D-amphetamine Sulfate Research Articles

Amphetamine increases vascular permeability by modulating endothelial actin cytoskeleton and NO synthase via PAR-1 and VEGF-R

Abuse of amphetamine-type stimulants is linked to cardiovascular adverse effects like arrhythmias, accelerated atherosclerosis, acute coronary syndromes and sudden cardiac death. Excessive catecholamine release following amphetamine use causes vasoconstriction and vasospasms, over time leading to hypertension, endothelial dysfunction or even cardiotoxicity. However, immediate vascular pathomechanisms related to amphetamine exposure, especially endothelial function, remain incompletely understood and were analyzed in this study. Pharmaco-pathological effects of acute d-amphetamine-sulfate (DAM) were investigated ex vivo using contraction–force measurements of rat carotid artery rings and in vitro using label-free, real-time electrochemical impedance spectroscopy (EIS) on endothelial and smooth muscle cells. Specific receptor and target blocking was used to identify molecular targets and to characterize intracellular signaling. DAM induced vasodilation represented by 29.3±2.5% decrease in vascular tone (p<0.001) involving vascular endothelial growth factor receptor (VEGF-R) and protease activated receptor 1 (PAR-1). EIS revealed that DAM induces endothelial barrier disruption (−75.9±1.1% of initial cellular impedance, p<0.001) also involving VEGF-R and PAR-1. Further, in response to DAM, Rho-associated protein kinase (ROCK) mediated reversible contraction of actin cytoskeleton resulting in endothelial barrier disruption. Dephosphorylation of Serine1177 (−50.8±3.7%, p<0.001) and Threonine495 (−44.8±6.5%, p=0.0103) of the endothelial NO synthase (eNOS) were also observed. Blocking of VEGF-R and PAR-1 restored baseline eNOS Threonine495 phosphorylation. DAM induced vasodilation, enhanced vascular permeability and actin cytoskeleton contraction and induced eNOS hypophosphorylation involving VEGF-R, PAR-1 and ROCK. These results may contribute to a better understanding of severe adverse cardiovascular effects in amphetamine abuse.

Hyperdopaminergia in rats is associated with reverse effort-cost dependent performance.

Dopamine is implicated in the effort-based control of motivational processes; however, whether tonic dopamine regulates the effort-cost impact on motivation, is still debated. The rats lacking the dopamine transporter (DAT), which have dramatically increased levels of the synaptic dopamine, were used in the present study to elucidate the role of the synaptic dopamine in motivational processes. To study the reward-related processes, the progressive ratio 3 (PR3) operant schedule of food reinforcement (the ratio increases by 3 after each earned reinforcer) was performed in adult male rats (DAT knockouts (DAT-KO), heterozygotes (DAT-HT) and wild-types (DAT-WT)). During the PR3 session, the response rate of DAT-KO rats was gradually increased following the augmented required number of responses. In contrast, the local response rate of DAT-WT and DAT-HT decreased. d-Amphetamine sulfate salt (3 mg/kg, i.p.) altered the local response rate dynamics in DAT-WT, which became similar to that of DAT-KO. Interestingly, the reduction in response rate at low effort demands was associated with decreased rate of entries into the magazine tray in DAT-WT rats treated with amphetamine (3 mg/kg) but not in DAT-KO rats. Our results suggest that the elevated tonic synaptic dopamine can strongly affect motivation/effort-cost relation in rodents.

