High-dose Methamphetamine Research Articles

Out the Gate: Towards a Rhizomatic Understanding of Methamphetamine Use in Aotearoa-New Zealand

As part of an interview-based qualitative study on the life-course of people who formally used methamphetamine in Aotearoa-New Zealand, this paper uses Deleuze and Guattari's rhizomatic perspective to trace the specific effects and particular relations involved in methamphetamine use. The methamphetamine-using trajectory for the 42 former users is a multifaceted and constantly fluctuating process involving multiple entries, exists, pathways, and restarts. By amplifying and enlightening the user, methamphetamine use begins by liberating desire through sending the user “out the gate,” but long-term high-dose use can end up constraining and repressing subjectivity and cyclically producing adverse psychological, emotional, interpersonal, and social effects. As a metamorphic process that produces transformative change, long-term high-dose methamphetamine use is a nonlinear rollercoaster ride that typically leads to a downward spiral whereby life stagnates, shrinks, or regresses. By undermining productive and transformative connections, the life of the long-term high-dose methamphetamine user typically—but not inevitably—involves revolving instead of evolving. Against a linear and deterministic popular media-generated narrative about methamphetamine use, a rhizomatic perspective emphasizes the potential for transformation by focusing upon the situational and interactional processes involved in users who undergo complex and varied temporary changes. From Deleuze and Guattari's perspective, disentangling from long-term high-dose methamphetamine use requires activating new relationships and possibilities for desire by forming meaningful biopsychosocial connections.

Effects of Multiple High-Dose Methamphetamine Administration on Enteric Dopaminergic Neurons and Intestinal Motility in the Rat Model.

Several studies have identified the effects of methamphetamine (MA) on central dopaminergic neurons, but its effects on enteric dopaminergic neurons (EDNs) are unclear. The aim of this study was to investigate the effects of MA on EDNs and intestinal motility. Male Sprague-Dawley rats were randomly divided into MA group and saline group. The MA group received the multiple high-dose MA treatment paradigm, while the controls received the same saline treatment. After enteric motility was assessed, different intestinal segments (i.e., duodenum, jejunum, ileum, and colon) were taken for histopathological, molecular biological, and immunological analysis. The EDNs were assessed by measuring the expression of two dopaminergic neuronal markers, dopamine transporter (DAT) and tyrosine hydroxylase (TH), at the transcriptional and protein levels. We also used c-Fos protein, a marker of neural activity, to detect the activation of EDNs. MA resulted in a significant reduction in TH and DAT mRNA expression as well as in the number of EDNs in the duodenum and jejunum (p < 0.05). MA caused a dramatic increase in c-Fos expression of EDNs in the ileum (p < 0.001). The positional variability of MA effects on EDNs paralleled the positional variability of its effect on intestinal motility, as evidenced by the marked inhibitory effect of MA on small intestinal motility (p < 0.0001). This study found significant effects of MA on EDNs with locational variability, which might be relevant to locational variability in the potential effects of MA on intestinal functions, such as motility.

Effects of adolescent methylphenidate administration on methamphetamine conditioned place preference in an animal model of attention-deficit/hyperactivity disorder: Examination of potential sex differences

BackgroundIndividuals with attention-deficit/hyperactivity disorder (ADHD) are more likely to be diagnosed with a substance use disorder; however, the effects of long-term psychostimulant treatment on addiction are mixed. Preclinical studies are useful for further elucidating the relationship between ADHD and addiction-like behaviors, but these studies have focused on male subjects only. The goal of the current study was to determine if early-life administration of methylphenidate (MPH) augments methamphetamine (METH) conditioned place preference (CPP) and/or potentiates reinstatement of CPP in both male and female rats. MethodsMale and female spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats (WKYs) received either MPH (1.5mg/kg; p.o.) or vehicle (1.0ml/kg) during adolescence (postnatal day [PND] ~29–57). Two weeks after cessation of MPH treatment, rats were tested for METH CPP (1.0mg/kg or 2.0mg/kg; s.c.). Rats were then given extinction sessions. Once rats met extinction criteria, they were tested for reinstatement of CPP following a priming injection of METH (0.25mg/kg; s.c.). ResultsAll groups developed METH CPP, except vehicle-treated SHR males and vehicle-treated WKY females conditioned with the higher dose of METH (2.0mg/kg). Female SHRs treated with MPH showed greater reinstatement of METH CPP compared to female SHRs treated with vehicle. Adolescent MPH treatment did not augment the locomotor-stimulant effects of METH in adulthood. ConclusionsThese results demonstrate the importance of considering biological sex when prescribing psychostimulant medications for ADHD as long-term MPH administration may increase the risk of continued drug use in females with ADHD following a period of abstinence.

