Heroin Exposure Research Articles

Disruption of the development of cholinergic-induced translocation/activation of PKC isoforms after prenatal heroin exposure

Prenatal exposure of mice to heroin resulted in behavioral deficits present at adulthood, and related to septohippocampal cholinergic innervation accompanied by both pre- and postsynaptic cholinergic hyperactivity; including an increase in membrane PKC activity, and a desensitization of PKC to cholinergic input, which correlated highly with the behavioral performance, and was reversed by cholinergic grafting. The effect was shown in the behaviorally relevant PKCγ and β whereas the less behaviorally relevant PKCα isoform was not affected. The present study was designed to establish the effect of heroin exposure on the expression of the PKC isoforms level and on the more functionally relevant cholinergic translocation/activation of the isoforms throughout postnatal development. The hippocampi of mice pups, exposed to heroin transplacentally, were assayed after incubation with carbachol for PKC isoforms on postnatal days (PN) 1, 7, 14, 21, 30 and 50. Prenatal heroin exposure increased basal PKCγ, β and α levels. PKCγ and α levels returned to control levels on PN50. While in PKCβ, this increase lasted until PN50. Translocation/activation of the PKC isoforms γ and β by cholinergic receptor stimulation was present from PN1, concurrent with the presence of the isoforms. Prenatal exposure to heroin completely abolished the translocation/activation throughout the entire postnatal development. This defect was shown from the very beginning, PN1, the day when the PKC isoforms appear. The results suggest that the PKCγ and β isoforms are functional concurrent with their developmental appearance. Unlike findings on some other teratogens, the prenatal heroin effect on the isoforms function is similar throughout postnatal development.

Heroin affects purine nucleotides catabolism in rats in vivo

To investigate the effect of heroin on purine nucleotides catabolism, a rat model of heroin administration and withdrawal was established. Concentrations of uric acid, creatinine, and urea nitrogen in plasma and ADA in plasma, brain, liver, and small intestine were tested. When two heroin administration groups were compared with the control group, the concentrations of plasma uric acid and ADA in plasma, brain, liver, and small intestine increased, whereas the plasma urea nitrogen concentrations in two heroin administration groups and the plasma creatinine concentration in the 3-day heroin administration group did not increase. It seemed that heroin exposure for a short time did not affect renal clearance rate notably. When two withdrawal groups were compared with two heroin administration groups, the concentrations of plasma uric acid and ADA in liver and small intestine decreased, but there was no significant reduction in ADA concentrations of the brain, while the plasma ADA concentrations in the two withdrawal groups were significantly higher than those of two heroin administration groups. When the two withdrawal groups were compared with the control group, there was no significant difference in the concentrations of plasma uric acid and ADA in liver and small intestine, while the concentrations of ADA in plasma and brain were still higher than those of the control group. The results imply that heroin administration may enhance the catabolism of purine nucleotides in the brain and other tissues by increased concentration of ADA and the effect may last for a long time in the brain.

Convergent Effects on Cell Signaling Mechanisms Mediate the Actions of Different Neurobehavioral Teratogens: Alterations in Cholinergic Regulation of Protein Kinase C in Chick and Avian Models

Although the actions of heroin on central nervous system (CNS) development are mediated through opioid receptors, the net effects converge on dysfunction of cholinergic systems. We explored the mechanisms underlying neurobehavioral deficits in mouse and avian (chick, Cayuga duck) models. In mice, prenatal heroin exposure (10 mg/kg on gestation days 9-18) elicited deficits in behaviors related to hippocampal cholinergic innervation, characterized by concomitant pre- and postsynaptic hyperactivity, but ending in a reduction of basal levels of protein kinase C (PKC) isoforms betaII and gamma and their desensitization to cholinergic receptor-induced activation. PKCalpha, which is not involved in the behaviors studied, was unaffected. Because mammalian models possess inherent confounding factors from maternal effects, we conducted parallel studies using avian embryos, evaluating hyperstriatal nucleus (intermedial part of the hyperstriatum ventrale, IMHV)-related, filial imprinting behavior. Heroin injection to the eggs (20 mg/kg) on incubation days 0 and 5 diminished the post-hatch imprinting ability and reduced PKCg and bII content in the IMHV membrane fraction. Two otherwise unrelated agents that converge on cholinergic systems, chlorpyrifos and nicotine, elicited the same spectrum of effects on PKC isoforms and imprinting but had more robust actions. Pharmacological characterization also excluded direct effects of opioid receptors on the expression of imprinting; instead, it indicated participation of serotonergic innervation. The avian models can provide rapid screening of neuroteratogens, exploration of common mechanisms of behavioral disruption, and the potential design of therapies to reverse neurobehavioral deficits.

