Doses Of Methamphetamine Research Articles

Ultra-low doses of methamphetamine suppress 5-hydroxytryptophan-induced head-twitch response in mice during aging.

The head-twitch response (HTR) in mice is considered a behavioral assay for activation of 5-HT 2A receptors in rodents. It can be evoked by direct-acting 5-HT 2A receptor agonists such as (±)-2,5-dimethoxy-4-iodoamphetamine, 5-hydroxytryptamine precursors [e.g. 5-hydroxytryptophan (5-HTP)], and selective 5-hydroxytryptamine releasers (e.g. d -fenfluramine). The nonselective monoamine releaser methamphetamine by itself does not produce the HTR but can suppress both (±)-2,5-dimethoxy-4-iodoamphetamine- and d -fenfluramine-evoked HTRs across ages via concomitant activation of the inhibitory serotonergic 5-HT 1A or adrenergic α 2 receptors. Currently, we investigated: (1) the ontogenic development of 5-HTP-induced HTR in 20-, 30-, and 60-day-old mice; (2) whether pretreatment with ultra-low doses of methamphetamine (0.1, 0.25, and 0.5 mg/kg, intraperitoneally) can suppress the frequency of 5-HTP-induced HTR at different ages; and (3) whether the inhibitory serotonergic 5-HT 1A or adrenergic α 2 receptors may account for the potential inhibitory effect of methamphetamine on 5-HTP-induced HTR. In the presence of a peripheral decarboxylase inhibitor (carbidopa), 5-HTP produced maximal frequency of HTRs in 20-day-old mice which rapidly subsided during aging. Methamphetamine dose-dependently suppressed 5-HTP-evoked HTR in 20- and 30-day-old mice. The selective 5-HT 1A -receptor antagonist WAY 100635 reversed the inhibitory effect of methamphetamine on 5-HTP-induced HTR in 30-day-old mice, whereas the selective adrenergic α 2 -receptor antagonist RS 79948 failed to reverse methamphetamine's inhibition at any tested age. These findings suggest an ontogenic rationale for methamphetamine's inhibitory 5-HT 1A receptor component of action in its suppressive effect on 5-HTP-induced HTR during development which is not maximally active at a very early age.

The Effects of Subchronic Methamphetamine Administration on the NLRP3 Inflammasome, Memory Function, and Hippocampal Morphology

Background: While it is established that addictive doses of methamphetamine correlate with inflammation-mediated neurotoxic pathways, the extent of toxicity resulting from subchronic administration at lower doses remains uncertain. Objectives: This study aimed to investigate the subtle effects of daily subchronic methamphetamine (MA) administration on neuroinflammatory processes, cognitive dimensions, gene expression, and hippocampal morphology. Methods: The experimental study employed a longitudinal design with three groups (G1B, G2B, G3B) receiving methamphetamine (5 mg/kg, intraperitoneally, once daily) for 1, 2, or 3 weeks, respectively. Corresponding control groups (G1A, G2A, G3A) received 0.2 mL of normal saline. Spatial learning, novel object recognition, and passive avoidance tests were conducted to assess spatial, recognition, and fear avoidance memories. Hippocampal morphology was evaluated using Nissl staining, and the expressions of NLRP3, ASC, and caspase-1 genes were measured as markers of neuroinflammation. Results: Statistical analyses, including one-way and two-way ANOVA, showed that subchronic low-dose administration of MA led to significant activation of the inflammasome (NLRP3, ASC, and caspase-1), which may have resulted in pyramidal cell death in the hippocampus. The hippocampal structure in the CA1 region was completely disrupted. Spatial memory and passive avoidance learning were impaired in the MA groups, while recognition memory remained unaffected. Conclusions: The findings suggest that prolonged administration of 5 mg/kg of methamphetamine may be associated with significant inflammasome activation, pyramidal cell death, and mild cognitive decline. Contrary to previous evidence, even lower doses of methamphetamine taken over an extended period could be neurotoxic.

