The interference of stress on physostigmine pretreatment against soman intoxication in guinea pigs

During research efforts towards finding effective drugs are performed in a standard laboratory situation. However, in a more realistic situation other factors may interfere with the treatment regime. There is growing evidence that stress occurring during military operations can impair the efficacy and appearance of side effects of medical treatment. It is known that stress can change the kinetics of the pretreatment (1) and, therefore, affect the protective ratio and evoke the appearance of side effects. During operation Desert Storm soldiers were given pyridostigmine (PYR) tablets against intoxication with acetylcholinesterase (AChE) inhibitors. The employed dose of PYR was expected not to show undesirable cholinergic effects. Nevertheless, peripheral and central side effects were recorded (2). These effects could be the result of stress. First of all, stress itself could be an important factor. It induces prolonged corticosterone secretion that leads to a reduction of hippocampal corticosteroid receptors, which affects other transmitter systems, such as acetylcholine (3). Secondly, stress enhances the passage across the blood-brain barrier (1). In operation Desert Storm nine cases of PYR self-poisoning were encountered. These individuals only suffered from peripheral cholinergic symptoms, whereas no effects on the central nervous system were observed (4). This supports the idea that a combination of many factors including stress plays a role in the appearance of side effects. In earlier studies pretreatment with physostigmine (PHY) has proved to be very effective against sarin or soman-intoxication (5). Furthermore, PHY was found to be more effective against soman intoxication than PYR in rats (6,7) and in guinea pigs (8). In the course of these studies it was realised that the protective efficacy and the side effects of the pretreatment should also be examined in stressful situations. Therefore,in tn this study the effects of stress on side effects of PHY (0.025 mg/kg/hr) pretreatment and its efficacy against soman intoxication was determined in guinea pigs. To prevent unwanted side effects due to AChE inhibition PHY the pretreatment was combined with the muscarinic receptor antagonist scopolamine (SCO) (0.018 mg/kg/hr) (9). Stress factors were chosen to represent military conditions: emotional stress, physical stress and psychological stress. Most effects can be expected to be centrally mediated effects that may induce changes in different types of behavior. For this reason behavioral read-out systems were used to elucidate the severity of PHY side effects and soman induced incapacitation.