NBTS36

Acoustic startle behavior is moderately altered by lifetimeacrylamide (ACR) treatment in rats

Merle Paule, Melody Smith, Joan Garey, Sherry FergusonUSFDA's National Center for Toxicological Research, United States

We reported earlier a significant ACR effect on postnatal day(PND) 151 acoustic startle; here, those results are replicated andextended. Pregnant Fischer 344 rats (n=8–9/dose) were gavagedwith 0, 0.1, 0.3, 1.0, or 5.0 mg/kg/day ACR on GDs 6–22. Pups weregavaged directly through weaning then treatment continued viadrinking water. On PNDs 172 and 354, the same male and femalepairs (one/litter) were assessed for acoustic startle. Maximalresponses and latencies to maximal responses were obtained for45 trials. Overall, maximal response was ≈10% lower at PND 354and ≈28% less in females (Pb0.05). Latency was longer at PND 172(Pb0.05). ANOVAs including data from both ages indicated asignificant main effect of treatment (Pb0.003); however, notreatment groups were significantly different from controls. The5.0 mg/kg group exhibited the lowest maximal response (28% lessthan controls) while the 0.1, 0.3, and 1.0mg/kg groupswere 4–21%higher than controls. Additionally, the 5.0 mg/kg group wassomewhat slower in reaching maximal response (69 vs. 53 ms for5.0 and 0.0 mg/kg, respectively). These ACR effects, while notstatistically significant, are nearly identical to those previouslyreported for rats tested at PND 151 (Garey et al., 2006), indicatingthe reproducibility and reliability of acoustic startle responses.(Supported by NTP 224-07-007 and ORISE (JDG)).

doi:10.1016/j.ntt.2008.03.039

NBTS37

The effect of lifelong acrylamide exposure on auditorydiscrimination task performance in Fischer 344 rats

Joan Garey, Merle PauleDivision of Neurotoxicology, National Center for Toxicological Research/FDA, United States

In NCTR's study of the developmental neurotoxicity of acryl-amide (ACR) in rats, performance in operant and non-operant testsis being assessed. In our auditory discrimination (AD) task, rats aretrained to press (for food) the left response lever for a 350 Hz toneand the right response lever for a 1450 Hz tone. Rats were dosedwith 0, 0.1, 0.3, 1.0 or 5.0 mg/kg/day ACR via gavage to their damsfrom gestation day 6 through parturition. Pups were gavaged withthese same doses on postnatal days 1–22. Postweaning ACR expo-sure occurred via their drinking water at comparable doses. Onefemale and one male rat/litter (8–9 litters/dose) were tested. Wepreviously reported that the 5.0 mg/kg/day group required signifi-cantly more sessions to complete AD training. Here, full taskperformance was analyzed over the first 40 sessions. A linearimprovement in accuracyover time (Pb0.0001)was observed for alltreatment groups combined. No significant treatment effects wereobserved for accuracy, response rate, reinforcers earned, or percenttask completed; the 5.0 mg/kg/day group routinely exhibited theworst performance. Hence, ACR treatment (1) influenced taskacquisition/training, but not performance; and (2) did not impairlocomotor or auditory capabilities, suggesting that treatment-related effects observed in other operant tasks, as well as in

auditory startle responding, are unrelated to locomotor or auditorydeficits. (Supported by ORISE (JDG) and NTP IAG 224-07-007).

doi:10.1016/j.ntt.2008.03.040

NBTS38

The effects of oral administration of methylphenidate on activity,emotion and attention in juvenile rats