Agathobaculum butyriciproducens Shows Neuroprotective Effects in a 6-OHDA-Induced Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is the second-most prevalent neurodegenerative disease and is characterized by dopaminergic neuronal death in the midbrain. Recently, the association between alterations in PD pathology and the gut microbiota has been explored. Microbiota-targeted interventions have been suggested as a novel therapeutic approach for PD. Agathobaculum butyriciproducens SR79T (SR79) is an anaerobic bacterium. Previously, we showed that SR79 treatment induced cognitive improvement and reduced Alzheimer's disease pathologies in a mouse model. In this study, we hypothesized that SR79 treatment may have beneficial effects on PD pathology. To investigate the therapeutic effects of SR79 on PD, 6-hydroxydopamine (6-OHDA)-induced mouse models were used. D-Amphetamine sulfate (d-AMPH)-induced behavioral rotations and dopaminergic cell death were analyzed in unilateral 6-OHDA-lesioned mice. Treatment with SR79 significantly decreased ipsilateral rotations induced by d-AMPH. Moreover, SR79 treatment markedly activated the AKT/GSK3β signaling pathway in the striatum. In addition, SR79 treatment affected the Nrf2/ARE signaling pathway and its downstream target genes in the striatum of 6-OHDA-lesioned mice. Our findings suggest a protective role of SR79 in 6-OHDA-induced toxicity by regulating the AKT/Nrf2/ARE signaling pathway and astrocyte activation. Thus, SR79 may be a potential microbe-based intervention and therapeutic strategy for PD.

NMDA Receptor‐ Mediated Release of Norepinephrine and Dopamine in Rat Brain: Effects of Ageing

A greater understanding of the neural changes occurring in the aging brain can facilitate the identification of possible molecular target(s) for pharmacological intervention to offset age-related cognitive deficits. Selective age-related vulnerabilities of glutamate neurotransmission have been found, as well as studies indicating age-related changes in the interaction between glutamate and other neurotransmitters (e.g. norepinephrine, dopamine). Previously, we have demonstrated that in brains from aged Fischer 344 rats, a model of neurocognitive aging, there is a marked deficit in glutamate-stimulated norepinephrine (NE) release measured in vitro in the hippocampus and cerebral cortex, and that this deficit is rescued by the addition of d-amphetamine sulfate (Dezfuli et al., 2019). Thus, amphetamine potentiates glutamate-stimulated NE release (and possibly release of other neurotransmitters). The purpose of the present study was to expand on our previous findings by (a) determining if glutamate-stimulated NE release is mediated by NMDA receptors and (b) investigating if there is a comparable deficit in glutamate-stimulated dopamine (DA) release in the aged Fischer 344 rat brain and whether it can also be rescued by amphetamine. To this end, experiments were performed in both young (2-3 months old) and aged Fischer 344 rats (18-22-month-old). The cerebral cortex was used for measuring glutamate-stimulated NE release, and the olfactory tubercle and striatum were used for measuring glutamate-stimulated DA release. Our results show that glutamate-stimulated NE release in the rat cortex is mediated exclusively by NMDA receptors. Results from the dopamine studies are ongoing and will be reported.

The Decline of Glutamate‐Stimulated Norepinephrine Release in Aging Rat Brain

Unravelling and understanding the molecular and neurochemical changes of the aging brain is key to early intervention strategies. Glutamate (Glu) neurotransmission, the major excitatory neurotransmitter in the brain, is mechanistically involved in memory, learning performance, and other aspects of cognition. Moreover, as the brain ages, the glutamatergic signaling system mediated through brain N‐methyl‐D‐aspartate (NMDA) receptors becomes hypofunctional, and this decline may be associated with cognitive dysfunction in normal aging and in disease states. We have developed an in vitro assay that measures Glu‐stimulated release of neurotransmitters in rat brain slices. Using this assay, we compared changes in Glu‐stimulated release of [3H]‐norepinephrine (NE) from the cerebral cortex and hippocampus in young (2–3 months old) versus old (21–23 months old) Fischer F344 rats. Our findings demonstrate that that there is a pronounced deficit (approximately 30–40%) of Glu‐stimulated [3H]‐NE release in the aged rat brain in comparison to younger controls. In the same tissues, potassium (K+) stimulated‐NE release is similar in brains from young and old rats, suggesting that the age‐related decline in in Glu‐stimulated NE release is related to a change in NMDA receptors. Notably, the deficit in Glu‐stimulated [3H]‐NE release in both brain regions was completely rescued by the addition of 1 uM d‐amphetamine sulfate to the tissue slices. Overall, these findings reveal an important deficit in NE release in the aging brain, which may have important implications for cognitive dysfunction in aging. Moreover, this deficit can be reversed with amphetamine and possibly with similar drugs. These studies have clear clinical implications for the use of CNS stimulants as a therapeutic intervention for early cognitive impairment.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Characterization of locomotor response to psychostimulants in the parthenogenetic marbled crayfish (Procambarus fallax forma virginalis): A promising model for studying the neural and molecular mechanisms of drug addiction

