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Several synthetic nucleoside analogues, including AZT(RETROVIR), ddC (HIVID), ddI (VIDEX), and d4T (ZERIT), are currently being used in the treatment of HIV infection. Unfortunately, in clinical use the appearance of severe and sometimes debilitating peripheral neuropathy and pain has been associated with the long-term use of several of these drugs (i.e., ddC, ddI and d4T), although not with AZT. To date, standard pre-clinical animal toxicity studies have failed to reveal any adverse neurologic effects of these compounds. However, previously reported preliminary findings suggest that ddC may alter several neuro-behavioral parameters (including locomotor activity, acoustic startle responding, and aggression) in rats and mice following presentation in the animals' drinking water for 7 days. The current series of experiments examined effects of acutely administered ddC and AZT on spontaneous locomotor activity and acoustic startle responses (with and without pre-pulse) in female Sprague–Dawley rats. Following intragastric administration, ddC reduced locomotion at all but the highest dose, whereas AZT had no significant effect on locomotor activity. Acutely administered ddC had no effect on ASR, whereas AZT increased ASR at the highest stimulus intensity. These data support the use of behavioral testing in the development of the antiviral nucleoside analogues, as behavioral testing may be more effective in identifying the neurologically active agents than is standard toxicity testing. Published by Elsevier Science Inc., 1997

Two experiments examined the effects of age, genetic strain, and nicotine on acoustic startle response (ASR) amplitude and prepulse inhibition (PPI) in rats. ASR amplitude measures reactivity to external stimulation, and PPI is used as an index of sensory gating related to attention. Both ASR amplitude and PPI have been previously reported to be increased by nicotine in adult rats. Experiment 1 examined effects of chronically administered nicotine and saline on ASR and PPI in Wistar, Long-Evans, and Sprague-Dawley rats (40 days of age). Experiment 2 examined the effects of chronically administered nicotine and saline in Sprague-Dawley rats of two age groups: 40 and 70 days of age at the beginning of the study. ASR amplitude differed significantly across strains with the values for Wistar > Sprague-Dawley > Long-Evans, and there were no differences in percent of PPI among the three strains. In addition, results of Experiment 2 indicated that older rats had significantly greater ASR amplitudes and PPI than younger rats. Consistent with previous reports, nicotine increased ASR and PPI in the older rats; however, there were no significant differences in the younger rats. Therefore, age and genetic strain are important variables in the analysis of nicotine's effects on startle behaviors in rats.

The present experiments examined the effects of different environmental conditions on acute morphine sensitivity and morphine self-administration in two genetically diverse inbred strains of rats. Fischer-344 and Lewis rats were subjects because they are related to the commonly used Sprague-Dawley strain, but differ from each other in behavioral and biological responses to opioids and environmental conditions. It was hypothesized that differential behavioral and biological responses to morphine under the various environmental conditions would be strain dependent. In Experiment 1, behavioral and biological effects of acute morphine injections were examined in 96 Fischer-344 and 96 Lewis rats that were either group housed, individually housed, or group housed and immobilized. F-344 rats were more sensitive to morphine's analgesic and locomotor effects, whereas Lewis rats were more sensitive to morphine's effects on body temperature, vertical movements, and rotarod performance. Strain-dependent environmental effects on the acoustic startle response, vertical activity, speed, and body temperature also were found. Further, environmental conditions interacted with strain of rat to produce differential effects of morphine on hot-plate and speed of locomotion. Specifically, F-344 rats had different responses to morphine under the different environmental conditions, whereas for Lewis rats the responses to morphine did not change on these measures. In addition to behavioral changes, strain-dependent environmental influences on peripheral and central morphine levels also were found. In Experiment 2, the effects of the same environmental conditions on subsequent morphine self-administration were examined in 30 Fischer-344 and 30 Lewis rats. Morphine self- administration of F-344 rats was more affected by the different environmental conditions than was the self-administration behavior of Lewis rats.