Showing papers on "Meth- published in 2012"

Methamphetamine-Associated Psychosis

Abstract: Methamphetamine (METH) is a frequent drug of abuse in U.S. populations and commonly associated with psychosis. This may be a factor in frequent criminal justice referrals and lengthy treatment required by METH users. Persecutory delusions and auditory hallucinations are the most consistent symptoms of METH-associated psychosis (MAP). MAP has largely been studied in Asian populations and risk factors have varied across studies. Duration, frequency and amount of use as well as sexual abuse, family history, other substance use, and co-occurring personality and mood disorders are risk factors for MAP. MAP may be unique with its long duration of psychosis and recurrence without relapse to METH. Seven candidate genes have been identified that may be associated with MAP. Six of these genes are also associated with susceptibility, symptoms, or treatment of schizophrenia and most are linked to glutamatergic neurotransmission. Animal studies of pre-pulse inhibition, attenuation of social interaction, and stereotypy and alterations in locomotion are used to study MAP in rodents. Employing various models, rodent studies have identified neuroanatomical and neurochemical changes associated with METH use. Throughout this review, we identify key gaps in our understanding of MAP and suggest potential directions for future research.

Decreased dopamine activity predicts relapse in methamphetamine abusers.

Abstract: Studies in methamphetamine (METH) abusers showed that the decreases in brain dopamine (DA) function might recover with protracted detoxification. However, the extent to which striatal DA function in METH predicts recovery has not been evaluated. Here we assessed whether striatal DA activity in METH abusers is associated with clinical outcomes. Brain DA D2 receptor (D2R) availability was measured with positron emission tomography and [(11)C]raclopride in 16 METH abusers, both after placebo and after challenge with 60 mg oral methylphenidate (MPH) (to measure DA release) to assess whether it predicted clinical outcomes. For this purpose, METH abusers were tested within 6 months of last METH use and then followed up for 9 months of abstinence. In parallel, 15 healthy controls were tested. METH abusers had lower D2R availability in caudate than in controls. Both METH abusers and controls showed decreased striatal D2R availability after MPH and these decreases were smaller in METH than in controls in left putamen. The six METH abusers who relapsed during the follow-up period had lower D2R availability in dorsal striatum than in controls, and had no D2R changes after MPH challenge. The 10 METH abusers who completed detoxification did not differ from controls neither in striatal D2R availability nor in MPH-induced striatal DA changes. These results provide preliminary evidence that low striatal DA function in METH abusers is associated with a greater likelihood of relapse during treatment. Detection of the extent of DA dysfunction may be helpful in predicting therapeutic outcomes.

Sex differences in escalation of methamphetamine self-administration: cognitive and motivational consequences in rats.

Abstract: Male rats escalate methamphetamine (meth) intake during long-access meth self-administration, show enhanced reinstatement of meth-seeking, and exhibit meth-induced memory impairments. However, the impact of long-access daily meth self-administration on reinstatement and cognitive dysfunction has not been assessed in females, even though clinical studies on meth addiction have shown differences between men and women. This study determined whether male and freely cycling female rats: (1) escalate meth intake in a 6-h daily-access period relative to 1-h access; (2) show different sensitivity to meth primed reinstatement after short- and long-access conditions; and (3) show deficits in novel object and object in place recognition memory. Male and female Long–Evans rats self-administered meth in limited (1-h/day) or extended (6-h/day) daily access sessions. After 21 days, meth access was discontinued, and rats entered an abstinence period. On the seventh and 14th days of abstinence, rats were assessed for recognition memory using tests for: (a) novel object recognition memory and (b) object-in-place memory. Rats were tested for reinstatement of meth-seeking following extinction of responding. Female rats self-administered more meth and escalated intake faster than males during extended, but not limited, daily access. Both males and females in the extended, but not limited, access groups showed memory deficits on both tasks. Female rats showed greater reinstatement to meth-seeking with lower doses of meth priming injections than males. Relative to males, females were equally susceptible to meth-induced memory deficits but exhibited higher meth intake and greater relapse to meth-seeking.