Low and high dose methamphetamine differentially regulate synaptic structural plasticity in cortex and hippocampus.

Psychostimulants, such as methamphetamine (METH) can induce structural remodeling of synapses by remodeling presynaptic and postsynaptic morphology. Escalating or long-lasting high dose METH accounts for neurodegeneration by targeting multiple neurotransmitters. However, the effects of low dose METH on synaptic structure and the modulation mechanism remain elusive. This study aims to assess the effects of low dose (2 mg/kg) and high dose (10 mg/kg) of METH on synaptic structure alternation in hippocampus and prefrontal cortex (PFC) and to reveal the underlying mechanism involved in the process. Low dose METH promoted spine formation, synaptic number increase, post-synaptic density length elongation, and memory function. High dose of METH induced synaptic degeneration, neuronal number loss and memory impairment. Moreover, high dose, but not low dose, of METH caused gliosis in PFC and hippocampus. Mechanism-wise, low dose METH inactivated ras-related C3 botulinum toxin substrate 1 (Rac1) and activated cell division control protein 42 homolog (Cdc42); whereas high dose METH inactivated Cdc42 and activated Rac1. We provided evidence that low and high doses of METH differentially regulate synaptic plasticity in cortex and hippocampus.

The neuroprotective role of melatonin against methamphetamine toxicity-induced neurotransmission dysregulation and cognitive deficits in rats

Methamphetamine (MA) is a psychostimulant and addictive substance. Long-term uses and toxic high doses of MA can induce neurotoxicity. The present study aimed to investigate the protective role of melatonin against MA toxicity-induced dysregulation of the neurotransmission related to cognitive function in rats. The adult male Sprague Dawley rats were intraperitoneally injected with 5 mg/kg MA for 7 consecutive days with or without subcutaneously injected with 10 mg/kg melatonin before MA injection. Some rats were injected with saline solution (control) or 10 mg/kg melatonin. MA administration induced reduction in total weight gain, neurotoxic features of stereotyped behaviors, deficits in cognitive flexibility, and significantly increased lipid peroxidation in the brain which diminished in melatonin pretreatment. The neurotoxic effect of MA on glutamate, dopamine and GABA transmitters was represented by the alteration of the GluR1, DARPP-32 and parvalbumin (PV) levels, respectively. A significant decrease in the GluR1 was observed in the prefrontal cortex of MA administration in rats. MA administration significantly increased the DARPP-32 but decreased PV in the striatum. Pretreatment of melatonin can abolish the neurotoxic effect of MA on neurotransmission dysregulation. These findings might reveal the antioxidative role of melatonin to restore neurotransmission dysregulation related to cognitive deficits in MA-induced neurotoxicity.

Parkin-deficient rats are resistant to neurotoxicity of chronic high-dose methamphetamine

Methamphetamine (METH) is a highly addictive and powerful central nervous system psychostimulant with no FDA-approved pharmacotherapy. Parkin is a neuroprotective protein and its loss of function contributes to Parkinson’s disease. This study used 3-month-old homozygous parkin knockout (PKO) rats to determine whether loss of parkin protein potentiates neurotoxicity of chronic METH to the nigrostriatal dopamine pathway. PKO rats were chronically treated with 10 mg/kg METH for 10 consecutive days and assessed for neurotoxicity markers in the striatum on the 5th and 10th day of withdrawal from METH. The PKO rats showed higher METH-induced hyperthermia; however, they did not display augmented deficits in dopaminergic and serotonergic neurotoxicity markers, astrocyte activation or decreased mitochondrial enzyme levels as compared to wild-type (WT) rats. Interestingly, saline-treated PKO rats had lower levels of dopamine (DA) as well as mitochondrial complex I and II levels while having increased basal levels of glial fibrillary acidic protein (GFAP), a marker of gliosis. These results indicate PKO display a certain resistance to METH neurotoxicity, possibly mediated by lowered DA levels and downregulated mitochondria.

