Motivation deficit in ADHD is associated with dysfunction of the dopamine reward pathway.

Attention-deficit hyperactivity disorder (ADHD) is typically characterized as a disorder of inattention and hyperactivity/impulsivity but there is increasing evidence of deficits in motivation. Using positron emission tomography (PET), we showed decreased function in the brain dopamine reward pathway in adults with ADHD, which, we hypothesized, could underlie the motivation deficits in this disorder. To evaluate this hypothesis, we performed secondary analyses to assess the correlation between the PET measures of dopamine D2/D3 receptor and dopamine transporter availability (obtained with [(11)C]raclopride and [(11)C]cocaine, respectively) in the dopamine reward pathway (midbrain and nucleus accumbens) and a surrogate measure of trait motivation (assessed using the Achievement scale on the Multidimensional Personality Questionnaire or MPQ) in 45 ADHD participants and 41 controls. The Achievement scale was lower in ADHD participants than in controls (11±5 vs 14±3, P<0.001) and was significantly correlated with D2/D3 receptors (accumbens: r=0.39, P<0.008; midbrain: r=0.41, P<0.005) and transporters (accumbens: r=0.35, P<0.02) in ADHD participants, but not in controls. ADHD participants also had lower values in the Constraint factor and higher values in the Negative Emotionality factor of the MPQ but did not differ in the Positive Emotionality factor-and none of these were correlated with the dopamine measures. In ADHD participants, scores in the Achievement scale were also negatively correlated with symptoms of inattention (CAARS A, E and SWAN I). These findings provide evidence that disruption of the dopamine reward pathway is associated with motivation deficits in ADHD adults, which may contribute to attention deficits and supports the use of therapeutic interventions to enhance motivation in ADHD.

The use of a laboratory school protocol to evaluate concepts about efficacy and side effects of new formulations of stimulant medications.

Recently, new long-acting formulations of racemic methylphenidate (MPH: Ritalin LA, Metadate CD and Concerta) and amphetamine (AMP: Adderall XR) were developed and are now approved by the Food and Drug Administration (FDA). In addition, dexmethylphenidate (Focalin), the pharmacologically active d-threo enantiomer of MPH, also was approved by the FDA. In the initial phases of development, prototypes of these five new formulations were evaluated using the University of California, Irvine (UCI) Laboratory School Protocol (LSP), in which surrogate measures of efficacy are collected in highly controlled settings rather than clinical measures of effectiveness in the less-controlled, natural environments of home or school. The LSP studies were followed by large effectiveness and safety studies required for gaining FDA approval. These initial efficacy and side effect studies in the LSP provided missing information about the basic pharmacokinetic (PK) and pharmacodynamic (PD) properties of MPH and AMP and produced some new discoveries (i.e., acute tolerance) that were used to help design the final products. The final once-a-day formulations used different drug delivery systems to achieve long-acting efficacy (Ritalin LA, Metadate CD, Concerta, Adderall XR). All four drug delivery systems were based on two processes: first, a bolus delivery (BD) process to achieve rapid onset of efficacy (mg), and second, a controlled delivery (CD) process to achieve rates of delivery (mg/hr) or a delayed bolus (mg) to maintain efficacy. A theoretical approach was used to compare and contrast the new once-a day formulations of MPH by selecting total daily doses (mg/d) that would equate drug delivery by the first process (mg of the initial bolus) and the second process (mg/hr over specified time period). In addition to efficacy, applications of the LSP to measure common side effects related to eating and sleeping were described and discussed.

The ecological validity of delay aversion and response inhibition as measures of impulsivity in AD/HD: a supplement to the NIMH multimodal treatment study of AD/HD.

Impulsivity is a primary symptom of the combined type of Attention Deficit/Hyperactivity Disorder (AD/HD). The Stop Signal Paradigm is premised upon a primary deficit in inhibitory control in AD/HD, whereas the Delay Aversion Hypothesis, by contrast, conceptualizes impulsivity in AD/HD, not as an inability to inhibit a response, but rather as a choice to avoid delay. This study compared the ecological validity of the Stop Signal Task (SST) and Choice-Delay Task (C-DT) measure of delay aversion, with respect to their relative utility in discriminating AD/HD children from normal control participants, and their correlations with classroom observations and with ratings of impulsivity and other core AD/HD symptoms on the Conners and SNAP-IV checklists. The tasks exhibited modest discriminant validity when used individually and excellent discriminant validity when used in combination. The C-DT correlated with teacher ratings of impulsivity, hyperactivity, and conduct problems, and with observations of gross motor activity, physical aggression, and an AD/HD composite score. The SST correlated with the observations only. These results suggest that delay aversion is associated with a broad range of AD/HD characteristics whereas inhibitory failure seems to tap a more discrete dimension of executive control.