Fentanyl self-administration is accelerated by methamphetamine co-use and results in worsened hypodopaminergia in male, but not female rats.

Combined use of fentanyl and methamphetamine (FENT + METH) has increased in recent years and has been documented in a growing number overdose deaths each year. The impact of FENT + METH on behavior and neurobiology is not well understood. In this study, male and female Long Evans rats were tested on a limited access, fixed ratio 1 self-administration schedule for increasing doses (1.25-5 μg/kg/infusion; iv) of fentanyl, with and without a single dose (0.1 mg/kg/infusion; iv) of methamphetamine, for 15 days. FENT + METH abolished dose responsiveness to fentanyl in all rats and accelerated intake in males, resulting in patterns of responding that may be more likely to result in adverse effects. Ex vivo slice voltammetry in the nucleus accumbens core showed decreases in dopamine release and reuptake (Vmax) following FENT + METH exposure, compared with saline, fentanyl, and methamphetamine alone groups at baseline parameters. Further, significant decreases in dopamine release were observed across a range of stimulation intensities following FENT + METH exposure. Overall, male and female rats displayed sex-specific behavioral and neurobiological responses to FENT + METH exposure, with males displaying increased vulnerability.

Methamphetamine Increases Tubulo-Vesicular Areas While Dissipating Proteins from Vesicles Involved in Cell Clearance.

Cytopathology induced by methamphetamine (METH) is reminiscent of degenerative disorders such as Parkinson's disease, and it is characterized by membrane organelles arranged in tubulo-vesicular structures. These areas, appearing as clusters of vesicles, have never been defined concerning the presence of specific organelles. Therefore, the present study aimed to identify the relative and absolute area of specific membrane-bound organelles following a moderate dose (100 µM) of METH administered to catecholamine-containing PC12 cells. Organelles and antigens were detected by immunofluorescence, and they were further quantified by plain electron microscopy and in situ stoichiometry. This analysis indicated an increase in autophagosomes and damaged mitochondria along with a decrease in lysosomes and healthy mitochondria. Following METH, a severe dissipation of hallmark proteins from their own vesicles was measured. In fact, the amounts of LC3 and p62 were reduced within autophagy vacuoles compared with the whole cytosol. Similarly, LAMP1 and Cathepsin-D within lysosomes were reduced. These findings suggest a loss of compartmentalization and confirm a decrease in the competence of cell clearing organelles during catecholamine degeneration. Such cell entropy is consistent with a loss of energy stores, which routinely govern appropriate subcellular compartmentalization.

Impact of childhood adversity on acute subjective effects of stimulant and opioid drugs: Evidence from placebo-controlled studies in healthy volunteers.

Early-life adversities are known to alter drug reward processing in rodents. Despite the well-known link between early adversity and the risk of substance use disorder, few studies have measured how childhood adversity affects human drug reward. Here, we assessed the relationship between historical childhood adversities and responses to single doses of methamphetamine, d-amphetamine or buprenorphine in healthy participants. Using a secondary analysis approach, we assessed the impact of childhood adversity on drug effects from three randomised, placebo-controlled studies in which healthy volunteers received methamphetamine (20 mg oral; n = 35), d-amphetamine (20 mg oral; n = 54) or buprenorphine (0.2 mg sublingual; n = 35). Ratings of feeling effect, liking, disliking, feeling high and wanting more of the drug were collected 15-210 min post-administration, and heart rate changes were analysed using random-intercept mixed-effect models. The area under the curve from these and previous studies was calculated to visualise the relationship between childhood adversity severity and drug effects. Greater childhood adversity was associated with reduced feel effects (significant three-way interactions b = -0.07, 95% CI [-0.12, -0.02], p = 0.009), like effects (b = -0.07, 95% CI [-0.13, -0.00], p = 0.038) and feel high (b = -0.06, 95% CI [-0.10, -0.01], p = 0.020) towards the stimulant drugs 90-180 min post-administration. Childhood adversity was not significantly associated with other subjective or heart rate responses to the drugs. Overall, participants with more childhood adversities reported dampened subjective responses to stimulant drugs, but not to buprenorphine. Future studies should examine the generalisability of these relationships, to identify the mechanisms underlying the link between childhood adversity and drug responsiveness.