Although scientific research using mammalian models has made great strides in uncovering the enigmatic neural and molecular mechanisms orchestrating the state of drug addiction, a complete understanding has thus far eluded researchers. The complexity of the task has led to the use of invertebrate model systems to complement the research of drug-induced reward in mammalian systems. Invertebrates, such as crayfish, offer excellent model systems to help reveal the underlying mechanisms of drug addiction as they retain the ancestral neural reward circuit that is evolutionarily conserved across taxa, and they possess relatively few, large neurons, laid out in an accessible, modularly organized nervous system. Crayfish offer the benefits of delineated developmental life stages, a large body size suitable for a variety of experimental methods, and stereotyped behaviors. Unique among crayfish is the parthenogenetic marbled crayfish (Procambarus fallax forma virginalis), a species of asexually reproducing, genetically identical clones. With the benefits of reduced individual variation, high fecundity, and easy lab husbandry, the marbled crayfish would make a particularly powerful addition to the animal model repertoire. Here we characterize the locomotor response of juvenile P. f. f. virginalis exposed to the psychostimulant, d-amphetamine sulfate. Custom video-tracking software was used to record the movement patterns of juveniles exposed to water infused with varying concentrations of d-amphetamine sulfate. ANOVA demonstrated that crayfish locomotion was significantly impacted by drug concentration. These psychostimulant effects provide the foundation of P. f. f. virginalis as a model for parsing the neural and molecular mechanisms of drug addiction.

False-negative results in the immunoassay analysis of drugs of abuse: can adulterants be detected by sample check test?

Background The dilution or adulteration of urine is a serious problem in drugs of abuse testing. Tests to identify adulteration are currently available. This study investigated the ability of the CEDIA® sample check to detect adulteration. Methods Eight different drugs of abuse were added to a urine sample obtained from a healthy, drug-free subject: 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), 3,4-methylenedioxyamphetamine, benzoylecgonine, D-amphetamine sulphate, ethyl-D-glucuronide, morphine sulphate, oxazepam, (-)-11-nor-9-carboxy-Δ9-tetrahydrocannabinol. Urine samples were diluted to yield three samples of drugs of abuse concentrations close to general cut-offs as used in methadone treatment centres, by health authorities for psychological tests and in traffic medicine. Aspirin, citric acid, CrO3, H2O2, soap, sodium metaborate, vitamin C were added in three, HCl and NaOH in one, and NaN3 in two concentrations. All samples were measured with commercially available immunological assays shortly after sample preparation and 24 h later. All samples were further analysed with the CEDIA® sample check reaction which may identify adulteration. Results Oxidizing reagents (H2O2 or CrO3) are most effective in interfering in the measurement of benzoylecgonine, EDDP, ethyl-D-glucuronide and morphine sulphate. The measurement of (-)-11-nor-9-carboxy-Δ9-tetrahydrocannabinol is affected by many adulterants. Adulteration with HCl and NaOH was identified with the sample check reaction. NaN3 generated false negative results for a number of drugs of abuse. Conclusions Urine samples with drugs of abuse concentrations above cut-offs can be successfully tampered with adulterants in a way which cannot be detected with the CEDIA® sample check assay.

Dopamine dependent setting of a circadian oscillator underlying the memory for time of day

Animals learn and remember the time of day that significant conditions occur, and anticipate recurrence at 24-h intervals, even after only one exposure to the condition. On several place-conditioning tasks, animals show context avoidance or preference only near the time of day of the experience. The memory for time of day is registered by a circadian oscillator that is set at the time of the training. We show that manipulations of dopamine (DA) neurotransmission can set a time memory in place preference and avoidance tasks, indicating that time of day is part of the context that is learned. Single injections of the DA agonist, d-amphetamine sulfate given without further exposure to the conditioning apparatus, can reset the timing of anticipatory behavior evoked by previously acquired place-event associations. The data support a model for time memory in which DA signaling sets the phase of a circadian oscillator, which returns to the same state at regular 24-h intervals. The data also raise the possibility that some apparent impairments of memory formation or retention could reflect post-experience resetting of the optimal retrieval time rather than impairment of memory or retrieval per se.