Methamphetamine causes differential alterations in gene expression and patterns of histone acetylation/hypoacetylation in the rat nucleus accumbens.

Abstract: Methamphetamine (METH) addiction is associated with several neuropsychiatric symptoms. Little is known about the effects of METH on gene expression and epigenetic modifications in the rat nucleus accumbens (NAC). Our study investigated the effects of a non-toxic METH injection (20 mg/kg) on gene expression, histone acetylation, and the expression of the histone acetyltransferase (HAT), ATF2, and of the histone deacetylases (HDACs), HDAC1 and HDAC2, in that structure. Microarray analyses done at 1, 8, 16 and 24 hrs after the METH injection identified METH-induced changes in the expression of genes previously implicated in the acute and longterm effects of psychostimulants, including immediate early genes and corticotropin-releasing factor (Crf). In contrast, the METH injection caused time-dependent decreases in the expression of other genes including Npas4 and cholecystokinin (Cck). Pathway analyses showed that genes with altered expression participated in behavioral performance, cell-to-cell signaling, and regulation of gene expression. PCR analyses confirmed the changes in the expression of c-fos, fosB, Crf, Cck, and Npas4 transcripts. To determine if the METH injection caused post-translational changes in histone markers, we used western blot analyses and identified METH-mediated decreases in histone H3 acetylated at lysine 9 (H3K9ac) and lysine 18 (H3K18ac) in nuclear sub-fractions. In contrast, the METH injection caused time-dependent increases in acetylated H4K5 and H4K8. The changes in histone acetylation were accompanied by decreased expression of HDAC1 but increased expression of HDAC2 protein levels. The histone acetyltransferase, ATF2, showed significant METH-induced increased in protein expression. These results suggest that METH-induced alterations in global gene expression seen in rat NAC might be related, in part, to METH-induced changes in histone acetylation secondary to changes in HAT and HDAC expression. The causal role that HATs and HDACs might play in METH-induced gene expression needs to be investigated further.

Methamphetamine use and neuropsychiatric factors are associated with antiretroviral non-adherence

Abstract: The present study assesses the impact of methamphetamine (METH) on antiretroviral therapy (ART) adherence among HIV+ persons, as well as examines the contribution of neurocognitive impairment and other neuropsychiatric factors [i.e., major depressive disorder (MDD), antisocial personality disorder (ASPD), and attention deficit disorder (ADHD)] for ART non-adherence. We examined HIV+ persons with DSM-IV-diagnosed lifetime history of METH abuse/dependence (HIV+ /METH+ ; n=67) as compared to HIV+ participants with no history of METH abuse/dependence (HIV+ /METH - ; n=50). Ancillary analyses compared these groups with a small group of HIV+ /METH+ persons with current METH abuse/dependence (HIV+ /CU METH+ ; n=8). Non-adherence was defined as self-report of any skipped ART dose in the last four days. Neurocognitive functioning was assessed with a comprehensive battery, covering seven neuropsychological domains. Lifetime METH diagnosis was associated with higher rates of detectable levels of plasma and CSF HIV RNA. When combing groups (i.e., METH+ and METH- participants), univariate analyses indicated co-occurring ADHD, ASPD, and MDD predicted ART non-adherence (p's < 0.10; not lifetime METH status or neurocognitive impairment). A significant multivariable model including these variables indicated that only MDD uniquely predicted ART non-adherence after controlling for the other variables (p<0.05). Ancillary analyses indicated that current METH users (use within 30 days) were significantly less adherent (50% prevalence of non-adherence) than lifetime METH+ users and HIV+ /METH- participants and that neurocognitive impairment was associated with non-adherence (p's < 0.05). METH use disorders are associated with worse HIV disease outcomes and ART medication non-adherence. Interventions often target substance use behaviors alone to enhance antiretroviral treatment outcomes; however, in addition to targeting substance use behaviors, interventions to improve ART adherence may also need to address coexisting neuropsychiatric factors and cognitive impairment to improve ART medication taking.

