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Made available in DSpace on 2022-04-29T08:28:34Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-01-01 Introduction: The prenatal period is highly sensitive to pharmacological interventions. The psychoactive compounds of Cannabis act directly on the endocannabinoid system, and the deleterious effects of external cannabinoids during gestation may be related to negative interference in the central nervous system (CNS) formation, structuring and functioning of the respiratory system. Nevertheless, the influence of external cannabinoids on the ventilatory network development as well as in the chemosensitivity and the future consequences during neonatal and juvenile period is still unclear. Objective: To evaluate the effects of exposure to cannabinoid during the whole gestational period on the respiratory control system at P0, P6-7, P12-13 and P27-28 male and female rats. Material and Methods: Osmotic pumps were implanted subcutaneously in pregnant rats at embryonic day 0 and delivered vehicle (VEH) or CB1 receptor agonist (WIN 55212-2, 0.5 mg/Kg/day) for 21 days. Ventilation (VE) of animals was recorded by pressure-plethysmography (P0, P6-7 and P12-13) and whole body plethysmography (P27-28) during normoxia, hypercapnia (7% CO2) and hypoxia (10% O2), as well as the O2 consumption (VO2) was measured. Results: At P0, WIN-treated male rats had a higher resting ventilation (~45%), hypercapnic (HCVR, ~41%) and hypoxic ventilatory response (HVR, ~35%) compared to vehicle group. At P6-7, WIN male group had a decreased HCVR (~19%) and also a lower HVR (~16%). For P12-13 animals, both male and female WIN-treated rats had an increase in the response to CO2 (male-33% and female-18%). For P27-28 rats, the HCVR was significantly higher for male (~21%) as well as for female (~25%) WIN-treated groups, no difference was observed for HVR. All the respiratory changes observed were not caused by metabolic issues since no difference was observed in the VO2. Conclusions: A chronic and over activation of endocannabinoid system during gestation promotes alteration in the respiratory system development affecting the chemosensitivity to CO2 and O2 during neonatal and juvenile period. Financial support: FAPESP and CNPq. Dept of Animal Morphology and Physiology São Paulo State University FCAVJ Dept of Animal Morphology and Physiology São Paulo State University FCAVJ

Made available in DSpace on 2020-12-12T01:14:26Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-01-01 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Introduction: Breathing is an important motor behavior that contributes to the maintenance of homeostasis. This behavior depends on the proper development of respiratory network located in brainstem that generates and controls the respiratory rhythm during the embryonic and post-natal ages. The development of this network can be affected by the use of psychiatric medications prescribed to mothers to treat general anxiety or panic disorders. One of the most common drugs prescribed is Diazepam (DZP), a benzodiazepine that binds to gamma-aminobutyric acid (GABAA) receptors enhancing the permeability of chloride channels. However, it is still unknown if the administration of DZP during pregnancy could have deleterious effects on breathing control during post-natal life. Objective: To understand the consequences of intrauterine exposure to DZP on the ventilatory responses of newborns rats, Material and Methods: We administered DZP (1mg/Kg) or its vehicle, via osmotic pump, to pregnant rats during whole pregnancy (21 day). We used newborns rats (male and female) at post-natal day 0 (P0) and P12. Ventilation (VE), tidal volume (VT), respiratory frequency (fR) and oxygen consumption (VO2) were measured by using head-out plethysmograph during 20 minutes of normocapnia, hypercapnia (7% CO2) and hypoxia (10% O2). Results: At P0, females treated with DZP had an attenuation of VT during hypoxia. At P12, males and females presented a decrease on VE during hypoxia and VE/VO2 was lower in DZP-treated animals. At this age, hypercapnic ventilatory response was also reduced in DZP groups due to an attenuation of VT. Conclusions: DZP during pregnancy promotes a decrease in ventilatory responses to CO2 and O2 in males and females, and this disturbance occurs at P12 that is considered the critical period for breathing control. Sao Paulo State University FCAV/UNESP University Of Alberta Sao Paulo State University FCAV/UNESP

