Showing papers on "Meth- published in 2009"
TL;DR: The accumulated evidence indicates that multiple events converge to mediate METH-induced terminal degeneration and neuronal apoptosis, and suggest that pharmacological strategies geared towards the prevention and treatment of the deleterious effects of this drug will need to attack the various pathways that form the substrates of METH toxicity.
553 citations
TL;DR: It is reported that METH increases BBB permeability in vivo, and exposure of primary human brain microvascular endothelial cells (BMVEC) to METH diminishes the tightness of BMVEC monolayers in a dose- and time-dependent manner by decreasing the expression of cell membrane-associated tight junction (TJ) proteins.
Abstract: Methamphetamine (METH), a potent stimulant with strong euphoric properties, has a high abuse liability and long-lasting neurotoxic effects. Recent studies in animal models have indicated that METH can induce impairment of the blood-brain barrier (BBB), thus suggesting that some of the neurotoxic effects resulting from METH abuse could be the outcome of barrier disruption. In this study, we provide evidence that METH alters BBB function through direct effects on endothelial cells and explore possible underlying mechanisms leading to endothelial injury. We report that METH increases BBB permeability in vivo, and exposure of primary human brain microvascular endothelial cells (BMVEC) to METH diminishes the tightness of BMVEC monolayers in a dose- and time-dependent manner by decreasing the expression of cell membrane-associated tight junction (TJ) proteins. These changes were accompanied by the enhanced production of reactive oxygen species, increased monocyte migration across METH-treated endothelial monolayers, and activation of myosin light chain kinase (MLCK) in BMVEC. Antioxidant treatment attenuated or completely reversed all tested aspects of METH-induced BBB dysfunction. Our data suggest that BBB injury is caused by METH-mediated oxidative stress, which activates MLCK and negatively affects the TJ complex. These observations provide a basis for antioxidant protection against brain endothelial injury caused by METH exposure.
191 citations
TL;DR: In this article, the authors review cellular and molecular mechanisms that might be responsible for METH neurotoxicity, including oxidative stress, activation of transcription factors, DNA damage, excitotoxicity, blood-brain barrier breakdown, microglial activation, and various apoptotic pathways.
Abstract: Methamphetamine (METH) is a highly addictive psychostimulant drug, whose abuse has reached epidemic proportions worldwide. The addiction to METH is a major public concern because its chronic abuse is associated with serious health complications including deficits in attention, memory, and executive functions in humans. These neuropsychiatric complications might, in part, be related to drug-induced neurotoxic effects, which include damage to dopaminergic and serotonergic terminals, neuronal apoptosis, as well as activated astroglial and microglial cells in the brain. Thus, the purpose of the present paper is to review cellular and molecular mechanisms that might be responsible for METH neurotoxicity. These include oxidative stress, activation of transcription factors, DNA damage, excitotoxicity, blood–brain barrier breakdown, microglial activation, and various apoptotic pathways. Several approaches that allow protection against METH-induced neurotoxic effects are also discussed. Better understanding of the cellular and molecular mechanisms involved in METH toxicity should help to generate modern therapeutic approaches to prevent or attenuate the long-term consequences of psychostimulant use disorders in humans.
190 citations
TL;DR: The data show that modafinil interacts with DAT sites in rat brain, a property shared with agonist medications under investigation for treating cocaine dependence, and suggest that modAFinil should be tested as an adjunct for treating METH addiction.
Abstract: Modafinil is prescribed for numerous medical conditions, but the drug's mechanism of action is unclear. Here, we examined the interaction of modafinil with receptors and transporters in vitro and compared pharmacological effects of the drug with those produced by indirect dopamine (DA) agonists 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR12909) and (+)-methamphetamine (METH). Modafinil was screened at various receptors and transporters using binding assays. Transporter-mediated uptake and release were examined in rat brain synaptosomes. Effects of modafinil on motor activity and neurochemistry were determined in rats undergoing in vivo microdialysis in nucleus accumbens. Of the receptors and transporters assayed, modafinil displayed measurable potency only at DA transporters (DAT), inhibiting [3H]DA uptake, with an IC50 value of 4.0 μM. Accordingly, modafinil pretreatment (10 μM) antagonized METH-induced release of the DAT substrate [3H]1-methyl-4-phenylpyridinium. Intravenous modafinil (20 and 60 mg/kg) produced dose-dependent increases in motor activity and extracellular DA, without affecting serotonin (5-HT). Analogous results were observed for GBR12909 (1 and 3 mg/kg), whereas METH (0.3 and 1 mg/kg) increased DA and 5-HT. Locomotor effects of all drugs were positively correlated with dialysate DA ( P < 0.001). Interestingly, modafinil pretreatment reduced METH-induced ambulation and DA release. Our data show that modafinil interacts with DAT sites in rat brain, a property shared with agonist medications under investigation for treating cocaine dependence. Nondopaminergic mechanisms may also contribute to the pharmacology of modafinil. Finally, the results suggest that modafinil should be tested as an adjunct for treating METH addiction.
