Acute Methamphetamine Administration Research Articles

Effects of methamphetamine on actigraphy-based sleep parameters in female rhesus monkeys: Orexin receptor mechanisms

BackgroundThe orexin system has been implicated as a mechanism underlying insomnia and methamphetamine-induced sleep disruptions, with a potential role for OX2 receptors in the sleep-modulating effects of orexin. The aim of the present study was to investigate the extent to which orexin receptors mediate the effects of acute methamphetamine administration on actigraphy-based sleep in female rhesus monkeys. MethodsActigraphy-based sleep measures were obtained in female rhesus monkeys (n=5) under baseline and acute test conditions. First, morning (10h) i.m. injections of methamphetamine (0.03 – 0.56mg/kg) were administered to determine the effects of methamphetamine alone. Then, saline or methamphetamine (0.3mg/kg) were administered at 10h, and evening (17h30) oral treatments with vehicle, the non-selective orexin receptor antagonist suvorexant (1 – 10mg/kg, p.o.), or the OX2-selective orexin receptor antagonist MK-1064 (1 – 10mg/kg, p.o.) were given. The ability of suvorexant and MK-1064 (10mg/kg, p.o.) to improve actigraphy-based sleep was also assessed in a group of female monkeys quantitatively identified with “short-duration sleep” (n=4). ResultsMethamphetamine dose-dependently disrupted actigraphy-based sleep parameters. Treatment with either suvorexant or MK-1064 dose-dependently improved actigraphy-based sleep in monkeys treated with methamphetamine. Additionally, both suvorexant and MK-1064 promoted actigraphy-based sleep in a group of monkeys with baseline short actigraphy-based sleep. ConclusionsThese findings suggest that orexin-mediated mechanisms play a role in the effects of methamphetamine on actigraphy-based sleep in female monkeys. Targeting the orexin system, in particular OX2 receptors, could be an effective option for treating sleep disruptions observed in individuals with methamphetamine use disorder.

Heterozygous and homozygous gene knockout of the 5-HT1B receptor have different effects on methamphetamine-induced behavioral sensitization.

The psychostimulant drug methamphetamine (METH) causes euphoria in humans and locomotor hyperactivity in rodents by acting on the mesolimbic dopamine (DA) pathway and has severe abuse and addiction liability. Behavioral sensitization, an increased behavioral response to a drug with repeated administration, can persist for many months after the last administration. Research has shown that the serotonin 1B (5-HT1B) receptor plays a critical role in the development and maintenance of drug addiction, as well as other addictive behaviors. This study examined the role of 5-HT1B receptors in METH-induced locomotor sensitization using 5-HT1B knockout (KO) mice. To clarify the action of METH in 5-HT1B KO mice the effects of METH on extracellular levels of DA (DAec) and 5-HT (5-HTec) in the caudate putamen (CPu) and the nucleus accumbens (NAc) were examined. Locomotor sensitization and extracellular monoamine levels were determined in wild-type mice (5-HT1B +/+), heterozygous 5-HT1B receptor KO (5-HT1B +/-) mice and homozygous 5-HT1B receptor KO mice (5-HT1B -/-). Behavioral sensitization to METH was enhanced in 5-HT1B -/- mice compared to 5-HT1B +/+ mice but was attenuated in 5-HT1B +/- mice compared to 5-HT1B +/+ and 5-HT1B -/- mice. In vivo, microdialysis demonstrated that acute administration of METH increases DAec levels in the CPu and NAc of 5-HT1B KO mice compared to saline groups. In 5-HT1B +/- mice, METH increased 5-HTec levels in the CPu, and DAec levels in the NAc were higher than in others.5-HT1B receptors play an important role in regulating METH-induced behavioral sensitization.

Psilocin suppresses methamphetamine-induced hyperlocomotion and acquisition of conditioned place preference via D2R-mediated ERK signaling.

