Prenatal AZT or 3TC and mouse development of locomotor activity and hot-plate responding upon administration of the GABA(A) receptor agonist muscimol.
BACKGROUND
Zidovudine (AZT) and lamivudine (3TC) are nucleoside analogues administered prenatally in clinical practice, separately or in combination, as antiretroviral drugs to prevent HIV mother-to-child transmission by inhibiting viral reverse transcriptase. In animal studies pre- and/or perinatal exposure to AZT and 3TC induce age- and sex-dependent neurobehavioural alterations in the offspring.


OBJECTIVE
Investigation of short- and medium-term effects of in utero exposure to AZT or 3TC on development of the GABAergic system.


METHODS
Pregnant CD-1 mice were given orally twice daily AZT (160 mg/kg), 3TC (500 mg/kg) or vehicle solution (NaCl 0.9%) from pregnancy day 10 to delivery. Offspring locomotion and nociceptive sensitivity were examined on postnatal day (pnd) 8, 14, and 28 after administration of two doses of GABAergic agonist muscimol (pnd 8 and 14: 0.05 and 0.2 mg/kg; pnd 28: 0.2 and 1.0 mg/kg). A 30-min locomotor activity test and a 60 s hot-plate test (50+/-1 degrees C) were used.


RESULTS
AZT and 3TC treated mice showed a mild increase of locomotor activity after administration of the high dose muscimol on pnd 8. On pnd 14 the low muscimol dose enhanced locomotor activity in vehicle and 3TC, but not in AZT pups, whereas no prenatal treatment effect was evident on pnd 28. AZT increased nociceptive sensitivity at all ages considered.


CONCLUSIONS
Prenatal AZT effects on locomotor activity appear clearly detectable after GABAergic challenge and seem to be transient. AZT effects on pain sensitivity did not appear to be dependent on GABA regulated nociceptive mechanisms. Prenatal 3TC exposure had rather limited effects on locomotor activity development, and no effect on nociception.
Laboratorio di Fisiopatologia di Organo e di Sistema, Istituto Superiore di Sanità, Roma, Italy.
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Ricceri
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Venerosi
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Valanzano
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Sorace
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Alleva
D000818:Animals; D019380:Anti-HIV Agents / Q000633:toxicity*; D005260:Female; D018755:GABA Agonists / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists; D006185:Habituation, Psychophysiologic; D019259:Lamivudine / Q000633:toxicity*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D009118:Muscimol / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011930:Reaction Time / Q000187:drug effects; D013997:Time Factors; D015215:Zidovudine / Q000633:toxicity*
D019380:Anti-HIV Agents; D018755:GABA Agonists; D058785:GABA-A Receptor Agonists; D009118:Muscimol; D019259:Lamivudine; D015215:Zidovudine