Browsing by Author "Levin, ED"

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Open Access
A Behavioral Test Battery to Assess Larval and Adult Zebrafish After Developmental Neurotoxic Exposure
(2021-01-01) Hawkey, AB; Holloway, Z; Levin, ED
Behavioral test batteries are valuable methods which allow outcomes with varying characteristics and neurobiological bases to be assessed and compared in the same animals. This allows investigators to construct a profile of impairments produced by a pharmacological or toxicological challenge, and to propose mechanisms for further study based on those findings. This profile is valuable in the assessment of potentially hazardous substances, including environmental toxicants, drugs of abuse, and other neuropharmacologically active agents. Behavioral tests and batteries have been developed for a number of species, including a relatively recent and growing body of work with the zebrafish, Danio rerio. This chapter discusses the current zebrafish behavioral battery used in our laboratory, and some of the main factors that drove its development. The principal tests include a motility assay for larval fish (6 days post fertilization, dpf), and a battery intended for adolescent (2–3 months) and adult fish (5+ months), which assay sensorimotor, affective, and cognitive-like functions in these fish. Significant progress has been made in the areas of zebrafish neurobehavioral analysis, although further studies, refinements, and task development efforts will be needed to strengthen this approach in the future.
Open Access
Behavioral toxicology
(2023-01-01) Levin, ED
(A) Definition. Behavioral toxicology analyzes the adverse functional effects of toxic actions in the brain. (B) Process. This section presents the spectrum of behavioral tests of cognition, emotional functions, as well as other behavioral functions, their use across ages and species and the integration of behavioral toxicology with other neurotoxicology approaches. Mechanistic analysis from behavioral function back to more component processes can converge with the forward mechanistic analysis. (C) Conclusion. Behavioral toxicology provides a clear link of toxicant exposure to the functions of concern to human neurotoxicity and provides a way to discern which neurotoxic effects cause functional impairment.
Open Access
Corrigendum to "Paternal cannabis extract exposure in rats: Preconception timing effects on neurobehavioral effects in offspring" [Neurotoxicology 81 (2020) 180-188].
(Neurotoxicology, 2021-12) Holloway, Z; Hawkey, AB; Pippen, E; White, H; Katragadda, V; Kenou, B; Wells, C; Murphy, SK; Rezvani, AH; Levin, ED
The authors regret that the type of cannabis extract provided from the NIDA drug supply program was not the same as was ordered. The authors just recently discovered this. The cannabis extract used in this study provided by the NIDA drug Supply Program was a heated cannabis chemical extract rather than a cannabis smoke extract. The content of delta-9-THC in the extract was the same as reported in the article as verified in chemical analysis of the sample from Research Triangle Institute International (see supplemental material). The authors would like to apologise for any inconvenience caused.
Open Access
Developmental exposure to a complex PAH mixture causes persistent behavioral effects in naive Fundulus heteroclitus (killifish) but not in a population of PAH-adapted killifish.
(Neurotoxicol Teratol, 2016-01) Brown, DR; Bailey, JM; Oliveri, AN; Levin, ED; Di Giulio, RT
Acute exposures to some individual polycyclic aromatic hydrocarbons (PAHs) and complex PAH mixtures are known to cause cardiac malformations and edema in the developing fish embryo. However, the heart is not the only organ impacted by developmental PAH exposure. The developing brain is also affected, resulting in lasting behavioral dysfunction. While acute exposures to some PAHs are teratogenically lethal in fish, little is known about the later life consequences of early life, lower dose subteratogenic PAH exposures. We sought to determine and characterize the long-term behavioral consequences of subteratogenic developmental PAH mixture exposure in both naive killifish and PAH-adapted killifish using sediment pore water derived from the Atlantic Wood Industries Superfund Site. Killifish offspring were embryonically treated with two low-level PAH mixture dilutions of Elizabeth River sediment extract (ERSE) (TPAH 5.04 μg/L and 50.4 μg/L) at 24h post fertilization. Following exposure, killifish were raised to larval, juvenile, and adult life stages and subjected to a series of behavioral tests including: a locomotor activity test (4 days post-hatch), a sensorimotor response tap/habituation test (3 months post hatch), and a novel tank diving and exploration test (3months post hatch). Killifish were also monitored for survival at 1, 2, and 5 months over 5-month rearing period. Developmental PAH exposure caused short-term as well as persistent behavioral impairments in naive killifish. In contrast, the PAH-adapted killifish did not show behavioral alterations following PAH exposure. PAH mixture exposure caused increased mortality in reference killifish over time; yet, the PAH-adapted killifish, while demonstrating long-term rearing mortality, had no significant changes in mortality associated with ERSE exposure. This study demonstrated that early embryonic exposure to PAH-contaminated sediment pore water caused long-term locomotor and behavioral alterations in killifish, and that locomotor alterations could be observed in early larval stages. Additionally, our study highlights the resistance to behavioral alterations caused by low-level PAH mixture exposure in the adapted killifish population. Furthermore, this is the first longitudinal behavioral study to use killifish, an environmentally important estuarine teleost fish, and this testing framework can be used for future contaminant assessment.
