Doses Of Methamphetamine Research Articles

Effect of methamphetamine exposure on sexual behavior and locomotor activity of adult male rats.

Drug addiction and its consequences on social life and behavior is currently a worldwide problem. Methamphetamine (MA) is one of the most abused psychostimulants in the Czech Republic. MA elevates mood, increases concentration, reduces appetite, and promotes weight loss. However, high doses and long-term abuse can induce psychosis, hallucinations, paranoia, violent behavior, and can lead to cardiovascular problems. Regarding its high prevalence and negative impact on health and social life, MA needs to be fully investigated. Previous studies have demonstrated the impairing effect of MA drug abuse on female behavior. However, MA's influence on male sexual behavior is not entirely clear. The aim of this study was to examine the effect of MA exposure on sexual behavior and spontaneous locomotor activity of adult male rats. MA was administrated subcutaneously at a dose of 5 mg/kg daily for a period of 30 days. The control group was exposed to saline (SA) at the same time and same volume. At the end of the application period, exposed male rats were paired with non-treated female rats, and their behavior was recorded for 2 h. Sexual mating behavior was described in terms of mounting frequency, intromission frequency, ejaculation frequency, sniffing time, intromission latency and the post-ejaculatory interval. Spontaneous locomotor activity in postnatally exposed male rats was studied using the Laboras apparatus. Acute doses of MA (1 mg/kg) or SA were administrated to probe the sensitizing effect of previous chronic MA exposure. Afterward, the animal was placed in an unknown environment and monitored for 1 h. Behavior was automatically evaluated using Laboras software by analyzing the following parameters: duration of locomotion (s), duration of immobility (s), rearing (vertical exploratory behavior), time spent grooming (s), average speed (mm/s), and distance traveled (m). Our results indicate that MA administration has a negligible effect on the sexual behavior of adult male rats. However, more experiments have to be performed to examine the influence of MA exposure on spermatogenesis and the behavior of offspring. Data from the Laboras test showed that MA exposure has a significant effect on locomotor activity in both acute as well as subchronic MA application. In conclusion, our results show that administration of MA in adult male rats does not affect sexual performance and motivation but does increase locomotor and exploratory activity in an unknown environment.

Lithium Pharmacology and a Potential Role of Lithium on Methamphetamine Abuse and Dependence.

The effectiveness of lithium salts in neuropsychiatric disorders such as bipolar disorder, Alzheimer's disease, and treatment-resistant depression has been documented in an extensive scientific literature. Lithium inhibits inositol monophosphatase, inositol polyphosphate 1- phosphatase, and glycogen synthase kinase-3 and decreases expression level of tryptophan hydroxylase 2, conceivably underlying the mood stabilizing effects of lithium, as well as procognitive and neuroprotective effects. However, the exact molecular mechanisms of action of lithium on mood stabilizing and pro-cognitive effects in humans are still largely unknown. On the basis of the known aspects of lithium pharmacology, this review will discuss the possible mechanisms underlying the therapeutic effects of lithium on positive symptoms of methamphetamine abuse and dependence. It is possible that lithium treatment reduces the amount of newly synthesized phosphatidylinositol, potentially preventing or reversing neuroadaptations contributing to behavioral sensitization induced by methamphetamine. In addition, it is suggested that exposure to repeated doses of methamphetamine induces hyperactivation of glycogen synthase kinase-3β in the nucleus accumbens and in dorsal hippocampus, resulting in a long-term alterations in synaptic plasticity underlying behavioral sensitization as well as other behavioral deficits in memory-related behavior. Therefore it is clear that glycogen synthase kinase-3β inhibitors can be considered as a potential candidate for the treatment of methamphetamine abuse and dependence.

Voluntary exercise ameliorates anxiogenic effects of acute methamphetamine exposure in Swiss-Webster mice.