Parkin regulates drug-taking behavior in rat model of methamphetamine use disorder

There is no FDA-approved medication for methamphetamine (METH) use disorder. New therapeutic approaches are needed, especially for people who use METH heavily and are at high risk for overdose. This study used genetically engineered rats to evaluate PARKIN as a potential target for METH use disorder. PARKIN knockout, PARKIN-overexpressing, and wild-type young adult male Long Evans rats were trained to self-administer high doses of METH using an extended-access METH self-administration paradigm. Reinforcing/rewarding properties of METH were assessed by quantifying drug-taking behavior and time spent in a METH-paired environment. PARKIN knockout rats self-administered more METH and spent more time in the METH-paired environment than wild-type rats. Wild-type rats overexpressing PARKIN self-administered less METH and spent less time in the METH-paired environment. PARKIN knockout rats overexpressing PARKIN self-administered less METH during the first half of drug self-administration days than PARKIN-deficient rats. The results indicate that rats with PARKIN excess or PARKIN deficit are useful models for studying neural substrates underlying “resilience” or vulnerability to METH use disorder and identify PARKIN as a novel potential drug target to treat heavy use of METH.

The acute effects of multiple doses of methamphetamine on locomotor activity and anxiety-like behavior in adolescent and adult mice

Methamphetamine (MA) is a highly addictive psychomotor stimulant drug. Research has shown that the acute effects of MA can be modulated by age, although previous findings from our lab do not find age differences in the effects of MA. Relatively little research has examined the effects of adolescent MA exposure; thus, it is important to understand how MA affects adolescent behavior and brain function compared to adults. In order to better understand the age differences in the effects of acute MA exposure, this research examined the effects of MA exposure on locomotor and anxiety-like behavior and plasma corticosterone levels in adolescent and adult C57BL/6 J mice. Mice were exposed to saline, 2 mg/kg MA, or 4 mg/kg MA and behavior was measured in the open field test. Immediately following behavioral testing, serum was collected, and plasma corticosterone levels were measured. MA-exposed mice showed increased locomotor activity and anxiety-like behavior compared to saline controls, regardless of age and dose of MA. However, adolescent mice showed the greatest locomotor response to the high dose of MA (4 mg/kg), whereas the adult mice showed the greatest locomotor response to the low dose of MA (2 mg/kg). There were no differences in stereotyped behavior between the adolescent and adult mice exposed to the low dose of MA (2 mg/kg) and the high dose of MA (4 mg/kg). There was no effect of MA exposure on plasma corticosterone levels. These data suggest age modulates the locomotor response to MA and further research is warranted to determine the developmental neurobiological mechanism underlying the dose-response age differences in the response to acute MA exposure.

Differential Responses of LINE-1 in the Dentate Gyrus, Striatum and Prefrontal Cortex to Chronic Neurotoxic Methamphetamine: A Study in Rat Brain.

Methamphetamine (METH) is a widely abused psychostimulant with the potential to cause a broad range of severe cognitive deficits as well as neurobehavioral abnormalities when abused chronically, particularly at high doses. Cognitive deficits are related to METH neurotoxicity in the striatum and hippocampus. The activation of transposable Long INterspersed Nuclear Element 1 (LINE-1) is associated with several neurological diseases and drug abuse, but there are very limited data regarding the effects of high-dose METH on the activity of LINE-1 in the adult brain. Using real-time quantitative PCR, the present study demonstrates that the chronic administration of neurotoxic METH doses results in the increased expression of LINE-1-encoded Open Reading Frame 1 (ORF-1) in rat striatum shortly after the last dose of the drug and decreased ORF-1 expression during METH withdrawal, with dentate gyrus potentially developing “tolerance” to these METH effects. LINE-1 activation may be a new factor mediating the neurotoxic effects of chronic METH in the striatum and, therefore, a new drug target against METH-induced psychomotor impairments in chronic METH users.