The General Neurocognitive Decline in Patients with Methamphetamine Use and Transient Methamphetamine-induced Psychosis is Primarily Determined by Oxidative and AGE-RAGE Stress.

Chronic Methamphetamine (MA) usage is linked to oxidative and AGE (advanced glycation end products) - RAGE (receptors for AGEs) stress, changes in magnesium, calcium, and copper, increased psychotic symptoms, and neurocognitive deficits. Nevertheless, it is still unclear whether these biological pathways mediate the latter impairments. This study aimed to investigate the relationships between neurocognition, the aforementioned biomarkers, and psychotic symptoms. We recruited 67 participants, namely 40 patients diagnosed with MA-substance use and 27 healthy controls, and assessed the Brief Assessment of Cognition in Schizophrenia (BACS), symptoms of psychosis, excitation, and formal thought disorders, oxidative toxicity (computed as the sum of myeloperoxidase (MPO), oxidized high-density lipoprotein (HDL), oxidized low-DL, and malondialdehyde), antioxidant defenses (catalase, glutathione peroxidase, total antioxidant capacity, zinc, and HDL), and increased AGEs and RAGEs. We were able to extract one validated latent vector from the Mini-Mental State Examination score and the BACS test results (including executive functions, verbal fluency, and attention), labeled general cognitive decline (G-CoDe). We found that 76.1% of the variance in the G-CoDe was explained by increased oxidative toxicity, lowered antioxidant defenses, number of psychotic episodes, and MA dose. In patients with MA use, MPO was significantly associated with the GCoDe. The use of MA induced mild cognitive impairments through MA-induced activation of detrimental outcome pathways, including oxidative and AGE-RAGE stress, and suppression of protective antioxidant pathways. Increased MPO, oxidative, and AGE-RAGE stress are new drug targets to prevent neurocognitive deficits and psychosis due to MA use.

Neurotoxic Methamphetamine Doses Alter CDCel-1 Levels and Its Interaction with Vesicular Monoamine Transporter-2 in Rat Striatum.

In recent years, methamphetamine METH misuse in the US has been rapidly increasing and there is no FDA-approved pharmacotherapy for METH use disorder (MUD). In addition to being dependent on the drug, people with MUD develop a variety of neurological problems related to the toxicity of this drug. A variety of molecular mechanisms underlying METH neurotoxicity has been identified, including dysfunction of the neuroprotective protein parkin. However, it is not known whether parkin loss of function within striatal dopaminergic (DAergic) terminals translates into a decrease in DA storage capacity. This study examined the relationship between parkin, its substrate cell division cycle related-1 (CDCrel-1), and vesicular monoamine transporter-2 (VMAT2) in METH neurotoxicity in male Sprague Dawley rats. To also assess individual differences in response to METH's neurotoxic effects, a large group of rats was treated with binge METH or saline and sacrificed 1h or 24h later. This study is the first to show that binge METH alters the levels and subcellular localization of CDCrel-1 and that CDCrel-1 interacts with VMAT2 and increases its levels at the plasma membrane. Furthermore, we found wide individual differences in the responses of measured indices to METH. Proteomic analysis of VMAT-2-associated proteins revealed upregulation of several proteins involved in the exocytosis/endocytosis cycle. The results suggest that at 1h after METH binge, DAergic neurons are engaged in counteracting METH-induced toxic effects, including oxidative stress- and hyperthermia-induced inhibition of synaptic vesicle cycling, with the responses varying between individual rats. Studying CDCrel-1, VMAT2, and other proteins in large groups of outbred rats can help define individual genetic and molecular differences in responses to METH neurotoxicity which, in turn, will aid treating humans suffering from METH use disorder and its neurological consequences.