The present experiment examined the ability of voluntary exercise (i.e., home-cage wheel running; HCWR) to ameliorate anxiety-like behavior associated with acute methamphetamine exposure in male, Swiss-Webster mice. Mice were permitted access to home-cage running wheels (Exercise), locked home-cage running wheels or no home-cage running wheels (Sedentary) for 6 weeks and then exposed to different methamphetamine doses (vehicle, 0.25, 0.5, or 1.0 mg/kg) once weekly during an 8 h open-field session for 4 weeks. Group differences in hypothalamic-pituitary-adrenal (HPA) activity also were assessed by weighing adrenal glands. It was found that HCWR ameliorated anxiety-like behavior after an injection of either the 0.5 or 1.0 mg/kg methamphetamine dose. Adrenal weights did not differ between Exercise and Sedentary mice. Taken together, these results suggest that voluntary exercise ameliorates the anxiogenic effects of methamphetamine depending on the dose, perhaps via a non-HPA mechanism.

A Single Prior Injection of Methamphetamine Enhances Methamphetamine Self-Administration (SA) and Blocks SA-Induced Changes in DNA Methylation and mRNA Expression of Potassium Channels in the Rat Nucleus Accumbens

The transition from occasional to escalated psychostimulant use is accelerated by prior drug exposure. These behavioral observations may be related to long-lasting transcriptional and/or epigenetic changes induced by the drug pre-exposure. Herein, we investigated if a single methamphetamine (METH) injection would enhance METH self-administration (SA) and impact any METH SA-induced epigenetic or transcriptional alterations. We thus injected a single METH dose (10 mg/kg) or saline to rats before training them to self-administer METH or saline. There were three experimental groups in SA experiments: (1) a single saline injection followed by saline SA (SS); (2) a single saline injection followed by METH SA (SM); and (3) a single METH injection followed by METH SA (MM). METH-pretreated rats escalated METH SA earlier and took more METH than saline-pretreated animals. Both groups showed similar incubation of cue-induced METH craving. Because compulsive METH takers and METH-abstinent rats show differences in potassium (K+) channel mRNA levels in their nucleus accumbens (NAc), we wondered if K+ channel expression might also help to distinguish between SM and MM groups. We found increases in mRNA and protein expression of shaker-related voltage-gated K+ channels (Kv1: Kcna1, Kcna3, and Kcna6) and calcium-activated K+ channels (Kcnn1) in the SM compared to MM rats. SM rats also showed decreased DNA methylation at the CpG-rich sites near the promoter region of Kcna1, Kcna3 and Kcnn1 genes in comparison to MM rats. Together, these results provide additional evidence for potentially using K+ channels as therapeutic targets against METH use disorder.

Time and region-dependent manner of increased brain derived neurotrophic factor and TrkB in rat brain after binge-like methamphetamine exposure

Methamphetamine (MA), a synthetic derivate of amphetamine, has become a major drug of abuse worldwide. This study investigated the effect of binge-like MA dosing (4 x 4 mg/kg, s.c., 2 h (h) apart) at a range of different time points (from 2 h to 7 days after treatment) on brain-derived neurotrophic factor (BDNF) levels and its receptors, TrkB and p75NTR. BDNF levels were significantly increased in the frontal cortex from 2 to 36 h after treatment, returning to normal within 48 h after treatment. In the striatum, BDNF expression was increased at 12 and 24 h after binge-like MA treatment and had returned to normal at 36 h. Increased expression of the TrkB receptor was observed in the frontal cortex at 2, 24 and 48 h after MA treatment and in the striatum at 24 and 48 h after the MA regimen. A significant increase in the p75NTR receptor was also noted in the striatum but not the frontal cortex, and it was less pronounced than the effect on TrkB receptor expression. These findings show that the binge-like regimen of MA affects expression of BDNF and its receptors, particularly the TrkB receptor, in a time and region dependent manner, and highlights the importance of the frontal cortex and the striatum in the response following MA binge-like dosing.

