ONE EXPERIENCE WITH LOWER OR HIGHER INTENSITY STRESSORS, RESPECTIVELY ENHANCES OR DIMINISHES RESPONSIVENESS TO HALOPERIDOL WEEKS LATER - IMPLICATIONS FOR UNDERSTANDING DRUG VARIABILITY

This laboratory has previously shown that acute exposure to a variety of brief stressful events can have a very long-lasting influence on subsequent responsiveness to pharmacological and non-pharmacological stressors. In some cases the response to these agents is enhanced, while in others it is diminished: the common denominator being that in each instance the influence of the initial stressor grows stronger with the passage of time. Here, we identify one factor that determines which time-dependent effect is manifest. In 3 separate experiments, male rats were subjected to a single exposure to stressors of either lower or higher intensity and their effects on haloperidol-induced catalepsy and dopamine and dihydroxyphenylacetic acid levels in the nucleus accumbens and medial frontal cortex, measured either 1-2 h or 2 weeks later. The stressors were either environmental (needle jab or 1 h of immobilization), metabolic (200 or 750 mg/kg, i.p. of 2-deoxy-D-glucose), or pharmacological (0.5 g/kg or 2.0 g/kg, ethanol). Degree of stressfulness was indexed by measuring plasma corticosterone levels. There was no effect on haloperidol-induced catalepsy when stressors preceded such behavioral testing by 1-2 h. By contrast, when the interval was 2 weeks, the lower-intensity stressors all increased haloperidol catalepsy, whereas the higher-intensity stressors decreased the same response. In other words, a process that progressed with the passage of time was observed regardless of whether sensitization or diminution of haloperidol's action occurred. In contrast to the uniform bipolar behavioral effects observed, depending on the intensity of the prestressor, the neurochemical findings failed to show any evidence of bipolarity whatever. Instead, both environmental and pharmacological stressors induced long-term, generally time-dependent changes, suggestive of a persistent decrease in dopamine utilization, while our metabolic stressor had no effect. Our results demonstrate a stressor-induced, time-dependent process that either increases or decreases responsiveness to drugs, depending on the intensity of the earlier stressor. They may be relevant to the variability in response to drugs frequently encountered in both the experimental and clinical literatures.