Prenatal administration of methadone in the rat increases offspring acoustic startle amplitude at age 3 weeks.

Two doses of methadone were administered by osmotic minipump from Day 8 of gestation through parturition, a dosing technique previously shown to produce physical dependence in the dams. A pair-fed control group received saline via minipump and was allowed to eat and drink only the amount consumed by the high dose group on the same gestation days. A nontreated control group was left undisturbed during pregnancy. All treated and control litters were fostered at birth to untreated dams. The effects of methadone on maternal and offspring toxicity replicated our previous findings. At 21-23 days of age, acoustic startle amplitude was measured for each treated and control animal. Because prenatal methadone exposure resulted in reduced body weight at the time of testing, it was necessary to analyze startle amplitude using weight as a covariate. This analysis showed that the methadone treated offspring had a significantly enhanced mean startle amplitude compared with the controls. These findings support the hypothesis derived from our earlier research that prenatal exposure to methadone produces a prolonged state of CNS hyperexcitability similar to clinical descriptions of human infants undergoing opiate abstinence.

Methadone during pregnancy: the search for a valid animal model.

It has long been known that maternal addiction to opiates during pregnancy produces passive addiction in the newborn. When the synthetic opiate, methadone, became widely used for the treatment of heroin addiction, attention was focused on its possible reproductive and developmental toxicity. The clinical data clearly indicate that prenatal exposure to methadone produces a neonatal abstinence syndrome and that the symptoms, characterized by generalized CNS arousal, persist for as long as 4-6 month after birth. Long-term neurobehavioral follow-up studies to pre-school age have not found any obvious cognitive impairments or deficits in IQ. Some of the children, however, may be at risk for developing problems of fine motor coordination and attention deficit disorder that are likely to lead to poor school performance. These effects probably have complex origins and include primary drugs effects, postnatal/environmental interactions and genetic susceptibilities. Regardless of their interpretation, however, it is important to emphasize that from a risk/benefit point of view, most workers would agree that methadone maintenance poses far fewer hazards, both to the mother and her offspring, than continued abuse of heroin with its associated medical complications, psychosocial turmoil, but most importantly, risk of HIV infection. Because of their pharmacological relevance to the issue of human kinetics, it is hoped that the more recent animal studies of prenatal methadone exposure using the osmotic mini-pump will shed more light on the problem of developmental toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of prenatal exposure to cocaine on the rest-activity cycle of the preweanling rat.

Either 45 or 60 mg/kg cocaine HCl was administered from days 8-22 of gestation. Pair-fed and nontreated groups served as controls and all treated and control litters were fostered at birth to untreated dams. To examine whether cocaine produces effects on the rest-activity cycle of the offspring, groups of three littermates from each of the treated and control groups were tested for an 8-h observation period on electronic activity monitors at 22 days of age. Neither activity level nor the rest-activity pattern were affected by cocaine. These findings are discussed in relation to previous studies of cannabis and methadone effects on the rest-activity measure.

Prenatal administration of methadone using the osmotic minipump: effects on maternal and offspring toxicity, growth, and behavior in the rat.

Two doses of methadone were administered by osmotic minipump from day 8 of gestation through parturition. A pair-fed control group received saline via minipump and was allowed to eat and drink only the amount consumed by the high dose group on the same gestation days. A nontreated control group was left undisturbed during pregnancy. All treated and control litters were fostered at birth to untreated dams. Naloxone challenge of the dams after parturition showed that drug treatment produced physical dependence. Methadone treatment reduced maternal weight gain but had no effect on either the frequency of resorptions or birthweight. Both doses of methadone increased perinatal mortality but only the high dose produced a decrement in postnatal growth. To examine the effects of methadone on the rest-activity cycle of the offspring, groups of three littermates from each of the treated and control groups were tested for an 8 h observation period on electronic activity monitors at 22 days of age. No behavioral effects were observed for either control group or the low dose methadone group. The high dose methadone offspring, however, spent less time resting, showed disrupted rhythmicity, and poor state regulation. These findings are discussed in relation to earlier studies using once per day methadone administration as well as clinical descriptions of infants undergoing opiate abstinence.