Interaction of stress and stimulants in female rats: Role of chronic stress on later reactivity to methamphetamine

Previous research in humans and animals suggests that prior exposure to stress alters responsivity to drugs of abuse, including psychostimulants. Male rats show an augmented striatal dopamine response to methamphetamine following exposure to chronic unpredictable stress (CUS). Compared to males, female rats have been shown to be highly sensitive to the effects of stimulants and stress independently, however few studies have examined the interaction between stress and stimulants in female rats. Therefore, the current study investigated whether prior exposure to chronic stress potentiated the behavioral and neurochemical responses to an acute injection of methamphetamine in female rats. Adult female Sprague-Dawley rats were either exposed to CUS or left undisturbed (control) and then two weeks later received an injection of 1.0 or 7.5 mg/kg methamphetamine. Based on open field findings, a subsequent group of rats were exposed to CUS or left undisturbed and then two weeks later received 7.5 mg/kg methamphetamine and either dopamine efflux in the dorsal striatum or nucleus accumbens was measured or methamphetamine and amphetamine levels were measured in the brain and plasma. Female rats exposed to CUS traveled greater distances in the open field immediately following an injection of 7.5 mg/kg, but not 1.0 mg/kg, of methamphetamine and then showed high levels or stereotypy similar to control rats. Animals exposed to CUS had significantly greater increases in dorsal striatum dopamine following an acute injection of 7.5 mg/kg methamphetamine compared to control rats, but not in the nucleus accumbens. These differences were not due to group differences in levels of methamphetamine or amphetamine in the brain or plasma. The current findings demonstrate stress-augmented neurochemical responses to a dose of methamphetamine, similar to that self-administered, which increases understanding of the cross-sensitization between stress and methamphetamine in females.

Evaluation the multi-organs toxicity of methamphetamine (METH) in rats

Methamphetamine (METH) is a high stimulant for the nervous system, which is widely abused. Clinical reports indicated that METH has damaging effects on many organs. This study was done to assess the hepatotoxicity, nephrotoxicity and hematotoxicity of METH in rat model. Different doses of METH were used to assess its toxic effects on the liver, kidney and blood in rat model. To evaluate toxicity, serum biochemical markers such as ALT, AST, ALP, Cr, BUN, antioxidant parameters, histopathological examination as well as blood parameters were measured. Administration of METH significantly increased the liver enzymes and induced oxidative damage in the liver, which confirmed by histopathology. Also, in the kidney, minor increases in BUN and Cr and slight oxidative damage were observed. In the blood, METH-induced reduced WBC level and slightly increased RBC and platelet concentrations and RBC indexes. Also, the total antioxidant capacity of the blood dropped. Our finding showed severe liver damage and relatively less kidney damage as well as changes in blood parameters due to methamphetamine administration. Also, this study confirmed that oxidative stress plays key roles in the METH-induced damage.

Parental morphine exposure enhances morphine (but not methamphetamine) preference and increases monoamine oxidase-B level in the nucleus accumbens.

Opioid addiction is one of the most crucial issues in the world. Opioid abuse by parents makes children more prone to many psychological disorders such as drug addiction. Therefore, this study was carried out to examine the effect of morphine exposure 10 days before gestation on morphine and methamphetamine preference in male offspring. Adult Wistar rats (male and female) received morphine orally for 21 days and were drug free for 10 days. Thereafter, they were allowed to mate with either a morphine-abstinent or drug-naive rat. The male offspring were tested for morphine and methamphetamine preference with a three-bottle choice test. Moreover, the rewarding effects of morphine and methamphetamine were evaluated using a conditioned place preference test. To determine the mechanisms underlying these changes, monoamine oxidase-B (MAO-B) level was measured in the nucleus accumbens (NAC). Offspring of morphine-abstinent mothers and offspring of both-abstinent parents were found to consume morphine more than those of other groups, but in the case of methamphetamine, there were no differences. In addition, the offspring of morphine-abstinent parent(s) did not condition with a high dose of morphine in the conditioned place preference test. Administration of methamphetamine induced conditioning at different doses in controls and offspring of one or two morphine-abstinent parent(s), and there were no effects of parental morphine exposure on the dose of methamphetamine that was required for conditioning. Moreover, the level of MAO-B was increased in the NAC of offspring of morphine-abstinent parents as compared with the control group. These results demonstrate that offspring of a morphine-abstinent mother and a drug-naive father and offspring of two morphine-abstinent parents were more susceptible to opioid but not methamphetamine addiction. Moreover, parental morphine consumption did not have any effect on the reinforcing effect of methamphetamine in their offspring but induced morphine tolerance in the offspring. Although the level of MAO-B was elevated in the NAC, this did not correlate with the methamphetamine preference in offspring.

