Early clinical reports of severe morbidity and mortality in infants born passively addicted to opiates are being reinterpreted in light of recent reports of an improved prognosis in children born to women on methadone maintenance programs who avail themselves of antenatal and well-baby clinics, and in whom illicit polydrug abuse and poor nutrition are kept to a minimum (Finnegan, 1978, 1983). Most of the preclinical animal literature dealing with effects of methadone during development would suggest that methadone should never have been released for clinical use by people of childbearing age or who are pregnant. However, we believe that there are many flaws in the design and interpretation of these experiments and have completed or are in the process of extending a series of experiments with the opiate 1-alpha-acetylmethadol (LAAM) or its active metabolites in which we can duplicate many effects reported for methadone but which appear to be preventable or nonexistent, if careful attention is paid to animal modeling and potential epiphenomena. We propose to continue these studies as well as incorporate several new studies to determine the relevance (i.e. generality or specificity) of our observations with LAAM, to study the consequences of hypoxia and hypercapnia equivalent to that produced by (acutely toxic) doses of methadone typically used by other laboratories for such studies, to directly test the importance of opiate-type withdrawal, to study the interactive effects of neonatal opiate-type withdrawal with a model of maternal neglect engendered by rearing pups in large litters of 24, and to use biochemical, endocrinological and functional (e.g. behavioral) data derived from our studies to determine the possible mechanisms whereby exposure to opiates imparts the sundry congenital effects which have bean reported.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA001880-13
Application #
2116472
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1977-07-01
Project End
1993-09-30
Budget Start
1992-04-01
Budget End
1993-09-30
Support Year
13
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pharmacology
Type
Schools of Medicine
DUNS #
168559177
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Sparber, S B; Rizzo, A; Berra, B (1996) Excessive stimulation of serotonin2 (5-HT2) receptors during late development of chicken embryos causes decreased embryonic motility, interferes with hatching, and induces herniated umbilici. Pharmacol Biochem Behav 53:603-11
Sparber, S B; O'Callaghan, J P; Berra, B (1992) Ganglioside treatment partially counteracts neurotoxic effects of trimethyltin but may itself cause neurotoxicity in rats: experimental results and a critical review. Neurotoxicology 13:679-700
Neal, B S; Messing, R B; Sparber, S B (1991) Long-term effects of neonatal exposure to isobutylmethylxanthine. II. Attenuation of acute morphine withdrawal in mature rats. Psychopharmacology (Berl) 103:398-406
Neal, B S; Sparber, S B (1991) Long-term effects of neonatal exposure to isobutylmethylxanthine. I. Retardation of learning with antagonism by mianserin. Psychopharmacology (Berl) 103:388-97
Sparber, S B (1991) Measurement of drug-induced physical and behavioral delays and abnormalities in animal studies: a general framework. NIDA Res Monogr 114:148-64
Cohen, C A; Tonkiss, J; Sparber, S B (1991) Acute opiate withdrawal in rats undernourished during infancy: impact of the undernutrition method. Pharmacol Biochem Behav 39:329-35
Coveney, J R; Neal, B S; Sparber, S B (1990) Food deprivation alters behavioral and plasma corticosterone responses to phencyclidine in rats. Pharmacol Biochem Behav 36:451-6
Neal, B S; Sparber, S B (1990) The serotonin2 antagonist ritanserin blocks quasi-morphine withdrawal at a time when mianserin is no longer effective. Psychopharmacology (Berl) 100:258-66
Coveney, J R; Sparber, S B (1990) Delayed effects of amphetamine or phencyclidine: interaction of food deprivation, stress and dose. Pharmacol Biochem Behav 36:443-9
Kleven, M S; Sparber, S B (1989) Modification of quasi-morphine withdrawal with serotonin agonists and antagonists: evidence for a role of serotonin in the expression of opiate withdrawal. Psychopharmacology (Berl) 98:231-5

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