Psilocin is an active metabolite form of psilocybin and exerts psychoactive effects. Recent studies suggest that psilocin may have regulatory effects on abuse drugs, but the mechanisms remain unclear. In this study, we want to explore the effects of psilocin on methamphetamine (METH)-induced alterations of behavior in mice and its molecular mechanisms. Acute METH administration model and conditioned place preference (CPP) model were used to investigate the effects of psilocin on METH-induced alterations of behavior. Western blot was used to detect the expression of proteins. In the acute 2mg/kg METH administration model, 1mg/kg psilocin counteracted METH-induced elevation of activity. In the 1mg/kg METH-induced CPP model, 1mg/kg psilocin inhibited CPP formation during the acquisition phase. However, psilocin did not impact METH extinction and relapse. Molecular results showed that the regulatory effect of psilocin on METH was underscored by altered expression of dopamine 2 receptor (D2R) and phosphorylated extra-cellular signal-regulated kinase (p-ERK) in the prefrontal cortex (PFC), nucleus accumbens (NAc), and ventral tegmental area (VTA). Trifluoperazine (TFP)-2HCl is a D2R inhibitor, and SCH772984 is a selective extra-cellular signal-regulated kinase (ERK) inhibitor that effectively inhibits ERK1/2 phosphorylation. The results indicated that 2mg/kg TFP-2HCl and 10mg/kg SCH772984 blocked METH-induced hyperactivity and acquisition of METH-induced CPP. Psilocin has regulatory effects on METH-induced alterations of behavior in mice via D2R-mediated signal regulation of ERK phosphorylation.

Evidence for Dopamine Abnormalities Following Acute Methamphetamine Exposure Assessed by Neuromelanin-Sensitive Magnetic Resonance Imaging

BackgroundNeuromelanin-sensitive magnetic resonance imaging (NM-MRI) is a newly developed MRI technique that provides a non-invasive way to indirectly measure of dopamine (DA) function. This study aimed to determine NM concentrations in brain regions following acute methamphetamine (MA) administration using NM-MRI and to explore whether NM-MRI can be used as a biomarker of DA function in non-neurodegenerative diseases.MethodsBaseline NM-MRI, T1-weighted and T2-weighted images were acquired from 27 rats before drug/placebo injection. The control group (n = 11) received acute placebo (Normal saline), while the experimental group (n = 16) received acute MA. NM-MRI scans were performed 5, 30, 60 and 90 min after injection. Regions of interest (ROIs), including the caudate putamen (CP), nucleus accumbens (NAc), hippocampus (HIP), substantia nigra (SN) and crus cerebri (CC), were manually drawn by an experienced radiologist. NM-MRI signal intensity in five brain regions at different time points (baseline and 5, 30, 60, and 90 min) were analyzed.ResultsIn both the control and experimental groups, at each time point (baseline and 5, 30, 60, and 90 min), the SN exhibited significantly higher NM-MRI signal intensity than the other brain regions (P < 0.05). In addition, acute MA administration resulted in a continuous upward trend in NM-MRI signal intensity in each brain region over time. However, there was no such trend over time in the control group. The NM-MRI signal intensity of SN in the experimental group was significantly higher at the 60 and 90 min compared with that in the control group (P values were 0.042 and 0.042 respectively). Within experimental group, the NM-MRI signal intensity of SN was significantly higher at the 60 and 90 min compared with that before MA administration (P values were 0.023 and 0.011 respectively). Increased amplitudes and rates of NM-MRI signal intensity were higher in the SN than in other brain regions after MA administration.ConclusionOur results indicated that NM was mainly deposited in the SN, and the conversion of DA to NM was most significant in the SN after acute MA exposure. Increased DA release induced by acute MA exposure may lead to increased accumulation of NM in multiple brain regions that can be revealed by NM-MRI. NM-MRI may serve as a powerful imaging tool that could have diverse research and clinical applications for detecting pathological changes in drug addiction and related non-neurodegenerative diseases.

W85. GENDER DIFFERENCES IN THE ASSOCIATION OF POLYMORPHIC VARIANTS OF THE 5-HT2C RECEPTOR GENE AND ANTIPSYCHOTIC-INDUCED HYPERPROLACTINEMIA IN PATIENTS WITH SCHIZOPHRENIA

Methamphetamine (METH) is a stimulant of the central nervous system (CNS) that causes behavioral changes in users. METH is slowly cleared from brain tissue and its chronic use is neurotoxic. METH also alters the cellular and chemical components of inflammation. However, little is known about the effect of a single intravenous dose of METH followed by bacterial lipopolysaccharide (LPS) injection on cellular infiltration and cytokine release in brain tissue. Using a murine model of acute METH administration and flow cytometry, we found that combination of METH and LPS stimulate the infiltration of macrophages (F4/80+ cells) and neutrophils (Ly-6G+ cells) into the CNS. Histological sections of the brainstem of METH-treated and LPS-challenged C57BL/6 mice demonstrated considerable leukocyte infiltration relative to untreated, LPS, and METH groups. Moreover, rodents treated with LPS alone or combined with METH showed elevated levels of pro-inflammatory cytokines mRNA in brain tissue. Our observations are important because recognizing neuroinflammatory changes after acute METH administration might help us to understand METH-induced neurotoxicity in users.

