12 months, suggesting significant risk for later learning problems inMDMA-exposed infants.

doi:10.1016/j.ntt.2012.05.022

NBTS 22L-carnitine attenuates anesthetic-induced increases in a markerof glial activation in the developing monkey brain

Merle Paulea, Xuan Zhanga, Glenn Newporta, Shuliang Liua, Fang Liua,Ralph Callicotta, Marc Berridgeb, Scott Apanab, Joseph Hanigc, WilliamSlikkera, Cheng WangaaNational Center for Toxicological Research/FDA, Jefferson, AR,United Statesb3D-Imaging, Little Rock, AR, United StatescCenter For Drug Evaluation and Research/FDA, White Oak, MD,United States

The inhalation anesthetics nitrous oxide (N2O) and isoflurane(ISO) are commonly used for surgical procedures in human infants.Combined exposures to N20 and ISO are known to cause neurotoxicity(abnormal apoptotic cell death) in pediatric animal models. L-carnitine,an anti-oxidant dietary supplement, has been reported to minimizeneuronal damage in some models of neurotoxicity. MicroPET/CTimaging is capable of detecting and localizing changes in cellularmarkers of brain damage associated with developmental exposures togeneral anesthetics. Bymonitoring changes in the uptake of the specificradiotracer [18F]-FEPPA – thought to highlight glial activation associatedwith neurotoxicity – it should be possible to determine the severity,duration and location of neuronal damage associated with exposureto general anesthetics. On postnatal day (PND) 5, rhesus monkeys (4/group)were exposed to amixture of 70%N2O, 29%oxygenplus1% ISO, orthis anesthetic mixture plus acetyl-L-carnitine (aLc) (100 mg/kg) for8 h; control monkeys were exposed to room air only. [18F]-FEPPA(FEPPA), a peripheral benzodiazepine receptor marker thought tohighlight glial activation, was injected intravenously and microPET/CTimageswere obtained one day and one and threeweeks after anestheticexposure. One day after anesthetic exposure, the uptake of FEPPA wassignificantly increased only in the temporal lobe. One week afterexposure, uptakewas significantly increased in only the frontal lobe. Nosignificant differences in uptakewere seen in anyarea after 3 weeks. Co-administration of aLc effectively blocked the increase in FEPPAuptake inboth the temporal and frontal lobes. These findings suggest thatmicroPET/CT imaging of FEPPA uptake may be useful for monitoringthe time-course and location of adverse neural events that areassociated with developmental exposures to general anesthetics. Inaddition, aLc appears to be a compound capable of protecting against atleast some of the adverse effects associated with such exposures. (Thiswork was supported by E-7285-NCTR/FDA and CDER/FDA.)

doi:10.1016/j.ntt.2012.05.023

NBTS 23Addiction: A developmental disorder

Joseph FrascellaNational Institute on Drug Abuse, Bethesda, MD, United States

Recent research supports the notion that addiction is a complexbrain, behavioral, and developmental disorder that often has itsorigins in childhood and adolescence–a period of dramatic change inbrain structure and function. The relative vulnerability of the brainduring the transition from childhood to adulthood may explain the

heightened propensity of adolescents to act impulsively and to ignorethe negative consequences of their behavior, both of which increasethe risk for self-administration of drugs and for substance abuse atthis stage of development. Since drugs of abuse interact with anumber of neurotransmitter systems essential in brain development,exposure during the adolescent period may be particularly harmful tothe still-developing brain. The presence of a mental disorder furtherincreases an adolescent's risk of drug abuse and addiction and posesan added challenge to their prevention and treatment. Thispresentationwill highlight recent evidence demonstrating the impactdrugs of abuse can have on the adolescent prefrontal cortex and otherareas of the brain critical to memory, impulse control and decision-making, as well as the implications these findings have for developingeffective prevention and treatment strategies.

doi:10.1016/j.ntt.2012.05.024

NBTS 24Growth and neurodevelopmental outcomes in children prenatallyexposed to methamphetamine