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.

Diffusion Kurtosis Imaging Detects Microstructural Changes in a Methamphetamine-Induced Mouse Model of Parkinson's Disease.

Methamphetamine (METH) abuse is known to increase the risk of Parkinson's disease (PD) due to its dopaminergic neurotoxicity. This is the rationale for the METH model of PD developed by toxic METH dosing (10mg/kg four times every 2h) which features robust neurodegeneration and typical motor impairment in mice. In this study, we used diffusion kurtosis imaging to reveal microstructural brain changes caused by METH-induced neurodegeneration. The METH-treated mice and saline-treated controls underwent diffusion kurtosis imaging scanning using the Bruker Avance 9.4 Tesla MRI system at two time-points: 5days and 1month to capture both early and late changes induced by METH. At 5days, we found a decrease in kurtosis in substantia nigra, striatum and sensorimotor cortex, which is likely to indicate loss of DAergic neurons. At 1month, we found an increase of kurtosis in striatum and sensorimotor cortex and hippocampus, which may reflect certain recovery processes. Furthermore, we performed tract-based spatial statistics analysis in the white matter and at 1month, we observed increased kurtosis in ventral nucleus of the lateral lemniscus and some of the lateral thalamic nuclei. No changes were present at the early stage. This study confirms the ability of diffusion kurtosis imaging to detect microstructural pathological processes in both grey and white matter in the METH model of PD. The exact mechanisms underlying the kurtosis changes remain to be elucidated but kurtosis seems to be a valuable biomarker for tracking microstructural brain changes in PD and potentially other neurodegenerative disorders.

Methamphetamine acutely alters frontostriatal resting state functional connectivity in healthy young adults.

Chronic use of methamphetamine impairs frontostriatal structure and function, which may result in increased incentive-motivational responses to drug cues and decreased regulation of drug-seeking behavior. However, less is known regarding how the drug affects these circuits after acute administration. The current study examined the effects of a single dose of methamphetamine on resting state frontostriatal functional connectivity in healthy volunteers. Participants (n=22, 12 female) completed two sessions in which they received methamphetamine (20mg) and placebo before a resting state scan during functional magnetic resonance imaging. Participants also provided self-report measures of euphoria and stimulation at regular intervals. We conducted seed-based voxelwise functional connectivity analyses using three bilateral striatal seed regions: nucleus accumbens (NAcc), caudate, and putamen and compared connectivity following methamphetamine versus placebo administration. Additionally, we conducted correlational analyses to assess if drug-induced changes in functional connectivity were related to changes in subjective response. Methamphetamine increased NAcc functional connectivity with medial frontal regions (ie, orbitofrontal cortex, medial frontal gyrus, and superior frontal gyrus) and decreased NAcc functional connectivity with subgenual anterior cingulate cortex (ACC). Methamphetamine also increased functional connectivity between putamen and left inferior frontal gyrus (IFG), and individuals who displayed greater drug-induced increase in connectivity reported less euphoria and stimulation. These findings provide important information regarding the effects of methamphetamine on brain function in nonaddicted individuals. Further studies will reveal whether such effects contribute to the abuse potential of the drug and whether they are related to the frontostriatal impairments observed after chronic methamphetamine use.