Motivation of heroin-seeking elicited by drug-associated cues is related to total amount of heroin exposure during self-administration in rats

Conditioned stimuli (CSs) previously associated with heroin are critically involved in activating long-lasting relapse and compulsive drug seeking. This study examined the magnitude of heroin seeking induced by drug-related cues in relation to the total amount of drug exposure during training. Five groups of male Sprague–Dawley rats ( n=6/group) were trained by the nose-poking response to self-administer different doses of heroin (0, 0.01, 0.025, 0.05, and 0.1 mg/kg per infusion respectively, one 4-h session daily, limited to 25 infusions per session) under an identical progressive ratio schedule with gradual incremental response requirements. All the rats established stable heroin self-administration within 14 days of self-administration training, and the time needed to obtain all the 25 heroin infusions decreased across sessions. After 14 days of abstinence, heroin seeking elicited by contextual cues (self-administration chamber) or discrete contingent CSs previously associated with heroin infusions was measured in two consecutive 1-h test phases. During both test phases, the rats trained with heroin even at the lowest dose (0.01 mg/kg) showed higher active responses than saline controls, and the active responses were also higher in rats trained with doses of 0.025, 0.05, and 0.10 mg/kg in comparison with those trained with a dose of 0.01 mg/kg. There was no observable dose-dependence increase of responses at doses above 0.025 mg/kg. The results suggested that an increased motivation to seek heroin induced by drug-related cues is associated with the total amount of heroin intake.

Postmortem distribution of heroin metabolites in femoral blood, liver, cerebrospinal fluid, and vitreous humor.

The presence of 6-monoacetylmorphine (6-MAM) is often used to distinguish between heroin (diacetylmorphine) and morphine exposures. 6-MAM, however, is rapidly metabolized to morphine and may not be present in detectable quantities in blood following heroin exposure. Recent studies have shown that 6-MAM may persist in cerebrospinal fluid (CSF) and this specimen may be preferable for establishing heroin exposure. This study reports postmortem distribution of 6-MAM, unconjugated morphine, and codeine in different tissues from 25 deceased individuals. In all cases, 6-MAM was detected in vitreous humor, and in CSF in 16 of the 25 cases (64%). When 6-MAM was detected in blood (13 of 25 cases), the level of 6-MAM in vitreous humor and CSF was higher than in blood, with a mean concentration ratio of 11.3 (range: 1.7-27) for vitreous humor and 6.6 (range: 2.6-17.3) for CSF. 6-MAM was not detected in liver in any of the cases examined. Free morphine levels were highest in liver, followed by blood, CSF, and vitreous humor. The concentration ratios (mean +/- standard deviation) for free morphine in vitreous humor, CSF, and liver to that in blood were 0.36 +/- 0.18, 0.64 +/- 0.27, and 2.99 +/- 2.12, respectively. The liver/blood ratio was consistent with previously reported values for morphine in heart and femoral blood. Codeine levels following heroin overdose were consistently low relative to the morphine concentration. For blood, liver, and CSF, the ratio of codeine to morphine was essentially the same (0.06), whereas the vitreous codeine/morphine concentration ratio was slightly higher (0.19). These results characterize the distribution of heroin metabolites in postmortem tissues. Vitreous humor appears to be a useful specimen for determining 6-MAM and establishing the morphine was derived from heroin.

Prenatal heroin exposure alters cholinergic receptor stimulated activation of the PKC$beta;II and PKC$gamma; isoforms

