MA-induced Changes Research Articles

Neuropharmacological Evidence Implicating Drug-Induced Glutamate Receptor Dysfunction in Affective and Cognitive Sequelae of Subchronic Methamphetamine Self-Administration in Mice.

Methamphetamine (MA) is a highly addictive drug, and MA use disorder is often comorbid with anxiety and cognitive impairment. These comorbid conditions are theorized to reflect glutamate-related neurotoxicity within the frontal cortical regions. However, our prior studies of MA-sensitized mice indicate that subchronic, behaviorally non-contingent MA treatment is sufficient to dysregulate glutamate transmission in mouse brain. Here, we extend this prior work to a mouse model of high-dose oral MA self-administration (0.8, 1.6, or 3.2 g/L; 1 h sessions × 7 days) and show that while female C57BL/6J mice consumed more MA than males, MA-experienced mice of both sexes exhibited some signs of anxiety-like behavior in a behavioral test battery, although not all effects were concentration-dependent. No MA effects were detected for our measures of visually cued spatial navigation, spatial learning, or memory in the Morris water maze; however, females with a history of 3.2 g/L MA exhibited reversal-learning deficits in this task, and mice with a history of 1.6 g/L MA committed more working-memory incorrect errors and relied upon a non-spatial navigation strategy during the radial-arm maze testing. Relative to naïve controls, MA-experienced mice exhibited several changes in the expression of certain glutamate receptor-related proteins and their downstream effectors within the ventral and dorsal areas of the prefrontal cortex, the hippocampus, and the amygdala, many of which were sex-selective. Systemic pretreatment with the mGlu1-negative allosteric modulator JNJ 162596858 reversed the anxiety-like behavior expressed by MA-experienced mice in the marble-burying test, while systemic pretreatment with NMDA or the NMDA antagonist MK-801 bi-directionally affected the MA-induced reversal-learning deficit. Taken together, these data indicate that a relatively brief history of oral MA is sufficient to induce some signs of anxiety-like behavior and cognitive dysfunction during early withdrawal that reflect, at least in part, MA-induced changes in the corticolimbic expression of certain glutamate receptor subtypes of potential relevance to treating symptoms of MA use disorder.

Role of Differential Estrogen Receptor Activation in Airway Hyperreactivity and Remodeling in a Murine Model of Asthma.

Evidence suggests that airway hyperresponsiveness (AHR) is a characteristic feature of asthma. Epidemiological studies have confirmed that the severity of asthma is greater in women, suggesting a critical role of female sex steroid hormones (especially estrogen). Very few in vivo studies have examined the role of sex steroid hormones in asthma, and the sequence of events that occur through differential activation of estrogen receptors (ERs) remains to be determined in asthmatic airways. Our recent in vitro findings indicated that ERβ had increased expression in asthmatic airway smooth muscle (ASM), and that its activation by an ERβ-specific agonist downregulated airway remodeling. In this study, we translated the in vitro findings to a murine asthma model and examined the differential role of ER activation in modulating lung mechanics. C57BL/6J male, female, and ovariectomized mice were exposed to mixed allergen (MA) and subcutaneously implanted with sustained-release pellets of placebo, an ERα agonist (4,4',4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol [PPT]), and/or an ERβ agonist (WAY-200070). We then evaluated the effects of these treatments on airway mechanics, biochemical, molecular, and histological parameters. Mice exposed to MA showed a significant increase in airway resistance, elastance, and tissue damping, and a decrease in compliance; pronounced effects were observed in females. Compared with PPT, WAY treatment significantly reversed the MA-induced changes. The increased mRNA/protein expression of ERα, ERβ, and remodeling genes observed in MA-treated mice was significantly reversed in WAY-treated mice. This novel study indicates that activation of ERβ signaling downregulates AHR and airway remodeling, and is a promising target in the development of treatments for asthma.

Methamphetamine (MA) Use Induces Specific Changes in LINE-1 Partial Methylation Patterns, Which Are Associated with MA-Induced Paranoia: a Multivariate and Neuronal Network Study.