Ning Zhu, Diana Dow-EdwardsSUNY Downstate Medial Center, United States

Attention deficit hyperactivity disorder (ADHD) affects 3% to 7%of school-aged children in theU.S.Methylphenidate (MPD,Ritalin) iscommonly prescribed for ADHD. Since it is difficult to conductcontrolled studies in patients taking methylphenidate, animalmodels of low, clinically-relevant doses and routes of administrationare necessary to study the effects of methylphenidate. We havedeveloped a model wherein juvenile rats receive methylphenidateorally on a cracker. Performance on the radial arm maze was im-proved in ourmodel. Thepresent study furtherexplored the effect oforal methylphenidate on activity, emotion and attention in juvenilerats. Male and female SD rats were mildly food-deprived andbeginning on postnatal day (PND) 22, methylphenidate (3.0 mg/kg)or sterile water (control) was delivered on small crackers. 30 minafter dosing, rats were put on an elevated plus-maze with short railon each open arm and video-recorded for 10 min. Time spentbeyond the rails in the females and risk-assessment behaviors inboth sexes suggested an anxiolytic-like effect of oral methylpheni-date. Also grid crossings on the plus-maze indicated that oralmethylphenidate increased locomotor activity, as did activityrecording in the photo-beam box on PND 23. Additionally, pre-liminary data from animals that underwent a multi-trial attentiontask from PND 23 to PND 34 indicated that oral methylphenidateimprovedperformanceon this task. Together thesedata suggest thatoral methylphenidate has multifaceted effects on juvenile ratswhich result in overall improved cognitive performance.

doi:10.1016/j.ntt.2008.03.041

NBTS39

The interaction of age, sex, peer influence, and ethanol impactsmeasures of anxiety in mice

Brian Kelley, John Doyon, Julia Sirpoli, Curtis Bradley, Buddy Swick,Kathryn Taylor, Mackenzie Grimes, Ashley ReidBridgewater College, United States

Although it is clear that changes in brain function duringadolescence impacts drug initiation and abuse, little research hasfocused on the important relationship between neurobiologicalchanges and peer influence. Behavioral pharmacological methodsassociated with anxiety (elevated plus-maze, EPM, and open field,OF) were used to examine the impact of age (adolescent vs. adult),sex (male vs. female), and peer influence (saline–saline vs.ethanol–ethanol vs. saline–ethanol pairs) on ethanol (1 g/kg, IP)sensitivity. Mice (N=96, male=48, female=48) were pair-housedupon arrival on postnatal day (PND) 23 and randomly assigned toone of three peer test conditions (n=16). Ten minutes prior tobehavioral testing, saline–saline pairs were injected with saline

254 M. Stanton et al. / Neurotoxicology and Teratology 30 (2008) 243–259

and ethanol–ethanol pairs were injected with ethanol; however,with the saline–ethanol pairs, one was injected with saline whilethe other with ethanol. Pair-housed mice were tested simulta-neously in the same apparatus. EPM (6 min) tests were followedimmediately by OF tests (6 min) and occurred across threeconsecutive days. Testing began on PND 32 and again on day 72.Significant interactions were noted across age, sex, and peerinfluence. However, the most notable finding was related to peer-influence. Mice injected with saline but tested with an ethanol-injected peer, showed ethanol-like behavior. This finding wasgreatest inmales and decreasedwith age. This study demonstratesthat high-risk, ethanol-induced behaviors can be elicited solely bypeer influence and are most pronounced in adolescent males.

doi:10.1016/j.ntt.2008.03.042

NBTS40

Comparison of training procedures for self-administration ofcocaine in female rats

Cindy Roegge, Amanda Evans, Melissa Beck, Philip Atterson,Don Stump, Mark Nemec, Joseph HolsonWIL Research Laboratories, LLC, United States

The need to evaluate the abuse potential of drug candidates is onthe rise as pharmaceutical companies are now facing increasingregulatory demands. While developing self-administration testingcapabilities in the laboratory, we recently conducted a study tocompare fourdifferent trainingprocedures for self-administrationofcocaine in female rats. Following recovery from surgerical implanta-tion of the indwelling femoral vein catheter, Groups 1 and 2 [n=7–8female Crl:CD(SD) rats/group] began self-administration testingwith no previous experience in the two-lever operant chambers,whereas Groups 3 and 4 received lever-press training for foodreward prior to surgery and subsequent self-administration testing.To simulate drug candidates without reinforcing properties, Groups1 and 3 began self-administration testing receiving subthresholddoses of cocaine (0.05 mg of cocaine/infusion), and in later sessionsthe dose of cocainewas escalated until self-administration occurred.In contrast, Groups 2 and 4 began self-administration testing with adose of cocaine expected to be reinforcing (0.32 mg of cocaine/infusion). Although self-administration of cocaine was observed inthe majority of rats in each group after 3 weeks of testing, wedetermined that prior lever-press training for food reward wasnot necessary. For abuse potential screening, the best approachmaybe self-administration training with a reference drug withknown reinforcing properties (i.e. prototypic drug from pharmaco-logical class or appropriately-selected reference substance for newmolecular entities) prior to sessions with the drug candidate.

