Abolishment of Serotonergic Neurotransmission to Cardiac Vagal Neurons During and After Hypoxia and Hypercapnia With Prenatal Nicotine Exposure

1 Department of Pharmacology and Physiology, The George Washington University, Washington, DC; and 2 Departments of Biology and Psychiatry, University of Utah, Salt Lake City, Utah Submitted 13 June 2008; accepted in final form 15 December 2008 Abstract Cardioinhibitory cardiac vagal neurons (CVNs) do not receive inspiratory-related excitatory inputs under normal conditions. However, excitatory purinergic and serotonergic pathways are recruited during inspiratory activity after episodes of hypoxia and hypercapnia (H/H). Prenatal nicotine (PNN) exposure is known to dramatically change cardiorespiratory responses and decrease the ability to resuscitate from H/H. This study tested whether PNN exposure alters excitatory neurotransmission to CVNs in the nucleus ambiguus during and after H/H. Spontaneous and inspiratory evoked excitatory postsynaptic currents were recorded in CVNs from rats that were exposed to nicotine (6 mg·kg –1 ·d –1 ) throughout the prenatal period. In contrast to unexposed animals, in PNN animals H/H recruited excitatory neurotransmission to CVNs during inspiratory-related activity that was blocked by the 3β4 nicotinic acetylcholine receptor (nAChR) blocker -conotoxin AuIB ( -CTX AuIB, 100 µM) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 50 µM) and D (–)-2-amino-5-phosphonopentanoic acid (AP5, 50 µM), selective AMPA/kainate and N -methyl- D -aspartate receptor blockers, respectively. Following H/H, there was a significant increase in inspiratory-related excitatory postsynaptic currents that were unaltered by -CTX AuIB or ondansetron, a 5-HT3 receptor blocker, but were subsequently inhibited by pyridoxalphosphate-6-azophenyl-2', 4'-disulphonic acid (100 µM), a purinergic receptor blocker and CNQX and AP5. The results from this study demonstrate that with PNN exposure, an excitatory neurotransmission to CVNs is recruited during H/H that is glutamatergic and dependent on activation of 3β4-containing nAChRs. Furthermore, exposure to PNN abolishes a serotonergic long-lasting inspiratory-related excitation of CVNs that is replaced by recruitment of a glutamatergic pathway to CVNs post H/H. Address for reprint requests and other correspondence: D. Mendelowitz, Dept. of Pharmacology and Physiology, George Washington University, 2300 Eye St. NW., Washington, DC 20037 (E-mail: dmendel{at}gwu.edu )