title: Long-term reduction of brain-derived neurotrophic factor levels and signaling impairment following prenatal treatment with the cannabinoid receptor 1 receptor agonist (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinyl-methyl) pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1- naphthalenylmethanone.
abstract: It is well accepted that adverse life events occurring early in development may alter the correct program of brain maturation leading to enhanced vulnerability to neuropsychiatric disorders. It has recently been demonstrated that prenatal exposure to the cannabinoid receptor 1 agonist (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinyl-methyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN 55,212-2) produces memory deficit in adulthood, an effect associated with a reduced functionality of the glutamatergic system. The aim of our study was to identify molecular changes produced by prenatal exposure to WIN 55,212-2 that might contribute to late disruption in synaptic plasticity and cognition. For this purpose, WIN 55,212-2 was injected in pregnant wistar rats from gestation day 5 to 20 and a detailed analysis of the levels of the neurotrophin brain-derived neurotrophic factor (BDNF) as well as of the signaling molecules extracellular signal-regulated kinase (ERK)1/2 and alpha-calcium/calmodulin-dependent protein kinase II (alpha-CaMKII) was carried out in adult offspring. We found that exposure to WIN 55,212-2 significantly reduced BDNF levels in hippocampus and frontal cortex. This effect was associated with decreased activation of pathways linked to neurotrophin and glutamate receptor signaling. In particular, prenatal cannabinoid treatment reduced the phosphorylated levels of ERK1/2 in selected subcellular compartments of hippocampus, frontal and prefrontal cortex, whereas no changes were observed in the total levels of these proteins. Furthermore, a robust reduction of total and phospho-alpha-CaMKII was found in the hippocampus of rats prenatally exposed to WIN 55,212-2. In summary, the present data suggest that deficits of BDNF levels and signaling through ERK1/2 and alpha-CaMKII might contribute to cognitive and neuroplastic defects associated with prenatal exposure to cannabinoids.
authors.affiliation: Center of Neuropharmacology, Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy.
authors.forename: Paola Francesca
authors.initials: PF
authors.lastname: Maj
authors.forename: Maria
authors.initials: M
authors.lastname: Collu
authors.forename: Paola
authors.initials: P
authors.lastname: Fadda
authors.forename: Annamaria
authors.initials: A
authors.lastname: Cattaneo
authors.forename: Giorgio
authors.initials: G
authors.lastname: Racagni
authors.forename: Marco Andrea
authors.initials: MA
authors.lastname: Riva
mesh_terms: D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D048588:Benzoxazines; D019208:Brain-Derived Neurotrophic Factor; D002121:Calcium Channel Blockers; D009025:Morpholines; D009281:Naphthalenes; 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