Persistent Neuroinflammatory Effects of Serial Exposure to Stress and Methamphetamine on the Blood-Brain Barrier

Abstract: Studies of methamphetamine (Meth)-induced neurotoxicity have traditionally focused on monoaminergic terminal damage while more recent studies have found that stress exacerbates these damaging effects of Meth. Similarities that exist between the mechanisms that cause monoaminergic terminal damage in response to stress and Meth and those capable of producing a disruption of the blood-brain barrier (BBB) suggest that the well-known high co-morbidity of stress and Meth could produce long-lasting structural and functional BBB disruption. The current studies examined the role of neuroinflammation in mediating the effects of exposure to chronic stress and/or Meth on BBB structure and function. Rats were pre-exposed to chronic unpredictable stress (CUS) and/or challenged with Meth. Twenty-four hours after the treatment of Meth in rats pre-exposed to CUS, occludin and claudin-5 immunoreactivity were decreased while truncation of β-dystroglycan, as well as FITC-dextran and water extravasation was increased. All changes other than β-dystroglycan and edema persisted 7 days later, occurred with increases in GFAP and COX-2, and were blocked by ketoprofen after Meth treatment. In addition, persistent increases in FITC-dextran extravasation were prevented by treatment with an EP1 receptor antagonist after Meth exposure. The results indicate that CUS and Meth synergize to produce long-lasting structural and functional BBB disruptions that are mediated by cyclooxygenase and protracted increases in inflammation. These results suggest that stress and Meth can synergize to produce a long-lasting vulnerability of the brain to subsequent environmental insults resulting from the persistent breach of the BBB.

Chronic exposure to corticosterone enhances the neuroinflammatory and neurotoxic responses to methamphetamine

Abstract: Up-regulation of proinflammatory cytokines and chemokines in brain ("neuroinflammation") accompanies neurological disease and neurotoxicity. Previously, we documented a striatal neuroinflammatory response to acute administration of a neurotoxic dose of methamphetamine (METH), i.e. one associated with evidence of dopaminergic terminal damage and activation of microglia and astroglia. When we used minocycline to suppress METH-induced neuroinflammation, indices of dopaminergic neurotoxicity were not affected, but suppression of neuroinflammation was incomplete. Here, we administered the classic anti-inflammatory glucocorticoid, corticosterone (CORT), in an attempt to completely suppress METH-related neuroinflammation. METH alone caused large increases in striatal proinflammatory cytokine/chemokine mRNA and subsequent astrocytic hypertrophy, microglial activation, and dopaminergic nerve terminal damage. Pre-treatment of mice with acute CORT failed to prevent neuroinflammatory responses to METH. Surprisingly, when mice were pre-treated with chronic CORT in the drinking water, an enhanced striatal neuroinflammatory response to METH was observed, an effect that was accompanied by enhanced METH-induced astrogliosis and dopaminergic neurotoxicity. Chronic CORT pre-treatment also sensitized frontal cortex and hippocampus to mount a neuroinflammatory response to METH. Because the levels of chronic CORT used are associated with high physiological stress, our data suggest that chronic CORT therapy or sustained physiological stress may sensitize the neuroinflammatory and neurotoxicity responses to METH.