Epigallocatechin Gallate Mitigates the Methamphetamine-Induced Striatal Dopamine Terminal Toxicity by Preventing Oxidative Stress in the Mouse Brain.

Methamphetamine (METH) is a popular psychostimulant due to its long-lasting effects and inexpensive production. METH intoxication is known to increase oxidative stress leading to neuronal damage. Thus, preventing the METH-induced oxidative stress can potentially mitigate neuronal damage. Previously, our laboratory found that epigallocatechin gallate (EGCG), a strong antioxidant found in green tea, can protect against the METH-induced apoptosis and dopamine terminal toxicity in the striatum of mice. In the present study, we evaluated the anti-oxidative properties of EGCG on the METH-induced oxidative stress using CD-1 mice. First, we demonstrated that mice pretreated with EGCG 30min prior to the METH injection (30mg/kg, ip) showed protection against the striatal METH-induced reduction of tyrosine hydroxylase without mitigating hyperthermia. In addition, injecting a single high dose of METH caused the reduction of striatal glutathione peroxidase activity at 24h after the METH injection. Interestingly, pretreatment with EGCG 30min prior to the METH injection prevented the METH-induced reduction of glutathione peroxidase activity. Moreover, we utilized Western blots to quantify the glutathione peroxidase 4 protein level in the striatum. The results showed that METH decreased striatal glutathione peroxidase 4 protein level, and the reduction was prevented by EGCG pretreatment. Finally, we observed that the METH-induced increase of striatal catalase and copper/zinc superoxide dismutase protein levels were also attenuated by pretreatment with EGCG. Taken together, our data indicate that EGCG is an effective agent that can be used to mitigate the METH-induced striatal toxicity in the mouse brain.

Microglia imaging in methamphetamine use disorder: a positron emission tomography study with the 18 kDa translocator protein radioligand [F-18]FEPPA.

Activation of brain microglial cells, microgliosis, has been linked to methamphetamine (MA)-seeking behavior, suggesting that microglia could be a new therapeutic target for MA use disorder. Animal data show marked brain microglial activation following acute high-dose MA, but microglial status in human MA users is uncertain, with one positron emission tomography (PET) investigation reporting massively and globally increased translocator protein 18 kDa (TSPO; [C-11](R)-PK11195) binding, a biomarker for microgliosis, in MA users. Our aim was to measure binding of a second-generation TSPO radioligand, [F-18]FEPPA, in brain of human chronic MA users. Regional total volume of distribution (VT ) of [F-18]FEPPA was estimated with a two-tissue compartment model with arterial plasma input function for 10 regions of interest in 11 actively using MA users and 26 controls. A RM-ANOVA corrected for TSPO rs6971 polymorphism was employed to test significance. There was no main effect of group on [F-18]FEPPA VT (P = .81). No significant correlations between [F-18]FEPPA VT and MA use duration, weekly dosage, blood MA concentrations, regional brain volumes, and self-reported craving were observed. Our preliminary findings, consistent with our earlier postmortem data, do not suggest substantial brain microgliosis in MA use disorder but do not rule out microglia as a therapeutic target in MA addiction. Absence of increased [F-18]FEPPA TSPO binding might be related to insufficient MA dose or blunting of microglial response following repeated MA exposure, as suggested by some animal data.

Tea Polyphenols Attenuate Methamphetamine-Induced Neuronal Damage in PC12 Cells by Alleviating Oxidative Stress and Promoting DNA Repair.