Thyroid hormone treatment alleviates the impairments of neurogenesis, mitochondrial biogenesis and memory performance induced by methamphetamine

Chronic use of methamphetamine (MA), a neurotoxic psychostimulant, leads to long-lasting cognitive dysfunctions in humans and animal models. Thyroid hormones (THs) have several physiological actions and are crucial for normal behavioral, intellectual and neurological development. Considering the importance of THs in the cognitive processes, the present study was designed to evaluate the therapeutic effects of THs on cognitive and neurological impairments induced by MA. Escalating doses of MA (1–10 mg/kg, IP) were injected twice daily for 10 consecutive days in rats and cognitive functions were evaluated using behavioral tests. The expression of factors involved in neurogenesis (NES and DCX), mitochondrial biogenesis (PGC-1α, NRF-1, and TFAM), neuroinflammation (GFAP, Iba-1, and COX-2) as well as Reelin and NT-3 (synaptic plasticity and neurotrophic factor, respectively) was measured in the hippocampus of MA-treated animals. The effects of three different doses of T4 (20, 40 or 80 μg/kg; intraperitoneally) or T3 (20, 40 or 80 μg/rat; 2.5 μl/nostril; intranasal) treatment, once a day for one week after MA cessation, were assessed in MA-treated rats. After the last behavioral test, serum T4 and T3 levels were measured using radioimmunoassay. The results revealed that repeated escalating regimen of MA impaired cognitive functions concomitant with neurogenesis and synaptic plasticity impairments, mitochondrial dysfunction, and neuroinflammation. T4 or T3 treatment partially decreased the alterations induced by MA. These findings suggest that THs can be considered as potential candidates for the reduction of MA abuse related neurocognitive disturbances.

A history of ethanol drinking increases locomotor stimulation and blunts enhancement of dendritic dopamine transmission by methamphetamine.

Ethanol and psychostimulant use disorders exhibit comorbidity in humans and cross-sensitization in animal models, but the neurobiological underpinnings of this are not well understood. Ethanol acutely increases dopamine neuron excitability, and psychostimulants such as cocaine or methamphetamine increase extracellular dopamine through inhibition of uptake through the dopamine transporter (DAT) and/or vesicular monoamine transporter 2 (VMAT2). Psychostimulants also depress dopamine neuron activity by enhancing dendritic dopamine neurotransmission. Here, we show that mice with a previous history of ethanol drinking are more sensitive to the locomotor-stimulating effects of a high dose (5mg/kg), but not lower doses (1 and 3mg/kg) of methamphetamine or any tested dose of cocaine (3, 10, and 18mg/kg), compared with water-drinking controls. We next investigated the impact of a history of ethanol drinking, in a separate group of mice, on methamphetamine- or cocaine-induced enhancement of dendritic dopamine transmission using whole-cell voltage clamp electrophysiology in mouse brain slices. Methamphetamine, applied at a concentration (10μM) that affects both DAT and VMAT2, enhanced D2 receptor-mediated inhibitory postsynaptic currents (D2-IPSCs) in both groups, but this effect was blunted in mice with a history of ethanol drinking. As methamphetamine action at VMAT2 disrupts dopamine neurotransmission, these results may suggest enhanced action of methamphetamine at VMAT2. Furthermore, there were no differences in low-dose methamphetamine or cocaine-induced enhancement of D2-IPSCs, suggesting intact DAT function. Disruption of methamphetamine-induced enhancement of dendritic dopamine transmission would result in decreased inhibition of dopamine neurons, ultimately increasing downstream release and the behavioral effects of methamphetamine.

Are women interested in Acupressure to increase spontaneous onset of labour?

Methamphetamine (METH) abuse by pregnant women is a commonly observed phenomenon. While the harmful effects of METH are well described for adults, there is only limited knowledge of the effects of METH use during pregnancy on the developing child. In the present study, we investigated how intraveneous (iv) METH self-administration throughout pregnancy affected rat dams and their offspring through weaning, compared to controls.Female rats (n = 16) were trained to self-administer METH iv; every drug infusion by a dam also resulted in a saline injection to a yoked control (n = 16). When stable levels of self-administration were reached, all females were mated. Daily, 2-h self-administration sessions continued until litters were born. General health and weight was assessed daily in dams and pups. In addition, pups were evaluated for achievement of age-appropriate developmental milestones (i.e., righting reflex, negative geotaxis, pinna detachment, fur appearance, incisor eruption and eye opening).Dams self-administered 2–3 mg/kg/day METH throughout gestation without consequence to dam health or weight gain during pregnancy. All females produced viable litters, and litter size and composition did not differ between saline and METH dams. Similarly, maternal pup-directed behavior was not affected by prior METH self-administration. However, despite a lack of weight difference in pups, METH-exposed pups were significantly delayed in reaching all assessed developmental milestones compared to controls.These results indicate that in utero exposure to moderate METH doses can profoundly and adversely affect offspring development, suggesting that even recreational METH use during pregnancy has potential for harm.