Mechanistic assessment of the analgesic, anti-inflammatory and antipyretic actions of Dalbergia saxatilis in animal models

Context: Aqueous root extract of Dalbergia saxatilis, Hook, f., (Leguminosae) (DS) is reported useful for toothache, pains, and fever, but not scientifically proven. Objective: This study determined its effectiveness in pain, inflammation, and fever, applying scientific models. Materials and methods: Swiss mice or Sprague–Dawley rats (n = 5) were pretreated with distilled water, DS (100 or 200 mg/kg), or standard drug for 30 min. The analgesic activity was measured by acetic acid writhing, tail flick, tail immersion, tail clip, hot plate, and formalin pain tests; anti-inflammatory effects were determined via carrageenan and dextran rat paw oedema tests; antipyretic activity was measured by Escherichia coli lipopolysaccharide (ECL) and turpentine in rabbits, and d-amphetamine sulphate (d-AS) pyrexia test in rats. Results: Writhing frequency inhibition was produced by 200 mg/kg DS (33.10%), aspirin (38.19%) and morphine (93.68%). Unlike morphine, DS did not produce significant prolongation of the reaction times in the hot-plate, tail immersion, tail flick, and tail clip tests. In the first and second phases of formalin test, respectively, % inhibition was: 200 mg/kg DS (25.70% and 0%), aspirin (4.76% and 67.33%), morphine (81.42% and 66.11%); for carrageenan and dextran tests, significant difference was recorded between 200 mg/kg DS and control up to 6 h. Significant reduction in ECL, turpentine and d-AS pyrexia was recorded at 100 and 200 mg/kg DS. Conclusion: DS produces mild non-steroidal analgesic and anti-inflammatory, as well as significant antipyretic actions involving cyclooxygenase, α2 adrenoceptor and interleukin-1 β1 due to any of glycosides, saponins or phenolic tannins.

Sex, drugs, and adult neurogenesis: Sex‐dependent effects of escalating adolescent cannabinoid exposure on adult hippocampal neurogenesis, stress reactivity, and amphetamine sensitization

Cannabinoid exposure during adolescence has adverse effects on neuroplasticity, emotional behavior, cognition, and reward sensitivity in adult rats. We investigated whether escalating doses of the cannabinoid receptor 1 (CB1 R) agonist, HU-210, in adolescence would affect adult hippocampal neurogenesis and behavioral processes putatively modulated by hippocampal neurogenesis, in adult male and female Sprague-Dawley rats. Escalating doses of HU-210 (25, 50, and 100 µg/kg), or vehicle were administered from postnatal day (PND) 35 to 46. Animals were left undisturbed until PND 70, when they were treated with 5-bromo-2-deoxyuridine (BrdU; 200 mg/kg) and perfused 21 days later to examine density of BrdU-ir and BrdU/NeuN cells in the dentate gyrus. In another cohort, hypothalamic-pituitary-adrenal (HPA) axis reactivity to an acute restraint stress (30 min; PND 75) and behavioral sensitization to d-amphetamine sulfate (1-2 mg/kg; PND 105-134) were assessed in adulthood. Adolescent HU-210 administration suppressed the density of BrdU-ir cells in the dentate gyrus in adult male, but not adult female rats. Adolescent HU-210 administration also induced significantly higher peak corticosterone levels and reminiscent of the changes in neurogenesis, this effect was more pronounced in adult males than females. However, adolescent cannabinoid treatment resulted in significantly higher stereotypy scores in adult female, but not male, rats. Thus, adolescent CB1 R activation suppressed hippocampal neurogenesis and increased stress responsivity in adult males, but not females, and enhanced amphetamine sensitization in adult female, but not male, rats. Taken together, increased CB1 R activation during adolescence results in sex-dependent, long-term, changes to hippocampal structure and function, an effect that may shed light on differing vulnerabilities to developing disorders following adolescent cannabinoid exposure, based on sex.

