Prenatal chronic stimulation of the endocannabinoid system affects the respiratory motor outputs of juvenile male and female rats

The use of drugs of abuse during pregnancy can severely affect the development of physiological systems including the central respiratory network, mainly because prenatal period is extremely susceptible to external and pharmacological interventions that may cause postnatal consequences to the offspring. The endocannabinoid system is already present in the central nervous system in early stages of embryonic development, including in areas responsible for respiratory control. Nevertheless, the effect of external cannabinoids on the central cardiorespiratory network development as well as in the chemosensitivity and the future consequences during juvenile period is still unclear. Here, we evaluate the effects of prenatal exposure to cannabinoid on the respiratory motor outputs of juvenile (P27–28) male and female rats by using a decerebrated, arterially perfused in situ preparation. To this end, 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. In situ preparations of juvenile rats were used for recording the respiratory motor and sympathetic outputs during normocapnia (5% CO 2 ), hypercapnia (8% CO 2 ) and stimulation of peripheral chemoreceptors with potassium cyanide (KCN; 25 μg in 50 μL). Our data showed that prenatal WIN exposure resulted in a tonic increase in phrenic burst amplitude in male animals, which was sustained during the KCN and CO 2 challenge, while WIN‐treated females exhibited elevated phrenic burst frequency. The activity of the vagus nerve was also higher in male WIN‐treated animals, either under basal condition, KCN or hypercapnic exposure, although no effects were observed in the female group. The frequency of late‐expiratory events in abdominal activity, which indicate active expiration, was significantly higher (37%) for male treated animals during KCN stimulus, with no significant effects in the female group. In both sexes, prenatal WIN treatment did not modify the levels of thoracic sympathetic activity. These results suggest that prenatal chronic stimulation of endocannabinoid system promotes alterations in the respiratory network development affecting the activity of nerves responsible for the ventilatory motor drive during juvenile period. These effects seem to be potentiated in males. Support or Funding Information FAPESP and CNPq