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1.
Int J Mol Sci ; 22(16)2021 Aug 18.
Artículo en Inglés | MEDLINE | ID: mdl-34445602

RESUMEN

Cannabis is the most-used recreational drug worldwide, with a high prevalence of use among adolescents. In animal models, long-term adverse effects were reported following chronic adolescent exposure to the main psychotomimetic component of the plant, delta-9-tetrahydrocannabinol (THC). However, these studies investigated the effects of pure THC, without taking into account other cannabinoids present in the cannabis plant. Interestingly, cannabidiol (CBD) content seems to mitigate some of the side effects of THC, at least in adult animals. Thus, in female rats, we evaluated the long-term consequences of a co-administration of THC and CBD at a 3:1 ratio, chosen based on the analysis of recently confiscated illegal cannabis samples in Europe. CBD content is able to mitigate some of the long-term behavioral alterations induced by adolescent THC exposure as well as long-term changes in CB1 receptor and microglia activation in the prefrontal cortex (PFC). We also investigated, for the first time, possible long-term effects of chronic administration of a THC/CBD combination reminiscent of "light cannabis" (CBD:THC in a 33:1 ratio; total THC 0.3%). Repeated administration of this CBD:THC combination has long-term adverse effects on cognition and leads to anhedonia. Concomitantly, it boosts Glutamic Acid Decarboxylase-67 (GAD67) levels in the PFC, suggesting a possible lasting effect on GABAergic neurotransmission.


Asunto(s)
Conducta Animal/efectos de los fármacos , Cannabidiol/administración & dosificación , Cognición/efectos de los fármacos , Dronabinol/administración & dosificación , Alucinógenos/administración & dosificación , Corteza Prefrontal/efectos de los fármacos , Animales , Femenino , Memoria/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Transmisión Sináptica
2.
Pharmacol Ther ; 226: 107878, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-33895189

RESUMEN

Recent years have seen a renewed interest on the possible therapeutic exploitations of specific cannabinoids derived from the Cannabis sativa plant. Thus far, the most studied non-psychotomimetic cannabinoid is cannabidiol (CBD), which has shown promising therapeutic potential for relieving a variety of neurological diseases. However, also its propyl analogue, cannabidivarin (CBDV), has recently gained much attention as a potential therapeutic agent for the management of disabling neurological conditions. This review aims at providing a comprehensive and updated overview of the available animal and human data, which have investigated the possible therapeutic potential of CBDV for the management of epilepsy and autism spectrum disorder.


Asunto(s)
Trastorno del Espectro Autista , Cannabinoides , Epilepsia , Animales , Trastorno del Espectro Autista/tratamiento farmacológico , Cannabinoides/uso terapéutico , Epilepsia/tratamiento farmacológico , Humanos
3.
Pharmacol Res ; 111: 459-470, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27422357

RESUMEN

Cannabis use has been frequently associated with sex-dependent effects on brain and behavior. We previously demonstrated that adult female rats exposed to delta-9-tetrahydrocannabinol (THC) during adolescence develop long-term alterations in cognitive performances and emotional reactivity, whereas preliminary evidence suggests the presence of a different phenotype in male rats. To thoroughly depict the behavioral phenotype induced by adolescent THC exposure in male rats, we treated adolescent animals with increasing doses of THC twice a day (PND 35-45) and, at adulthood, we performed a battery of behavioral tests to measure affective- and psychotic-like symptoms as well as cognition. Poorer memory performance and psychotic-like behaviors were present after adolescent THC treatment in male rats, without alterations in the emotional component. At cellular level, the expression of the NMDA receptor subunit, GluN2B, as well as the levels of the AMPA subunits, GluA1 and GluA2, were significantly increased in hippocampal post-synaptic fractions from THC-exposed rats compared to controls. Furthermore, increases in the levels of the pre-synaptic marker, synaptophysin, and the post-synaptic marker, PSD95, were also present. Interestingly, KCl-induced [(3)H]D-ASP release from hippocampal synaptosomes, but not gliosomes, was significantly enhanced in THC-treated rats compared to controls. Moreover, in the same brain region, adolescent THC treatment also resulted in a persistent neuroinflammatory state, characterized by increased expression of the astrocyte marker, GFAP, increased levels of the pro-inflammatory markers, TNF-α, iNOS and COX-2, as well as a concomitant reduction of the anti-inflammatory cytokine, IL-10. Notably, none of these alterations was observed in the prefrontal cortex (PFC). Together with our previous findings in females, these data suggest that the sex-dependent detrimental effects induced by adolescent THC exposure on adult behavior may rely on its ability to trigger different region-dependent changes in glutamate synapse and glial cells. The phenotype observed in males is mainly associated with marked dysregulations in the hippocampus, whereas the prevalence of alterations in the emotional sphere in females is associated with profound changes in the PFC.