D1R/PP2A/p-CaMKIIα signaling in the caudate putamen is involved in acute methamphetamine-induced hyperlocomotion

Drug addiction is underscored by the transition from experimental use to dependent use of addictive drugs. Acute use of methamphetamine (METH) causes a range of clinical symptoms, including hyperlocomotion. Dopamine D1 receptor (D1R)-mediated negative regulation of phosphorylated calcium/calmodulin-dependent protein kinase IIα (p-CaMKIIα, threonine [Thr] 286) is involved in the acute effects induced by single METH administration. Protein phosphatase 2A (PP2A) is a potential bridge that links D1R and p-CaMKIIα (Thr 286) after acute METH administration. However, the mechanisms underlying hyperlocomotion induced by single METH administration remain unclear. In this study, SCH23390 (a D1R inhibitor) and LB100 (a PP2A inhibitor) were administered to examine the involvement of D1R and PP2A signaling in acute METH-induced hyperlocomotion in mice. The protein levels of methylated PP2A-C (m-PP2A-C, leucine [Leu] 309), phosphorylated PP2A-C (p-PP2A-C, tyrosine [Tyr] 307), PP2A-C, p-CaMKIIα (Thr 286), and CaMKIIα in the prefrontal cortex (PFc), nucleus accumbens (NAc), and caudate putamen (CPu) were measured. Administration of 0.5 mg/kg SCH23390 reversed the acute METH-induced increase in protein levels of m-PP2A-C (Leu 309) and the decrease in protein levels of p-PP2A-C (Tyr 307) in the CPu, but not in the PFC and NAc. Moreover, prior administration of 0.1 mg/kg LB100 attenuated hyperlocomotion induced by single METH administration and reversed the decrease in protein levels of p-CaMKII (Thr 286) in the PFC, NAc, and CPu. Collectively, these results indicate that the D1R/PP2A/p-CaMKIIα signaling cascade in the CPu may be involved in hyperlocomotion after a single administration of METH.

Perinatal Stress and Methamphetamine Exposure Decreases Anxiety-Like Behavior in Adult Male Rats.

Methamphetamine (MA) is an illicit synthetic psychostimulant drug, and its abuse is growing worldwide. MA has been reported as the primary drug of choice, by drug-abusing women, during pregnancy. Since MA easily crosses the placental barrier, the fetus is exposed to MA in a similar fashion to the mother. This study aimed to evaluate the effect of long-term perinatal stressors and drug exposure on anxiety-like behavior in adult male rats using the open field test (OF) and elevated plus maze (EPM). Dams were divided into three groups according to drug treatment during pregnancy: controls (C), saline—SA [subcutaneous (s.c.), 1 ml/kg], and MA (s.c., 5 mg/kg). Litters were divided into four groups according to postnatal stressors: non-stressed controls (N), maternal separation (S), maternal cold water stress (W), and maternal separation plus maternal cold water stress (SW). Forty-five minutes before testing (in both OF and EPM), one-half of adult male rats received an (s.c.) injection of MA and the other half received an SA injection. Prenatal MA/stress exposure did not affect anxiety-like behavior in adult male rats in both tests. In the OF, an acute MA dose in adulthood increased the time spent in the central disk area, decreased time spent in the corners, and decreased time spent immobile and grooming. Also, postnatal stress increased time spent in the central disk area, decreased time spent in corners, and increased mobility compared to controls. All groups of rats exposed to postnatal stressors spent significantly less time in the closed arms of the EPM compared to controls. Overall, our results indicate that early postnatal stress and a single acute MA administration in adulthood decreases the parameters of anxiety-like behavior in adult male rats regardless of prenatal MA exposure. Moreover, postnatal stress via maternal separation impacts the effect of acute MA administration in adulthood. Long-term postnatal stress may thus result in improved adaptation to subsequent stressful experiences later in life.