Findings from the NIMH Multimodal Treatment Study of ADHD (MTA): implications and applications for primary care providers.

In 1992, the National Institute of Mental Health and 6 teams of investigators began a multisite clinical trial, the Multimodal Treatment of Attention-Deficit Hyperactivity Disorder (MTA) study. Five hundred seventy-nine children were randomly assigned to either routine community care (CC) or one of three study-delivered treatments, all lasting 14 months. The three MTA treatments-monthly medication management (usually methylphenidate) following weekly titration (MedMgt), intensive behavioral treatment (Beh), and the combination (Comb)-were designed to reflect known best practices within each treatment approach. Children were assessed at four time points in multiple outcome. Results indicated that Comb and MedMgt interventions were substantially superior to Beh and CC interventions for attention-deficit hyperactivity disorder symptoms. For other functioning domains (social skills, academics, parent-child relations, oppositional behavior, anxiety/depression), results suggested slight advantages of Comb over single treatments (MedMgt, Beh) and community care. High quality medication treatment characterized by careful yet adequate dosing, three times daily methylphenidate administration, monthly follow-up visits, and communication with schools conveyed substantial benefits to those children that received it. In contrast to the overall study findings that showed the largest benefits for high quality medication management (regardless of whether given in the MedMgt or Comb group), secondary analyses revealed that Comb had a significant incremental effect over MedMgt (with a small effect size for this comparison) when categorical indicators of excellent response and when composite outcome measures were used. In addition, children with parent-defined comorbid anxiety disorders, particularly those with overlapping disruptive disorder comorbidities, showed preferential benefits to the Beh and Comb interventions. Parental attitudes and disciplinary practices appeared to mediate improved response to the Beh and Comb interventions.

Symptom profiles in children with ADHD: effects of comorbidity and gender.

OBJECTIVE: To examine ratings and objective measures of attention-deficit/hyperactivity disorder (ADHD) symptoms to assess whether ADHD children with and without comorbid conditions have equally high levels of core symptoms and whether symptom profiles differ as a function of comorbidity and gender. METHOD: Four hundred ninety-eight children from the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA) were divided into comorbid groups based on the parent Diagnostic Interview Schedule for Children and assessed via parents' and teachers' Swanson, Nolan, and Pelham (SNAP) ratings and a continuous performance test (CPT). Comorbidity and gender effects were examined using analyses of covariance controlled for age and site. RESULTS: CPT inattention, impulsivity, and dyscontrol errors were high in all ADHD groups. Children with ADHD + oppositional defiant or conduct disorder were rated as more impulsive than inattentive, while children with ADHD + anxiety disorders (ANX) were relatively more inattentive than impulsive. Girls were less impaired than boys on most ratings and several CPT indices, particularly impulsivity, and girls with ADHD + ANX made fewer CPT impulsivity errors than girls with ADHD-only. CONCLUSIONS: Children with ADHD have high levels of core symptoms as measured by rating scales and CPT, irrespective of comorbidity. However, there are important differences in symptomatology as a function of comorbidity and gender.

ADHD comorbidity findings from the MTA study: comparing comorbid subgroups.

OBJECTIVES: Previous research has been inconclusive whether attention-deficit/hyperactivity disorder (ADHD), when comorbid with disruptive disorders (oppositional defiant disorder [ODD] or conduct disorder [CD]), with the internalizing disorders (anxiety and/or depression), or with both, should constitute separate clinical entities. Determination of the clinical significance of potential ADHD + internalizing disorder or ADHD + ODD/CD syndromes could yield better diagnostic decision-making, treatment planning, and treatment outcomes. METHOD: Drawing upon cross-sectional and longitudinal information from 579 children (aged 7-9.9 years) with ADHD participating in the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA), investigators applied validational criteria to compare ADHD subjects with and without comorbid internalizing disorders and ODD/CD. RESULTS: Substantial evidence of main effects of internalizing and externalizing comorbid disorders was found. Moderate evidence of interactions of parent-reported anxiety and ODD/CD status were noted on response to treatment, indicating that children with ADHD and anxiety disorders (but no ODD/CD) were likely to respond equally well to the MTA behavioral and medication treatments. Children with ADHD-only or ADHD with ODD/CD (but without anxiety disorders) responded best to MTA medication treatments (with or without behavioral treatments), while children with multiple comorbid disorders (anxiety and ODD/CD) responded optimally to combined (medication and behavioral) treatments. CONCLUSIONS: Findings indicate that three clinical profiles, ADHD co-occurring with internalizing disorders (principally parent-reported anxiety disorders) absent any concurrent disruptive disorder (ADHD + ANX), ADHD co-occurring with ODD/CD but no anxiety (ADHD + ODD/CD), and ADHD with both anxiety and ODD/CD (ADHD + ANX + ODD/CD) may be sufficiently distinct to warrant classification as ADHD subtypes different from "pure" ADHD with neither comorbidity. Future clinical, etiological, and genetics research should explore the merits of these three ADHD classification options.

