The aims of this proposal are to: 1. determine if substances interacting with the benzodiazepine receptor (agonists, antagonists and inverse agonists) alter cardiorespiratory activity, 2. determine if these effects are exerted at sites where gamma- aminobutyric acid (GABA) affects cardiorespiratory activity and if GABA is involved in these responses, 3. Determine whether intravenous administration of substances that influence the activity of the benzodiazepine receptor affect cardiorespiratory function and if so to find their CNS site of action and, 4. test the hypothesis that hypoxia, opioids, alcohol and anesthetics enhance the cardiorespiratory effects of benzodiazepines and this is due to changes in GABAergic activity. To achieve these aims, blood pressure, tracheal airflow and end tidal CO2 will be monitored in anesthetized cats with a pneumotachograph and a CO2 analyzer. Studies will be done also in debuffered and decerebrate cats while monitoring phrenic, hypoglossal and recurrent laryngeal nerve activity. To determine if substances interacting with the benzodiazepine receptor alter cardiorespiratory activity, we will test agonists, antagonists, inverse agonists and an endogenous peptide at the ventral surface of the medulla and at several CNS sites where GABA influences cardiorespiratory function. To obtain evidence that these substances exert their effects by interacting with the benzodiazepine receptor we will attempt to counteract their effects with antagonists at those sites. The role of GABA will be assessed by attempting to reverse or prevent the effects of benzodiazepine agonists, with GABA antagonists. To study the actions and determine the site of action for intravenously administered benzodiazepine agonists we will compare the results of these studies with those obtained in aim 1 and administer an antagonist to the specific areas of the brain in an attempt to reverse the effects of the agonist. To assess the role of GABA in the potentiation of the cardiorespiratory effects of benzodiazepine by hypoxia and CNS depressant drugs we will test the effects of these interventions on central respiratory drive while simultaneously changing brain GABA activity. Data obtained from the proposed studies should: 1. establish the mechanism and site of action for the cardiorespiratory effects of benzodiazepines, 2. provide a basis for development of drugs to treat cardiorespiratory depression and 3. enable us to learn more about the role of GABA in cardiorespiratory depression associated with hypoxia, anesthesia and abuse of CNS depressants such as alcohol and opiates.