doi:10.1016/j.ntt.2008.03.043

NBTS41

Incidence of major malformations in infants followingantidepressant exposure in pregnancy: Results of a largecohort study

Adrienne Einarson, Jacquelyn Choi, Gideon KorenHospital for Sick Children, Canada

Background. To date, a number of published epidemiologicstudies have not documented an increase risk for majormalformations associated with antidepressant use in pregnancy.However, controversy still surrounds the use of these drugs inpregnancy and warnings have been released by national healthagencies regarding the possible adverse effects to infantsfollowing exposure during pregnancy. Our objective was to ascer-tain if antidepressants as a group increases the risk for majormalformations, as well as assessing each individual antidepres-sant. Methods. At The Motherisk Program, we analyzed preg-nancy outcomes of 1243 women from our prospectively collectedcases in our data base, who were exposed to antidepressantsduring their pregnancy. We then compared them to a matchedcomparison group of 1243 women who were not exposed (non-teratogen group). Results. 928 women who fit the criteria forinclusionwhowere exposed in the 1st trimester of pregnancy andalso gave birth to a live born infant, were matched to 928 in thecomparison group. There were 30 (3.2%) major malformations inthe antidepressant group and 31 (3.3%) in the comparison group.OR 0.9 (95% CI 0.5–1.61). The antidepressants included in theanalysis were: bupropion (113), citalopram (184), escitalopram(21), fluvoxamine (52) nefazodone (49), paroxetine (148), mirta-zepine (68), fluoxetine (61), trazodone (17), venlafaxine (154),sertraline (61). Conclusion. Use of antidepressants as a group inthe first trimester of pregnancy, is not associated with an increaserisk for major malformation above the baseline. No individualantidepressant was associated with an increase risk of a specificmalformation.

doi:10.1016/j.ntt.2008.03.044

NBTS42

Antiepileptic drugs as cognitive teratogens: A prospective study ofcreativity in children exposed to valproate, carbamazepine, andlamotrigine monotherapy

Kelly Marie McVearrya, Kimford MeadorbaGeorgetown University Department of Neurology, United StatesbUniversity of Florida McKnight Brain Institute, United States

Background. Rodent studies demonstrate that antiepilepticdrugs (AEDs) induce a proapoptotic effect during rapid braingrowth and synaptogenesis that, in humans, equates to the thirdtrimester and early postnatal development. Third trimesterapoptosis in cortical regions that develop to mediate associativeneural activity would be expected to impair associative cognitiveprocesses — associative processes like divergent thinking thatcomprise the human capacity for creativity. Objectives. Thisprospective observation study investigates differential cognitiveoutcomes for three commonly used antiepileptic drugs (carba-mazepine, lamotrigine, and valproate), with an emphasis onoutcomes indicative of impaired creativity. Methods. Operatio-nalizing creativity as ‘divergent thinking’, we measure cognitivefluency and originality using the Torrance Thinking Creatively inAction and Movement (TCAM). Subjects include a prospectiveclinical cohort (n=42) between 3.5 and 5 years of age (meanage=4.17 years) from mother–child pairs who were exposed inutero to AED monotherapy for the management of maternalepilepsy. Results. Across monotherapy groups, this population ofchildren show mean fluency of 91.2 (SD=16.0), which issignificantly lower than the normal population (p=0.001). Thisdifference is not evident for originality (mean=97.7, SD=15.7).

255M. Stanton et al. / Neurotoxicology and Teratology 30 (2008) 243–259