Regulation of miR-128 in the nucleus accumbens affects methamphetamine-induced behavioral sensitization by modulating proteins involved in neuroplasticity.

Methamphetamine (METH) -induced behavioral sensitization depends on long-term neuroplasticity in the mesolimbic dopamine system, especially in the nucleus accumbens (NAc). miR-128, a brain enriched miRNA, was found to have abilities in regulating neuronal excitability and formation of fear-extinction memory. Here, we aim to identify the role of miR-128 on METH-induced locomotor sensitization of male mice. We identified a significant increase of miR-128 in the NAc of mice upon repeated-intermittent METH exposure but not acute METH administration. Microinjection of adeno-associated virus (AAV)-miR-128 over-expression and inhibition constructs into the NAc of mice resulted in enhanced METH-induced locomotor sensitization and attenuated effects of METH respectively. Isobaric tags for relative and absolute quantification (iTRAQ) technology and ingenuity pathway analysis (IPA) were carried out to uncover the potential molecular mechanisms underlying miR-128-regulated METH sensitization. Differentially expressed proteins, including 25 potential targets for miR-128 were annotated in regulatory pathways that modulate dendritic spines, synaptic transmission and neuritogenesis. Of which, Arf6, Cpeb3 and Nlgn1, were found to be participating in miR-128-regulated METH sensitization. Consistently, METH-induced abnormal changes of Arf6, Cpeb3 and Nlgn1 in the NAc of mice were also detected by qPCR and validated by western blot analysis. Thus, miR-128 may contribute to METH sensitization through controlling neuroplasticity. Our study suggested miR-128 was an important regulator of METH- induced sensitization and also provided the potential molecular networks of miR-128 in regulating METH-induced sensitization.

Role of the central amygdala in acupuncture inhibition of methamphetamine-induced behaviors in rats.

Methamphetamine (METH) enhances dopamine (DA) transmission in the mesolimbic system implicated in its reinforcing effects. Our previous studies have shown that acupuncture attenuates drug-seeking behaviors by modulating GABAergic transmission in the ventral tegmental area and DA release in the nucleus accumbens (NAc) of the striatum. The effects of acupuncture on METH-induced behaviors and its mediation by neural pathways remain a relatively understudied area of research. The central amygdala (CeA) plays a critical role in physiological and behavioral responses to somatosensory and drug stimuli and has been implicated in negative reinforcement. Thus, we evaluated the role of the CeA in acupuncture effects on locomotor activity, positive affective states, and DA release in the NAc following acute administration of METH. Acupuncture at acupoint HT7 reduced locomotor activity, 50-kHz ultrasonic vocalizations (USVs), and NAc DA release following systemic injection of METH, which was prevented by electrolytic lesions or optogenetic inhibition of the CeA. Acupuncture alone excited CeA neurons and reversed the suppression of CeA neurons induced by METH. These results suggest that acupuncture can relieve psychomotor responses and positive affective states following METH by inhibiting NAc DA release and this effect is mediated by activation of CeA neurons.

Combination of acute intravenous methamphetamine injection and LPS challenge facilitate leukocyte infiltration into the central nervous system of C57BL/6 mice

Methamphetamine (METH) is a stimulant of the central nervous system (CNS) that causes behavioral changes in users. METH is slowly cleared from brain tissue and its chronic use is neurotoxic. METH also alters the cellular and chemical components of inflammation. However, little is known about the effect of a single intravenous dose of METH followed by bacterial lipopolysaccharide (LPS) injection on cellular infiltration and cytokine release in brain tissue. Using a murine model of acute METH administration and flow cytometry, we found that combination of METH and LPS stimulate the infiltration of macrophages (F4/80+cells) and neutrophils (Ly-6G+cells) into the CNS. Histological sections of the brainstem of METH-treated and LPS-challenged C57BL/6 mice demonstrated considerable leukocyte infiltration relative to untreated, LPS, and METH groups. Moreover, rodents treated with LPS alone or combined with METH showed elevated levels of pro-inflammatory cytokines mRNA in brain tissue. Our observations are important because recognizing neuroinflammatory changes after acute METH administration might help us to understand METH-induced neurotoxicity in users.