The use of psychoactive substances, including methamphetamine (MA) may cause changes in DNA methylation. The aim of this study was to examine the effects of MA use on long interspersed element-1 (LINE-1) methylation patterns in association with MA-induced paranoia. This study recruited 123 normal controls and 974 MA users, 302 with and 672 without MA-induced paranoia. The Semi-Structured Assessment for Drug Dependence and Alcoholism was used to assess demographic and substance use variables. Patterns of LINE-1 methylation were assessed in peripheral blood mononuclear cells and a combined bisulfite restriction analysis (COBRA) was used to estimate overall LINE-1 methylation (mC) while COBRA classified LINE-alleles into four patterns based on the methylation status of two CpG dinucleotides on each strand from 5' to 3', namely two methylated (mCmC) and two unmethylated (uCuC) CpGs and two types of partially methylated loci (mCuC that is 5'm with 3'u and uCmC that is 5'u with 3'm CpGs). MA users showed higher % mCuC and % mCuC + uCmC levels than controls. Use of solvents and opioids, but not cannabis and alcohol dependence, significantly lowered % uCmC levels, while current smoking significantly increased % uCuC levels. MA-induced paranoia was strongly associated with changes in LINE-1 partial methylation patterns (lowered % uCmC), heavy MA use, lower age at onset of MA use, and alcohol dependence. Women who took contraceptives showed significantly lower LINE-1 % mC and % mCmC and higher % uCuC levels than women without contraceptive use and men. The results show that MA-induced changes in LINE-1 partial methylation patterns are associated with MA-induced paranoia and could explain in part the pathophysiology of this type of psychosis. It is argued that MA-induced neuro-oxidative pathways may have altered LINE-1 partial methylation patterns, which in turn may regulate neuro-oxidative and immune pathways, which may increase risk to develop MA-induced paranoia.

Exposure to Far Infrared Ray Protects Methamphetamine-Induced Behavioral Sensitization in Glutathione Peroxidase-1 Knockout Mice via Attenuating Mitochondrial Burdens and Dopamine D1 Receptor Activation

Evidence indicates that stress conditions might lead to drug dependence. Recently, we have demonstrated that exposure to far infrared ray (FIR) attenuates acute restraint stress via induction of glutathione peroxidase-1 (GPx-1) gene. We investigated whether FIR affects methamphetamine (MA)-induced behavioral sensitization and whether FIR-mediated pharmacological activity requires interaction between dopamine receptor and GPx-1 gene. We observed that MA treatment significantly increased GPx-1 expression in the striatum of wild-type (WT) mice. Interestingly, exposure to FIR potentiated MA-induced increase in GPx-1 expression. This phenomenon was also observed in animals receiving MA with dopamine D1 receptor antagonist SCH23390. However, dopamine D2 receptor antagonist sulpiride did not affect MA-induced GPx-1 expression. FIR exposure or SCH23390, but not sulpiride, significantly attenuated MA-induced behavioral sensitization. Exposure to FIR significantly attenuated MA-induced dopamine D1 receptor expression, c-Fos induction and oxidative burdens. FIR-mediated antioxidant effects were also more pronounced in mitochondrial- than cytosolic-fraction. In addition, FIR significantly attenuated against MA-induced changes in mitochondrial superoxide dismutase and mitochondrial GPx activities, mitochondrial transmembrane potential, intramitochondrial Ca2+ level, mitochondrial complex-I activity, and mitochondrial oxidative burdens. The attenuation by FIR was paralleled that by SCH23390. Effects of FIR or SCH23390 were more sensitive to GPx-1 KO than WT mice, while SCH23390 treatment did not exhibit any additive effects on the protective activity mediated by FIR, indicating that dopamine D1 receptor constitutes a molecular target of FIR. Our result suggests that exposure to FIR ameliorates MA-induced behavioral sensitization via possible interaction between dopamine D1 receptor and GPx-1 gene.

Chronic Exposure to Methamphetamine Disrupts Reinforcement-Based Decision Making in Rats.