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) It is well know that the respiratory network, undergoes significant development in the postnatal period. Among various processes, the maturing of the catecholaminergic (CA) system shows to be an important factor in the control and modulation of respiratory rhythmogenesis. Studies have also shown that these neurons are widely distributed in the Central Nervous System (CNS), including the A1/C1, A2/C2, C3, A5, A6 and A7 regions, having numerous projections to many regions of the brain. However, the development of respiratory network as well as its effect on the control of ventilation, is not yet fully understood. Thus, understanding the participation of CA neurons in the respiratory control during postnatal development is of most importance for a better understanding of some clinical disorders including Rett Syndrome, Sudden Infant Death Syndrome (SIDS) and Central Congenital Hypoventilation Syndrome (CCHS). Therefore, this study aimed to investigate the involvement of CA neurons in the brainstem on respiratory control in normoxic normocapnic, hypercapnic and hypoxic conditions during the postnatal period of male and female neonatal rats, through chemical injury with conjugated saporin anti-dopamine beta-hydroxylase (DBH-SAP). Thus, DBH-SAP (42 ng/100 nL – 1L), saporin (SAP – 1L) or phosphate buffered solution vehicle (PBS, 0.01M, pH 7.4 – 1L) were injected into the 4th ventricle in male and female neonates Wistar rats P0-1. Pulmonary ventilation ( EV ) was recorded in unanesthetized neonates (P7-8) by pressure plethysmography during normocapnia, hypercapnia (7% CO2) and hypoxia (10% O2) at 10 and 20 min after the start of exposure. Our data demonstrate that lesion of brainstem CA neurons increased ventilation in males and females newborn under room air conditions. In addition, the ventilatory response to hypercapnia was significantly reduced in male (57%) and female (55%) lesioned neonatal rats (Male – SAP group: 212.8 ± 7.0; PBS group: 203.9 ± 10.3; lesioned group: 151.1 ± 7.4; P < 0,001; Female – SAP group: 218.2 ± 10.4; PBS group: 200.0 ± 6.4; lesioned group: 154.0 ± 9.6; P < 0,001; all values relative to % of baseline). Also, a similar reduction was observed in the hypoxic condition (Male – SAP group: 185.2 ± 15.3; PBS group: 167.4 ± 5.0; lesioned group: 110.8 ± 9.2; P < 0,001; Female – SAP group: 197.3 ± 11.8; PBS group: 179.5 ± 13.7; lesioned: 129.4 ± 5.9; P < 0,001; all values relative to % of baseline). Additionally, the values for metabolic rate of control and lesioned groups, both males and females, did not differ significantly, whether in normoxic normocapnic, hypercapnic or hypoxic conditions. These results suggest that brainstem CA neurons exert a tonic inhibitory role in neonatal ventilation and promote an important excitatory modulation in CO2 and O2 chemosensitivity in unanesthetized males and females neonatal rats (P7-8). Sabe-se que o sistema respiratório, bem como suas vias de controle, sofrem significativo desenvolvimento no período pós-natal. Dentre vários processos, o amadurecimento do sistema catecolaminérgico (CA) mostra-se como um importante fator no controle e modulação da ritmogênese respiratória. Estudos demonstram que esses neurônios estão amplamente distribuídos pelo Sistema Nervo Central (SNC), incluindo as regiões A1/C1, A2/C2, C3, A5, A6 e A7, e que apresentam inúmeras projeções para várias regiões do encéfalo. No entanto, a participação dos neurônios CA no controle respiratório durante o desenvolvimento pós-natal não está bem esclarecido, e esse entendimento é de extrema importância para uma melhor compreensão de alguns problemas clínicos que inclui a Síndrome de Rett, Síndrome da Morte Súbita Infantil (SIDS) e a Síndrome da Hipoventilação Central Congênita (CCHS). Sendo assim, o presente estudo teve por objetivo investigar a participação dos neurônios CA do tronco encefálico no controle respiratório em situações normóxica normocápnicas, hipercápnicas e hipóxicas durante o período pós-natal de ratas e ratos (P7-8), por meio de lesão química com saporina conjugada com anti-dopamina beta-hidroxilase (DBHSAP). Assim, DBH-SAP (42 ng/100 nL – 1L), Saporina (SAP – 1 L) ou veículo solução fosfato tamponado (PBS 0,01 M, pH 7,4 – 1 L) foram injetados no 4° ventrículo de ratas e ratos neonatos Wistar P0-1. A ventilação pulmonar ( EV ) foi registrada em neonatos não anestesiados (P7-8) por pletismografia de pressão, durante normóxia normocápnica, hipercapnia (7% CO2) e hipóxia (10% O2) aos 10 e 20 min após o início da exposição. Nossos dados demonstram que a lesão dos neurônios catecolaminérgicos do tronco encefálico promove um aumento da ventilação em neonatos machos e fêmeas durante a normóxia normocápnica. A resposta ventilatória à hipercapnia foi significativamente reduzida em ratos neonatos lesados (57%) e ratas (55%) (Machos – grupo SAP: 212,8 ± 7,0; grupo PBS: 203,9 ± 10,3; grupo lesado: 151,1 ± 7,4; P < 0,001; Fêmeas – grupo SAP: 218,2 ± 10,4; grupo PBS: 200,0 ± 6,4; grupo lesado: 154,0 ± 9,6; P < 0,001; todos os valores relativos à % do basal). Uma redução similar foi observada na resposta ventilatória à hipóxia (Machos – grupo SAP: 185,2 ± 15,3; grupo PBS: 167,4 ± 5,0; grupo lesado: 110,8 ± 9,2; P < 0,001; Fêmeas – grupo SAP: 197,3 ± 11,8; grupo PBS: 179,5 ± 13,7; grupo lesado: 129,4 ± 5,9; P < 0,001; todos os valores relativos à % do basal). Adicionalmente, os valores referentes às taxas metabólicas de neonatos machos e fêmeas lesados e controles não diferiram significativamente, seja em condição de normóxia normocápnica, hipercapnia ou hipóxia. Esses resultados sugerem que os neurônios catecolaminérgicos localizados no tronco encefálico exercem um papel inibitório tônico sobre ventilação em neonatos P7-8 e apresentam uma importante modulação excitatória na resposta ventilatória ao CO2 e hipóxia em ratas e ratos neonatos (P7-8) não anestesiados.