Prevention of methamphetamine-induced microglial cell death by TNF-α and IL-6 through activation of the JAK-STAT pathway

Abstract: It is well known that methamphetamine (METH) is neurotoxic and recent studies have suggested the involvement of neuroinflammatory processes in brain dysfunction induced by misuse of this drug. Indeed, glial cells seem to be activated in response to METH, but its effects on microglial cells are not fully understood. Moreover, it has been shown that cytokines, which are normally released by activated microglia, may have a dual role in response to brain injury. This led us to study the toxic effect of METH on microglial cells by looking to cell death and alterations of tumor necrosis factor-alpha (TNF-α) and interleukine-6 (IL-6) systems, as well as the role played by these cytokines. We used the N9 microglial cell line, and cell death and proliferation were evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling assay and incorporation of bromodeoxyuridine, respectively. The TNF-α and IL-6 content was quantified by enzyme-linked immunosorbent assay, and changes in TNF receptor 1, IL-6 receptor-alpha, Bax and Bcl-2 protein levels by western blotting. Immunocytochemistry analysis was also performed to evaluate alterations in microglial morphology and in the protein expression of phospho-signal transducer and activator of transcription 3 (pSTAT3). METH induced microglial cell death in a concentration-dependent manner (EC50 = 1 mM), and also led to significant morphological changes and decreased cell proliferation. Additionally, this drug increased TNF-α extracellular and intracellular levels, as well as its receptor protein levels at 1 h, whereas IL-6 and its receptor levels were increased at 24 h post-exposure. However, the endogenous proinflammatory cytokines did not contribute to METH-induced microglial cell death. On the other hand, exogenous low concentrations of TNF-α or IL-6 had a protective effect. Interestingly, we also verified that the anti-apoptotic role of TNF-α was mediated by activation of IL-6 signaling, specifically the janus kinase (JAK)-STAT3 pathway, which in turn induced down-regulation of the Bax/Bcl-2 ratio. These findings show that TNF-α and IL-6 have a protective role against METH-induced microglial cell death via the IL-6 receptor, specifically through activation of the JAK-STAT3 pathway, with consequent changes in pro- and anti-apoptotic proteins.

Methamphetamine self-administration causes persistent striatal dopaminergic alterations and mitigates the deficits caused by a subsequent methamphetamine exposure

Abstract: Preclinical studies have demonstrated that repeated methamphetamine (METH) injections (referred to herein as a “binge” treatment) cause persistent dopaminergic deficits. A few studies have also examined the persistent neurochemical impact of METH self-administration in rats, but with variable results. These latter studies are important because: 1) they have relevance to the study of METH abuse; and 2) the effects of noncontingent METH treatment do not necessarily predict effects of contingent exposure. Accordingly, the present study investigated the impact of METH self-administration on dopaminergic neuronal function. Results revealed that self-administration of METH, given according to a regimen that produces brain METH levels comparable with those reported postmortem in human METH abusers (0.06 mg/infusion; 8-h sessions for 7 days), decreased striatal dopamine transporter (DAT) uptake and/or immunoreactivity as assessed 8 or 30 days after the last self-administration session. Increasing the METH dose per infusion did not exacerbate these deficits. These deficits were similar in magnitude to decreases in DAT densities reported in imaging studies of abstinent METH abusers. It is noteworthy that METH self-administration mitigated the persistent deficits in dopaminergic neuronal function, as well as the increases in glial fibrillary acidic protein immunoreactivity, caused by a subsequent binge METH exposure. This protection was independent of alterations in METH pharmacokinetics, but may have been attributable (at least in part) to a pretreatment-induced attenuation of binge-induced hyperthermia. Taken together, these results may provide insight into the neurochemical deficits reported in human METH abusers.

Effect of methamphetamine dependence on heart rate variability.

Abstract: Methamphetamine (METH) is an increasing popular and highly addictive stimulant associated with autonomic nervous system (ANS) dysfunction, cardiovascular pathology and neurotoxicity. Heart rate variability (HRV) has been used to assess autonomic function and predict mortality in cardiac disorders and drug intoxication, but has not been characterized in METH use. We recorded HRV in a sample of currently abstinent individuals with a history of METH dependence compared to age- and gender-matched drug-free comparison subjects. HRV was assessed using time domain, frequency domain, and non-linear entropic analyses in 17 previously METH-dependent and 21 drug-free comparison individuals during a 5 minute rest period. The METH-dependent group demonstrated significant reduction in HRV, reduced parasympathetic activity, and diminished heartbeat complexity relative to comparison participants. More recent METH use was associated with increased sympathetic tone. Chronic METH exposure may be associated with decreased HRV, impaired vagal function, and reduction in heart rate complexity as assessed by multiple methods of analysis. We discuss and review evidence that impaired HRV may be related to the cardiotoxic or neurotoxic effects of prolonged METH use.