The persistent use of psychostimulant drugs, despite the detrimental outcomes associated with continued drug use, may be because of disruptions in reinforcement-learning processes that enable behavior to remain flexible and goal directed in dynamic environments. To identify the reinforcement-learning processes that are affected by chronic exposure to the psychostimulant methamphetamine (MA), the current study sought to use computational and biochemical analyses to characterize decision-making processes, assessed by probabilistic reversal learning, in rats before and after they were exposed to an escalating dose regimen of MA (or saline control). The ability of rats to use flexible and adaptive decision-making strategies following changes in stimulus-reward contingencies was significantly impaired following exposure to MA. Computational analyses of parameters that track choice and outcome behavior indicated that exposure to MA significantly impaired the ability of rats to use negative outcomes effectively. These MA-induced changes in decision making were similar to those observed in rats following administration of a dopamine D2/3 receptor antagonist. These data use computational models to provide insight into drug-induced maladaptive decision making that may ultimately identify novel targets for the treatment of psychostimulant addiction. We suggest that the disruption in utilization of negative outcomes to adaptively guide dynamic decision making is a new behavioral mechanism by which MA rigidly biases choice behavior.

Tetrahydropalmatine protects against methamphetamine-induced spatial learning and memory impairment in mice

The purpose of this study was to investigate the effect of methamphetamine (MA) on spatial learning and memory and the role of tetrahydropalmatine (THP) in MA-induced changes in these phenomena in mice. Male C57BL/6 mice were randomly divided into eight groups, according to different doses of MA, different doses of THP, treatment with both MA and THP, and saline controls. Spatial learning and memory were assessed using the Morris water maze. Western blot was used to detect the expression of extracellular signal-regulated protein kinase (ERK) in the mouse prefrontal cortex (PFC) and hippocampus. Repeated MA treatment significantly increased the escape latency in the learning phase and decreased the number of platform site crossings in the memory-test phase. ERK1/2 expression was decreased in the PFC but not in the hippocampus of the MA-treated mice. Repeated THP treatment alone did not affect the escape latency, the number of platform site crossings or the total ERK1/2 expression in the brain. Statistically significantly shorter escape latencies and more platform site crossings occurred in MA+THP-treated mice than in MA-treated mice. Repeated MA administration impairs spatial learning and memory in mice, and its co-administration with THP prevents this impairment, which is probably attributable to changed ERK1/2 expression in the PFC. This study contributes to uncovering the mechanism underlying MA abuse, and to exploring potential therapies.

Methamphetamine causes sustained depression in cerebral blood flow

The use prevalence of the highly addictive psychostimulant methamphetamine (MA) has been steadily increasing over the past decade. MA abuse has been associated with both transient and permanent alterations in cerebral blood flow (CBF), hemorrhage, cerebrovascular accidents and death. To understand MA-induced changes in CBF, we exposed C56BL/6 mice to an acute bolus of MA (5mg/kg MA, delivered IP). This elicited a biphasic CBF response, characterized by an initial transient increase (~5minutes) followed by a prolonged decrease (~30minutes) of approximately 25% relative to baseline CBF—as measured by laser Doppler flowmetry over the somatosensory cortex. To assess if this was due to catecholamine derived vasoconstriction, phentolamine, an α-adrenergic antagonist was administered prior to MA treatment. This reduced the initial increase in CBF but failed to prevent the subsequent, sustained decrease in CBF. Consistent with prior reports, MA caused a transient increase in mean arterial blood pressure, body temperature and respiratory rate. Elevated respiratory rate resulted in hypocapnia. When respiratory rate was controlled by artificially ventilating mice, blood PaCO2 levels after MA exposure remained unchanged from physiologic levels, and the MA-induced decrease in CBF was abolished. In vivo two-photon imaging of cerebral blood vessels revealed sustained MA-induced vasoconstriction of pial arterioles, consistent with laser Doppler flowmetry data. These findings show that even a single, acute exposure to MA can result in profound changes in CBF, with potentially deleterious consequences for brain function.