Melatonin pretreatment attenuates acute methamphetamine-induced aggression in male ICR mice

Aggression is one of the symptoms of methamphetamine (MA) use and withdrawal, which can exacerbate MA addiction and relapse. Many studies have demonstrated that poor sleep is significantly associated with aggression. Melatonin has been indicated to be effective in treating sleep disorders induced by MA, and it can also protect neuronal cells against MA-induced neurotoxicity. However, the underlying effects of melatonin on MA-reduced aggression remain unclarified. This study was designed to evaluate the effects of melatonin on acute MA-induced aggressive behavior in male ICR mice and the effects on neurotransmitters related to aggression. Fifty male ICR mice were randomly assigned to control and treatment groups pretreated with MA (3 mg/kg) or melatonin (2.5, 5, 10 mg/kg) plus MA. Aggressive behaviors were observed through isolation-induced aggression in the resident-intruder model. High-performance liquid chromatography combined with electrochemical detection (HPLC-ECD) was used to anatomize the levels of dopamine (DA) and its metabolites, 3,4-dihydroxyphenyl acetic acid (DOPAC) and homovanillic acid (HVA), and the concentrations of serotonin (5-HT) and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA), in the hippocampus involved in behavior processing. The results showed that acute MA administration decreased latency to initial attacks and thereby increased the number and total duration of attacks. Furthermore, HVA level as well as 5-HIAA and 5-HT turnover estimated by 5-HIAA/5-HT ratios declined compared to those in the vehicle group. The medium melatonin pretreatment dose (5 mg/kg) could significantly reverse acute MA-induced aggressive behavior in the form of prolonging latency to initial attacks and thereby attenuating the number of attacks and total duration of attacks. HVA and 5-HIAA levels, 5-HT turnover estimated by 5-HIAA/5-HT ratios, and DA turnover estimated by HVA/DA ratios and (DOPAC + HVA)/DA ratios were elevated compared to those in the MA group. These results indicate that the DA and 5-HT systems are involved in the processes of MA-induced aggressive behaviors and that melatonin has the capacity to reverse MA-induced aggressive behaviors.

AAV‐7F9‐Fc Protects Against METH‐Induced Hyperthermia and Decreases in Blood Brain Barrier Tight Junction Expression in a Rodent Model

Methamphetamine (METH) is a potent psychostimulant, with no FDA‐approved pharmacological treatment options. METH can adversely affect brain homeostasis by initiating dysfunction in the Blood Brain Barrier (BBB) and hyperthermia. The BBB is a semipermeable barrier composed of endothelial cells and pericytes along blood capillaries. These cells are held together by tight junction (TJ) proteins (e.g., claudin‐5, occludin, etc) which limit paracellular transport and help regulate body temperature. METH can decrease the expression of these TJ proteins and induce hyperthermia leading to BBB dysfunction. Thus, a novel therapy that could mitigate these effects is needed.A novel treatment under evaluation in our laboratory is an anti‐METH single chain variable antibody‐fusion antibody (7F9‐Fc) packaged into adeno‐associated virus (AAV8) particles. AAV‐7F9‐Fc works as a pharmacokinetic antagonist to slow and reduce entry of METH into the brain. AAV‐7F9‐Fc has achieved long‐term serum concentrations in mice (&gt;7 months from a single dose) and has been shown to alter locomotor effects of METH in mice. This treatment could have clinical potential to attenuate the effects of METH during drug use and aid addiction recovery.We hypothesized that an AAV delivered anti‐METH antibody fragment (AAV‐7F9‐Fc) will mitigate METH‐induced hyperthermia and BBB dysfunction. To begin to test this hypothesis, we recorded baseline temperatures of mice 1 h before administration of either saline or METH (10 mg/kg). Male BALB/c mice were randomized into one of five groups (n=5/group); 1) Saline + Saline, 2) Saline + METH, 3) AAV‐7F9‐Fc + Saline, 4) AAV‐7F9‐Fc + METH, 5) AAV‐empty vector + saline. After administration of either Saline or METH, rectal temperatures were probed for 1 h, and brains were collected at the 3 h time point. Brains were dissected on dry ice into key dopaminergic regions such as the Frontal Cortex and Hippocampus. After dissection, proteins were extracted via RIPA buffer and analyzed for their expression by Western Blot. In Saline+METH treated mice, a 40% decrease in expression of Claudin‐5 and a 45% decrease in expression of Occludin (p &lt; 0.05) were observed in the Frontal Cortex. These results were mitigated in AAV‐7F9‐Fc + METH mice in the Frontal Cortex and Hippocampus. These results indicate two important findings in an acute setting. This indicates that AAV‐7F9‐Fc has the potential to mitigate in an acute administration of METH, 1). the ability of METH to induce Hyperthermia, and 2). cause a reduction of critical tight junction protein expression in the CNS.Support or Funding InformationThis research was funded by NIH/NIDA:R01‐DA036600 &amp; R01 DA036600‐03S1, NIH/NIGMS:T32‐GM106999, and R25GM083297.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Different Oxytocin Responses to Acute Methamphetamine Treatment in Juvenile Female Rats Perinatally Exposed to Stress and/or Methamphetamine Administration.

