omdm-2-cpd and arachidonoylserotonin

Adult animals submitted to a single prolonged episode of maternal deprivation (MD) [24 h, postnatal days (PND) 9-10] show behavioral alterations that resemble specific symptoms of schizophrenia. These behavioral impairments may be related to neuronal loss in the hippocampus triggered by elevated glucocorticoids. Furthermore, our previous data suggested functional relationships between MD stress and the endocannabinoid system. In this study, we addressed the effects of MD on hippocampal glial cells and the possible relationship with changes in plasma corticosterone (CORT) levels. In addition, we investigated the putative involvement of the endocannabinoid system by evaluating (a) the effects of MD on hippocampal levels of endocannabinoids (b) The modulation of MD effects by two inhibitors of endocannabinoids inactivation, the fatty acid amide hydrolase inhibitor N-arachidonoyl-serotonin (AA-5-HT), and the endocannabinoid reuptake inhibitor, OMDM-2. Drug treatments were administered once daily from PND 7 to PND 12 at a dose of 5 mg/kg, and the animals were sacrificed at PND 13. MD induced increased CORT levels in both genders. MD males also showed an increased number of astrocytes in CA1 and CA3 areas and a significant increase in hippocampal 2-arachidonoylglycerol. The cannabinoid compounds reversed the endocrine and cellular effects of maternal deprivation. We provide direct evidence for gender-dependent cellular and biochemical effects of MD on developmental hippocampus, including changes in the endocannabinoid system.

Topics: Animals; Animals, Newborn; Arachidonic Acids; Astrocytes; Benzyl Compounds; Cannabinoid Receptor Modulators; Corticosterone; Drug Administration Schedule; Endocannabinoids; Female; Glial Fibrillary Acidic Protein; Gliosis; Glycerides; Hippocampus; Male; Maternal Deprivation; Rats; Rats, Wistar; Serotonin; Sex Characteristics; Stress, Psychological; Up-Regulation

Adult animals submitted to a single prolonged episode of maternal deprivation (MD) [24 h, postnatal day 9-10] show behavioral alterations that resemble specific symptoms of schizophrenia. Accordingly, this experimental procedure has been proposed as an animal model of schizophrenia based on the neurodevelopmental hypothesis. We have recently reported that MD-induced sex-dependent alterations in the hippocampus of neonatal rats. In view of recent evidence for important implications of the cerebellum in neurodevelopmental psychiatric diseases, we have now addressed possible degenerative changes in the cerebellar cortex of neonatal Wistar rats of both genders. To evaluate the presence of degenerated nerve cells, we used Fluoro-Jade C staining and for the study of astrocytes, we employed glial fibrillary acidic protein. Further, we analyzed the modulatory actions of two inhibitors of endocannabinoids inactivation, the fatty acid amide hydrolase inhibitor N-arachidonoyl-serotonin, AA-5-HT, and the endocannabinoid reuptake inhibitor, OMDM-2 (daily subcutaneous injections during the postnatal period 7-12). The animals were sacrificed at postnatal Day 13. MD induced significant increases in the number of Fluoro-Jade C positive cells (indicative of degenerating neurons) and in the number of glial fibrillary acidic protein positive cells, only in males. The two cannabinoid compounds reversed or attenuated these effects. The present results provide new insights regarding the psychopathological implications of the cerebellum, the role of the endocannabinoid system in neural development, and the possible neurodevelopmental basis of gender differences in schizophrenia.

Topics: Amidohydrolases; Animals; Animals, Newborn; Arachidonic Acids; Astrocytes; Benzyl Compounds; Cannabinoid Receptor Modulators; Cerebellar Cortex; Endocannabinoids; Female; Fluoresceins; Fluorescent Dyes; Glial Fibrillary Acidic Protein; Immunohistochemistry; Injections, Subcutaneous; Male; Maternal Deprivation; Neuroglia; Neurons; Organic Chemicals; Rats; Rats, Wistar; Serotonin; Sex Factors

Several selective inhibitors of endocannabinoid inactivation via either the fatty acid amide hydrolase (FAAH) or the putative endocannabinoid transporter have been developed so far. Here, we have studied the effect in rats of a subchronic intraperitoneal treatment with three recently developed selective inhibitors of endocannabinoid uptake (VDM-11, UCM-707 and OMDM-2) or with a selective FAAH inhibitor (N-arachidonoyl-serotonin, AA-5-HT), on the brain levels of anandamide and 2-arachidonoylglycerol (2-AG) measured by means of isotope dilution LC-MS 1, 5 and 12 h after the last treatment. OMDM-2 was the most efficacious compound at enhancing the levels of anandamide at all time points, with a maximal effect (1.9-fold enhancement) after 5h. This compound also enhanced 2-AG levels by approximately 1.3-fold, but only 5 and 12h from administration. VDM-11 slightly, albeit significantly, enhanced anandamide levels (1.3-fold) only at 1h from administration and 2-AG levels (1.3-fold) only after 5h. Finally, UCM-707 only affected 2-AG levels (by two-fold) at only 1h from administration. FAAH inhibition by AA-5-HT significantly enhanced the levels of both anandamide (between 1.3- and 1.5-fold, maximal effect after 1 h) and 2-AG (between 1.3- and 1.6-fold, maximal effect after 12 h) at all time points. Brains from rats treated with AA-5-HT did never exhibit enhanced levels of serotonin, thus pointing to the metabolic stability of this FAAH inhibitor. These data indicate that: (1) the pharmacological effects reported so far for the four compounds under study in animal models of diseases may be due to enhancement of both anandamide and 2-AG levels; (2) 2-AG seems to need a longer time after the last administration in order to be augmented; (3) OMDM-2 and AA-5-HT should be regarded as enhancers of endocannabinoid levels suitable for use in vivo.

Topics: Animals; Arachidonic Acids; Benzyl Compounds; Brain; Brain Chemistry; Cannabinoid Receptor Modulators; Drug Administration Schedule; Endocannabinoids; Furans; Injections, Intraperitoneal; Male; Polyunsaturated Alkamides; Rats; Rats, Wistar; Serotonin