DNA integrity plays a crucial role in cell survival. Methamphetamine (METH) is an illegal psychoactive substance that is abused worldwide, and repeated exposure to METH could form mass free radicals and induce neuronal apoptosis. It has been reported that free radicals generated by METH treatment can oxidize DNA and hence produce strand breaks, but whether oxidative DNA damage is involved in the neurotoxicity caused by METH remains unclear. Tea polyphenols exert bioactivities through antioxidant-related mechanisms. However, the potential neuroprotective effect of tea polyphenols on METH-induced nerve cell damage and the underlying mechanism remain to be clarified. In this study, oxidative stress, DNA damage, and cell apoptosis were increased after METH exposure, and the expressions of DNA repair-associated proteins, including the phosphorylation of ataxia telangiectasia mutant (p-ATM) and checkpoint kinase 2 (p-Chk2), significantly declined in PC12 cells after high-dose or long-time METH treatment. Additionally, tea polyphenols could protect PC12 cells against METH-induced cell viability loss, reactive oxide species and nitric oxide production, and mitochondrial dysfunction and suppress METH-induced apoptosis. Furthermore, tea polyphenols could increase the antioxidant capacities and expressions of p-ATM and p-Chk2 and then attenuate DNA damage via activating the DNA repair signaling pathway. These findings indicate that METH is likely to induce neurotoxicity by inducing DNA damage, which can be reversed by tea polyphenols. Supplementation with tea polyphenols could be an effective nutritional prevention strategy for METH-induced neurotoxicity and neurodegenerative disease.

Effects of Molecular Hydrogen on Methamphetamine-Induced Neurotoxicity and Spatial Memory Impairment.

Methamphetamine (METH) is a highly addictive stimulant, and METH exposure can induce irreversible neuronal damage and cause neuropsychiatric and cognitive disorders. The ever-increasing levels of METH abuse worldwide have necessitated the identification of effective intervention strategies to protect the brain against METH-induced neurotoxicity. The protective effects of molecular hydrogen on oxidative stress and related neurodegenerative diseases have been recently elucidated. Herein, we investigated whether treatment with molecular hydrogen ameliorated the METH-induced neurotoxicity and spatial learning and memory impairments. Male C57BL/6 mice received four intraperitoneal METH injections (10 mg/kg, 3-h interval), and stereotypic behaviors and hyperthermia were observed. After METH treatment and behavioral observation, the mice were returned to their home cages, where they received water or hydrogen-rich water (HRW) ad libitum for 7 days. We found that the molecular hydrogen delivered by ad libitum HRW consumption significantly inhibited the METH-induced spatial learning impairment and memory loss evidenced in the Barnes maze and Morris water maze tests. Furthermore, molecular hydrogen significantly restrained the neuronal damage in the hippocampus after high-dose METH exposure. Ad libitum HRW consumption also had an inhibitory effect on the METH-induced increase in the expression of Bax/Bcl-2, cleaved caspase-3, glucose-related protein 78 (GRP 78), CCAAT/enhancer-binding protein homologous protein (CHOP), and p-NF-kB p65 expression and elevation of interleukin (IL)-6 and tumor necrosis factor (TNF)-α levels in the hippocampus. These are the first findings to indicate that hydrogen might ameliorate METH-induced neurotoxicity and has a potential application in reducing the risk of neurodegeneration frequently observed in METH abusers.

Demand for Methamphetamine and Methcathinone Under Fixed Ratio and Second‐Order Schedules of Reinforcement

Behavioral economic procedures, e.g., demand curve analysis, provide powerful quantitative metrics for scaling the strength of drugs of abuse. Most studies that have utilized such procedures employ simple fixed ratio (FR) schedules of reinforcement to generate demand curves. However, second‐order schedules, in which a subject responds under one schedule of conditioned reinforcement (e.g., for presentation of a brief light stimulus) that is nested within a second schedule of primary reinforcement, have been suggested to more accurately reflect the complex patterns of behavior that accompany human drug taking. Further, the conditioned stimulus presented during second order schedules may develop conditioned reinforcer properties that serve to maintain drug‐taking behavior in their own right. The objective of the present study was to begin to compare self‐administration and demand for intravenous methamphetamine and methcathinone under both simple FR and second‐order schedules of reinforcement in nonhuman primates. Adult male squirrel monkeys (N=4) with histories of stimulant self‐administration responded for intravenous methamphetamine and methcathinone injections under FR10 and FR10(FR5:S) schedules of reinforcement. After self‐administration of vehicle and a range of methamphetamine (0.001–0.1 mg/kg) and methcathinone (0.001–0.1 mg/kg) doses were evaluated under each schedule, two doses of each drug (0.01 and 0.03 mg/kg/inj) were studied using a demand procedure; for the FR condition, the response requirement for drug delivery increased across multiple sessions in an ascending order, i.e. FR 10, 30, 56, 100, etc. For the second‐order condition, the response requirement for the drug delivery schedule increased according to a similar progression (i.e., FR10(FR5:S), FR30(FR5:S), FR56(FR5:S), etc.). Each condition was presented in a random order that was counterbalanced across subjects. Results indicate that methamphetamine and methcathinone self‐administration followed an inverted‐U shaped pattern with similar total intake (mg/kg) under the two schedules of reinforcement. During demand procedures, both methamphetamine and methcathinone self‐administration gradually decreased as the response requirement was increased. Application of the exponential model of demand shows that the higher dose of methamphetamine (0.03 mg/kg) produced slightly greater breakpoints than the lower dose (0.01 mg/kg) under both schedule conditions whereas demand for methcathinone was generally higher under FR than second‐order schedules regardless of dose. Interestingly, demand for the high doses of the two drugs was less elastic under the FR condition, whereas demand for the lower doses was more elastic under the second‐order schedule. These results suggest that the demand for self‐administered drugs may be influenced by schedule of reinforcement in a manner that varies across drugs. Further, the present results do not support a facilitative influence of conditioned reinforcement on the reinforcing strength of self‐administered drugs.Support or Funding InformationThis work was funded by National Institutes of Health grants DA002519 and DA039306This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Pre-administration of low-dose methamphetamine enhances movement and neural activity after high-dose methamphetamine administration in the striatum