Multimodal treatment of ADHD in the MTA: an alternative outcome analysis.

OBJECTIVE: To conduct a post hoc investigation of the utility of a single composite measure of treatment outcome for the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA) at 14 months postbaseline. BACKGROUND: Examination of multiple measures one at a time in the main MTA intent-to-treat outcome analyses failed to detect a statistically significant advantage of combined treatment (Comb) over medication management (MedMgt). A measure that increases power and precision using a single outcome score may be a useful alternative to multiple outcome measures. METHOD: Factor analysis of baseline scores yielded two "source factors" (parent and teacher) and one "instrument factor" (parent-child interactions). A composite score was created from the average of standardized parent and teacher measures. RESULTS: The composite was internally consistent (alpha = .83), reliable (test-retest over 3 months = 0.86), and correlated 0.61 with clinician global judgments. In an intent-to-treat analysis, Comb was statistically significantly better than all other treatments, with effect sizes ranging from small (0.28) versus MedMgt, to moderately large (0.70) versus a community comparison group. CONCLUSIONS: A composite of ADHD variables may be an important tool in future treatment trials with ADHD and may avoid some of the statistical limitations of multiple measures.

Clinical relevance of the primary findings of the MTA: success rates based on severity of ADHD and ODD symptoms at the end of treatment.

OBJECTIVES: To develop a categorical outcome measure related to clinical decisions and to perform secondary analyses to supplement the primary analyses of the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA). METHOD: End-of-treatment status was summarized by averaging the parent and teacher ratings of attention-deficit/hyperactivity disorder and oppositional defiant disorder symptoms on the Swanson, Nolan, and Pelham, version IV (SNAP-IV) scale, and low symptom-severity ("Just a Little") on this continuous measure was set as a clinical cutoff to form a categorical outcome measure reflecting successful treatment. Three orthogonal comparisons of the treatment groups (combined treatment [Comb], medication management [MedMgt], behavioral treatment [Beh], and community comparison [CC]) evaluated hypotheses about the MTA medication algorithm ("Comb + MedMgt versus Beh + CC"), multimodality superiority ("Comb versus MedMgt"), and psychosocial substitution ("Beh versus CC"). RESULTS: The summary of SNAP-IV ratings across sources and domains increased the precision of measurement by 30%. The secondary analyses of group differences in success rates (Comb = 68%; MedMgt = 56%; Beh = 34%; CC = 25%) confirmed the large effect of the MTA medication algorithm and a smaller effect of multimodality superiority, which was now statistically significant (p < .05). The psychosocial substitution effect remained negligible and nonsignificant. CONCLUSION: These secondary analyses confirm the primary findings and clarify clinical decisions about the choice between multimodal and unimodal treatment with medication.

Impairment and deportment responses to different methylphenidate doses in children with ADHD: the MTA titration trial.

OBJECTIVE: Results of the NIMH Collaborative Multisite Multimodal Treatment Study of Children With Attention-Deficit/Hyperactivity Disorder (MTA) were analyzed to determine whether a double-blind, placebo-controlled methylphenidate (MPH) titration trial identified the best MPH dose for each child with attention-deficit/hyperactivity disorder (ADHD). METHOD: Children with ADHD assigned to MTA medication treatment groups (n = 289) underwent a controlled 28-day titration protocol that administered different MPH doses (placebo, low, middle, and high) on successive days. RESULTS: A repeated-measures analysis of variance revealed main effects for MPH dose with greater effects on teacher ratings of impairment and deportment (F3 = 100.6, n = 223, p = .0001; effect sizes 0.8-1.3) than on parent ratings of similar endpoints (F3 = 55.61, n = 253, p = .00001; effect sizes 0.4-0.6). Dose did not interact with period, dose order, comorbid diagnosis, site, or treatment group. CONCLUSIONS: The MTA titration protocol validated the efficacy of weekend MPH dosing and established a total daily dose limit of 35 mg of MPH for children weighing less than 25 kg. It replicated previously reported MPH response rates (77%), distribution of best doses (10-50 mg/day) across subjects, effect sizes on impairment and deportment, as well as dose-related adverse events.

