Bruce Ladenheim

United States Department of Health and Human Services

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Jean Lud Cadet

National Institute on Drug Abuse

Michael T. McCoy

National Institute on Drug Abuse

Subramaniam Jayanthi

United States Department of Health and Human Services

Irina N. Krasnova

Russian State University of Justice

Kevin G. Becker

Institute on Aging

Christie Brannock

National Institute on Drug Abuse

Mark P. Mattson

Johns Hopkins University

Xiaolin Deng

Huazhong University of Science and Technology

Geneviève Beauvais

Children's Hospital of Philadelphia

Amber B. Hodges

Morgan State University

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National Institutes of Health

129

National Institute on Drug Abuse

118

Johns Hopkins University

Johns Hopkins Medicine

United States Department of Health and Human Services

National Institute on Aging

Institute on Aging

University of Maryland, Baltimore

The University of Tokyo

University Medical Center Utrecht

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A single high dose of methamphetamine increases cocaine self-administration by depletion of striatal dopamine in rats

Neuroscience (2009)

Zheng‐Xiong Xi Hayley K. Kleitz Xiaolin Deng Bruce Ladenheim Xiao‐Qing Peng

Meth-

Methamphetamine

Self-administration

Neurotoxicity

Dopamine Uptake Inhibitors

10.1016/j.neuroscience.2009.03.060

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Citations (37)

Neurotoxic doses of methamphetamine cause neurocognitive abnormalities in mice

The FASEB Journal (2007)

Irina N. Krasnova Amber B. Hodges Bruce Ladenheim Raina Rhoades Nadia Desir

Methamphetamine (METH) is a neurotoxic psychostimulant that causes damage to striatal dopamine (DA) terminals and to non-monoaminergic cells in the striatum (STR) and cortex of rodents. The aim of the present study was to investigate short- and long-term consequences of neurotoxic METH doses on mice behaviors. Male BALB/c mice, 12–14 weeks old, were injected with dl-METH (i.p., 7.5 mg/kg x 4 times, every 2 hours) or saline. Behaviors were accessed at 10 days after drug treatment. METH administration caused significant decreases in responding to object displacement using an Open Field Object Recognition test. In contrast, METH caused increased response to object novelty. There were no drug-induced effects on locomotor activity. Moreover, repeated METH injections resulted in significant decreases in dopamine (DA) levels in the STR, frontal cortex (FC) and olfactory bulb (OB) in mice sacrificed 10 days after drug treatment. Furthermore, as previously reported for the cortex and striatum, METH administration caused marked increases in the number of cells that were positive for TUNEL staining in the OB at 3 days, observations that are indicative of drug-induced enhancement of cell death in that structure. When taken together, these results suggest that METH caused impairments in spatial learning and/or memory as a consequence of its neurodegenerative effects. This research was supported by the Intramural Research Program of the NIH, NIDA.

Meth-

Methamphetamine

Monoaminergic

Neurotoxicity

10.1096/fasebj.21.6.a1174-d

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Escalated Oxycodone Self-Administration and Punishment: Differential Expression of Opioid Receptors and Immediate Early Genes in the Rat Dorsal Striatum and Prefrontal Cortex

Frontiers in Neuroscience (2020)

Christopher A. Blackwood Michael T. McCoy Bruce Ladenheim Jean Lud Cadet

Opioid use disorder (OUD) is characterized by compulsive drug taking despite adverse life consequences. Here we sought to identify neurobiological consequences associated with the behavioral effects of contingent footshocks administered after escalation of oxycodone self-administration. To reach these goals, Sprague-Dawley rats were trained to self-administer oxycodone for four weeks and were then exposed to contingent electric footshocks. This paradigm helped to dichotomize rats into two distinct behavioral phenotypes: (1) those that reduce lever pressing (shock-sensitive) and (2) others that continue lever pressing (shock-resistant) for oxycodone during contingent punishment. The rats were euthanized at two hours after the last oxycodone plus footshock session. The dorsal striata and prefrontal cortices were dissected for use in western blot and RT-qPCR analyses. All oxycodone self-administration rats showed significant decreased expression of Mu and Kappa opioid receptor proteins only in the dorsal striatum. However, expression of Delta opioid receptor protein was decreased in both brain regions. RT-qPCR analyses documented significant decreases in the expression of c-fos, fosB, fra2, junB, egr1 and egr2 mRNAs in the dorsal striatum (but not in PFC) of the shock-sensitive rats. In the PFC, junD expression was reduced in both phenotypes. However, egr3 mRNA expression was increased in the PFC of only shock-resistant rats. These results reveal that, similar to psychostimulants and alcohol, footshocks can dichotomize rats that escalated their intake of oxycodone into two distinct behavioral phenotypes. These animals also show significant differences in the mRNA expression of immediate early genes (IEGs), mainly, in the dorsal striatum. The increases in PFC egr3 expression in the shock-resistant rats suggest that Egr3 might be involved in the persistence of oxycodone-associated memory under aversive conditions. This punishment-driven model may help to identify neurobiological substrates of persistent oxycodone taking and abstinence in the presence of adverse consequences.