Methamphetamine-induced adaptation of learning rate dynamics depend on baseline performance.

The ability to calibrate learning according to new information is a fundamental component of an organism's ability to adapt to changing conditions. Yet, the exact neural mechanisms guiding dynamic learning rate adjustments remain unclear. Catecholamines appear to play a critical role in adjusting the degree to which we use new information over time, but individuals vary widely in the manner in which they adjust to changes. Here, we studied the effects of a low dose of methamphetamine (MA), and individual differences in these effects, on probabilistic reversal learning dynamics in a within-subject, double-blind, randomized design. Participants first completed a reversal learning task during a drug-free baseline session to provide a measure of baseline performance. Then they completed the task during two sessions, one with MA (20 mg oral) and one with placebo (PL). First, we showed that, relative to PL, MA modulates the ability to dynamically adjust learning from prediction errors. Second, this effect was more pronounced in participants who performed poorly at baseline. These results present novel evidence for the involvement of catecholaminergic transmission on learning flexibility and highlights that baseline performance modulates the effect of the drug.

Different Doses of Methamphetamine Are Needed to Produce Locomotor or Blood Pressure Sensitization in Mice.

Methamphetamine (METH) exposure increases locomotor sensitization. However, no study has explored the occurrence of cardiovascular sensitization. The present study, carried out in mice, analyzed the following: (i) METH sensitization extending to systolic blood pressure (SBP); (ii) a potential correlation between ambulatory and cardiovascular sensitization; and (iii) morphological alterations within meso-striatal, meso-limbic and pontine catecholamine systems including c-fos expression. Locomotor activity, SBP and occurrence of morphological alterations of catecholaminergic neurons were assessed in C57Bl/6J mice following daily i.p. injections of either saline or METH (1, 2 or 5 mg/kg) for 5 consecutive days and following 6 days of withdrawal. Reiterated exposure to the lower doses of METH (1 mg/kg and 2 mg/kg) produced in mice locomotor sensitization without altering SBP. In contrast, repeated treatment with the highest dose of METH (5 mg/kg) produced sensitization of SBP in the absence of locomotor sensitization. No morphological alterations but increases in c-fos expression within neurons of locus coeruleus and nucleus accumbens were detected. The present data suggest that METH produces plastic changes that extend beyond the motor systems to alter autonomic regulation. This cardiovascular sensitization occurs independently of locomotor sensitization. The persistency of increased blood pressure may underlie specific mechanisms operating in producing hypertension.

The Effects of Mkpuru Mmiri Consumption on Cognitive Performance and Brain Histology in an Animal Study

Mkpuru mmiri, popularly known as ice or methamphetamine (METH) is one of the illegal substances that young people in Nigeria abuse most frequently. The purpose of the study is to determine how methamphetamine affects the cognitive-motor behavior of Wistar rats. In the study, twenty-five Wistar rats weighing between 117 and 138 grams were split into five groups: group A had only rat feed and water, group B - D received doses of METH ranging from 5 mg/kg to 20 mg/kg, and group E received a dose of 5 mg/kg of diazepam. Neurobehavioral tools such as the navigator maze test, elevated plus maze and beam walk were used to assess the rats’ memory, anxiety-related behavior, balance, motor coordination, and working memory respectively. Two weeks after the injection, samples were taken and examined for oxidative stress markers (Malondialdehyde - MDA) and tissue antioxidant indicators (Superoxide dismutase - SOD, Glutathione - GSH, and Total Antioxidant Capacity - TAC). The data were analyzed using SPSS and post hoc LSD and the significance level was established at p<0.05. The results showed that the test groups' body weight was significantly lower than the control groups' (p<0.05). The test groups' relative brain weights increased significantly (p<0.05) when compared to the control group. The data also showed a significantly (p<0.05), level of antioxidant enzymes (SOD, GSH, and TAC levels) and a significantly (p<0.05) greater level of MDA when compared to the control group. When comparing the test groups' cognitive abilities to the controls, the experimental rats' cognitive powers significantly declined. The study's conclusion demonstrated that chronic consumption of methamphetamine may deteriorate cognitive function.