184 citations
TL;DR: It is demonstrated that METH has a stronger effect on DAT-mediated cell physiology than AMPH, which may contribute to the euphoric and addictive properties of METH compared with AMPH.
172 citations
TL;DR: Findings illustrate that lithium and VPA enhance mitochondrial function and protect against mitochondrially mediated toxicity, and may have potential clinical utility in the treatment of other diseases associated with impaired mitochondrial function, such as neurodegenerative diseases and schizophrenia.
Abstract: Accumulating evidence suggests that mitochondrial dysfunction plays a critical role in the progression of a variety of neurodegenerative and psychiatric disorders. Thus, enhancing mitochondrial function could potentially help ameliorate the impairments of neural plasticity and cellular resilience associated with a variety of neuropsychiatric disorders. A series of studies was undertaken to investigate the effects of mood stabilizers on mitochondrial function, and against mitochondrially mediated neurotoxicity. We found that long-term treatment with lithium and valproate (VPA) enhanced cell respiration rate. Furthermore, chronic treatment with lithium or VPA enhanced mitochondrial function as determined by mitochondrial membrane potential, and mitochondrial oxidation in SH-SY5Y cells. In-vivo studies showed that long-term treatment with lithium or VPA protected against methamphetamine (Meth)-induced toxicity at the mitochondrial level. Furthermore, these agents prevented the Meth-induced reduction of mitochondrial cytochrome c, the mitochondrial anti-apoptotic Bcl-2/Bax ratio, and mitochondrial cytochrome oxidase (COX) activity. Oligoarray analysis demonstrated that the gene expression of several proteins related to the apoptotic pathway and mitochondrial functions were altered by Meth, and these changes were attenuated by treatment with lithium or VPA. One of the genes, Bcl-2, is a common target for lithium and VPA. Knock-down of Bcl-2 with specific Bcl-2 siRNA reduced the lithium- and VPA-induced increases in mitochondrial oxidation. These findings illustrate that lithium and VPA enhance mitochondrial function and protect against mitochondrially mediated toxicity. These agents may have potential clinical utility in the treatment of other diseases associated with impaired mitochondrial function, such as neurodegenerative diseases and schizophrenia.
150 citations
TL;DR: Significant abnormalities in neuronal, glial, and endothelial cells are revealed during acute methamphetamine (METH) intoxication in the rat, suggesting leakage of the BBB, acutely developing brain edema, and serious shifts in brain ion homeostasis as leading factors underlying brain abnormalities.
117 citations
TL;DR: The results suggest that NACA protects the BBB integrity in vitro, which could prevent oxidative stress-induced damage; therefore, the effectiveness of this antioxidant should be evaluated for the treatment of neurodegenerative diseases in the future.
102 citations
TL;DR: Observations suggest that METH exposure, like TBI, can cause substantial damage to the brain by causing both apoptotic and necrotic cell death in the brains of METH addicts who use large doses of the drug during their lifetimes.
98 citations
TL;DR: In this paper, the authors show that acute METH intoxication induces robust, widespread but structure-specific leakage of the BBB, acute glial activation, and increased water content (edema), which are related to drug-induced brain hyperthermia.
Abstract: Methamphetamine (METH) is a powerful and often abused stimulant with potent addictive and neurotoxic properties. While it is generally assumed that multiple chemical substances released in the brain following METH-induced metabolic activation (or oxidative stress) are primary factors underlying damage of neural cells, in this work we present data suggesting a role of brain hyperthermia and associated leakage of the blood-brain barrier (BBB) in acute METH-induced toxicity. First, we show that METH induces a dose-dependent brain and body hyperthermia, which is strongly potentiated by associated physiological activation and in warm environments that prevent proper heat dissipation to the external environment. Second, we demonstrate that acute METH intoxication induces robust, widespread but structure-specific leakage of the BBB, acute glial activation, and increased water content (edema), which are related to drug-induced brain hyperthermia. Third, we document widespread morphological abnormalities of brain cells, including neurons, glia, epithelial, and endothelial cells developing rapidly during acute METH intoxication. These structural abnormalities are tightly related to the extent of brain hyperthermia, leakage of the BBB, and brain edema. While it is unclear whether these rapidly developed morphological abnormalities are reversible, this study demonstrates that METH induces multiple functional and structural perturbations in the brain, determining its acute toxicity and possibly contributing to neurotoxicity.