FOSB

μ-opioid receptor

Self-administration

10.3389/fnins.2019.01392

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Citations (32)

An Acute Methamphetamine Injection Downregulates the Expression of Several Histone Deacetylases (HDACs) in the Mouse Nucleus Accumbens: Potential Regulatory Role of HDAC2 Expression

Neurotoxicity Research (2015)

Oscar V. Torres Bruce Ladenheim Subramaniam Jayanthi Michael T. McCoy Irina N. Krasnova

Meth-

Histone deacetylase 2

Methamphetamine

HDAC4

10.1007/s12640-015-9591-3

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Citations (20)

Elevated body fat increases amphetamine accumulation in brain: evidence from genetic and diet-induced forms of adiposity

Translational Psychiatry (2021)

Xiuping Fu Aparna Shah Jacqueline D. Keighron Ta-Chung M. Mou Bruce Ladenheim

Abstract Despite the high prevalence of obesity, little is known about its potential impact on the pharmacokinetics of psychotropic drugs. In the course of investigating the role of the microRNA system on neuronal signaling, we found that mice lacking the translin/trax microRNA-degrading enzyme display an exaggerated locomotor response to amphetamine. As these mice display robust adiposity in the context of normal body weight, we checked whether this phenotype might reflect elevated brain levels of amphetamine. To assess this hypothesis, we compared plasma and brain amphetamine levels of wild type and Tsn KO mice. Furthermore, we checked the effect of diet-induced increases in adiposity on plasma and brain amphetamine levels in wild type mice. Brain amphetamine levels were higher in Tsn KO mice than in wild type littermates and correlated with adiposity. Analysis of the effect of diet-induced increases in adiposity in wild type mice on brain amphetamine levels also demonstrated that brain amphetamine levels correlate with adiposity. Increased adiposity displayed by Tsn KO mice or by wild type mice fed a high-fat diet correlates with elevated brain amphetamine levels. As amphetamine and its analogues are widely used to treat attention deficit disorder, which is associated with obesity, further studies are warranted to assess the impact of adiposity on amphetamine levels in these patients.

10.1038/s41398-021-01547-9

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Differential Reinforcing Effects of Cocaine and GBR-12909: Biochemical Evidence for Divergent Neuroadaptive Changes in the Mesolimbic Dopaminergic System

Journal of Neuroscience (1996)

Srihari R. Tella Bruce Ladenheim Anne M. Andrews Steven R. Goldberg Jean Lud Cadet

The dopamine (DA) transporter is thought to be the primary mediator of reinforcing effects of cocaine. In the present study, an intravenous drug self-administration procedure, in vitro autoradiography, and HPLC methods were used to investigate possible differences in reinforcing and neuroadaptive responses to cocaine versus GBR-12909, a selective inhibitor of the DA transporter with a postulated therapeutic use in cocaine abuse. Drug-naive rats readily acquired and subsequently maintained cocaine self-administration behavior during 2 hr daily sessions over a prolonged period. In contrast, although GBR-12909 was initially self-administered, both cocaine-naive and cocaine-trained rats failed to maintain self-administration behavior for GBR-12909 over prolonged periods of time. After self-administration responding decreased with GBR-12909, rats showed a delay of 6.6 ± 1.3 sessions in reacquiring consistent cocaine self-administration. Moreover, when GBR-12909 was again substituted for cocaine, they failed to self-administer GBR-12909, even during the initial days of testing. In contrast, after extinction of self-administration responding by water substitution, rats readily self-administered both cocaine and GBR-12909. Cocaine self-administration upregulated DA transporters, whereas water-substituted cocaine withdrawal upregulated both DA transporters and D1 receptors. Unlike cocaine, GBR-12909 self-administration by itself altered neither DA transporters nor D1 or D2 receptors. Nevertheless, substitution of GBR-12909 for cocaine reversed the cocaine-induced upregulation of DA transporters and reduced DA and dihydroxyphenylacetic acid levels in the mesolimbic system. These data suggest that cocaine and GBR-12909 differentially affect dopaminergic systems and also cause different reinforcing and neuroadaptive effects. GBR-12909-like compounds may be useful pharmacotherapeutic agents for cocaine addiction. Upregulation of DA transporters and D1 receptors might play important roles in the neuroadaptive cascade that leads to cocaine addiction and withdrawal.