Methamphetamine effects in zebrafish (Danio rerio) depend on behavioral endpoint, dose and test session duration

Research using zebrafish (Danio rerio) has begun to provide novel information in many fields, including the behavioral pharmacology of drug use and misuse. There have been limited studies on the effects of methamphetamine in adult zebrafish and the parameters of exposure (dose, test session length) have not been well-documented. Behavior following drug exposure is generally measured during relatively short sessions (6–10 min is common) in a novel tank environment. Many procedural variables (isolation, netting, novel tank) elicit anxiety-like behavior that is most apparent during the initial portion of a test session. This anxiety-like behavior might mask the initial effects of methamphetamine. During longer test sessions, these anxiety-like responses would be expected to habituate and drug effects should become more apparent. To test this idea, we measured several locomotor activity responses for 50-min following a range of methamphetamine doses (0.1–3.0 mg/L via immersion in methamphetamine solution). Methamphetamine failed to alter swimming velocity, distance travelled, or freezing time. In contrast, methamphetamine produced a dose-dependent decrease in time spent in the bottom of the tank, an increase in the number of visits to the top of the tank, and an increase in the number of transitions along the sides of the tank. The effects of methamphetamine were apparent 10–20 min following exposure and generally persisted throughout the session. These findings indicate that longer test sessions are required to measure methamphetamine-induced changes in behavior in zebrafish, as has been shown in other laboratory animals. The results also suggest that anxiety-like responses associated with various procedural aspects (netting, isolation, novel test apparatus) likely interfere with the ability to observe many behavioral effects of methamphetamine in zebrafish. Based on the current results, habituation to testing procedures to reduce anxiety-like behaviors is recommended in determining the effects of methamphetamine in zebrafish.

Neural complexity is increased after low doses of LSD, but not moderate to high doses of oral THC or methamphetamine.

Neural complexity correlates with one's level of consciousness. During coma, anesthesia, and sleep, complexity is reduced. During altered states, including after lysergic acid diethylamide (LSD), complexity is increased. In the present analysis, we examined whether low doses of LSD (13 and 26 µg) were sufficient to increase neural complexity in the absence of altered states of consciousness. In addition, neural complexity was assessed after doses of two other drugs that significantly altered consciousness and mood: delta-9-tetrahydrocannabinol (THC; 7.5 and 15 mg) and methamphetamine (MA; 10 and 20 mg). In three separate studies (N = 73; 21, LSD; 23, THC; 29, MA), healthy volunteers received placebo or drug in a within-subjects design over three laboratory visits. During anticipated peak drug effects, resting state electroencephalography (EEG) recorded Limpel-Ziv complexity and spectral power. LSD, but not THC or MA, dose-dependently increased neural complexity. LSD also reduced delta and theta power. THC reduced, and MA increased, alpha power, primarily in frontal regions. Neural complexity was not associated with any subjective drug effect; however, LSD-induced reductions in delta and theta were associated with elation, and THC-induced reductions in alpha were associated with altered states. These data inform relationships between neural complexity, spectral power, and subjective states, demonstrating that increased neural complexity is not necessary or sufficient for altered states of consciousness. Future studies should address whether greater complexity after low doses of LSD is related to cognitive, behavioral, or therapeutic outcomes, and further examine the role of alpha desynchronization in mediating altered states of consciousness.