Prenatal exposure of mice to heroin (SC injection of 10 mg/kg to the dams on gestational days 9–18) resulted at adulthood in behavioral deficits related to septohippocampal cholinergic innervation accompanied with both presynaptic and postsynaptic cholinergic hyperactivity; including an increase membrane PKC activity, and a desensitization of PKC to cholinergic input which were highly correlated with the behavioral performance and were reversed by cholinergic grafting. Therefore, we studied the receptor induced activation of the behaviorally relevant PKCγ and PKCβII isoforms and the less behaviorally relevant PKCα isoform. Time course studies revealed peak translocation after 40 min incubation with carbachol for PKCγ (110% increase from basal, i.e. no carbachol level, P < 0.01), 30 min for phosphorylated PKCβII (130%, P < 0.05) and 5 min for non-phosphorylated PKCβII (64%, P < 0.05) with no peak for alpha. Prenatal heroin abolished the translocation of PKCγ and PKCβII while PKCα remained unaffected. A decrease occurred in basal phosphorylated membrane (−45%, P < 0.01) and cytosol-associated (−29%, P < 0.01) PKCβII, in membrane-associated non-phosphorylated PKCβII (−32%, P < 0.01) and PKCγ (−25%, P < 0.01) and in cytosolic PKCα (−27%, P < 0.01), while membrane-associated PKCα was slightly increased (11%, P < 0.05). The results suggest that prenatal heroin disrupts cholinergic receptor induced PKC translocation and activation with the underlying mechanism of neuroteratogenicity potentially lying in the PKCγ and PKCβII, while PKCα remains unaffected.

Prenatal heroin exposure alters cholinergic receptor stimulated activation of the PKCβII and PKCγ isoforms

Prenatal exposure of mice to heroin (SC injection of 10 mg/kg to the dams on gestational days 9–18) resulted at adulthood in behavioral deficits related to septohippocampal cholinergic innervation accompanied with both presynaptic and postsynaptic cholinergic hyperactivity; including an increase membrane PKC activity, and a desensitization of PKC to cholinergic input which were highly correlated with the behavioral performance and were reversed by cholinergic grafting. Therefore, we studied the receptor induced activation of the behaviorally relevant PKCγ and PKCβII isoforms and the less behaviorally relevant PKCα isoform. Time course studies revealed peak translocation after 40 min incubation with carbachol for PKCγ (110% increase from basal, i.e. no carbachol level, P < 0.01), 30 min for phosphorylated PKCβII (130%, P < 0.05) and 5 min for non-phosphorylated PKCβII (64%, P < 0.05) with no peak for alpha. Prenatal heroin abolished the translocation of PKCγ and PKCβII while PKCα remained unaffected. A decrease occurred in basal phosphorylated membrane (−45%, P < 0.01) and cytosol-associated (−29%, P < 0.01) PKCβII, in membrane-associated non-phosphorylated PKCβII (−32%, P < 0.01) and PKCγ (−25%, P < 0.01) and in cytosolic PKCα (−27%, P < 0.01), while membrane-associated PKCα was slightly increased (11%, P < 0.05). The results suggest that prenatal heroin disrupts cholinergic receptor induced PKC translocation and activation with the underlying mechanism of neuroteratogenicity potentially lying in the PKCγ and PKCβII, while PKCα remains unaffected.

Altered localization of choline transporter sites in the mouse hippocampus after prenatal heroin exposure

Prenatal heroin exposure disrupts hippocampal cholinergic synaptic function and related behaviors. Biochemical studies indicate an increase in the number of presynaptic high-affinity choline transporter (HACT) sites, as assessed by [ 3 H ]hemicholinium-3 (HC-3) binding. The present study was designed to assess whether this effect involves global upregulation of the transporter, or whether disruption occurs with a specific tempero-spatial distribution. Pregnant mice were given 10 mg/kg per day of heroin subcutaneously on gestational days (GD) 9–18. Autoradiographic distribution of HC-3 binding sites was evaluated in the hippocampus of the offspring at postnatal days 15, 25, and 53. These results, suggestive of hippocampal “miswiring,” are likely to explain the net impairment of cholinergic synaptic function after prenatal heroin exposure, despite the simultaneous upregulation of both presynaptic cholinergic activity and postsynaptic receptors. Understanding the subregional selectivity of hippocampal defects can lead to the development of strategies that may potentially enable therapeutic interventions to offset or reverse the neurobehavioral defects.

Heroin neuroteratogenicity: delayed-onset deficits in catecholaminergic synaptic activity

Prenatal heroin exposure evokes neurochemical and behavioral deficits that, in part, reflect disruption of septohippocampal cholinergic function. In earlier studies, we found that cholinergic synaptic defects involve primary changes in cell signaling proteins that are shared by other transmitter systems. In the current study, we determined whether heroin also targets noradrenergic and dopaminergic inputs that operate through the same signaling cascades. Mice exposed to prenatal heroin showed significant deficits in norepinephrine and dopamine levels and much more pronounced effects on neurotransmitter turnover, an index of synaptic activity. Adverse effects were not present in the immediate postnatal period but rather emerged just before weaning and worsened subsequently. By young adulthood, the most highly-affected regions (hippocampus, cerebral cortex) displayed almost complete inactivation of noradrenergic and dopaminergic tonic activity. These effects arise after prior deficits in cell signaling are discernible, suggesting that the presynaptic effects are secondary to actions on signal transduction cascades shared by numerous neurotransmitter inputs and targeted by other neuroteratogens. These results may explain why apparently unrelated developmental neurotoxicants may ultimately produce a common set of neurochemical and behavioral anomalies.