Self-administration

Dopamine Uptake Inhibitors

10.1523/jneurosci.16-23-07416.1996

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Citations (78)

Incubation of Methamphetamine and Palatable Food Craving after Punishment-Induced Abstinence

Neuropsychopharmacology (2014)

Irina N. Krasnova Nathan J. Marchant Bruce Ladenheim Michael T. McCoy Leigh V. Panlilio

Methamphetamine

Punishment (psychology)

Self-administration

Extinction (optical mineralogy)

10.1038/npp.2014.50

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Citations (124)

( )-3,4-Methylenedioxymethamphetamine and Metabolite Disposition in Plasma and Striatum of Wild-Type and Multidrug Resistance Protein 1a Knock-Out Mice

Journal of Analytical Toxicology (2011)

Karl B. Scheidweiler Bruce Ladenheim Allan J. Barnes Jean Lud Cadet Marilyn A. Huestis

Mice lacking multidrug resistance protein 1a (mdr1a) are protected from methylenedioxymethamphetamine (MDMA)-induced neurotoxicity, suggesting mdr1a might play an important role in this phenomenon. We characterized MDMA pharmacokinetics in murine plasma and brain to determine if mdr1a alters MDMA distribution. Wild-type (mdr1a⁺/⁺) and mdr1a knock-out (mdr1a⁻/⁻) mice received i.p. 10, 20 or 40 mg/kg MDMA. Plasma and brain specimens were collected 0.3-4 h after MDMA, and striatum were dissected. MDMA and metabolites were quantified in plasma and striatum by gas chromatography-mass spectrometry. MDMA maximum plasma concentrations (C(max)) for both strains were 916- 1363, 1833-3546, and 5979-7948 μg/L, whereas brain C(max) were 6673-14,869, 23,428-29,433, and 52,735-66,525 μg/kg after 10, 20, or 40 mg/kg MDMA, respectively. MDMA and metabolite striatum/plasma AUC ratios were similar in both strains, inconsistent with observed MDMA neuroprotective effects in mdr1a⁻/⁻ mice. Ratios of methylenedioxyamphetamine (MDA) and 4-hydroxy-3-methoxymethamphetamine (HMMA) AUCs exceeded 18% of MDMA's in plasma, suggesting substantial MDMA hepatic metabolism in mice. MDMA, MDA, HMMA, and 4-hydroxy-3-methoxyamphetamine maximum concentrations and AUCs exhibited nonlinear relationships during dose-escalation studies, consistent with impaired enzymatic demethylenation. Nonlinear increases in MDMA plasma and brain concentrations with increased MDMA dose may potentiate MDMA effects and toxicity.

MDMA

Neurotoxicity

Active metabolite

10.1093/anatox/35.7.470

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Citations (10)

p53 inhibitors preserve dopamine neurons and motor function in experimental parkinsonism

Annals of Neurology (2002)

Wenzhen Duan Xiaoxiang Zhu Bruce Ladenheim Qian‐sheng Yu Zhihong Guo

Abstract Drugs currently used for patients with Parkinson's disease provide temporary relief of symptoms but do not halt or slow the underlying neurodegenerative disease process. Increasing evidence suggests that neurons die in Parkinson's disease by a process called apoptosis, which may be triggered by mitochondrial impairment and oxidative stress. We report that two novel synthetic inhibitors of the tumor suppressor protein p53, pifithrin‐α (PFT‐α) and Z‐1‐117, are highly effective in protecting midbrain dopaminergic neurons and improving behavioral outcome in a mouse model of Parkinson's disease. Mice given intraperitoneal injections of PFT‐α or Z‐1‐117 exhibited improved motor function, reduced damage to nigrostriatal dopaminergic neurons and reduced depletion of dopamine and its metabolites after exposure to the toxin 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). MPTP caused an increase in the level of the proapoptotic protein Bax, which was prevented by giving mice PFT‐α and Z‐1‐117. PFT‐α and Z‐1‐117 also suppressed Bax production and apoptosis in cultured dopaminergic cells exposed to MPP + . Our findings demonstrate a pivotal role for p53 in experimental parkinsonism and identify a novel class of synthetic p53 inhibitors with clinical potential.

MPTP

10.1002/ana.10350

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Citations (203)

Methamphetamine Preconditioning: Differential Protective Effects on Monoaminergic Systems in the Rat Brain

Neurotoxicity Research (2009)

Jean Lud Cadet Irina N. Krasnova Bruce Ladenheim Ning-Sheng Cai Michael T. McCoy

Monoaminergic

Neurochemistry

Methamphetamine

Differential effects

10.1007/s12640-009-9026-0

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Citations (40)