Effects of fentanyl and the adulterant levamisole on the rewarding and locomotor effects of methamphetamine in rats

BackgroundPeople who use psychostimulant substances can be exposed to unknown adulterants, such as the synthetic opioid fentanyl (FEN) and the anthelmintic cholinergic agent levamisole (LEV). This work explores the rewarding and locomotor effects of methamphetamine (METH) in combination with FEN or LEV. MethodsWe used adult male Wistar rats in the conditioned-place preference (CPP) paradigm (conditioning, extinction, and reinstatement phases) and in the open field test to study effective doses of METH, FEN, or LEV, or ineffective doses of METH+FEN or METH+LEV in combination. ResultsMETH and LEV, at 1mg/kg METH each, and 30µg/kg FEN produced CPP. Extinction to METH- or LEV-induced CPP occurred after eight saline injections, but it took 8–26 sessions to extinguish FEN-induced CPP. A challenge dose of 0.5mg/kg METH reinstated CPP. The same occurred with 15µg/kg FEN but not with 0.5 or 1mg/kg LEV. Training animals with ineffective doses of METH (0.01mg/kg) combined with either FEN (0.3µg/kg) or LEV (0.01mg/kg) produced CPP. Sub-effective doses of METH or FEN alone did not induce reinstatement after extinction. However, animals challenged with LEV, METH+FEN, or METH+LEV mixtures did it. Combining FEN (3µg/kg) with 0.1mg/kg METH increased locomotor activity. ConclusionIneffective FEN and LEV doses mixed with METH produce effects larger than would be expected based on the effects of either drug alone. This outcome suggests a supra-additive interaction, which could increase the risk of developing a METH use disorder.

Extinction and reinstatement of methamphetamine-induced conditioned place preference in zebrafish.

Conditioned place preference (CPP) paradigm in zebrafish has been used to measure drug reward, but there is limited research on CPP reinstatement to determine relapse vulnerability. The present study aimed to investigate extinction and reinstatement of methamphetamine (MA)-induced CPP in zebrafish and evaluate the model's predictive validity. Zebrafish received different doses of MA (0-60 mg/kg) during CPP training. The preferred dose of MA at 40 mg/kg was used for extinction via either confined or nonconfined procedures. The extinguished CPP was reinstated by administering a priming dose of MA (20 mg/kg) or various stressors. To assess persistent susceptibility to reinstatement, MA CPP and reinstatement were retested following 14 days of abstinence. In addition, the effects of SCH23390, naltrexone, and clonidine on MA CPP during acquisition, expression, or reinstatement phases were monitored. MA induced CPP in a dose-dependent manner. Both nonconfined and confined extinction procedures time-dependently reduced the time spent on the MA-paired side. A priming dose of MA, chasing stress, or yohimbine reinstated the extinguished CPP. After 14 days of abstinence, the MA CPP remained extinguished and was significantly reinstated by MA priming or chasing stress. Similar to the observations in rodents, SCH23390 suppressed the acquisition of MA CPP, naltrexone reduced the expression and MA priming-induced reinstatement, while clonidine prevented stress-induced reinstatement of MA CPP. This work expanded the zebrafish CPP paradigm to include extinction and reinstatement phases, demonstrating predictive validity and highlighting its potential as a valuable tool for exploring drug relapse.

Blockade of the orexin-2 receptors within the ventral tegmental area facilitates the extinction and prevents the reinstatement of methamphetamine-seeking behavior