Asunto(s)
Astrocitos/efectos de los fármacos , Dronabinol/farmacología , Hipocampo/efectos de los fármacos , Envejecimiento/fisiología , Animales , Conducta Animal/efectos de los fármacos , Ácido Glutámico , Hipocampo/metabolismo , Relaciones Interpersonales , Masculino , Memoria/efectos de los fármacos , Fenotipo , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Ratas Sprague-Dawley , Receptores Ionotrópicos de Glutamato/metabolismo , Natación , Sinapsis/efectos de los fármacos
4.
Eur Neuropsychopharmacol ; 25(12): 2404-15, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26499171

RESUMEN

Over 180 million people consume cannabis globally. Cannabis use peaks during adolescence with a trend for continued consumption by adults. Notably, several studies have shown that long-term and heavy cannabis use during adolescence can impair brain maturation and predispose to neurodevelopmental disorders, although the neurobiological mechanisms underlying this association remain largely unknown. In this study, we evaluated whether, in female rats, chronic administration of increasing doses of the psychotropic plant-derived cannabis constituent, delta-9-tetrahydrocannabinol (THC), during adolescence (PND 35-45) could affect microglia function in the long-term. Furthermore, we explored a possible contribution of microglia to the development of THC-induced alterations in mood and cognition in adult female rats. Present data indicate that adolescent THC administration induces a persistent neuroinflammatory state specifically localized within the adult prefrontal cortex (PFC), characterized by increased expression of the pro-inflammatory markers, TNF-α, iNOS and COX-2, and reduction of the anti-inflammatory cytokine, IL-10. This neuroinflammatory phenotype is associated with down-regulation of CB1 receptor on neuronal cells and up-regulation of CB2 on microglia cells, conversely. Interestingly, blocking microglia activation with ibudilast during THC treatment significantly attenuates short-term memory impairments in adulthood, simultaneously preventing the increases in TNF-α, iNOS, COX-2 levels as well as the up-regulation of CB2 receptors on microglia cells. In contrast, THC-induced depressive-like behaviors were unaffected by ibudilast treatment. Our findings demonstrate that adolescent THC administration is associated with persistent neuroinflammation within the PFC and provide evidence for a causal association between microglial activation and the development long-term cognitive deficits induced by adolescent THC treatment.


Asunto(s)
Trastornos del Conocimiento/etiología , Dronabinol/toxicidad , Encefalitis , Alucinógenos/toxicidad , Corteza Prefrontal/patología , Factores de Edad , Animales , Animales Recién Nacidos , Ciclooxigenasa 2/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Encefalitis/inducido químicamente , Encefalitis/complicaciones , Encefalitis/patología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Pérdida de Tono Postural/efectos de los fármacos , Relaciones Interpersonales , Óxido Nítrico Sintasa de Tipo II/metabolismo , Inhibidores de Fosfodiesterasa/farmacología , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Reconocimiento en Psicología/efectos de los fármacos , Natación/psicología
5.
Toxicol Appl Pharmacol ; 237(2): 127-36, 2009 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-19327374