Linkage of the dopamine D4 receptor gene and attention-deficit/hyperactivity disorder.

OBJECTIVE: There is considerable evidence supporting a genetic component in the etiology of attention-deficit/hyperactivity disorder (ADHD). Because stimulant medications act primarily on the dopaminergic system, dopamine system genes are prime candidates for genetic susceptibility factors for ADHD. Previous studies by several groups have observed a significant association of ADHD and an allele with 7 copies of the 48 base pair repeat in the third exon of the dopamine D4 receptor. METHOD: The authors sought to replicate these previous findings by collecting an independent sample of families from Toronto, Ontario, Canada, and confirming this finding in an expanded sample of ADHD families collected from Irvine, California. Using the transmission disequilibrium test (TDT), the authors tested for biased transmission of the 7-repeat allele at the exon III polymorphism of the dopamine D4 receptor locus in these samples of ADHD subjects. RESULTS: Biased transmission of the 7-repeat allele from parents to ADHD probands and their affected siblings was observed in the 2 new samples of families collected in Toronto and Irvine (TDT chi2 = 2.711, 1 df, one-sided p value = .050) and for these samples combined with the 52 families previously reported from Irvine (TDT chi2 = 6.426, 1 df, one-sided p value = .006). CONCLUSIONS: The results of this study further support the possibility of a role of the dopamine D4 receptor locus in ADHD.

Parenting and family stress treatment outcomes in attention deficit hyperactivity disorder (ADHD): an empirical analysis in the MTA study.

Parenting and family stress treatment outcomes in the MTA study were examined. Male and female (579), 7-9-year-old children with combined type Attention Deficit Hyperactivity Disorder (ADHD), were recruited at six sites around the United States and Canada, and randomly assigned to one of four groups: intensive, multi-faceted behavior therapy program alone (Beh); carefully titrated and monitored medication management strategy alone (MedMgt); a well-integrated combination of the two (Comb); or a community comparison group (CC). Treatment occurred over 14 months, and assessments were taken at baseline, 3, 9, and 14 months. Parenting behavior and family stress were assessed using parent-report and child-report inventories. Results showed that Beh alone, MedMgt alone, and Comb produced significantly greater decreases in a parent-rated measure of negative parenting, Negative/Ineffective Discipline, than did standard community treatment. The three MTA treatments did not differ significantly from each other on this domain. No differences were noted among the four groups on positive parenting or on family stress variables. Results are discussed in terms of the theoretical and empirically documented importance of negative parenting in the symptoms, comorbidities and long-term outcomes of ADHD.

Family processes and treatment outcome in the MTA: negative/ineffective parenting practices in relation to multimodal treatment.

To elucidate processes underlying therapeutic change in a large-scale randomized clinical trial, we examined whether alterations in self-reported parenting practices were associated with the effects of behavioral, medication, or combination treatments on teacher-reported outcomes (disruptive behavior, social skills, internalizing symptoms) in children with attention-deficit hyperactivity disorder (ADHD). Participants were 579 children with Combined-type ADHD, aged 7-9.9 years, in the Multimodal Treatment Study of Children with ADHD (MTA). We uncovered 2 second-order factors of parenting practices, entitled Positive Involvement and Negative/Ineffective Discipline. Although Positive Involvement was not associated with amelioration of the school-based outcome measures, reductions in Negative/Ineffective Discipline mediated improvement in children's social skills at school. For families showing the greatest reductions in Negative/Ineffective Discipline, effects of combined medication plus behavioral treatment were pronounced in relation to regular community care. Furthermore, only in combination treatment (and not in behavioral treatment alone) was decreased Negative/Ineffective Discipline associated with reduction in children's disruptive behavior at school. Here, children in families receiving combination treatment who showed the greatest reductions in Negative/Ineffective Discipline had teacher-reported disruptive behavior that was essentially normalized. Overall, the success of combination treatment for important school-related outcomes appears related to reductions in negative and ineffective parenting practices at home; we discuss problems in interpreting the temporal sequencing of such process-outcome linkages and the means by which multimodal treatment may be mediated by psychosocial processes related to parenting.

