Psychobiology of IV Naloxone &Lactate in Normals

DESCRIPTION (provided by applicant): Panic disorder (PD) is a serious public health burden. It is enmeshed with depression, alcoholism, tobacco dependence, pulmonary disease and has been linked to sudden cardiac death and stroke. The panic attack is distinctively characterized by acute dyspnea, tidal volume hyperventilation and surprising lack of HPA activation. Risk for developing PD is markedly increased by childhood Separation Anxiety Disorder. Both CO2 sensitivity and separation anxiety are regulated by the endogenous opioid system that I hypothesize malfunctions in PD. Normal unresponsiveness to I.V. lactate may stem from an intact endogenous opioid system. When a naloxone infusion preceded intravenous lactate, a pilot study of twelve normal subjects demonstrated a sharp increase in tidal volume and dyspneic distress. Extensive experience indicates that normal subjects do not have this reaction to I.V. lactate alone. Further, this paradigmatic increase in tidal volume and dyspneic distress was not reinstated when subjects were reinfused with naloxone alone. Therefore, we propose to extend this pilot study to definitively demonstrate that naloxone pretreatment is necessary for normal subjects to react as PD subjects do to I.V. lactate. We propose a double blind, randomized three group design in 90 normal subjects: 1) naloxone preceding lactate, 2) saline preceding lactate, 3) naloxone preceding saline. Measures of panic symptoms, air hunger, respiratory and cardiac variables will be analyzed. It is known that PD has a low heart rate variability (HRV) that is lowered further during a lactate induced panic. This feature of PD has been considered an important cardiac risk factor. To further validate our model we will analyze its effects on normal HRV. Positive findings would provide the basis for a controlled study of specific anti-panic agents to test whether they can blockade this reaction. This would further validate this model. It may also suggest new approaches to anti-panic agents, such as mixed opiate agonist-antagonist.