Mephedrone in Adolescent Rats: Residual Memory Impairment and Acute but Not Lasting 5-HT Depletion

Abstract: Mephedrone (4-methylmethcathinone, MMC) is a popular recreational drug, yet its potential harms are yet to be fully established. The current study examined the impact of single or repeated MMC exposure on various neurochemical and behavioral measures in rats. In Experiment 1 male adolescent Wistar rats received single or repeated (once a day for 10 days) injections of MMC (30 mg/kg) or the comparator drug methamphetamine (METH, 2.5 mg/kg). Both MMC and METH caused robust hyperactivity in the 1 h following injection although this effect did not tend to sensitize with repeated treatment. Striatal dopamine (DA) levels were increased 1 h following either METH or MMC while striatal and hippocampal serotonin (5-HT) levels were decreased 1 h following MMC but not METH. MMC caused greater increases in 5-HT metabolism and greater reductions in DA metabolism in rats that had been previously exposed to MMC. Autoradiographic analysis showed no signs of neuroinflammation ([125I]CLINDE ligand used as a marker for translocator protein (TSPO) expression) with repeated exposure to either MMC or METH. In Experiment 2, rats received repeated MMC (7.5, 15 or 30 mg/kg once a day for 10 days) and were examined for residual behavioral effects following treatment. Repeated high (30 mg/kg) dose MMC produced impaired novel object recognition 5 weeks after drug treatment. However, no residual changes in 5-HT or DA tissue levels were observed at 7 weeks post-treatment. Overall these results show that MMC causes acute but not lasting changes in DA and 5-HT tissue concentrations. MMC can also cause long-term memory impairment. Future studies of cognitive function in MMC users are clearly warranted.

Methamphetamine alters occludin expression via NADPH oxidase-induced oxidative insult and intact caveolae.

Abstract: Methamphetamine (METH) is a drug of abuse with neurotoxic and vascular effects that may be mediated by reactive oxygen species (ROS). However, potential sources of METH-induced generation of ROS are not fully understood. This study is focused on the role of NAD(P)H oxidase (NOX) in METH-induced dysfunction of brain endothelial cells. Treatment with METH induced a time-dependent increase in phosphorylation of NOX subunit p47, followed by its binding with gp91 and p22, and the formation of an active NOX complex. An increase in NOX activity was associated with elevated production of ROS, alterations of occludin levels and increased transendothelial migration of monocytes. Inhibition of NOX by NSC 23766 attenuated METH-induced ROS generation, changes in occludin protein levels and monocyte migration. Because an active NOX complex is localized to caveolae, we next evaluated the role of caveolae in METH-mediated toxicity to brain endothelial cells. Treatment with METH induced phosphorylation of ERK1/2 and caveolin-1 protein. Inhibition of ERK1/2 activity or caveolin-1 silencing protected against METH-induced alterations of occludin levels. These findings indicate an important role of NOX and functional caveolae in METH-induced oxidative stress in brain endothelial cells that contribute to the subsequent alterations of occludin levels and transendothelial migration of inflammatory cells.