Lynne Smitha, L. LaGasseb, C. Deraufc, E. Newmand, R. Shahe, A. Arriah,M. Huestisf, W. Haningc, A. Straussg, S. DellaGrottab, L. Dansereaub,C. Nealc, B. LesterbaHarbor-UCLA Medical, Los Angeles, CA, United StatesbBrown University, Providence, RI, United StatescUniversity of Hawaii, Honolulu, HI, United StatesdUniversity of Tulsa, Tulsa, OK, United StateseBlank Hospital Regional Child Protection Center, Des Moines, IA,United StatesfNational Institute on Drug Abuse, Baltimore, MD, United StatesgMiller Children's Hospital, Long Beach, CA, United StateshUniversity of Maryland School of Public Health, College Park,MD, United States

Methamphetamine (MA) use among pregnant women continuesto be a significant problem in the United States. The impact of MA onchildren prenatally exposed was not well characterized. Informationfrom the Infant Development, Environment, and Lifestyle (IDEAL)Study, a prospective, longitudinal study of prenatal MA exposure, ispresented. IDEAL enrolled 412 subjects (n=204 exposed). Exposedsubjects were identified by self-report and/or GC/MS confirmation ofamphetamine and metabolites in infant meconium. Comparisonsubjects were matched (race, birth weight, maternal education,insurance), denied amphetamine use, and had a negative meconiumscreen. Both groups included prenatal alcohol, tobacco and marijuanause, but excluded use of opiates, LSD, or PCP. Children exposed to MAduring gestation were more likely to be born small for gestationalage. Of the 351 children who attended at least two of the three followup visits prior to age 3, the exposed children were more likely to havea smaller head circumference and be shorter at birth; only decreasedheight trajectory remained significant by age 3. In newborns,exposure was associated with increased stress, with heavy exposureassociated with decreased arousal and increased lethargy andphysiological stress. Heavy exposure was associated with poorer finemotor skills as evidenced by a lower grasping score on the PeabodyDevelopmental Motor Scales at 1 and 3 years. No differences incognition at age 1 or 3 were found between the exposed andcomparison children. Exposure was associated with increasedemotional reactivity and anxious/depressed problems at 3 and5 years, and externalizing and ADHD problems by age 5. Heavyexposure was associated with attention problems and withdrawnbehavior at 3 and 5 years, as well as deficits in inhibitory control at

NBTS 2012 Abstracts 375

age 5.5. Prenatal MA exposure is associated with decreased growth,increased physiological stress, and poorer fine motor skills. While nodifferences in cognitionwere noted at 1 and 3 years, internalizing andexternalizing behaviors increased at ages 3 and 5 and deficits ininhibitory control were observed by age 5.5. These findings suggestthe developmental effects of prenatal MA persist and become morespecific with age.

doi:10.1016/j.ntt.2012.05.025

NBTS 25Brain imaging in children prenatally exposedto methamphetamine

Linda Changa, C. Cloaka, S. Buchthala, T. Wrighta, C. Jianga, K. Oishib,J. Skranesc, L. Fujimotoa, S. Morib, T. ErnstaaJohn Burns School of Medicine, University of Hawaii, Honolulu, HI,United StatesbJohns Hopkins University School ofMedicine, Baltimore, MD, United StatescNorwegian University of Science & Technology, Trondheim, Norway

Prenatal exposure with methamphetamine (METH) or nicotine(NIC) may be associated with abnormal brain development, althoughneuroimaging data in humans are limited. Neuroimaging data fromtwo prospective studies of neonates or children with prenatalexposure to these stimulants will be presented. The first studyincludes healthy neonates born full term (>36 weeks) without anydrug exposure, as well as neonates with METH+NIC or NIC exposureprenatally. The second study includes otherwise healthy youngchildren (ages 3–4 years) with or without prenatal stimulant(METH+NIC or NIC) exposure. All subjects were evaluated forneurometabolite concentrations with proton magnetic resonancespectroscopy, and for possible macroscopic structural (quantitativeMRI) and microscopic structural changes (with diffusion tensorimaging). All scans were performed at follow-ups in the neonates (atone month and two months of age) and in the children annually (upto 8 years of age). Neuropsychological testing was also performed inthe young children. Both the neonates and the young children withprenatal stimulant (METH+NIC or NIC) exposure had higher levelsof total creatine (tCr) in frontal white matter than their respectiveunexposed controls. Both infants and young children with NICexposure had higher glutamate and glutamine (Glx) in several brainregions than unexposed infants. Female NIC exposed children hadlower tCr than the unexposed girls. Choline-compounds andmyoinositol increased rather than decreased with age in neonateswith prenatal stimulant exposure. Similarly, less steep age-relatedchanges in axial and radial diffusion and fractional anisotropy werefound in many brain regions in stimulant exposed infants thancontrols, especially in the superior longitudinal fasciculus (SLF). Thelower than normal diffusion in the exposed children did not changeover three years. These neurometabolite abnormalities in theneonates are consistent with two previous studies of children withprenatal METH exposure, and suggest aberrant brain developmentthat is regional-and sex-dependent. The less steep age-related declinein diffusion suggests delayed myelination in neonates with stimulantexposure, which is consistent with prior reports of lower glialmetabolites in young children with prenatal nicotine exposure orreduced myelin in the optic nerves of rats treated with METHprenatally.