Effect of reinforcement on facial responsivity and persistence in children with attention-deficit hyperactivity disorder.

Children with Attention Deficit-Hyperactivity Disorder (ADHD) may learn poorly under conditions of inconsistent (partial) reinforcement because they are easily frustrated and fail to develop persistence. To test this hypothesis, a nonsense word spelling task was used with 22 ADHD and 20 control children to investigate the effects of partial and continuous reinforcement on facial responsivity (frustration measure), words spelled correctly (learning performance measure), and persistence ratings. Partially reinforced ADHD children manifested higher levels of frustration in both acquisition and extinction than any other group and gave significantly lower persistence ratings across acquisition than partially reinforced control children. ADHD children spelled fewer words correctly than controls, regardless of reinforcement schedule. These findings suggest that partial reinforcement training develops persistence in normal but not ADHD children. The findings have theoretical implications for the etiology of ADHD as well as practical implications for designing behavior modification programs to treat ADHD.

Association of the dopamine receptor D4 (DRD4) gene with a refined phenotype of attention deficit hyperactivity disorder (ADHD): a family-based approach.

Previously in this journal, we reported an association of the dopamine D4 receptor gene (DRD4) and attention deficit hyperactivity disorder (ADHD). In a population-association (case-control) study of 39 children with a refined phenotype of ADHD and 39 ethnically matched controls, we observed an increased percentage of the 7 repeat allele (29% vs 12%) and the 7+ genotype (49% vs 21%) in the ADHD group compared to the control group. In a replication and an extension of our initial study, we recruited another sample of ADHD subjects and found percentages of the 7 repeat allele (28%) and the 7+ genotype (48%) consistent with our previous findings. We used a family-based approach to evaluate a predicted association of DRD4 and ADHD based on a test of allele transmission focused on the 7 repeat allele. We identified 52 families based on the diagnosis of the refined phenotype of ADHD in the proband and the availability of DNA from both biological parents as well as the proband. Haplotype relative risk (HRR) analysis was performed to test our a priori hypothesis and produced significant results (chi-square = 4.65, P < 0.035). This provides additional evidence that the DRD4 gene is associated with a refined phenotype of ADHD.

Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder.

Dopamine is believed to play a major role in the manifestation of attention deficit hyperactivity disorder (ADHD), which affects 3-6% of school-age children and shows evidence of familiarity. The dopamine D4 receptor, which is preferentially distributed in cortical and limbic regions of the brain, is currently of major interest because of the high degree of functionally relevant variability in its gene (DRD4), and the association of this gene with Novelty Seeking behavior. We examined the variability in the length of a region of DRD4 that contains a 48-bp repeat sequence in children with ADHD and controls matched for ethnicity. ADHD children differed from controls in that the 7-fold repeat form of DRD4 occurred significantly more frequently than in the control sample. This form of the receptor has previously been shown to mediate a blunted intracellular response to dopamine. Although ADHD is likely to be multifactorial in its etiology and its heritability is likely to be polygenetic, the present findings suggest that polymorphic variation in the gene encoding the D4 dopamine receptor may be a contributing factor in the expression of symptoms associated with ADHD.

Effects of prenatal ethanol exposure on learned persistence and hippocampal neuroanatomy in infant, weanling and adult rats.

The present experiment examined whether deficits in learned persistence, previously seen in 15-day-old infant rats prenatally exposed to ethanol, would be present in weanling and adult animals. Three prenatal treatments, EtOH, PAIR-FED, and LAB CHOW, were combined factorially with partial (PRF) or continuous (CRF) reinforcement training followed by extinction, at 21 days or 6 months of age. The results at 21 days were virtually the same as our earlier findings for 15-day-olds: we did not find the higher level of persistence in PRF-trained EtOH pups relative to CRF-trained EtOH pups, which characterizes the partial reinforcement extinction effect (PREE). The EtOH-PRF and EtOH-CRF animals extinguished at about the same rate, both faster than PRF controls. However, when tested as adults, the EtOH-exposed animals showed a normal PREE, with no deficits relative to controls. An analysis of CA1 pyramidal cells in midtemporal hippocampus demonstrated no significant differences in cell density or in CA1 area among the 3 prenatal diet conditions; however, there was a significant reduction in cell density with age for all groups. These results suggest that a developmental delay, unrelated to these neuroanatomical measures, is responsible for the lack of persistence in young rats exposed prenatally to ethanol.