89 citations
TL;DR: It is reported for the first time that Meth fosters HIV-1 infection, potentially via upregulating coreceptor gene expression.
Abstract: The US is currently experiencing an epidemic of methamphetamine (Meth) use as a recreational drug. Recent studies also show a high prevalence of HIV-1 infection among Meth users. We report that Meth enhances HIV-1 infectivity of dendritic cells as measured by multinuclear activation of a galactosidase indicator (MAGI) cell assay, p24 assay, and LTR-RU5 amplification. Meth induces increased HIV-1 infection in association with an increase in the HIV-1 coreceptors, CXCR4 and CCR5, and infection is mediated by downregulation of extracellular-regulated kinase (ERK2) and the upregulation of p38 mitogen-activated protein kinase (MAPK). A p38 inhibitor (SB203580) specifically reversed the Meth-induced upregulation of the CCR5 HIV-1 coreceptor. The dopamine D2 receptor antagonist RS ± sulpiride significantly reversed the Meth-induced upregulation of CCR5, demonstrating that the Meth-induced effect is mediated via the D2 receptor. These studies report for the first time that Meth fosters HIV-1 infection, potentially via upregulating coreceptor gene expression. Further, Meth mediates its regulatory effects via dopamine receptors and via downregulating ERK2 with a reciprocal upregulation of p38 MAPK. Elucidation of the role of Meth in HIV-1 disease susceptibility and the mechanism through which Meth mediates its effects on HIV-1 infection may help to devise novel therapeutic strategies against HIV-1 infection in high-risk Meth-using HIV-1-infected subjects.
TL;DR: It is demonstrated that METH-mediated ROS generation results in the dysregulation of Drp1, which leads to mitochondrial fragmentation and subsequent apoptosis in rhNPC, which provides a potential mechanism for Meth-related neurodegenerative disorders, and also provides insight into therapeutic strategies for the neurodegenersative effects of METH.
Abstract: Methamphetamine (METH) induces neurodegeneration through damage and apoptosis of dopaminergic nerve terminals and striatal cells, presumably via cross-talk between the endoplasmic reticulum and mitochondria-dependent death cascades. However, the effects of METH on neural progenitor cells (NPC), an important reservoir for replacing neurons and glia during development and injury, remain elusive. Using a rat hippocampal NPC (rhNPC) culture, we characterized the METH-induced mitochondrial fragmentation, apoptosis, and its related signaling mechanism through immunocytochemistry, flow cytometry, and Western blotting. We observed that METH induced rhNPC mitochondrial fragmentation, apoptosis, and inhibited cell proliferation. The mitochondrial fission protein dynamin-related protein 1 (Drp1) and reactive oxygen species (ROS), but not calcium (Ca2+) influx, were involved in the regulation of METH-induced mitochondrial fragmentation. Furthermore, our results indicated that dysregulation of ROS contributed to the oligomerization and translocation of Drp1, resulting in mitochondrial fragmentation in rhNPC. Taken together, our data demonstrate that METH-mediated ROS generation results in the dysregulation of Drp1, which leads to mitochondrial fragmentation and subsequent apoptosis in rhNPC. This provides a potential mechanism for METH-related neurodegenerative disorders, and also provides insight into therapeutic strategies for the neurodegenerative effects of METH.
TL;DR: Investigation of transcriptional responses in the rat striatum and the role of DA D1 receptor stimulation on the expression of genes that participate in ER stress-mediated molecular events indicate that SCH23390 can provide protection against neuronal apoptosis by inhibiting METH-mediated DA D 1 receptor-mediated ER stress in the rats.