Lattice Dynamics through the Structural Phase Transition in d-Amphetamine Sulfate

The polarized infrared and Raman spectra of the single-crystalline D-amphetamine sulfate have been measured as a function of temperature in the vicinity of the structural phase transition. Infrared and Raman-active modes are identified and assigned. Significant signatures of the structural phase transition are observed in the temperature dependence of infrared modes both of the D-amphetamine unit and the sulfate anion. The changes reflect differences in the unit cell between low- and high-temperature phases of the D-amphetamine sulfate. Temperature dependence of the vibrational mode parameters displays pronounced hysteresis between 333 and 338 K that is extended over a smaller temperature range than 325-345 K found in the earlier DSC study.

Prenatal Amphetamine Exposure Effects on Dopaminergic Receptors and Transporter in Postnatal Rats

We investigated the influence of prenatal amphetamine exposure (PAE) on dopamine (DA) receptors, and dopamine transporter (DAT) in various striatal and limbic subregions and locomotor activity induced by novel environmental conditions and amphetamine at two postnatal ages, 35 days old (prepubertal) and 60 days old (postpubertal). Experiments were carried out on pregnant female Sprague-Dawley rats, which were daily injected with either d-amphetamine sulfate (1 mg/kg) or saline solution (0.9%) for 11 days, from gestation day 11-21. In PAE rats compared to control we found the following: at pre-pubertal age, an enhancement of DA D1 in the dorsolateral area of the caudate-putamen (CPu), CPu-ventral and shell of the nucleus accumbens (NAcc) with a decrement of the DA D3 receptors in NAcc, olfactory tubercle (OT), and the islands of Calleja (IoC); whereas at postpubertal age, an increase in the levels of DAT in the NAcc and fundus of the CPu, and OT along with a decrease in the expression of DA D2 receptors only in the NAcc shell were found in PAE rats compared to control. In addition, amphetamine induces a marked decrease in locomotor activity at postpubertal age in rats with PAE. These results suggest a differential effect of amphetamines on the DAT mechanism of the nervous system during embryonic development of animals with implications in behavior and drug addictions at adulthood age.

In Vitro and in Vivo Enhanced Generation of Human A9 Dopamine Neurons from Neural Stem Cells by Bcl-XL

Human neural stem cells derived from the ventral mesencephalon (VM) are powerful research tools and candidates for cell therapies in Parkinson disease. Previous studies with VM dopaminergic neuron (DAn) precursors indicated poor growth potential and unstable phenotypical properties. Using the model cell line hVM1 (human ventral mesencephalic neural stem cell line 1; a new human fetal VM stem cell line), we have found that Bcl-X(L) enhances the generation of DAn from VM human neural stem cells. Mechanistically, Bcl-X(L) not only exerts the expected antiapoptotic effect but also induces proneural (NGN2 and NEUROD1) and dopamine-related transcription factors, resulting in a high yield of DAn with the correct phenotype of substantia nigra pars compacta (SNpc). The expression of key genes directly involved in VM/SNpc dopaminergic patterning, differentiation, and maturation (EN1, LMX1B, PITX3, NURR1, VMAT2, GIRK2, and dopamine transporter) is thus enhanced by Bcl-X(L). These effects on neurogenesis occur in parallel to a decrease in glia generation. These in vitro Bcl-X(L) effects are paralleled in vivo, after transplantation in hemiparkinsonian rats, where hVM1-Bcl-X(L) cells survive, integrate, and differentiate into DAn, alleviating behavioral motor asymmetry. Bcl-X(L) then allows for human fetal VM stem cells to stably generate mature SNpc DAn both in vitro and in vivo and is thus proposed as a helpful factor for the development of cell therapies for neurodegenerative conditions, Parkinson disease in particular.