Methamphetamine (MA) is an addictive psychostimulant, often abused by drug-addicted women during pregnancy. The offspring of drug-addicted mothers are often exposed to perinatal stressors. The present study examines the effect of perinatal stressors and drug exposure on plasma oxytocin (OXY) levels in female progeny. Rat mothers were divided into three groups according to drug treatment during pregnancy: intact controls (C); saline (SA, s.c., 1 ml/kg); and MA (s.c., 5 mg/kg). Litters were divided into four groups according to postnatal stressors lasting from PD1 to 21: non-stressed controls (N); maternal separation (S); maternal cold-water stress (W); and maternal separation plus cold-water stress (SW). On postnatal day 30, acute MA or SA was administrated 1 h before the rats were sacrificed. Trunk blood was collected and plasma OXY was measured by specific ELISA after extraction. Our results showed that acute MA administration significantly increases plasma OXY levels in juvenile female rats; this effect was observed in prenatally intact rats only. Prenatal exposure of rats to mild stressor of daily SA injection prevented both acute MA-induced OXY stimulation and also stress-induced OXY inhibition. Although postnatal MA and stress exposure exert opposite effects on OXY release in juvenile rats, our data point out the modulatory role of prenatal mild stress in OXY response to postnatal stressors or MA treatment.

Regulation of microRNA-29c in the nucleus accumbens modulates methamphetamine -induced locomotor sensitization in mice

Changes in microRNA (miRNA)-mediated gene expression in the nucleus accumbens (NAc) may play important roles in regulating drug addiction. MiR-29c is a highly expressed miRNA in the human and rodent nervous systems where it plays a broad regulatory role. As the first step towards investigating potential functions of miR-29c in methamphetamine (METH) addiction, we used C57BL/6 mice in a model of METH-induced locomotor sensitization. We measured miR-29c expression changes in the NAc of the mice after repeated-intermittent METH exposure and acute METH administration respectively by using quantitative real-time PCR (qPCR). We found that miR-29c expression was significantly down-regulated in the NAc of METH-sensitized mice but not in the acute METH-treated mice. Then, we tested the respective effects of miR-29c over-expression and inhibition in the NAc on METH-induced locomotor sensitization. To reach this goal, we constructed adeno-associated virus (AAV)-expressing miR-29c (AAV-miR-29c) and its corresponding inhibitor - tough decoy (AAV-anti-miR-29c TuD) to over-express and inhibit miR-29c, respectively. We found that AAV-miR-29c over-expression in the NAc enhanced METH-induced locomotor sensitization, whereas AAV inhibition of miR-29c expression in the NAc attenuated the effects of METH. Moreover, we observed the participation of Dnmt3a, Dnmt3b, and Meg3 in the effects of miR-29c on METH sensitization. Our results suggest that miR-29c is an important epigenetic regulator of METH-induced behavioural sensitization and changes in gene expression. These data further suggest a potential role of miR-29c in regulating long-term METH-induced adaptation in the brain.

Acute methamphetamine administration impairs cognitive function in a mouse model of schizophrenia with both of CNV and SNV in ARHGAP10 gene that confer high risk of schizophrenia with severe clinical symptoms.

Acute methamphetamine administration impairs cognitive function in a mouse model of schizophrenia with both of CNV and SNV in ARHGAP10 gene that confer high risk of schizophrenia with severe clinical symptoms.