Role of the Serotonergic System in Reduced Pulmonary Function after Exposure to Methamphetamine

Although use of methamphetamine (MA) by smoking is the fastest growing method of administration, very limited data are available describing the effects of smoked MA. Using a murine inhalation exposure system, we explored the pulmonary effects of low-dose acute inhalation exposure to MA vapor (smoke). Inhalation of MA vapor resulted in transiently reduced pulmonary function, as measured by transpulmonary resistance, dynamic compliance, and whole-body plethysmography compared with unexposed control animals. These changes were associated with an approximately 34% reduction in serotonin (5-hydroxytryptamine [5-HT]) metabolism/inactivation to 5-hydroxyindolacetic acid, and a nearly 40% reduction in monoamine oxidase (MAO)-A activity in the lung. Pretreatment of mice with a selective 5-HT reuptake inhibitor completely ablated the MA-induced changes in pulmonary function, confirming a key role for the 5-HT transporter (serotonin transporter [SERT]) and the serotonergic system in this effect. Immunofluorescent staining of mouse lung tissue confirmed high expression of SERT in airway epithelial cells. Using mouse airway epithelial cell line, LA-4, and purified human MAO-A, it was demonstrated that MA impedes 5-HT metabolism through direct inhibition of MAO-A activity in vitro. Together, these data demonstrate that low-dose exposure to MA results in reduced pulmonary function mediated via SERT and subsequent perturbation of 5-HT metabolism in the lung. This supports a role for the serotonergic system in MA-mediated pulmonary effects.

PH sensitivity of ammonium transport by Rhbg

Rhbg, a non-erythroid glycoprotein, is localized to the basolateral membrane of renal intercalated cells and is involved in NH4+ transport. In this study we characterized the pH sensitivity of Rhbg expressed in Xenopus oocytes. We used two-electrode voltage clamp & ion-selective microelectrodes to measure NH4+currents (INH4+) & changes in pHi. In oocytes expressing Rhbg, 5mM NH4+ induced an inward INH4+ of −79 nA, decreased pHi by 0.13 at a rate of −27×10−4 pH/sec & depolarized the cell by 45 mV. These changes were significantly larger than in H2O-injected oocytes. Methyl ammonium (MA, 5 mM), often used as an NH4+ substrate, induced a current (IMA) of −63 nA in Rhbg oocytes but did not cause any change in control oocytes. Unlike NH4+, MA elicited a pHi increase but also induced a depolarization of the cell. Exposing the oocyte to MA at alkaline bath pH (8.2) enhanced both the pHi increase & IMA. Lowering bath pH to 6.5 inhibited the MA-induced changes completely. The NH4+-induced changes in pHi & current were similarly sensitive to pH. Exposing the oocyte to MA at low pHi (decreased by butyrate) abolished the MA-induced current however pHi still increased. These data indicate that: Rhbg transport of NH4+ is electrogenic. MA transport by Rhbg is both electroneutral and electrogenic. Electrogenic NH4+ and MA transport is pH sensitive. Electroneutral transport of MA by Rhbg is not affected by pH changes.

Maternal behavior is impaired by methamphetamine administered during pre-mating, gestation and lactation

Previous studies demonstrated that stimulant drugs, such as cocaine or amphetamine, administered during gestation or lactation may attenuate maternal behavior in rats. The effect of methamphetamine (MA), a drug whose usage has increased lately, on maternal behavior has not yet been investigated. The present study tested the effect of MA (5 mg/kg daily) administered prior to, during and after gestation on maternal behavior. Regularity of the estrous cycle, the incidence of impregnation, and the weight gain was compared between groups (control, saline- and MA-treated). Maternal behavior was examined using two tests: Observation test (without disturbance of the mother and pups) and Retrieval test (with short separation of pups from the mother). All tests were conducted prior to dosing each day. In the Observation test, MA decreased the blanket position of active nursing, while increasing passive nursing. There were no MA-induced changes in other maternal activities such as mother being in the nest, in contact with pups, or grooming pups. MA increased some non-maternal activities, such as drinking, eating, and sleeping, while decreasing stereotypic behavior (sniffing and rearing) when compared to controls. In the Retrieval test, MA-treated mothers were slower in retrieving the first pup, returning the first pup into the nest, and returning all pups into the nest. Interestingly, there were differences in maternal behavior also in saline-treated mothers relative to controls. Saline-treated mothers spent more time in the nest and groomed pups more than controls or MA-treated mothers. In conclusion, the present study demonstrates a novel finding that MA administered during pre-mating, gestational and lactational periods has a negative effect on maternal behavior toward pups.