Alterations in offspring behavior induced by chronic prenatal cocaine dosing.

Sperm-positive female Long-Evans hooded rats were dosed subcutaneously with 10 mg/kg/day cocaine or an equal volume of vehicle (0.9% sterile saline) from gestation day 4 (GD4) through GD18. Offspring were assessed for development of negative geotaxis, righting reflex, spontaneous alternation, and open field activity, and for adult behaviors including DRL-20 acquisition, water maze, visual discrimination, barbiturate sleep time, shuttlebox avoidance, footshock sensitivity, and tail flick latency. Cocaine dosing produced no significant effects on dam weight gain, any measure of litter size and weight, or early postnatal behavioral tests, but there were significant drug effects on development of spontaneous alternation, development of open field activity, DRL-20 acquisition, water maze performance, tail flick, and footshock sensitivity. These data suggest that chronic administration of a modest dose of cocaine during gestation in the rat alters a number of behaviors in the offspring.

Behavioral effects of prenatal exposure to lidocaine in the rat: effects of dosage and of gestational age at administration.

Pregnant Long-Evans hooded rats were dosed via injections into the gum with 3, 6, or 9 mg/kg lidocaine, or vehicle, or were uninjected, on gestational day 4 (GD4), GD11, or GD18. Offspring (8-11 litters/group) were tested on a variety of tests of behavioral development and adult behavior. No effects of any dose at any time of administration were found upon maternal weight gain in gestation, litter size, or initial birth weight or weight gain of the pups. Administration at GD4 produced few effects; only footshock sensitivity showed a significant effect of dosing, although there were trends toward dosing effects on spontaneous alternation. For administration on GD11, lidocaine was associated with slight but significant alterations in sex ratios, and a trend toward drug effects on development of spontaneous alternation. Vehicle administration at this age reduced barbiturate sleep time in offspring and slightly altered footshock sensitivity. Lidocaine dosing on GD18 was associated with a number of significant alterations of behavior, including visual discrimination, shuttlebox avoidance, tail flick, and water maze errors; there were also both vehicle and lidocaine effects on water maze latencies. These data reinforce our previous report that lidocaine may be a behavioral teratogen, and suggest that administration in later gestation in the rat may alter a broader range of behaviors than earlier in gestation.

Behavioral effects of mid-pregnancy administration of lidocaine and mepivacaine in the rat.

Sperm-positive female Long-Evans hooded rats were injected with 6 mg/kg lidocaine (with epinephrine), 6 mg/kg mepivacaine, or saline, into the masseter muscle of the jaw on Day 11 of gestation. Birth, growth, and litter composition were unaffected by the drug treatment, as was shuttle box acquisition. Offspring of drug-treated dams had longer latencies than controls on the first day of negative geotaxis training, and were more sensitive to electric footshock. Lidocaine-dosed offspring responded less in the presence of the correct cue in the visual discrimination task, and mepivacaine-dosed animals were hypoactive in the open field. In a second study, offspring of lidocaine-dosed dams were slower to develop the righting reflex, made more errors in acquiring a water maze, had longer suppression times in a conditioned suppression task, and had longer latencies in the tail flick test. Dosing had no effect upon birth and growth, shuttle box, or footshock sensitivity. These data demonstrate that midgestational exposure to lidocaine or mepivacaine at a dose near the limits of permissible human exposure produces significant behavioral changes in the offspring. This preliminary study suggests that development of some portion of the central nervous system is altered by such exposure. Further work is required to determine the parameters and the extent of the effect.