Abstract: Methamphetamine (METH) is an illicit toxic psychostimulant which is widely abused. Its toxic effects depend on the release of excessive levels of dopamine (DA) that activates striatal DA receptors. Inhibition of DA-mediated neurotransmission by the DA D1 receptor antagonist, SCH23390, protects against METH-induced neuronal apoptosis. The initial purpose of the present study was to investigate, using microarray analyses, the influence of SCH23390 on transcriptional responses in the rat striatum caused by a single METH injection at 2 and 4 hours after drug administration. We identified 545 out of a total of 22,227 genes as METH-responsive. These include genes which are involved in apoptotic pathways, endoplasmic reticulum (ER) stress, and in transcription regulation, among others. Of these, a total of 172 genes showed SCH23390-induced inhibition of METH-mediated changes. Among these SCH23390-responsive genes were several genes that are regulated during ER stress, namely ATF3, HSP27, Hmox1, HSP40, and CHOP/Gadd153. The secondary goal of the study was to investigate the role of DA D1 receptor stimulation on the expression of genes that participate in ER stress-mediated molecular events. We thus used quantitative PCR to confirm changes in the METH-responsive ER genes identified by the microarray analyses. We also measured the expression of these genes and of ATF4, ATF6, BiP/GRP78, and of GADD34 over a more extended time course. SCH23390 attenuated or blocked METH-induced increases in the expression of the majority of these genes. Western blot analysis revealed METH-induced increases in the expression of the antioxidant protein, Hmox1, which lasted for about 24 hours after the METH injection. Additionally, METH caused DA D1 receptor-dependent transit of the Hmox1 regulator protein, Nrf2, from cytosolic into nuclear fractions where the protein exerts its regulatory functions. When taken together, these findings indicate that SCH23390 can provide protection against neuronal apoptosis by inhibiting METH-mediated DA D1 receptor-mediated ER stress in the rat striatum. Our data also suggest that METH-induced toxicity might be a useful model to dissect molecular mechanisms involved in ER stress-dependent events in the rodent brain.
TL;DR: A pretreatment with melatonin enhances mTOR activity and 4EBP1 phosphorylation and protects against the formation of LC3‐II in SK‐N‐SH cells exposed to METH, demonstrating a novel role for melatonin as a neuroprotective agent against METH.
Abstract: Methamphetamine (METH) is a commonly abused drug that damages nerve terminals by causing reactive oxygen species (ROS) formation, apoptosis, and neuronal damage. Autophagy, a type of programmed cell death independent of apoptosis, is negatively regulated by the mammalian target of the rapamycin (mTOR) signaling pathway. It is not known, however, whether autophagy is involved in METH-induced neurotoxicity. Therefore, we investigated the effect of METH on autophagy and its upstream regulator, the mTOR signaling pathway. Using the SK-N-SH dopaminergic cell line, we found that METH induces the expression of LC3-II, a protein associated with the autophagosome membrane, in a dose-dependent manner. Moreover, METH inhibits the phosphorylation of mTOR and the action of its downstream target, the eukaryotic initiation factor (eIF)4E-binding protein, 4EBP1. Melatonin, a major secretory product of pineal, is a potent naturally produced antioxidant that acts through various mechanisms to ameliorate the toxic effects of ROS. We found that a pretreatment with melatonin enhances mTOR activity and 4EBP1 phosphorylation and protects against the formation of LC3-II in SK-N-SH cells exposed to METH. This work demonstrates a novel role for melatonin as a neuroprotective agent against METH.
TL;DR: Replication of the findings reviewed here along with further development of more rigorous methodologies and reporting protocols will aid in delineating the complex genetic epidemiology of METH use disorders.
Abstract: Efforts to understand the biological processes that increase susceptibility to methamphetamine (METH) use disorders (i.e., abuse, dependence, and psychosis) have uncovered several putative genotypic variants. However, to date a synthesis of this information has not been conducted. Thus, systematic searches of the current literature were undertaken for genetic-association studies of METH use disorders. Each gene's chromosomal location, function, and examined polymorphic markers were extracted. Frequencies, odds ratios and 95% confidence intervals for risk alleles, as well as sample size and power, were calculated. We uncovered 38 studies examining 39 genes, of which 18 were found to have a significant genotypic, allelic, and/or haplotypic association with METH use disorders. Three genes (COMT, DRD4, and GABRA1) were associated with METH abuse, nine (ARRB2, BDNF, CYP2D6, GLYT1, GSTM1, GSTP1, PDYN, PICK1, and SLC22A3) with METH dependence, two (AKT1 and GABRG2) with METH abuse/dependence, and four (DTNBP1, OPRM1, SNCA, and SOD2) with METH psychosis. Limitations related to phenotypic classification, statistical power, and potential publication bias in the current literature were noted. Similar to other behavioral, psychiatric, and substance use disorders, the genetic epidemiology of METH use disorders is complex and likely polygenic. National and international collaborative efforts are needed to increase the availability of large population-based samples and improve upon the power to detect genetic associations of small magnitude. Further, replication of the findings reviewed here along with further development of more rigorous methodologies and reporting protocols will aid in delineating the complex genetic epidemiology of METH use disorders.