The Effects of Eating a High Fat Diet on Methamphetamine‐Induced Conditioned Place Preference

Eating a high fat diet can cause several negative health consequences, including dysfunction to dopamine systems. For example, eating a high fat diet enhances sensitivity of rats to methamphetamine‐induced locomotion. However, it is not known if sensitivity to the rewarding effects of methamphetamine are similarly enhanced in rats eating a high fat diet. Females are more sensitive than males to the behavioral effects of stimulants in general, and therefore might also be particularly vulnerabile to high fat diet‐induced enhanced sensitivity to stimulant drugs. To test the hypothesis that eating high fat chow enhances sensitivity of rats to the rewarding effects of methamphetamine, female Sprague‐Dawley rats were fed standard laboratory chow (17% kcal from fat) or high fat chow (60% kcal from fat) for 4 weeks prior to conditioned place preference (CPP) training, using a biased design. Rats were trained on alternating days rats with saline or methamphetamine (0.32 or 1.0 mg/kg, i.p.) and were restricted to one of two sides (wire mesh vs rod flooring) of a CPP apparatus. After 8 alternating training days, rats had free access to the entire apparatus, and time spent in the drug‐paired side versus the saline‐paired side was examined. Methamphetmaine induced a significant CPP in all rats, regardless of diet or dose of methamphetamine; however, there were no differences in magnitude of CPP between rats eating high fat chow and rats eating standard chow. Previous literature suggests that females might be more sensitive to the rewarding effects of methamphetamine, necessitating the use of smaller doses. As such, future studies will examine a wider range of doses of methamphetamine, as well as other conditioned behavior (i.e., self‐administration) and will include male subjects to study potential sex differences.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Role of venlafaxine in relapse to methamphetamine seeking. Potential treatment option for drug dependence.

Objectives:To investigate the effects of venlafaxine (VEN) on the relapse of methamphetamine (METH)-induced conditioned place preference (CPP) in rats.Methods:This study was conducted at the Department of Pharmacology and Toxicology, and the Addiction and Neuroscience Research Unit, College of Pharmacy, Taif University, Taif, Kingdom of Saudi Arabia between May 2017 and October 2018. A total of 32 male Wistar rats were used in this study. Rats were divided to receive either METH or saline during the conditioning phase. Following the acquisition of METH-induced CPP, the animals were randomly divided to receive saline or VEN for 21 days instead of METH during the extinction training. The reinstatement was initiated by re-exposure to a single dose of METH to test any anti-reinstatement effects of VEN.Results:Two-way repeated measures Analysis of Variance (ANOVA) (time × chamber) was used to analyze time spent in conditioning chambers, while distance traveled was analyzed using one-way ANOVA. Saline or VEN, when administered alone, did not affect CPP or locomotor activity results. A priming intraperitoneal injection of METH reinstated CPP in the animals treated with saline during the extinction phase. Interestingly, VEN treatment blocked METH-induced CPP.Conclusion:Venlafaxine effects on the reinstatement of METH-induced CPP are not likely due to nonspecific effects on locomotor activity. This beneficial effect of VEN on relapse to METH-induced CPP could be due to its antidepressant effects. Venlafaxine can thus be a potential therapeutic option in the treatment of relapse to METH-seeking behaviors.

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.

Different doses of methamphetamine alter long-term potentiation, level of BDNF and neuronal apoptosis in the hippocampus of reinstated rats.