Heroin neuroteratogenicity: targeting adenylyl cyclase as an underlying biochemical mechanism

Prenatal heroin exposure evokes neurochemical and behavioral deficits that in part, reflect disruption of septohippocampal cholinergic function. In earlier studies, we found that cholinergic synaptic defects involve changes in proteins, like protein kinase C, that are essential to receptor-mediated signaling. In the current study, we determined whether heroin targets another signaling protein, adenylyl cyclase (AC), which regulates the production of cAMP. Mice exposed to prenatal heroin showed subsequent postnatal elevations of AC activity that lasted into adulthood. The effect was most robust with stimulants that activate AC directly (forskolin, Mn 2+), indicating increased expression of AC itself; we also identified shifts in catalytic properties suggestive of a change in the AC isoform. Superimposed on the overall induction of AC, there were transient deficits in the responses to stimulants working through G-proteins (NaF) or G-protein coupled receptors (isoproterenol, a β-adrenoceptor agonist), indicating alterations at other steps in the signaling pathway. Effects on the regulation of AC activity were seen in brain regions with widely disparate maturational timetables and also occurred in regions, like the cerebellum, that are sparse in cholinergic input. These results suggest that the expression and/or function of signaling proteins distal to neurotransmitter receptors represent a major target for neurobehavioral teratogenesis by heroin; the fact that these targets are shared by otherwise unrelated neuroteratogens may account for a common set of neurochemical and behavioral anomalies in response to prenatal exposure to drugs or environmental chemicals.

Striatal Dopaminergic and Serotonergic Markers in Human Heroin Users

To establish whether chronic opiate exposure might impair brain dopaminergic or serotonergic function in humans, we assessed biochemical indices of monoaminergic neurotransmitter activity and integrity in post mortem striatum of nine chronic heroin users and 14 control subjects. Striatal levels of the vesicular monoamine transporter were normal, suggesting that the density of dopamine nerve terminals is not reduced in heroin users. In nucleus accumbens, levels of tyrosine hydroxylase protein (-25%) and those of the dopamine metabolite homovanillic acid (-33%) were reduced significantly together with a trend for decreased dopamine (-32%) concentration. These changes could reflect either a compensatory downregulation of dopamine biosynthesis in response to prolonged dopaminergic stimulation caused by heroin, or reduced axoplasmic transport of tyrosine hydroxylase. Striatal levels of serotonin were either normal or elevated whereas concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid were decreased by 27-38%. Our data suggest that chronic heroin exposure might produce a modest reduction in dopaminergic and serotonergic activity that could affect motivational state and impulse control, respectively.

Prenatal heroin exposure: Effects on development, acoustic startle response, and locomotion in weanling rats

The purpose of this study was to investigate the effects of prenatal heroin exposure on the offspring in postnatal behavioral development. Pregnant Sprague-Dawley rats were injected daily (s.c.) with 10mg/kg of heroin from gestational day 8 to 20. The control dam received saline injections and the pair-fed dam received saline and was yoked to a weight-matched heroin-treated dam. Litters were culled to eight to ten pups and weighed at postnatal day (PND) 1, 8, 15, and 22. Acoustic prepulse inhibition and habituation were parameters used for evaluating the sensorimotor gating and simple form of learning respectively. Locomotor activity and rearing were assessed using the photobeam activity system. All behavioral tests were performed on the offspring at PND 21 to 23. Results showed that heroin treatment significantly reduced maternal food intake, water consumption, and weight gain. Both heroin-exposed and pair-fed groups showed a marked reduction in birth weight in both male and female pups when compared with controls; however the postnatal weight gain in heroin-exposed pups was significantly lower than the pair-fed group by 3 weeks postnatally, particularly in the female pups. These female pups also showed a significant increase in ambulation and rearing when compared to the pair-fed pups. The habituation rate in both types of behavioral tests was also decreased in these female pups as compared to control and pair-fed groups. The present study indicated that prenatal heroin exposure could result in a marked retardation of postnatal development and learning. These effects are sex related.