Open Access
Different lines of rats selectively-bred for high alcohol-drinking demonstrate disparate preferences for nicotine self-administration
(Journal of Drug and Alcohol Research, 2016-01-01) Rezvani, AH; Levin, ED; Wells, C; Slade, S; Morrison, M; Marshall, L; Morris, M; Confino, J; Allenby, C; Lumeng, L
© 2016 Amir H. Rezvani et al.Background. Alcohol and nicotine are commonly coabused. The search for a common core of neural, behavioral, and genetic factors underlying addiction has been the goal of addiction research. Purpose. Genetic predisposition to high alcohol intake has been studied in rats by selectively breeding rats that have high preference for alcohol. The current experiments were conducted to determine if the level of intravenous nicotine administration for the various lines of alcohol-preferring rats differs from that for nonalcohol-preferring controls. Study design. Adult alcohol-naïve selectively-bred alcohol-preferring male rats from four lines (P, AA, HAD-1, sP) and their control nonalcohol-preferring rats (NP, ANA, LAD-1, sNP) were trained and given access to self-administer nicotine (0.03mg/kg/infusion). Results. The results show that the P rats selfadministered significantly more nicotine than NP rats. In contrast, there were no significant differences in nicotine self-administration between the sP and sNP or the AA and ANA rats. Unexpectedly, high alcohol-drinking HAD-1 rats self-administered significantly less nicotine than low alcohol-drinking LAD-1 rats. Conclusion. This suggests that some genetic factors that underlie high-alcohol intake have more general effects in promoting high nicotine intake tendencies, while other genetic factors are more specific to only heavy drinking.
Open Access
Epigenetic alterations in cytochrome P450 oxidoreductase (Por) in sperm of rats exposed to tetrahydrocannabinol (THC)
(Scientific Reports, 2020-12-01) Acharya, KS; Schrott, R; Grenier, C; Huang, Z; Holloway, Z; Hawkey, A; Levin, ED; Murphy, SK
As marijuana legalization is increasing, research regarding possible long-term risks for users and their offspring is needed. Little data exists on effects of paternal tetrahydrocannabinol (THC) exposure prior to reproduction. This study determined if chronic THC exposure alters sperm DNA methylation (DNAm) and if such effects are intergenerationally transmitted. Adult male rats underwent oral gavage with THC or vehicle control. Differentially methylated (DM) loci in motile sperm were identified using reduced representation bisulfite sequencing (RRBS). Another cohort was injected with vehicle or THC, and sperm DNAm was analyzed. Finally, THC-exposed and control adult male rats were mated with THC-naïve females. DNAm levels of target genes in brain tissues of the offspring were determined by pyrosequencing. RRBS identified 2,940 DM CpGs mapping to 627 genes. Significant hypermethylation was confirmed (p < 0.05) following oral THC administration for cytochrome P450 oxidoreductase (Por), involved in toxin processing and disorders of sexual development. Por hypermethylation was not observed after THC injection or in the subsequent generation. These results support that THC alters DNAm in sperm and that route of exposure can have differential effects. Although we did not observe evidence of intergenerational transmission of the DNAm change, larger studies are required to definitively exclude this possibility.
Open Access
Neurotoxicology of nicotine and tobacco
(2022-01-01) Levin, ED
Nicotine exposure causes well characterized neurotoxic effects, which are highly dependent on the age of exposure. During early development, nicotine exposure causes persistent neural and behavioral impairments, even with low doses modeling second-hand or environmental tobacco smoke exposure. Nicotine-induced neurodevelopmental toxicity is seen across a variety of neural systems and behavioral functions in a spectrum of species from sea urchins, fish and birds to mice and rats to monkeys and humans. In addition to early development, adolescence is also a vulnerable period for nicotine neurotoxicity with persisting effects on nicotinic receptor regulation and increased liability to nicotine self-administration. Fewer neurotoxic signs of moderate doses of nicotine are seen in adults and during aging. In fact, there is some evidence for potential therapeutic effects of nicotine and similar chemicals for particularly for treating cognitive impairment. The principal neurotoxic effects of moderate nicotine doses in adults derive from the fact that nicotine is the main driving force underlying tobacco addiction resulting in the self-administration of a variety of neurotoxic chemicals. Future research concerning nicotine neurotoxicity should include the interactions of nicotine effects with other toxic chemicals in tobacco, in e-cigarettes, in co-administered drugs of abuse and environmental toxicants.
Open Access
Risk for opioid abuse is diminished by inhibiting aldehyde dehydrogenase-2 (ALDH-2) in rats
(Journal of Drug and Alcohol Research, 2019-01-01) Rezvani, AH; Wells, C; Strumph, P; Diamond, I; Blackburn, BK; Levin, ED
Significant opiate addiction is known to follow prescribed opiate use for pain. There is a serious unmet need for non-addicting medications to prevent subsequent opiate addiction after a short period of opioid treatment for temporary pain. Recent evidence indicates that selective inhibition of aldehyde dehydrogenase-2 (ALDH-2) reduces drug-seeking and trained self-administration of alcohol, cocaine and nicotine, apparently by preventing a concomitant surge of dopamine in the ventral tegmental area (VTA) and nucleus accumbens (NAc). Activation of the same dopaminergic pathway is also implicated in opioid-induced reinforcement. Therefore, we asked whether the selective ALDH-2 inhibitor, ANS-6637, would attenuate opioid self-administration in drug-naïve rats for opioid self-administration. Rats received oral doses of ANS-6637 (9, 18, 36 or 72 mg/kg) or an equal volume of control vehicle 2 h before exposure to remifentanil and a light cue to accentuate self-administration over 5 consecutive days. Self-administration and the numbers of lever presses on both active and inactive levers were recorded. ANS-6637 significantly reduces remifentanil self-administration over 5 sessions of treatment in rats without prior exposure to remifentanil. We also confirm that the highest dose of ANS-6637 (72 mg/kg) used in this study did not prevent remifentanil-induced analgesia using a classic hot plate test. Thus, ANS-6637 significantly reduces of initial exposure to remifentanil self-administration without affecting desired analgesia. These preliminary observations suggest that ANS-6637 appears to have potential value as a non-addictive therapeutic agent to prevent abuse of commonly used opiates in initiating pain management.