TL;DR: Investigating whether the Montana Meth Project reduced methamphetamine use among Montana's youth finds effects on meth use are statistically indistinguishable from zero, and complementary analysis of treatment admissions data from the Treatment Episode Data Set (TEDS) confirms the MMP has had no discernable impact.
Abstract: Are demand-side interventions effective at curbing drug use? To the extent demand-side programs are successful, their cost effectiveness can be appealing from a policy perspective. Established in 2005, the Montana Meth Project (MMP) employs a graphic advertising campaign aimed at deterring meth use among Montana's youth. Due to the apparent success of the MMP, seven other states have since adopted Meth Project campaigns that mirror the Montana model. Using data from the 1999-2009 Youth Risk Behavior Surveys (YRBS), this paper investigates whether the MMP reduced self-reported methamphetamine use among Montana teens. Initial results show that reported rates of meth use were approximately 1.5 to 4 percentage points lower after the adoption of the MMP. However, the data suggests the reduction is an artifact of a preexisting downward trend. When accounting for this preexisting trend, effects on meth use become small and statistically insignificant. These results are robust to using the related changes of meth use among individuals in states without exposure to the campaign as controls in a difference-in-difference estimation strategy. These null findings are robust to examining the impact of the anti-meth campaign on use rates among select subsamples of the population and on youth who may have been exposed to the campaign more than others. Lastly, evidence does not support the selective recruitment hypothesis. That is, youth who were least likely to try meth in the first place were no less likely to try meth after the MMP was put into place. These findings suggest that other factors, such as increased policing efforts that preceded the MMP, are more likely to have contributed to the decrease in the use of methamphetamines.
TL;DR: The ability of immune sera to bind a METH-modified target protein dramatically decreased during and shortly after the meth self-administration assay, suggesting effective sequestration of free meth.
TL;DR: The lower FA in the right frontal white matter suggests axonal injury in these METH users and the higher ADC in the basal ganglia suggests greater inflammation or less myelination in these brain regions of those with younger age of first METH use and greater METH usage.
Abstract: Methamphetamine (METH) users showed structural and chemical abnormalities on magnetic resonance (MRI) studies, particularly in the frontal and basal ganglia brain regions Diffusion tensor imaging (DTI) may provide further insights regarding the microstructural changes in METH users We investigated diffusion tensor measures in frontal white matter and basal ganglia of 30 adult METH users and 30 control subjects using a 3 T MR scanner Compared with healthy control subjects, METH users showed lower fractional anisotropy (FA) in right frontal white matter, and higher apparent diffusion coefficient (ADC) in left caudate and bilateral putamen Higher left putamen ADC was associated with earlier initiation of METH use, greater daily amounts, and a higher cumulative lifetime dose Similarly, higher right putamen ADC was associated with greater daily amounts and a higher cumulative lifetime dose The lower FA in the right frontal white matter suggests axonal injury in these METH users The higher ADC in the basal ganglia suggests greater inflammation or less myelination in these brain regions of those with younger age of first METH use and greater METH usage
TL;DR: The aim of this short review is to summarize the present knowledge of this subject and investigate the effects of METH and cocaine on BBB function.
Abstract: The integrity of the blood-brain barrier (BBB) plays an important role in maintaining a safe neural microenvironment in the brain. Loss of BBB integrity has been recognized as a major cause of profound brain alterations. Psychoactive drugs such as methamphetamine (METH) or cocaine are well-known drugs of abuse that can alter the permeability of the BBB via various mechanisms. In addition, the neurotoxicity of METH is well documented, and alterations in BBB function can contribute to this toxicity. A great deal of effort has been devoted to understanding the cellular and molecular mechanisms of the action of these drugs in the central nervous system. However, only a few investigations have focused on the effects of METH and cocaine on BBB function. The aim of this short review is to summarize our present knowledge of this subject.
TL;DR: It is confirmed that METH preconditioning can provide significant protection against METH-induced striatal dopamine depletion and suggest that multiple molecular pathways might work in tandem to protect the nigrostriatal dopaminergic pathway against the deleterious effects of the toxic psychostimulant.