Neural grafting as a tool for the study and reversal of neurobehavioral birth defects

The transplantation of fetal neurons has gained notoriety in recent years for its perceived potential to reverse neurological deficits caused by loss of one or another neuronal population. The present paper describes a neural grafting approach employed by our laboratory to gain more insight into the drug-induced neurobehavioral teratogenicity. Mice were exposed prenatally to phenobarbital by feeding the barbiturate to the pregnant dam on gestation days 9–18. Heroin exposure was accomplished by injecting dams during the same gestational period. At maturity, the drug-exposed offspring displayed profound deficits in specific behavioral tasks, suggesting alterations in the septohippocampal cholinergic pathway. Biochemically, we observed increased presynaptic activity in the pathway, which was not accompanied by a corresponding reduction in postsynaptic activity. Rather, there was a general hyperactivation along the different postsynaptic phases. In contrast, we noted a desensitization of protein kinase C activity in response to the exposure of a cholinergic agonist to the drug-exposed offspring. Subsequent transplantation of embryonic cholinergic cells from normal mice to the impaired hippocampus reversed the behavioral deficits, whereas sham-operated controls exhibited no improvement. Concomitantly, all the biochemical alterations studied, both presynaptic and postsynaptic, were either partially or completely reversed following grafting.

The developmental outcome of children born to heroin-dependent mothers, raised at home or adopted

In the present investigation we were interested to study the possible role of in-utero exposure to heroin and of the home environment in the etiology of long-term developmental problems in children born to heroin-dependent parents in comparison to matched controls. The children were examined at 5–6 years of age by a developmental pediatrician and a developmental psychologist using, for the children up to 2.5 years of age, the Bayley Developmental Scales, and for children aged 3–6 years the McCarthy Scales for Children's Abilities. We examined 83 children born to heroin-dependent mothers, and compared the results to those of 76 children born to heroin-dependent fathers and to three control groups; 50 children with environmental deprivation, 50 normal children from families of moderate or high socioeconomic class, without environmental deprivation, and 80 healthy children from kindergartens in Jerusalem. There were five children (6.0%) with significant neurological damage among the children born to heroin-dependent mothers and six (7.9%) children among those born to heroin-dependent fathers. The children born to heroin-dependent mothers had a lower birth weight and a lower head circumference at examination when compared to controls. The children born to heroin-dependent parents also had a high incidence of hyperactivity, inattention, and behavioral problems. The lowest DQ or IQ among the children with cognitive levels above 70 was found in the children with environmental deprivation, next was the DQ or IQ of children born to heroin-dependent fathers, then the DQ or IQ of the children born to heroin-dependent mothers. When the children born to heroin-dependent mothers were divided to those that were adopted at a very young age and to those raised at home, the adopted children were found to function similarly to the controls while those not adopted functioned significantly lower. Our results show that the developmental delay and behavioral disorders observed among children born to drug-dependent parents raised at home may primarily result from severe environmental deprivation and the fact that one or both parents are addicted. The specific role of the in-utero heroin exposure in the determination of the developmental outcome of these children (if they do not have significant neurological damage), seems to be less important in comparison to the home environment.

Biochemical adaptations in the mesolimbic dopamine system in response to heroin self-administration.

Previous studies have shown that chronic, forced exposure to opiates produces specific biochemical adaptations in the ventral tegmental area (VTA) and nucleus accumbens (NAc). The functional consequences of these adaptations have been hypothesized to contribute to certain motivational aspects of drug addiction. In this study, the possibility that similar adaptations could occur in response to intermittent heroin self-administration was tested by comparing homogenates of VTA and NAc from rats self-administering heroin, rats receiving yoked injections of heroin, and rats receiving yoked injections of saline (controls). Tyrosine hydroxylase (TH) immunoreactivity was increased (31-38%) in the VTA and decreased (11%) in the NAc of heroin-exposed rats relative to controls. Heroin exposure also increased cAMP-dependent protein kinase (PKA) activity in both particulate (19-27%) and soluble (17-20%) fractions of the NAc, and decreased (16-17%) the level of Gi alpha immunoreactivity in this brain region. In contrast, no significant biochemical changes were found in the substantia nigra or caudate-putamen, indicating a selective effect on the mesolimbic dopamine system. Overall, adaptations in the VTA and NAc of heroin-exposed rats were similar to, but generally smaller in magnitude than, adaptations produced by chronic morphine administration. However, in contrast to morphine-treated animals, heroin-exposed animals failed to display overt signs of opiate physical dependence, suggesting that adaptations in motivational systems may occur more readily than adaptations in brain regions associated with physical dependence.