Untargeted Metabolomic Analysis of Rat Neuroblastoma Cells as a Model System to Study the Biochemical Effects of the Acute Administration of Methamphetamine.

Methamphetamine is an illicit psychostimulant drug that is linked to a number of diseases of the nervous system. The downstream biochemical effects of its primary mechanisms are not well understood, and the objective of this study was to investigate whether untargeted metabolomic analysis of an in vitro model could generate data relevant to what is already known about this drug. Rat B50 neuroblastoma cells were treated with 1 mM methamphetamine for 48 h, and both intracellular and extracellular metabolites were profiled using gas chromatography–mass spectrometry. Principal component analysis of the data identified 35 metabolites that contributed most to the difference in metabolite profiles. Of these metabolites, the most notable changes were in amino acids, with significant increases observed in glutamate, aspartate and methionine, and decreases in phenylalanine and serine. The data demonstrated that glutamate release and, subsequently, excitotoxicity and oxidative stress were important in the response of the neuronal cell to methamphetamine. Following this, the cells appeared to engage amino acid-based mechanisms to reduce glutamate levels. The potential of untargeted metabolomic analysis has been highlighted, as it has generated biochemically relevant data and identified pathways significantly affected by methamphetamine. This combination of technologies has clear uses as a model for the study of neuronal toxicology.

Effect of Pentoxifylline on Apoptosis of Kidney’s Cells Following Acute Methamphetamine Administration in Male Wistar Rats

Objective(s): Methylenedioxymethamphetamine (MDMA) is a hallucinogenic drug of abuse which is the most popular drugs in the world and has been shown to induce apoptosis in kidney cells. As Pentoxifylline (PTX) increases cAMP and reduces tumor necrosis factor-α, the present study aimed to investigate the effects of pentoxifylline on kidney damage induced by acute administration of MDMA in male rat.&#x0D; Materials &amp; methods: Thirty male rats (250-300 g) were randomly divided into five groups: including control (without any intervention), MDMA group ,the group received 7.5 mg/kg MDMA three times at every two hours for one day ,first experimental group, received 100 mg/kg PTX a week before MDMA administration, second experimental group received 100 mg/kg PTX Just in the time of the third injection of MDMA and the third experimental group received 100 mg/kg PTX followed by one dose of MDMA. Two weeks later, kidneys were removed and prepared for H&amp;E staining, TUNEL and western blot techniques. &#x0D; Results: histopathological studies showed significantly decrease in the kidney cellular damage, in experimental group 1 compared to MDMA group. The number of TUNEL-positive cells was increased significantly in MDMA group. A significant difference was revealed in the mean number of TUNEL-positive cells between the rats treated with PTX before MDMA administration and MDMA group. Expression of active caspase-3 was significantly increased in the MDMA group. While the PTX treatment could significantly decrease when administrated before MDMA injections.&#x0D; Conclusion: Pentoxifylline can significantly reduce the severity of lesions in the kidney following administration of MDMA.

GABAergic mRNA expression is differentially expressed across the prelimbic and orbitofrontal cortices of rats sensitized to methamphetamine: Relevance to psychosis

Psychotic disorders, such as schizophrenia, are characterized by prevalent and persistent executive deficits that are believed to be the result of dysfunctional inhibitory gamma-aminobutyric acid (GABA) processing of the prefrontal cortex (PFC). Methamphetamine (METH) is a commonly used psychostimulant that can induce psychotic and cognitive symptoms that are indistinguishable to schizophrenia, suggesting that METH-induced psychosis may have a similar GABAergic profile of the PFC. As the PFC consists of multiple subregions, the aim of the current study was to investigate changes to GABAergic mRNA expression in the prelimbic (PRL) and orbitofrontal (OFC) cortices of the PFC in rats sensitized to repeated METH administration. Male Sprague Dawley rats underwent daily METH or saline injections for 7 days. Following 14 days of withdrawal, rats were challenged with acute METH administration, RNA was isolated from the PRL and OFC and quantitative PCR was used to compare the relative expression of GABA enzymes, transporters, metabolites and receptor subunits. GAD67, GAD65, GAT1, GAT3, VGAT and GABAT mRNA expression were upregulated in the PRL. Ionotropic GABAA receptor subunits α1, α3, α5 and β2 were specifically upregulated in the OFC. These findings suggest that alterations to GABAergic mRNA expression following sensitization to METH are biologically dissociated between the OFC and PRL, suggesting that GABAergic gene expression is significantly altered following chronic METH exposure in a brain-region and GABA-specific manner. These changes may lead to profound consequences on central inhibitory mechanisms of localized regions of the PFC and may underpin common behavioral phenotypes seen across psychotic disorders.

