Abstract â–¡ 111

Infants exposed in utero to addictive drugs, including cocaine, exhibit a number of developmental anomalies. Some studies have demonstrated an increased incidence of sudden infant death syndrome (SIDS) in infants of cocaine using mothers. Abnormalities in ventilatory control may contribute to SIDS. We and others had previously demonstrated maturation delay of ventilatory control in rat pups exposed in utero to cocaine. In this study we postulated that delayed maturation of hypercapnic ventilatory response may be correlated with abnormal levels of brain endorphins. Gravid Sprague-Dawley rats were randomly assigned to receive daily subcutaneous injections of cocaine (30 mg/kg) or saline from gravid day 8 (implantation) until delivery. At birth litters were culled to 8 - 10 pups each and cocaine exposed dams were weaned over 4 days from drug. A modification of the technique of barometric plethysmography was used to assess the ventilatory response to exposure to 6% CO2/21%O2/balance N2 (steady state exposure). This was calculated as percent change in respiratory rate (RR), tidal amplitude (AMP) and ventilatory effort (Ve = RR*AMP) during hypercapnia compared to steady room air measurements. Animals were tested at 2 days and 2 weeks of age, when previous studies had shown maximum difference in hypercapnic response. From 12 to 14 animals were used at each time period for each group. To assess endogenous opioid activity, changes in proenkephalin (PPE) and prodynorphin (PPD) were determined from the midbrain and brainstem of 4 animals at each time period. Total RNA was extracted and hybridized to 32P labeled RNA probes coding for PPE and PPD. Hypercapnic ventilatory response was small to absent in both groups at 2 days of age. By 2 weeks hypercapnic ventilatory response was present in normals (40% increase in ventilatory effort compared to room air), but absent in cocaine exposed animals. Most of the increase in ventilatory effort with hypercapnia was due to an increase in AMP. At 2 days there was no difference in PPE mRNA levels between groups in the brainstem. At 2 weeks old, in the cocaine group PPE and PPD mRNA levels were greater in the cocaine exposed than the control pups (94% and 30% greater respectively). We conclude that cocaine induced maturation in hypercapnic ventilatory response is associated with increased synthesis of PPE and PPD in the brainstem. Increased levels of endogenous opioids could be partly responsible for suppression and ventilatory control in maturing infants and possibly enhance the propensity for SIDS.