Behavioral and neuroanatomical effects of prenatal, postnatal, or combined exposure to ethanol in weanling rats.

Separate and combined effects of prenatal and postnatal exposure to ethanol on activity, emotionality, learning, and hippocampal neuroanatomy were examined in infant rats. Neonatal rats from mothers that were fed either a liquid ethanol (E) or control (C) diet on Gestational Days (G) 1-21 were artificially reared during Postnatal Days (P) 4-12 on either 3% ethanol (E) or isocaloric maltose/dextrin (C) in a milk formula. Pups in these treatment groups (EE, EC, CE, and CC) were tested for activity and emotionally in an open field on P19, for acquisition and extinction of an appetitive, straight runaway task on P20-P21, and for the effects of ethanol treatments on alterations in hippocampal neuroanatomy on P21. Differences in activity and emotionally were slight. Ethanol affected both the partial reinforcement acquisition effect and the partial reinforcement extinction effect. Hippocampal cell density (compared with Group CC) showed a 12% reduction in CA1 pyramidal cells and an 11% reduction in mature granule cells in Groups EC and EE; the CA4 area (compared with Group CC) was significantly larger after postnatal exposure (Groups CE and EE). Significant positive correlations were found between rate of extinction after partial reinforcement (PRF) training and CA1 pyramidal cell density in Groups CC and CE. A significant negative correlation was found between extinction rate after PRF training and CA4 area in Group EE.

Facilitation of acquisition and retention in preweanling but not postweanling rats by the presence of familiar home-nest material.

A series of four experiments examined the effect of the presence of stimuli from the home nest on the acquisition and retention of aversively motivated behaviors in preweanling and adult rats. In Experiment 1, training in the presence of home-nest shavings facilitated acquisition of a T-maze discrimination to escape footshock for 16-day-old rats but not for adults. Experiment 2 demonstrated that the extent to which preweanlings were familiar with the home shavings determines the degree to which these stimuli facilitate spatial discrimination learning. When clean shavings were made more familiar than soiled home-nest stimuli (by changing the shavings every day) clean shavings enhanced discrimination performance, whereas no enhancement of learning by home shavings was observed. Experiment 3 extended the generality of the enhancement effect to a conditioned location aversion and examined the extent to which this facilitative effect was due to the tendency for home-nest shavings to elicit approach responses. Expression of the conditioned aversion was enhanced in subjects conditioned in the presence of home shavings, regardless of whether the home shavings were presented with the CS+, the CS-, or both. Experiment 4 determined that the enhanced expression of learning in the context of home-nest stimuli observed for preweanlings did not occur among subjects trained shortly after weaning. Collectively, these data suggest that whereas the enhancement of learning and retention by familiar home-nest stimuli enjoys generality across a number of conditioning situations, the effect may be limited to a relatively brief period during ontogeny.

Sparing of patterned alternation but not partial reinforcement extinction effect after prenatal chronic exposure to ethanol in infant rats.

The effects of in utero administration of ethanol on single patterned alternation (PA) and the partial reinforcement extinction effect (PREE) were studied in 15-day-old rat pups. This fetal-alcohol treatment had no effect on PA but eliminated the PREE by reducing persistence in extinction after partial reinforcement (PRF) training to its level after continuous reinforcement (CRF) training, which was not affected by the treatment. The results are discussed in terms of prenatal damage to the hippocampus and in relation to an earlier experiment (Lobaugh, Bootin, & Amsel, 1985), which found no effect of infant hippocampal lesions on PA but an elimination of the PREE, which, unlike the fetal-alcohol case, resulted from PRF-like persistence in extinction following CRF training.

Effects on the partial reinforcement extinction effect and on physical and reflex development of short-term in utero exposure to ethanol at different periods of gestation.

Ethanol was intubated into pregnant rats at Gestational Days 7-9 (G7-9) or 14-16 (G14-16). At both gestational ages, ethanol intubation affected reflex development but not physical development of resulting offspring. At G14-16, but not at G7-9, ethanol intubation resulted in the elimination of the partial reinforcement extinction effect when pups were tested at 15 days of age. These latter results confirm and extend previous ones in which ethanol was administered in a liquid diet throughout gestation.