Amphetamine treatment during early postnatal development transiently restricts somatic growth

Aims Restricted somatic growth during fetal or early postnatal periods has been suggested to serve as a predictive indicator for neuroanatomical changes and behavioral impairments during adulthood. Here, the effects of d-amphetamine sulfate (AMPH) exposure during the brain growth spurt period on this potential indicator were evaluated. Main methods Rats received 0, 5, 15 or 25 mg/kg/day of AMPH via two daily intragastric intubations from PD4-9. Body weight data were collected every other day from PD1 to 21, and then weekly until PD59. On PD9, a subset of animals was terminated 90 min after the last amphetamine treatment and the weights of the cortex, cerebellum, and brainstem were collected. Weights of these brain regions from young adult rats were also assessed on PD68. Key findings AMPH exposure during early postnatal development limited somatic growth in a dose-related manner, with significantly lower body weights in animals assigned to the AMPH 25 and AMPH 15 groups. However, this was transient in nature, with no significant difference in weight observed after pups were weaned on PD21. Further, no differences in brain weight were observed at either age as a result of AMPH exposure. Significance These findings support the idea that developmental AMPH exposure transiently restricts somatic growth. Moreover, the lack of effect on brain weight shows that AMPH differentially affects somatic and brain growth. The current findings suggest that in addition to the immediate effects on body weight, amphetamine may alter the rate of growth, and increase the risk for weight-related adult diseases.

Acute neuroactive drug exposures alter locomotor activity in larval zebrafish

As part of the development of a rapid in vivo screen for prioritization of toxic chemicals, we have begun to characterize the locomotor activity of zebrafish ( Danio rerio) larvae by assessing the acute effects of prototypic drugs that act on the central nervous system. Initially, we chose ethanol, d-amphetamine, and cocaine, which are known, in mammals, to increase locomotion at low doses and decrease locomotion at higher doses. Wild-type larvae were individually maintained in 96-well microtiter plates at 26 °C, under a 14:10 h light:dark cycle, with lights on at 0830 h. At 6 days post-fertilization, ethanol (1–4% v/v), d-amphetamine sulfate (0.1–20.0 µM) or cocaine hydrochloride (0.2–50.0 µM) were administered to the larvae by immersion. Beginning 20 min into the exposure, locomotion was assessed for each animal for 70 min using 10-minute, alternating light (visible light) and dark (infrared light) periods. Low concentrations of ethanol and d-amphetamine increased activity, while higher concentrations of all three drugs decreased activity. Because ethanol effects occurred predominately during the light periods, whereas the d-amphetamine and cocaine effects occurred during the dark periods, alternating lighting conditions proved to be advantageous. These results indicate that zebrafish larvae are sensitive to neuroactive drugs, and their locomotor response is similar to that of mammals.

Neonatal amphetamine exposure and hippocampus-mediated behaviors

Previous studies linking amphetamine use during pregnancy to changes in the behavioral development of affected infants have greatly increased society’s level of concern regarding amphetamine use by women of reproductive age. The aim of this study was to investigate whether exposure to d-amphetamine sulfate during the brain growth spurt, the most dynamic period of brain development, alters hippocampus-mediated behaviors during both pre-adolescence and young adulthood. Sprague–Dawley rat pups were intragastrically administered a milk formula containing 0, 5, 15 or 25 mg/kg/day of amphetamine from postnatal day (PD) 4–9. Following weaning, the effects of neonatal amphetamine exposure on hippocampus-mediated behaviors were assessed using the open-field, the water maze, and the conditioned taste aversion behavioral tasks. Results from these behavioral tests revealed that while amphetamine exposure during the brain growth spurt alters behaviors in open-field testing, it does not interfere with performance in either the water maze or the conditioned taste aversion paradigm. These results offer speculation that the effects of neonatal amphetamine exposure on hippocampus-mediated behaviors may be related to interactions between the “temporal” (time of drug exposure) and “regional” (different regions of the hippocampus) vulnerability issues.

The crystal structure and evidence of the phase transition in d-amphetamine sulfate, as studied by X-ray crystallography, DSC and NMR spectroscopy

X-Ray crystallography, DSC and NMR spectroscopy methods have been used to study the phase transition of D-amphetamine sulfate. The phase transition temperature occurs at about 325 K, and belongs to the discontinuous type with a large temperature hysteresis. A change in the space group is observed from monoclinic P21 in the low temperature phase to monoclinic C2 in the high temperature phase. The transformation from phase I to phase II is a result of the ordering of the SO42−groups, allowing a T-shape interaction between D-amphetamine molecules. Proton relaxation rate data obtained for the studied compound have been analysed by assuming two dynamically-inequivalent methyl groups below the phase transition and only one type of ammonium group above the phase transition. The activation energies for the C3 reorientation of the methyl groups have been determined to be 7.31 and 11.89 kJ mol−1, whereas for the ammonium group it is 27.29 kJ mol−1.