Peripheral Ammonia as a Mediator of Methamphetamine Neurotoxicity

Abstract: Ammonia is metabolized by the liver and has established neurological effects. The current study examined the possibility that ammonia contributes to the neurotoxic effects of methamphetamine (METH). The results show that a binge dosing regimen of METH to the rat increased plasma and brain ammonia concentrations that were paralleled by evidence of hepatotoxicity. The role of peripheral ammonia in the neurotoxic effects of METH was further substantiated by the demonstration that the enhancement of peripheral ammonia excretion blocked the increases in brain and plasma ammonia and attenuated the long-term depletions of dopamine and serotonin typically produced by METH. Conversely, the localized perfusion of ammonia in combination with METH, but not METH alone or ammonia alone, into the striatum recapitulated the neuronal damage produced by the systemic administration of METH. Furthermore, this damage produced by the local administration of ammonia and METH was blocked by the GYKI 52466 [4-(8-methyl-9H-1,3-dioxolo[4,5-h][2,3]benzodiazepin-5-yl)-benzamine hydrochloride], an AMPA receptor antagonist. These findings highlight the importance of ammonia derived from the periphery as a small-molecule mediator of METH neurotoxicity and more broadly emphasize the importance of peripheral organ damage as a possible mechanism that mediates the neuropathology produced by drugs of abuse and other neuroactive molecules.

Methamphetamine activates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and induces human immunodeficiency virus (HIV) transcription in human microglial cells

Abstract: Human immunodeficiency virus (HIV) primarily infects glial cells in the central nervous system (CNS). Recent evidence suggests that HIV-infected individuals who abuse drugs such as methamphetamine (METH) have higher viral loads and experience more severe neurological complications than HIV-infected individuals who do not abuse drugs. The aim of this study was to determine the effect of METH on HIV expression from the HIV long terminal repeat (LTR) promoter and on an HIV integrated provirus in microglial cells, the primary host cells for HIV in the CNS. Primary human microglial cells immortalized with SV40 T antigen (CHME-5 cells) were cotransfected with an HIV LTR reporter and the HIV Tat gene, a key regulator of viral replication and gene expression, and exposed to METH. Our results demonstrate that METH treatment induced LTR activation, an effect potentiated in the presence of Tat. We also found that METH increased the nuclear translocation of the nuclear factor kappa B (NF-κB), a key cellular transcriptional regulator of the LTR promoter, and the activity of an NF-κB-specific reporter plasmid in CHME-5 cells. The presence of a dominant-negative regulator of NF-κB blocked METH-related activation of the HIV LTR. Furthermore, treatment of HIV-latently infected CHME-5 (CHME-5/HIV) cells with METH induced HIV expression and nuclear translocation of the p65 subunit of NF-κB. These results suggest that METH can stimulate HIV gene expression in microglia cells through activation of the NF-κB signaling pathway. This mechanism may outline the initial biochemical events leading to the observed increased neurodegeneration in HIV-positive individuals who use METH.

Methamphetamine administration targets multiple immune subsets and induces phenotypic alterations suggestive of immunosuppression.

Abstract: Methamphetamine (Meth) is a widely abused stimulant and its users are at increased risk for multiple infectious diseases. To determine the impact of meth on the immune system, we utilized a murine model that simulates the process of meth consumption in a typical addict. Our phenotypic analysis of leukocytes from this dose escalation model revealed that meth affected key immune subsets. Meth administration led to a decrease in abundance of natural killer (NK) cells and the remaining NK cells possessed a phenotype suggesting reduced responsiveness. Dendritic cells (DCs) and Gr-1high monocytes/macrophages were also decreased in abundance while Gr-1low monocytes/macrophages appear to show signs of perturbation. CD4 and CD8 T cell subsets were affected by methamphetamine, both showing a reduction in antigen-experienced subsets. CD4 T cells also exhibited signs of activation, with increased expression of CD150 on CD226-expressing cells and an expansion of KLRG1+, FoxP3− cells. These results exhibit that meth has the ability to disrupt immune homeostasis and impact key subsets of leukocytes which may leave users more vulnerable to pathogens.

Mechanism of action of methamphetamine within the catecholamine and serotonin areas of the central nervous system.