Repeated use of methamphetamine (METH) causes severe effects on the central nervous system, associated with an increased relapse rate. The orexinergic system is highly implicated in the reward circuitry and may be a promising target for treating psychostimulant dependency. The present study aimed to investigate the involvement of the orexin system, mainly the orexin-2 receptors (OX2R) in the ventral tegmental area (VTA) in the extinction and reinstatement of METH-seeking behavior using a conditioned place preference (CPP) paradigm. To this end, animals received METH (1 mg/kg; sc) for a 5-day conditioning period. Then, in the first set of experiments, different groups of rats were given intra-VTA TCS OX2 29 (1, 3, 10, or 30 nmol/0.3 μl DMSO) as an OX2R antagonist over a 10-day extinction period. In another experiment, after the extinction period, a different set of animals received a single dose of TCS OX2 29 (1, 3, 10, or 30 nmol) before the priming dose of METH (0.25 mg/kg; sc) on the reinstatement day. The results revealed that TCS OX2 29 (10 and 30 nmol) remarkably facilitated the extinction of rewarding properties of METH (P < 0.001 for both doses). Furthermore, TCS OX2 29 (3, 10, or 30 nmol) significantly suppressed the METH-induced reinstatement (3 nmol; P < 0.05, 10 nmol; P < 0.01, and 30 nmol; P < 0.001). In conclusion, the current study revealed that the orexinergic system, specifically the VTA OX2R, is involved in METH-seeking behaviors and that manipulation of this system can be considered a potential therapeutics in treating METH dependency.

Paternal methamphetamine exposure induces higher sensitivity to methamphetamine in male offspring through driving ADRB1 on CaMKII-positive neurons in mPFC

Paternal abuse of drugs, such as methamphetamine (METH), elevates the risk of developing addiction in subsequent generations, however, its underlying molecular mechanism remains poorly understood. Male adult mice (F0) were exposed to METH for 30 days, followed by mating with naïve female mice to create the first-generation mice (F1). When growing to adulthood, F1 were subjected to conditioned place preference (CPP) test. Subthreshold dose of METH (sd-METH), insufficient to induce CPP normally, were used in F1. Selective antagonist (betaxolol) for β1-adrenergic receptor (ADRB1) or its knocking-down virus were administrated into mPFC to regulate ADRB1 function and expression on CaMKII-positive neurons. METH-sired male F1 acquired sd-METH-induced CPP, indicating that paternal METH exposure induce higher sensitivity to METH in male F1. Compared with saline (SAL)-sired male F1, CaMKII-positive neuronal activity was normal without sd-METH, but strongly evoked after sd-METH treatment in METH-sired male F1 during adulthood. METH-sired male F1 had higher ADRB1 levels without sd-METH, which was kept at higher levels after sd-METH treatment in mPFC. Either inhibiting ADRB1 function with betaxolol, or knocking-down ADRB1 level on CaMKII-positive neurons (ADRB1CaMKII) with virus transfection efficiently suppressed sd-METH -evoked mPFC activation, and ultimately blocked sd-METH-induced CPP in METH-sired male F1. In the process, the p-ERK1/2 and ΔFosB may be potential subsequent signals of mPFC ADRB1CaMKII. The mPFC ADRB1CaMKII mediates paternal METH exposure-induced higher sensitivity to drug addiction in male offspring, raising a promising pharmacological target for predicting or treating transgenerational addiction.

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.

Increased AGE-RAGE axis stress in methamphetamine abuse and methamphetamine-induced psychosis: Associations with oxidative stress and increased atherogenicity.

Methamphetamine (MA)-induced psychosis (MIP) is associated with increased oxidative toxicity (especially lipid peroxidation) and lowered antioxidant defences. Advanced glycation end products (AGEs) cause oxidative stress upon ligand binding to AGE receptors (RAGEs). There is no data on whether MA use may cause AGE-RAGE stress or whether the latter is associated with MIP. This case-control study recruited 60 patients with MA use disorder and 30 normal controls and measured serum levels of oxidative stress toxicity (OSTOX, lipid peroxidation), antioxidant defences (ANTIOX), magnesium, copper, atherogenicity, AGE and soluble RAGE (sRAGE) and computed a composite reflecting AGE-RAGE axis activity. MA dependence and use were associated with elevated levels of AGE, sRAGE, OSTOX/ANTIOX, Castelli Risk Index 1 and atherogenic index of plasma. Increased sRAGE concentrations were strongly correlated with dependence severity and MA dose. Increased AGE-RAGE stress was correlated with OSTOX, OSTOX/ANTIOX and MA-induced intoxication symptoms, psychosis, hostility, excitement and formal thought disorders. The regression on AGE-RAGE, the OSTOX/ANTIOX ratio, decreased magnesium and increased copper explained 54.8% of the variance in MIP symptoms, and these biomarkers mediated the effects of increasing MA concentrations on MIP symptoms. OSTOX/ANTIOX, AGE-RAGE and insufficient magnesium were found to explain 36.0% of the variance in the atherogenicity indices. MA causes intertwined increases in AGE-RAGE axis stress and oxidative damage, which together predict the severity of MIP symptoms and increased atherogenicity.