Radioimmunoassay of hair for determination of cocaine, heroin, and marijuana exposure: comparison with self-report

Radioimmunoassay of hair for determination of cocaine, heroin, and marijuana exposure: comparison with self-report

Cognitive disorders in children

Cognitive disorders affect thinking and perceptual processes and the acquisition of knowledge and new information. They have an enormous societal impact because special educational resources are required, and independent living often cannot be achieved. Learning problems may lead to behavioral disorders in the home and community. The pathogenesis of most mild and moderate cognitive disorders is poorly understood. Severe cognitive impairment is usually accompanied by somatic abnormalities, and an etiology can be identified in many cases. Specific treatments are available for disorders such as cogenital hypothyroidism, some metabolic acidurias, and congenital toxoplasmosis. Other disorders affecting cognition such as fetal alcohol syndrome, maternal cocaine and heroin exposure, HIV encephalopathy, and prematurity require aggressive prevention and education to reduce their occurrence. The recent advances in molecular genetics offer a faster and better method of diagnosing fragile X syndrome, now recognized as the most common inheritable cause of mental retardation. In the future, DNA analysis may elucidate the basis of many other cognitive disorders.

Forensic Drug Testing for Opiates: I. Detection of 6-Acetylmorphine in Urine as an Indicator of Recent Heroin Exposure; Drug and Assay Considerations and Detection Times

The urinary excretion patterns of 6-acetylmorphine (6-AM), free morphine, and total morphine were determined by GC/MS assay for six human subjects who received single doses of 3.0 and 6.0 mg of heroin hydrochloride. Clinical specimens were collected and combined with standardized drug urines into a 400 specimen/standard set. The urines were coded, randomized, and analyzed under blind conditions. The GC/MS assay had a limit of sensitivity of 0.81 ng/mL for 6-AM and displayed a linear response across a concentration range of 1-100 ng/mL. Following heroin administration, 6-AM was excreted rapidly with an average half-life of 0.6 h. This resulted in a very short detection time for 6-AM with a range of 2-8 h at the most sensitive cutoff limit. This short detection time limits the usefulness of 6-AM as a marker for identification of heroin abusers to a period immediately after drug use. In contrast, free morphine and total morphine were detectable up to approximately 24 h after heroin administration. The average half-life for free morphine was 3.6 h and for total morphine was 7.9 h. After morphine and codeine administration, no 6-AM was detected by GC/MS above the 0.81-ng/mL detection limit of the assay. It is concluded that the presence of 6-AM in urine can be interpreted with confidence to mean that heroin, or 6-AM, was administered within 24 h of specimen collection and that the presence of 6-AM in urine is not caused by morphine or codeine administration.

Infrequent neonatal opiate withdrawal following maternal methadone detoxification during pregnancy

The influence of maternal participation in a methadone detoxification program as compared to street drug use on intrauterine growth and neonatal morbidity was analysed in 75 newborns. -58 of 75 pregnant addicts joined the methadone program; in 17 women with successful prepartal detoxification, we found a longer course of pregnancy as well as normalized birth weight, head circumference and respiratory status of the neonates. The HIV-status showed no influence on prenatal growth. 63% of all infants developed a neonatal abstinence syndrome; this incidence was lower after maternal participation in the methadone detoxification program: 55 vs. 88%, p less than 0.05. Postnatal respiratory insufficiency occurred more frequently after methadone exposure than after heroin exposure before birth (p less than 0.05).

DEVELOPMENTAL EFFECTS OF PERINATAL HEROIN AND METHADONE ADDICTION

To summarize the results of studies investigating the effects of perinatal methadone and heroin exposure on subsequent infant development is difficult. The research is confounded by the lack of controlled studies, variations in methodology, and problems inherent in using subjects with variable exposure to a wide range of drugs. Despite these limitations, consistencies across studies are found. These are developmental delays, particularly in habituation to visual stimuli and in complex motor skills, and behavior disturbances. Follow-up research is recommended to determine the persistence of these delays, and early intervention is recommended in the areas of improving prenatal health care and facilitating the parent-infant bond, thereby enhancing meaningful social and sensory stimulation for the infant prenatally exposed to methadone or heroin.