RESUMEN

Polychlorinated biphenyls (PCBs) are pollutants detected in animal tissues and breast milk. The experiments described in the present paper were aimed at evaluating whether the four PCB congeners most abundant in animal tissues (PCB-138, -153, -180 and -126), administered since fetal life till weaning, can induce long-term alterations of GH-axis activity and bone mass in the adult rat. We measured PCB accumulation in rat brain and liver, somatic growth, pituitary GH expression and plasma hormone concentrations at different ages. Finally, we studied hypothalamic somatostatin expression and bone structure in adulthood, following long-term PCB exposure. Dams were treated during pregnancy from GD15 to GD19 and during breast-feeding. A constant reduction of the growth rate in both male and female offspring from weaning to adulthood was observed in exposed animals. Long-lasting alterations on hypothalamic-pituitary GH axis were indeed observed in PCB-exposed rats in adulthood: increased somatostatin expression in hypothalamic periventricular nucleus (both males and females) and lateral arcuate nucleus (males, only) and decreased GH mRNA levels in the pituitary of male rats. Plasma IGF-1 levels were higher in PCB-exposed male and female animals as compared with controls at weaning and tended to be higher at PN60. Plasma testosterone and thyroid hormone concentrations were not significantly affected by exposure to PCBs. In adulthood, PCBs caused a significant reduction of bone mineral content and cortical bone thickness of tibiae in male rat joint to increased width of the epiphyseal cartilage disk. In conclusion, the developmental exposure to the four selected PCB compounds used in the present study induced far-reaching effects in the adult offspring, the male rats appearing more sensitive than females.


Asunto(s)
Densidad Ósea/efectos de los fármacos , Bifenilos Policlorados/administración & dosificación , Bifenilos Policlorados/toxicidad , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Animales , Encéfalo/metabolismo , Química Encefálica , Contaminantes Ambientales/administración & dosificación , Contaminantes Ambientales/química , Contaminantes Ambientales/toxicidad , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Hormona del Crecimiento/genética , Hormona del Crecimiento/metabolismo , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Hígado/química , Hígado/metabolismo , Masculino , Hipófisis/efectos de los fármacos , Hipófisis/metabolismo , Bifenilos Policlorados/química , Embarazo , Ratas , Somatostatina/metabolismo , Hormonas Tiroideas/sangre
6.
Hippocampus ; 19(8): 763-72, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19156848

RESUMEN

Marijuana and hashish are the illicit drugs most frequently used by human adolescents. Given the continued neurodevelopment throughout adolescence, adolescents may be more vulnerable than adults to certain neural consequences of heavy marijuana use. This study aimed to assess whether an experimental model of adolescent chronic exposure to Delta9-tetrahydrocannabinol (THC), may induce lasting effects on learning and memory. Adolescent rats have been treated with THC or its vehicle from 35 to 45 postnatal days (PND) and left undisturbed until their adulthood (75 PND) when aversive and spatial memory was assessed using the passive avoidance and radial maze tasks. No alteration was found in aversive memory, but in the radial maze THC pretreated animals exhibited a worse performance than vehicles, suggesting a deficit in spatial working memory. To correlate memory impairment to altered neuroplasticity, level of marker proteins was investigated in the hippocampus, the most relevant area mediating spatial memory. A significant decrease in the astroglial marker glial fibrillar acid protein was found as well as in pre- and postsynaptic protein expression (VAMP2, PSD95) and NMDA receptor levels in pretreated rats. To parallel these changes to alteration in dendritic morphology, Golgi-Cox staining was performed in the hippocampal dentate gyrus. Pretreated rats had a significantly lower total dendritic length and number than vehicles, as well as reduced spine density. Our data suggest that THC pretreated rats may establish less synaptic contacts and/or less efficient synaptic connections throughout the hippocampus and this could represent the molecular underpinning of the cognitive deficit induced by adolescent THC treatment.


Asunto(s)
Trastornos del Conocimiento/inducido químicamente , Dronabinol/farmacología , Hipocampo/citología , Hipocampo/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Psicotrópicos/farmacología , Envejecimiento/efectos de los fármacos , Animales , Reacción de Prevención/efectos de los fármacos , Reacción de Prevención/fisiología , Dendritas/efectos de los fármacos , Dendritas/fisiología , Homólogo 4 de la Proteína Discs Large , Proteína Ácida Fibrilar de la Glía/metabolismo , Hipocampo/fisiología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Proteínas de la Membrana/metabolismo , Memoria/efectos de los fármacos , Memoria/fisiología , Plasticidad Neuronal/fisiología , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/metabolismo , Sinaptofisina/metabolismo , Tubulina (Proteína)/metabolismo , Proteína 2 de Membrana Asociada a Vesículas/metabolismo
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