region. In the striatum, increased anandamide levels were associated with reduced FAAH and enhanced NAPE-PLD activities. Opposite changes in anandamide levels and enzymatic activities were detected in limbic areas of WIN 55,212-2-treated rats. Ambulatory activity between WIN 55,212-2- and vehicle-treated adult offspring did not vary. Our results show that prenatal exposure to cannabinoid agonist induces a long-term alteration of endocannabinoid system in brain areas involved in learning-memory, motor activity and emotional behavior.
Castelli
M Paola
MP
Bernard B. Brodie Department of Neuroscience, University of Cagliari, 09042 Monserrato, Italy. castelli@unica.it
Paola Piras
A
A
D'Agostino
Antonella
A
Pibiri
Fabio
F
Perra
Simona
S
Gessa
Gian Luigi
GL
Maccarrone
Mauro
M
Pistis
Marco
M
D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001095:Arachidonic Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D048588:Benzoxazines / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D063386:Cannabinoid Receptor Agonists; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism* / Q000494:pharmacology; D003511:Cyclohexanols / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D005260:Female; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism / Q000494:pharmacology; D008098:Litter Size / Q000187:drug effects; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000494:pharmacology*; D010739:Phospholipase D / Q000378:metabolism; D053284:Polyunsaturated Alkamides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000378:metabolism; D043882:Receptors, Cannabinoid / Q000378:metabolism; D013462:Sulfur Radioisotopes; D015430:Weight Gain / Q000187:drug effects
D000700:Analgesics; D001095:Arachidonic Acids; D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D063385:Cannabinoid Receptor Modulators; D003511:Cyclohexanols; D063388:Endocannabinoids; D009025:Morpholines; D009281:Naphthalenes; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D043882:Receptors, Cannabinoid; D013462:Sulfur Radioisotopes; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; C527163:Napepld protein, rat; D010739:Phospholipase D; C078814:anandamide