Effects of acute and chronic systemic methamphetamine on respiratory, cardiovascular and metabolic function, and cardiorespiratory reflexes.

Methamphetamine (METH) abuse is escalating worldwide, with the most common cause of death resulting from cardiovascular failure and hyperthermia; however, the underlying physiological mechanisms are poorly understood. Systemic administration of METH in anaesthetised rats reduced the effectiveness of some protective cardiorespiratory reflexes, increased central respiratory activity independently of metabolic function, and increased heart rate, metabolism and respiration in a pattern indicating that non-shivering thermogenesis contributes to the well-described hyperthermia. In animals that showed METH-induced behavioural sensitisation following chronic METH treatment, no changes were evident in baseline cardiovascular, respiratory and metabolic measures and the METH-evoked effects in these parameters were similar to those seen in saline-treated or drug naïve animals. Physiological effects evoked by METH were retained but were neither facilitated nor depressed following chronic treatment with METH. These data highlight and identify potential mechanisms for targeted intervention in patients vulnerable to METH overdose. Methamphetamine (METH) is known to promote cardiovascular failure or life-threatening hyperthermia; however, there is still limited understanding of the mechanisms responsible for evoking the physiological changes. In this study, we systematically determined the effects on both autonomic and respiratory outflows, as well as reflex function, following acute and repeated administration of METH, which enhances behavioural responses. Arterial pressure, heart rate, phrenic nerve discharge amplitude and frequency, lumbar and splanchnic sympathetic nerve discharge, interscapular brown adipose tissue and core temperatures, and expired CO2 were measured in urethane-anaesthetised male Sprague-Dawley rats. Novel findings include potent increases in central inspiratory drive and frequency that are not dependent on METH-evoked increases in expired CO2 levels. Increases in non-shivering thermogenesis correlate with well-described increases in body temperature and heart rate. Unexpectedly, METH evoked minor effects on both sympathetic outflows and mean arterial pressure. METH modified cardiorespiratory reflex function in response to hypoxia, hypercapnia and baroreceptor unloading. Chronically METH-treated rats failed to exhibit changes in baseline sympathetic, cardiovascular, respiratory and metabolic parameters. The tonic and reflex cardiovascular, respiratory and metabolic responses to METH challenge were similar to those seen in saline-treated and drug naive animals. Overall, these findings describe independent and compound associations between physiological systems evoked by METH and serve to highlight that a single dose of METH can significantly impact basic homeostatic systems and protective functions. These effects of METH persist even following chronic METH treatment.

L-Scoulerine attenuates behavioural changes induced by methamphetamine in zebrafish and mice

Methamphetamine (METH), a substance with a high potential for abuse and addiction, is a serious worldwide public health problem. METH addicts often show extreme paranoia, anxiety, and depression. Thus, there is no effective medication for the treatment of METH-induced abnormalities. In the present study, we investigated the effects of l-Scoulerine (l-SLR), a tetrahydroprotoberberine (THPBS) alkaloid, on METH-induced anxiety-like behaviour in zebrafish and METH-induced addictive behavior in mice. In the novel tank test, acute administration of METH (2mg/L) induced a significant decrease in the number of total vertical transitions and time spent in the upper zone. Moreover, METH produced significant avoidance behaviour showing increased swimming time in the central area and high speed movement in the mirror area in the mirror stimulation test; these anxiety-like changes were attenuated by l-SLR. Chronic administration of METH (2mg/kg) produced a steady increase in locomotor activity and conditioned place preference in mice. l–SLR (5mg/kg) failed to reduce acute METH-induced hyperlocomotion, but attenuated chronic METH-induced behavioural sensitization and significantly blocked the expression of conditioned place preference induced by METH in mice. The present study suggests that l-SLR may be a promising agent for the treatment of addiction and anxiety induced by METH.