Abstract: Methamphetamine (METH) is an illicit drug which is neurotoxic to the mammalian brain. Numerous studies have revealed significant decreases in dopamine and serotonin levels in the brains of animals exposed to moderate-to-large METH doses given within short intervals of time. In contrast, repeated injections of small nontoxic doses of the drug followed by a challenge with toxic METH doses afford significant protection against monoamine depletion. The present study was undertaken to test the possibility that repeated injections of the drug might be accompanied by transcriptional changes involved in rendering the nigrostriatal dopaminergic system refractory to METH toxicity. Our results confirm that METH preconditioning can provide significant protection against METH-induced striatal dopamine depletion. In addition, the presence and absence of METH preconditioning were associated with substantial differences in the identity of the genes whose expression was affected by a toxic METH challenge. Quantitative PCR confirmed METH-induced changes in genes of interest and identified additional genes that were differentially impacted by the toxic METH challenge in the presence of METH preconditioning. These genes include small heat shock 27 kD 27 protein 2 (HspB2), thyrotropin-releasing hormone (TRH), brain derived neurotrophic factor (BDNF), c-fos, and some encoding antioxidant proteins including CuZn superoxide dismutase (CuZnSOD), glutathione peroxidase (GPx)-1, and heme oxygenase-1 (Hmox-1). These observations are consistent, in part, with the transcriptional alterations reported in models of lethal ischemic injuries which are preceded by ischemic or pharmacological preconditioning. Our findings suggest that multiple molecular pathways might work in tandem to protect the nigrostriatal dopaminergic pathway against the deleterious effects of the toxic psychostimulant. Further analysis of the molecular and cellular pathways regulated by these genes should help to provide some insight into the neuroadaptive potentials of the brain when repeatedly exposed to drugs of abuse.
TL;DR: It is suggested that melatonin provides a protective effect against METH-induced nerve terminal degeneration in the immature rat brain probably via its antioxidant properties.
TL;DR: It is suggested that relatively brief substrate exposure results in greater down‐regulation of DAT activity in dorsal striatum than in nucleus accumbens, and exposure to AMPH appears to regulate striatal DATs in a biphasic manner.
Abstract: The neurotransmitter dopamine (DA) plays an essential role in normal CNS functions such as cognition, locomotion, and reward (Iversen and Iversen 2007). The duration and extent of DA neurotransmission is largely limited by DA transporters (DATs) (Jaber et al. 1997). The DAT is a member of the neurotransmitter:sodium symporter family, which also includes GABA, norepinephrine, and serotonin transporters (Chen et al. 2004). DATs are localized to dopaminergic neurons (Nirenberg et al. 1996), where they are functional when expressed on the plasma membrane. In particular, DATs located within striatal brain reward circuitry help to mediate the psychostimulant actions of d-amphetamine (AMPH) and methamphetamine (METH) (Koob and Nestler 1997; Wise and Bozarth 1987).
DAT function can be rapidly regulated by exposure to DAT substrates (e.g. DA, AMPH, and METH), DAT inhibitors (e.g. cocaine), ligands for various presynaptic receptors (e.g. DA D2 receptors), and several signaling systems (e.g. protein kinase C (PKC)) (for reviews see: Gulley and Zahniser 2003; Mortensen and Amara 2003). Here, we focused on further understanding the relatively rapid and transient down-regulation of DAT activity and cell surface expression induced by its substrates. This has been shown to occur following their initial uptake by DAT, inhibition/reversal of DAT, and ultra rapid up-regulation of DATs in dorsal striatum (dSTR) and cells expressing cloned DATs (Fleckenstein et al. 1997; Saunders et al. 2000; Chi and Reith 2003; Johnson et al. 2005; Kahlig et al. 2006; Boudanova et al. 2008). Although it may be counterintuitive why exposure to DAT substrates results in not only increased DA in the synapse, but also down-regulation of DAT uptake activity, this latter effect may be a protective mechanism since cytoplasmic DA can be toxic to neurons (Ziv et al. 1994).