Calcitriol protects against reductions in striatal serotonin in rats treated with neurotoxic doses of methamphetamine

The present experiments were designed to examine the ability of calcitriol to protect against methamphetamine (METH)-induced reductions in striatal serotonin (5-HT) release and content. Male Fischer-344 rats were administered vehicle or calcitriol (0.3, 1.0, or 3.0 μg/kg, s.c.) once a day for 8 consecutive days. After the seventh day of treatment the animals were given METH (5 mg/kg, s.c.) or saline 4 times in 1 day at 2 h intervals. Seven days after the METH or saline treatments in vivo microdialysis experiments were conducted to measure potassium and d-amphetamine evoked overflow of 5-HT from the striatum. In animals treated with vehicle and METH there were significant reductions in both potassium and d-amphetamine evoked overflow of 5-HT. The 1.0 and 3.0 μg/kg/day doses of calcitriol provided significant protection against the 5-HT depleting effects of METH. A similar pattern of neuroprotection was found for post-mortem tissue levels of 5-HT. The calcitriol treatments did not prevent hyperthermia during the multiple injections of METH, indicating that the protective effects of calcitriol are not due to prevention of METH-induced increases in body temperature. These results suggest that calcitriol can provide significant protection against the 5-HT depleting effects of neurotoxic doses of METH.

Synaptic remodeling of GluA1 and GluA2 expression in the nucleus accumbens promotes susceptibility to cognitive deficits concomitant with downstream GSK3β mediated neurotoxicity in female mice during abstinence from voluntary oral methamphetamine

Stimulant-use disorders can present with long-term cognitive and mental health deficits. Little is known about the underlying molecular mechanisms perpetuating sex differences in cognitive and behavioral deficits in preclinical models of addiction to stimulants such as methamphetamine (MA). The current study investigated the neurochemical shifts underlying sex disparities in MA-induced working memory deficits and an addictive phenotype following abstinence from chronic MA abuse. We used our previously reported mouse model of voluntary oral methamphetamine administration (VOMA) consisting of an acquisition phase (days 1–14) characterized by escalating doses of MA and a binge phase (days 14–28) characterized by static doses. Female VOMA mice exhibited sustained MA consumption during the binge phase, demonstrating sex-specific vulnerabilities to the maintenance of MA addiction. The 8-arm radial maze was used to test spatial working memory performance following abstinence from VOMA. Results indicate working memory deficits correlated to higher MA consumption in females only. Hippocampal and accumbal tissue were collected and analyzed by immunoblotting. Female VOMA mice had decreased GluA1, but not GluA2, in the hippocampus, which may perpetuate synaptic destabilization and working memory deficits. Female-specific increases in GluA1 and p-GSK3β expression in accumbal tissue suggest vulnerability toward abstinence-induced drug craving and heightened downstream neurotoxicity. Our study reveals female-specific neurochemical shifts in hippocampal and accumbal AMPA receptor signaling following abstinence from chronic MA consumption that may perpetuate female susceptibility to MA-induced cognitive deficits. These data demonstrate a novel molecular pathway that would exacerbate memory deficits and perpetuate an addictive phenotype in female populations following MA abuse.