Methamphetamine (METH) is a powerful stimulant drug of abuse, with potent addictive and neurotoxic properties. In this study, the effects of low-dose METH administration prior to high-dose METH administration on movement and neural activity in rats were examined. Rats were administered low-dose (1 mg/kg/day) METH or saline for 5 consecutive days (m5 and s5, respectively), followed by high-dose (10 mg/kg) METH on day 6 (m5M and s5M, respectively). An accelerometer was used to evaluate the frequency of movement when rats were placed in a cage for 30 min. The expression of c-fos, a neuronal activity marker, in the striatum was analyzed using immunohistochemistry. Striatal protein expression of neuronal markers, including vesicular glutamate transporter 2 (VGLUT2), glutamate decarboxylase 67 (GAD67), tyrosine hydroxylase (TH), tryptophan hydroxylase 2 (TPH2), and the glial marker, glial fibrillary acidic protein (GFAP), was analyzed by western blot. Accelerometer counts and the numbers of c-fos-positive cells in the striatum were significantly higher in the m5M than in the s5, m5, and s5M groups. The expression levels of VGLUT2 and GAD67, but not those of TH, TPH2, or GFAP, were significantly higher in the m5M than in the s5M group. These results suggest that pre-administration of low-dose METH prior to high-dose METH administration in rats may alter excitatory and inhibitory neurons in the striatum, thereby affecting movement and neural activity in rats.

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Journal Digest

Agmatine attenuates methamphetamine-induced passive avoidance learning and memory and CaMKII-α gene expression deteriorations in hippocampus of rat.

Methamphetamine (METH) abuse is one the most worldwide problems with wide-ranging effects on the central nervous system (CNS). Chronic METH abuse can associate with cognitive abnormalities and neurodegenerative changes in the brain. Agmatine, a cationic polyamine, has been proposed as a neuromodulator that modulates many effects of abused drugs. The aim of this study was to determine if agmatine can decrease the impairment effect of METH on memory and hippocampal CaMKII-α gene expression, a gene that plays a major role in memory. Male wistar rats (200-220 g) were allocated into 7 groups, including 5 groups of saline, METH (1, 2 mg/kg), Agmatine (5, 10 mg/kg) and 2 groups of agmatine (5, 10 mg/kg) with higher doses of METH (2 mg/kg) for 5 consecutive days (n = 8 in each group). All injections were done intraperitoneally and agmatine was administrated 10 min before METH treatment. Furthermore, Passive avoidance learning (PAL) test was assessed on the 5th day. Retention test was done 24 h after training and the rats were sacrificed immediately. Hippocampi were removed and stored at -80 °C. Finally, hippocampal CaMKII-α gene expression was measured using Quantitative Real-time PCR. Our data showed that chronic METH dose-dependently impaired PAL retrieval, as it decreased step-through latency (STL) and increased time spent in the dark compartment (TDC). While Agmatine with a higher dose (10 mg/kg) significantly decreased impairment effect of METH (2 mg/kg) on PAL and memory. Also, molecular results revealed that METH (2 mg/kg) markedly decreased hippocampal CaMKII-α gene expression while agmatine (10 mg/kg) co-adminstration prevented it. Taken together, the results propose that agmatine may provide a potential therapy for learning and memory deficits induced by METH.

