Prenatal AZT or 3TC and mouse development of locomotor activity and hot-plate responding upon administration of the GABA(A) receptor agonist muscimol

Rationale: Zidovudine (AZT and lamivudine (3TC) are nucleoside analogues ad ministered prenatally in clinical practice, separately or in combination, a s antiretroviral drugs to prevent HIV mother-to-child transmission by inhib iting viral reverse transcriptase. In animal studies pre- and/or perinatal exposure to AZT and 3TC induce age- and sex-dependent neurobehavioural alte rations in the offspring. Objective: Investigation of short- and medium-ter m effects of in utero exposure to AZT or 3TC on development of the GABAergi c system. Methods: Pregnant CD-1 mice were given orally twice daily AZT (16 0 mg/kg), 3TC (500 mg/kg) or vehicle solution (NaCl 0.9%) from pregnancy da y 10 to delivery. Offspring locomotion and nociceptive sensitivity were exa mined on postnatal day (pnd) 8, 14, and 28 after administration of two dose s 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 her-plate t est (50+/-1 degreesC) 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 activ ity 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 ap pear clearly detectable after GABAergic challenge and seem to be transient. AZT effects on pain sensitivity did not appear to be dependent on GABA reg ulated nociceptive mechanisms. Prenatal 3TC exposure had rather limited eff ects on locomotor activity development, and no effect on nociception.