Abstract: Addiction to methamphetamine (METH) is thought to be mediated by dopaminergic effects in the reward pathway in the brain via the A10 dopaminergic pathway. Herein we describe an overview of the results of the basic preclinical science undertaken to provide mechanistic insights into the action of amphetamines in general and METH in particular. A brief history of amphetamine and METH use and abuse is given, and an overview of the relevant chemical aspects of amphetamine as they relate to neurotransmitters in general is made. A review of the methods used to study the biochemical effects of METH is outlined. Finally, a focused analysis of the kinetic mechanisms of action of the amphetamines in general, and METH in particular, at the transmembrane transporters and at the intracellular vesicular storage sites is made. A description of how catecholaminergic and serotonergic nerve signaling may be altered by METH is proposed. Overall, the emphasis here is on differences in effects observed between the striatal (the A9 substantia nigral dopamine pathway) and nucleus accumbens (the A10, ventral tegmental pathway) areas of the brain following acute as well as repeated dosing and withdrawal.

Adolescent HIV-1 transgenic rats: evidence for dopaminergic alterations in behavior and neurochemistry revealed by methamphetamine challenge.

Abstract: Since the introduction of combination antiretroviral therapy (cART) in the mid-90s, the most severe forms of HIV-1-associated neurocognitive disorders (HAND) have diminished. However, milder forms of HAND remain prevalent. Basic and clinical studies implicate alterations in the dopaminergic (DAergic) system in HIV-1 infection. We used the Fischer 344 HIV-1 transgenic (HIV-1 Tg) rat, which expresses 7 of the 9 HIV-1 genes, to examine potential DAergic alterations. Animals were studied beginning at 35 days of age to assess early-onset DAergic alterations, well before any documented neurological symptoms or clinical signs of “wasting”. At 48 hr intervals, animals were administered a single dose of methamphetamine (METH) (0, 0.5, 1, 2.5 and 5 mg/kg/ml s.c.) and tested for the auditory startle response (ASR) and prepulse inhibition (PPI), using an auditory prepulse [85dB(A) broad-band noise stimulus] and an auditory startle stimulus [100 dB(A) broad-band noise stimulus] in a sound-attenuating chamber with a continuous 70dB(A) white noise background. The protocol used a 5-min acclimation period, 6 startle trials, and 36 PPI trials [ISIs of 0, 8, 40, 80, 120, and 4000 ms, 6-trial blocks, Latin square design]. As the dose of METH increased, PPI of the startle response decreased. The HIV-1 Tg rats displayed a greater dose-dependency to the METH-induced disruption of PPI compared to non-transgenic controls. Western blot analysis of midbrain extracts revealed lower tyrosine hydroxylase (TH) protein levels and higher monoamine oxidase A (MAO-A) protein levels in HIV-1 Tg rats treated with METH compared to non-transgenic controls. Early-detected cognitive alterations in the preattentive process of sensorimotor gating may have significant predictive utility regarding the progression of DAergic alterations in HIV-1 infection.

Common transcriptional effects in the mouse striatum following chronic treatment with heroin and methamphetamine.

Abstract: The molecular alterations that underlie the long-lasting behavioural effects of drugs of abuse, such as psychomotor sensitization and physical dependence, are still not known. Moreover, it is not known which molecular effects are similar for addictive drugs from various pharmacological classes. In this study, we utilized whole-genome microarray profiling to evaluate the detailed time-course of transcriptional alterations in the mouse striatum during chronic treatment with heroin (HER) and methamphetamine (METH) and after period of spontaneous withdrawal. We identified 27 genes regulated by chronic drug administration. The overlap between lists of HER- and METH-induced genes was highly significant. The most substantial impact on the gene expression profile was observed for circadian genes (Per1, Per2 and Nr1d1). However, changing the treatment scheme from diurnal to nocturnal was sufficient to attenuate the drug-induced changes in circadian gene mRNA levels. Both of the drugs caused a dose-dependent induction in glucocorticoid-dependent genes with relatively long mRNA half-lives (Fkbp5, Sult1a1 and Plin4). The analysis also showed a drug-regulated group of transcripts enriched in the nucleus accumbens and includes well known (Pdyn, Cartpt and Rgs2) as well as new (Fam40b and Inmt) candidate genes. All identified alterations in the striatal transcriptome were transient and persisted up to 6 days after withdrawal. Behavioural sensitization, however, was maintained throughout the 12-day withdrawal period for both HER and METH. We suggest that transient gene expression alterations during drug treatment and in the early period of withdrawal are involved in the establishment of persistent neuroplastic alterations responsible for the development of drug addiction.