Interestingly, two published studies have suggested that DAT activity may be differentially regulated by substrates within subregions of striatum (Kokoshka et al. 1998; Gulley et al. 2002;). Specifically, systemic administration of METH decreased DAT activity measured ex vivo in well-washed synaptosomes prepared from rat dSTR but not from nucleus accumbens (NAc) (Kokoshka et al. 1998). Additionally, brief, rapidly repeated local application of DA decreased in vivo DA clearance, consistent with loss of DATs, in rat dSTR but not in NAc (Gulley et al. 2002). Since NAc has 40-60% fewer DATs than dSTR (Marshall et al. 1990), it could be important for DATs in NAc to be more resistant to substrate-induced down-regulation. However, whether this is the case and the explanation for this putative brain regional difference are not known. The DAT protein is a single gene product, and to date only one regional difference has been identified (i.e. glycosylation of DATs differs in rat dSTR and NAc) (Lew et al. 1992). Although lack of N-glycosylation reduces DAT activity and surface expression, it is not essential for DAT surface expression (Li et al. 2004). Post-translational modifications and accessory proteins involved in DAT trafficking could also differ between dSTR and NAc, but these have not been reported.
It is important to understand if DATs in dSTR and NAc differ in substrate-induced regulation because this could contribute to the differential dopaminergic neuronal function reported for these two brain regions. For instance, AMPH- and cocaine-induced increases in extracellular DA are greater in NAc than in dSTR (Carboni et al. 1989; Cass et al. 1992; Kuczenski and Segal 1992), but the vulnerability to the neurotoxic effects of METH is greater in dSTR than in NAc (Haughey et al. 1999; Wallace et al. 1999). Furthermore, for psychostimulants (e.g. AMPH, METH, and cocaine), dSTR and NAc are suggested to play differing roles in the transition from initial drug use to drug addiction, with NAc being particularly important during the early stages and dSTR being more important in the later stages (Everitt and Robbins 2005).
Therefore, the purpose of the present study was to compare directly the effect of relatively brief in vitro pre-exposure to DAT substrates, with an emphasis on AMPH, on DAT uptake activity, kinetics, and cell surface expression in synaptosomes prepared from rat dSTR versus NAc. Since PKC has been previously shown to play a role in substrate-mediated regulation of DATs in dSTR and cells expressing cloned DATs (Giambalvo 1992a,b; Vaughan et al. 1997; Zhang et al. 1997; Zhu et al. 1997; Daniels and Amara 1999; Blakely and Bauman 2000; Chi and Reith 2003), follow-up experiments were performed to assess if this was also the case in NAc synaptosomes. Lastly, the effects of systemic administration of AMPH were compared on ex vivo DAT kinetics and surface expression to explore further regionally selective substrate-induced DAT regulation.
TL;DR: Independent effects of METH dependence and negative mood on condom use suggest that sexual risk reduction interventions for MSM should incorporate multi-faceted approaches, including substance abuse and mental health treatment.
TL;DR: A new generation of passive monoclonal antibodies and active immunization therapies are at an advanced stage of preclinical development and could play an essential role in a well planned recovery program from human METH addiction by providing long-lasting protection from the rewarding and reinforcing effect of METH.
Abstract: Methamphetamine (METH) abuse is a major worldwide epidemic, with no specific medications for treatment of chronic or acute effects. Anti-METH antibodies have the potential to save lives and reduce the crippling effects of METH abuse. While they are not expected to be the magic bullet to immediately cure addiction, immunotherapy could provide a breakthrough medication to continuously block or attenuate METH effects during a comprehensive addiction recovery plan. A unique challenge for METH antibody antagonists is the need to protect the brain from the complex direct and indirect adverse effects of long-term METH use. To meet this challenge, a new generation of passive monoclonal antibodies and active immunization therapies are at an advanced stage of preclinical development. Both of these vaccines could play an essential role in a well planned recovery program from human METH addiction by providing long-lasting protection from the rewarding and reinforcing effect of METH.
TL;DR: It is shown that METH administered unilaterally via a microdialysis probe to rats’ right dorsal hippocampus will induce drug-seeking and drug-taking behavior, and that both responses are dependent on local dopamine receptor activation.