doi:10.1016/j.ntt.2012.05.026

NBTS 26Rat model of third trimester methamphetamine exposure: Effectson behavior, neurotransmitters, and receptors

Charles V. VorheesCincinnati Children's Research Foundation, Cincinnati, OH, United States

Methamphetamine (MA) abuse has risen steadily over the lasttwo decades, including among pregnant women, yet little is knownabout the effects of such exposures on in utero brain developmentand later behavior. Drug treatment data show that as of 2006, 24% ofpregnant women entering treatment identify MA as their primarydrug of abuse, up from 8% in 1994. We developed an animal model ofthird trimester-equivalent exposure, which occurs postnatally in rats.Rats exposed to doses of MA (10 mg/kg×4/day) equivalent tomoderate doses taken by chronic abusers (~1.5 mg/kg/day) result inlong-term impairments in egocentric (Cincinnati water maze) andallocentric learning and reference memory (Morris water maze).Additional experiments established that these effects are notsecondary to MA-induced effects on performance such as swimspeed, levels of locomotor activity, or motivation to escape and, basedon related work, not attributable to litter factors such as changes ingrowth or maternal care. MA-exposed offspring also exhibit bio-chemical changes, including increases in plasma ACTH and corticos-terone, reductions in brain 5-HT, dopamine (DA), D2 receptornumbers, PKA activity, BDNF, altered locomotor responses to the D1agonist, SKF82958, and to the NMDA antagonist, MK-801, and region-specific changes in dendritic morphology. Attenuating MA-inducedcorticosterone release by severing the adrenals, but leaving them insitu to temporarily interrupt adrenal output during treatment beforethey engraft to surrounding organs, failed to improve cognitiveoutcome, indicating that corticosterone release is not contributory tolater learning impairments. Other mechanisms await hypothesistesting. The model shows that third-trimester equivalent (P11–20)rat MA exposure induces a complex pattern of biochemical changesand long-term cognitive deficits. However, the causal link betweenthese effects remains to be elucidated. To the extent that rodent datacan be extrapolated, the findings suggest that MAmay be a significantrisk factor to normal neurocognitive development when exposureoccurs during late pregnancy. Brain regions that mediate the higherfunctions affected by MA are developing crucial connections duringthe third trimester and appear vulnerable to MA with serious long-term consequences that may be irreversible. (Supported by NIH R01DA006733.)

doi:10.1016/j.ntt.2012.05.027

NBTS 27Fetal oxidative stress, DNA damage and repair inmethamphetamine neurodevelopmental deficits in mice

Peter Wellsa, L. Millerb, A. Ramkissoona, A. ShapiroaaFaculty of Pharmacy, University of Toronto, Toronto, ON, CanadabDept of Pharmacology & Toxicology, University of Toronto, Toronto,ON, Canada

Methamphetamine can enhance the formation of reactive oxygenspecies (ROS) in the adult and fetal brain via a number of mechanismsincluding its bioactivation by prostaglandin H synthases (PHSs) to a freeradical intermediate. ROS are implicated in developmental toxicity byaltering signal transduction and/or oxidatively damaging cellularmacromolecules including DNA. In mice, a single in utero exposure tomethamphetamine during the late embryonic or fetal periods can resultin enhanced levels of oxidatively damaged DNA, measured as 8-oxo-2′-

NBTS 2012 Abstracts376