Protective effects of the antioxidant sulforaphane on behavioral changes and neurotoxicity in mice after the administration of methamphetamine

Abstract: Methamphetamine (METH) is a powerfully addictive stimulant associated with serious health conditions. Accumulating evidence suggests a role of oxidative stress in METH-induced behavioral abnormalities. Sulforaphane (SFN), found in cruciferous vegetables, is a potent antioxidant. It is of interest to determine whether SFN can attenuate behavioral and neuropathological changes associated with METH exposure. This study was undertaken to examine the effects of SFN on behavioral changes and dopaminergic neurotoxicity in mice exposed to METH. The effects of SFN on acute hyperlocomotion and the development of behavioral sensitization induced by the administration of METH were examined. Levels of dopamine (DA) and its major metabolite 3,4-dihydroxyphenyl acetic acid (DOPAC) in the striatum were measured. In addition, DA transporter (DAT) immunoreactivity was also performed. Pretreatment with SFN at 1, 3, and 10 mg/kg elicited a dose-dependent attenuation of acute hyperlocomotion in mice, after a single administration of METH (3 mg/kg). The development of behavioral sensitization after repeated administrations of METH (3 mg/kg/day, once daily for 5 days) was significantly reduced by pretreatment with SFN (10 mg/kg). In addition, the lowering of DA levels and DOPAC as well as DAT immunoreactivity in the striatum, usually seen after repeated administration of METH, was significantly attenuated by both pretreatment and the subsequent administration of SFN. Furthermore, SFN significantly reduced microglial activation in the striatum after repeated exposure to METH. It is therefore likely that SFN can be a useful drug for the treatment of signs associated with METH abuse in humans.

Protective role of neuropeptide Y Y₂ receptors in cell death and microglial response following methamphetamine injury.

Abstract: It has been reported that the hippocampus is very susceptible to methamphetamine (METH) and that neuropeptide Y (NPY) is an important neuroprotective agent against hippocampal excitotoxicity. However, there is very little information regarding the role of the NPYergic system in this brain region under conditions of METH toxicity. To clarify this issue, we investigated the role of NPY and its receptors against METH-induced neuronal cell death in hippocampal organotypic slice cultures. Our data show that NPY (1 μm) is neuroprotective in DG, CA3 and CA1 subregions via Y(2) receptors. Moreover, the selective activation of Y(1) receptors (1 μm [Leu(31) ,Pro(34) ]NPY) partially prevented the toxicity induced by METH in DG and CA3 subfields, but completely blocked its toxicity in the CA1 pyramidal cell layer. Regarding Y(2) receptors, its activation (300 nm NPY13-36) completely prevented METH-induced toxicity in all subregions analysed, which involved changes in levels of pro- and anti-apoptotic proteins Bcl-2 and Bax, respectively. Besides neuronal cell death, we also showed that METH triggers a microglial response in the mouse hippocampus which was attenuated by Y(2) receptor activation. To better clarify the effect of METH and the NPY system on microglial cells, we further used the N9 microglial cell line. We found that both NPY and the Y(2) receptor agonist were able to protect microglia against METH-induced cell death. Overall, our data demonstrate that METH is toxic to both neurons and microglial cells, and that NPY, mainly via Y(2) receptors, has an important protective role against METH-induced cell death and microgliosis.