Methamphetamine (METH) is a psychostimulant. The precise mechanisms of its effects remain unknown and current relapse treatments have low efficacy. However, brain-derived neurotrophic factor (BDNF) and neuronal plasticity are essential contributors, despite paradoxical reports and a lack of comprehensive studies. Therefore, we investigated the effects of different doses of METH on long-term potentiation (LTP), BDNF expression and neuronal apoptosis in the hippocampus of reinstated rats. Rats were injected intraperitoneally with METH (1, 5, or 10mg/kg) or saline, and trained in a conditioned place preference paradigm. Following implementation of the reinstatement model, electrophysiology, western blotting and TUNEL assay were performed to assess behavior, LTP components, BDNF expression, and neuronal apoptosis, respectively. The results demonstrated that the preference scores, population spike amplitude and BDNF expression markedly decreased in the METH (10mg/kg) group compared with the other groups. In contrast, METH (5mg/kg) significantly increased these factors more than the control group. There was no change in variables between METH (1mg/kg) and the control group. Also, apoptosis of the hippocampus was increased in the METH (10mg/kg) group compared with the METH (5mg/kg) group. These results suggest that alterations in synaptic plasticity, expression of BDNF and neuronal apoptosis in the hippocampus has a vital role in the context-induced reinstatement of METH seeking.

Effect of acute and chronic restraint stress on electrical activity of prefrontal cortex neurons in the reinstatement of extinguished methamphetamine-induced conditioned place preference: An electrophysiological study

Increased vulnerability to drug abuse has been observed after exposure to stress and the prefrontal cortex (PFC) plays a major role in the control of the stress response and reward pathway. The current study was conducted to clarify the effects of acute and chronic restraint stress on PFC neural activity during the reinstatement of methamphetamine (METH)-induced conditioned place preference (CPP) in rats. Following the establishment of CPP (METH 0.5 mg/kg; s.c. for 3 days) and the extinction phase, male Wistar rats were divided into threshold (0.25 mg/kg; s.c.) and sub-threshold (0.125 mg/kg; s.c.) METH-treated super groups to induce reinstatement. Each super group contained control (non-stressed), acute restraint stress (ARS) and chronic restraint stress (CRS) groups. in vivo single unit recordings were performed on the urethane-anesthetized rats in these groups. After baseline recordings (10-min period) of the neurons in the PFC, their firing activity was recorded for 50 min during the reinstatement phase after injection of METH. The results showed that the threshold dose, but not the sub-threshold dose, of METH significantly increased PFC neural activity in the non-stressed animals. The sub-threshold dose of METH notably changed this activity in both the ARS and CRS groups. These changes in the excited neurons after the sub-threshold dose in the ARS and CRS groups were significantly higher than those in the non-stressed group. It appears that the PFC is implicated in the associated reward pathway and stress functions. METH affected the firing rate of PFC neurons and stress amplified the effect of METH on changes in the neuronal firing rate in the PFC.

Effects of methamphetamine on neural responses to visual stimuli.

The behavioral and reward-related effects of stimulant drugs have been studied extensively; yet the effect of stimulants on sensory processing is still relatively unknown. Prior brain imaging studies have shown that single doses of stimulant drugs increase neural function during cognitive and attentional processes. However, it is not clear if stimulant drugs such as methamphetamine (MA) affect neural responses to novel sensory stimuli, and whether these effects depend on the visual features of the stimuli. In this study, we examined the effects of a single dose of MA (20mg oral) on neural activation in response to visual stimuli that varied on "non-straight edges" (NSE), a low-level visual feature that quantifies curved/fragmented edges and is related to perceived image complexity. Healthy adult participants (n = 18) completed two sessions in which they received MA and placebo in counterbalanced order before an fMRI scan where they viewed both high and low NSE images. Participants also completed measures of subjective drug effects throughout both sessions. During both sessions, high NSE images activated primary visual cortex to a greater extent than low NSE images. Further, MA increased activation only for low NSE images in three areas of visual association cortex: left fusiform, right cingulate/precuneus, and posterior right middle temporal gyrus. This interaction was unrelated to subjective drug effects. These findings suggest that stimulant drugs may change the relative sensitivity of higher order sensory processing to increase visual attention when viewing less complex stimuli. Moreover, MA-induced alterations in this type of sensory processing appear to be independent of the drugs' ability to increase feelings of well-being.