Lack of Evidence for Methylenedioxypyrovalerone (MDPV)‐Induced Persistent Dopaminergic or Serotonergic Deficits: Comparison with Methamphetamine and Mephedrone

β‐Ketoamphetamines such as methylenedioxypyrovalerone (MDPV) and mephedrone (MEPH) are synthetic cathinones with a structural similarity to methamphetamine (METH) that may account for some similarities in behavioral effects. However, the persistent effects of repeated high‐dose MDPV exposures on striatal dopaminergic and hippocampal serotonergic systems remain to be fully elucidated. Accordingly, the persistent effects of repeated high‐dose MPDV administrations were investigated. Results revealed that MDPV treatment did not alter striatal dopaminergic or hippocampal serotonergic systems as assessed 7 days later in synaptosomes prepared from treated rats. Further, MDPV did not alter hippocampal serotonin or 5‐hydroxyindoleacetic acid content at this time point. These data stand in contrast to our previous report that repeated high‐dose MEPH administrations cause persistent hippocampal serotonergic deficits. These data also stand in contrast to effects of repeated high‐dose METH administrations that include persistent striatal dopaminergic and hippocampal serotonergic deficits. Noteworthy, in these studies MDPV did not induce hyperthermia to the degree reported in previous studies of MEPH and METH. Further, the impact of MDPV on the dopamine transporter and vesicular monoamine transporter‐2 appears distinct from that of MEPH and METH. Taken together, these latter findings may contribute to the differential impact of MDPV, MEPH, and METH on dopaminergic and serotonergic systems.Support or Funding InformationDA039145 and DA031883This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Methamphetamine psychosis: insights from the past.

To review early case reports and experimental inductions of amphetamine and methamphetamine psychosis, prior to the prohibition of these drugs, to gain a better understanding of the nature and aetiology of methamphetamine psychosis. Papers considered were historical case reports and case series of psychosis relating to the use and misuse of prescription amphetamine, focusing upon papers by Young & Scoville (1938), Connell (1958), and three subsequent experimental studies published in the early 1970s (Griffith 1972, Angrist & Gershon 1970 and Bell 1973), where psychosis was induced in volunteers using high-dose amphetamine and methamphetamine. High-dose methamphetamine and amphetamine can result in a paranoid psychosis which remits rapidly (within days) of discontinuing use. The central feature is paranoia occurring in a clear state of consciousness. This may be accompanied by other psychotic symptoms (e.g. hallucinations). Pre-existing schizophrenia is not necessary, and the syndrome is not due to sleep deprivation. Research findings from the 1930s to the 1970s suggest that paranoid psychosis should be considered a probable consequence of high-dose methamphetamine use. Individuals who experience psychotic symptoms for any substantive period after intoxication has ended should be suspected of having a functional non-organic psychosis, or a latent vulnerability thereto.

The inhibitory effect of levo-tetrahydropalmatine on the methamphetamine-induced spatial memory impairment in mice

Methamphetamine (METH) administration results in addiction and memory impairment. Previous studies have suggested that levo-tetrahydropalmatine (l-THP), an alkaloid purified from the Chinese herb Corydalis, attenuates the behavioral changes induced by METH. Therefore, in this study, we explored whether l-THP could also protect against the METH-induced memory impairment examined using the Morris water maze (MWM). We found that low dose of METH (1.0 mg/kg) treated for 20 consecutive days prior to the MWM experiment impaired spatial memory retention but not acquisition in mice. In addition, high dose of METH (10.0 mg/kg) treated during the spatial learning phase for five consecutive days impaired both the acquisition and retention of spatial memory. Moreover, both of these impairments induced by METH were reversed by l-THP treatment, indicating a potential protective role of l-THP in METH use.