Poststroke Treatment

See related article, pages 294–302. Stroke research has primarily focused on prevention and acute treatment. Yet, there is a window of opportunity to provide treatments that will increase functional recovery by capitalizing on the brain’s neural plastic responses during postacute and chronic periods.1,2 Papadopoulos and colleagues’ study in this issue of Stroke is consistent with decades of research demonstrating that coupling of D-amphetamine administration with motor practice can enhance motor recovery after brain injury in animal models.3,4 This study elegantly shows that short-term, postacute administration of D-amphetamine sulfate combined with focused physical activity and housing in an “enriched” environment improves motor recovery markedly. These improvements are associated with increased axonal sprouting in corticoefferent pathways to the red nucleus and cervical spinal cord from …

Human pharmacology of intravenous lisdexamfetamine dimesylate: abuse liability in adult stimulant abusers

The objective of this study is to determine the safety, tolerability and abuse liability of single intravenous (i.v.) doses of lisdexamfetamine dimesylate (LDX) and immediate-release d-amphetamine sulphate in adult stimulant abusers compared with placebo. Adult substance abusers were enrolled in this phase I, randomized, single-centre, double-blind study. An initial cohort of three subjects was enrolled to assess safety followed by a primary cohort that consisted of nine subjects. Single i.v. doses of LDX (25 or 50 mg), immediate-release d-amphetamine sulphate (10 or 20 mg) or placebo were administered at a minimum of 48-h intervals in a single-dose, three-way crossover design. 20 mg of d-amphetamine showed significantly increased abuse-related liking scores compared with placebo (P < 0.05), whereas the liking effects of 50 mg LDX did not significantly differ from placebo. The mean C(max) of d-amphetamine was 38.9 +/- 8.1 and 105 +/- 91.4 ng/ml after the administration of 50 mg LDX and 20 mg d-amphetamine respectively. The mean T(max) of d-amphetamine was 2.51 h after the administration of 50 mg LDX and 0.82 h after the administration of 20 mg d-amphetamine. LDX was well tolerated in this population. In contrast to d-amphetamine, LDX administered intravenously did not produce significant subjective abuse-related liking scores at assessed doses.

Persistent downregulation of hippocampal CREB mRNA parallels a Y‐maze deficit in adolescent rats following semi‐chronic amphetamine administration

We investigated possible differences in the impact of chronic amphetamine administration during adolescence and adulthood on aspects of behaviour and brain chemistry. Adult (n=32) and adolescent (n=32) male Sprague-Dawley rats were given either D-amphetamine sulphate (10 mg kg(-1) daily, i.p.) or saline (1 mL kg(-1), i.p.) for 10 days. Rats were subsequently tested for anxiety-like behaviour, learning and memory, and sensorimotor gating. Nine weeks later, rats received saline (1 mL kg(-1)) or acute amphetamine challenge (1.5 mg kg(-1)) and the expression levels of mRNA for tyrosine kinase B (TrkB) or cAMP response element-binding protein (CREB) were measured in the hippocampus. The adolescent amphetamine pretreated group revealed a deficit in exploration on the Y-maze during a 6 h retention test. The frequency of visits to the novel arm was 35% lower for the amphetamine group compared with controls. In parallel, a 43% decrease in hippocampal CREB mRNA, but not TrkB mRNA, was observed in periadolescent rats treated chronically with amphetamine 9 weeks earlier. None of the effects were detected in the adult treated cohort. Chronic amphetamine treatment during periadolescence resulted in altered behaviour on the Y-maze and persistent downregulation of hippocampal CREB mRNA expression. Given that this group had intact spatial learning and reference memory, it would appear that the deficits observed on the Y-maze reflect a dysfunction in response to novelty. Because no effects of amphetamine treatment were observed in the adult cohort, these data suggest idiosyncratic sensitivity of periadolescence to the long-term effects of psychostimulants.