Effects of ddC and AZT on locomotion and acoustic startle. I: Acute effects in female rats.
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.
Morse
D E
DE
U.S. Food and Drug Administration, Division of Antiviral Drug Products, Rockville, MD 20857, USA.
Davis
H D
HD
Popke
E J
EJ
Brown
K J
KJ
O'Donoghue
V A
VA
Grunberg
N E
NE
D000161:Acoustic Stimulation; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D005260:Female; D009043:Motor Activity / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects*; D016047:Zalcitabine / Q000494:pharmacology*; D015215:Zidovudine / Q000494:pharmacology*
D019380:Anti-HIV Agents; D015215:Zidovudine; D016047:Zalcitabine