Abstract: Drug abuse and addiction are major problems in the United States In particular methamphetamine (METH) use has increased dramatically A greater understanding of how METH acts on the brain to induce addiction may lead to better therapeutic targets for this problem The hippocampus is recognized as an important structure in learning and memory, but is not typically associated with drug reinforcement or reward processes Here, the focus is on the hippocampus which has been largely ignored in the addiction literature as compared to the nucleus accumbens (NAc), ventral tegmental area (VTA), and prefrontal cortex (PFC) The results show that METH administered unilaterally via a microdialysis probe to rats’ right dorsal hippocampus will induce drug-seeking (place preference) and drug-taking (lever-pressing) behavior Furthermore, both of these responses are dependent on local dopamine (DA) receptor activation, as they are impaired by a selective D1/D5 receptor antagonist The results suggest that the hippocampus is part of the brain’s reward circuitry that underlies addiction
TL;DR: Increases in cytoplasmic DA dramatically broaden the neurotoxic profile of METH to include brain structures not normally targeted for damage by METH alone, and resistance of the NAc to METH‐induced neurotoxicity and its ability to recover reveal a fundamentally different neuroplasticity by comparison to the CPu.
Abstract: Methamphetamine (METH) is a neurotoxic drug of abuse that damages the dopamine (DA) neuronal system in a highly delimited manner. The brain structure most affected by METH is the caudate-putamen (CPu) where long-term DA depletion and microglial activation are most evident. Even damage within the CPu is remarkably heterogenous with lateral and ventral aspects showing the greatest deficits. The nucleus accumbens (NAc) is largely spared of the damage that accompanies binge METH intoxication. Increases in cytoplasmic DA produced by reserpine, L-DOPA or clorgyline prior to METH uncover damage in the NAc as evidenced by microglial activation and depletion of DA, tyrosine hydroxylase (TH), and the DA transporter. These effects do not occur in the NAc after treatment with METH alone. In contrast to the CPu where DA, TH, and DA transporter levels remain depleted chronically, DA nerve ending alterations in the NAc show a partial recovery over time. None of the treatments that enhance METH toxicity in the NAc and CPu lead to losses of TH protein or DA cell bodies in the substantia nigra or the ventral tegmentum. These data show that increases in cytoplasmic DA dramatically broaden the neurotoxic profile of METH to include brain structures not normally targeted for damage by METH alone. The resistance of the NAc to METH-induced neurotoxicity and its ability to recover reveal a fundamentally different neuroplasticity by comparison to the CPu. Recruitment of the NAc as a target of METH neurotoxicity by alterations in DA homeostasis is significant in light of the important roles played by this brain structure.
TL;DR: Results suggest that induction of HO-1 by METH via the p38 signaling pathway may be protective, albeit insufficient to completely protect cortical neurons from METH toxicity.
TL;DR: Results indicate that METH-induced behavioral sensitization is greater in the presence of HIV infection and suggest that D1R expression in the prefrontal cortex may play a role in METH addiction in HIV-positive individuals.
Abstract: Methamphetamine (METH) addiction is prevalent among individuals with HIV infection. We hypothesize that HIV-positive individuals are more prone to METH use and to the development of METH dependence. To test this hypothesis, we examined the effects of METH (daily intraperitoneal injection 2.5 mg/kg for 6 days) on rearing and head movement in 12–13-week-old male HIV-1 transgenic (HIV-1Tg) rats compared to F344 control rats as an indicator of behavioral sensitization, also representing neural adaptation underlying drug dependence and addiction. Body and brain weights were also recorded. The involvement of the dopaminergic system was investigated by examining dopamine receptors 1 (D1R) and 2 (D2R) and dopamine transporter (DAT) expression in the striatum and prefrontal cortex. METH increased rearing number and duration in both F344 and HIV-1Tg rats. Rearing number was attenuated over time, whereas rearing duration remained constant. METH also induced a progressive increase in stereotypical head movement in both F344 and HIV-1Tg rats, but it was greater in the HIV-1Tg rats than in the F344 animals. The brain to body weight ratio was significantly lower in METH-treated HIV-1Tg rats compared to F344 controls. There was no significant difference in striatal D1R, D2R, or DAT messenger RNA in HIV-1Tg and F344 rats. However, D1R expression was greater in the prefrontal cortex of HIV-1Tg rats than F344 rats and was attenuated by METH. Our results indicate that METH-induced behavioral sensitization is greater in the presence of HIV infection and suggest that D1R expression in the prefrontal cortex may play a role in METH addiction in HIV-positive individuals.
TL;DR: The results of these studies suggest that D1 activation in the mPFC plays a significant role in AMPH- and METH-induced hyperactivity.
TL;DR: Immunohistochemical detection of dopaminergic terminal marker deficits, glial reactions, and HSP induction might provide useful information regarding the pathophysiology of chronic and/or lethal METH use in cases of METH-related deaths, where METH intoxication may not be toxicologically demonstrated.