AMPH Research Articles

Acis-Octahedral Dichloro Complex of FeIIIwith a Tetradentate Dipyridyl–Diamino Ligand

In [N,N'-bis(2-pyridylmethyl)-1,3-propandiamine-N,N',N′′,N′′′]dichloroiron(III) perchlorate, [FeCl2(C15H20N4)][ClO4, the linear tetradentate ligand adopts the cis-β configuration which provides a favourable geometry for the six-membered chelate ring. The Fe—N distances show lengthening from the trans-influence of the chloride ligands with Fe—Npy values of 2.152 (3) and 2.179 (3) Å and Fe—Namine distances of 2.141 (4) and 2.178 (4) Å.

Gluconeogenic Activity in Response to Chronic Administration of Amphetamine Sulphate and Drug Withdrawal

1. Chronic amphetamine administration (10 mg/kg ) to young rats (Rattus norvegius) (40–90 g) produced an initial hyperglycemia following the initial drug administration. This was followed by progressive hypoglycemia with the continuous drug treatment. 2. The present data also demonstrate increases in levels of serum ACTH and corticosterone that were maintained after drug withdrawal, in the case of corticosterone. 3. The Analysis of the transaminase activity revealed the occurrence of significant increases in serum GOT level. Furthermore, progressive increase in the G-6-Pase activity was recorded, reaching its maximum level by the end of the experiment, which demonstrates that induced amphetamine toxicity is time-dependent.

Long-Term Stimulant Therapy and ADHD Outcome

The long-term effects of amphetamine sulfate (5 mg AM and lunchtime, increasing to a mean dose of 17 mg/d, 0.52 mg/kg body weight, and a maximum of 45 mg/d) were evaluated in 62 children, aged 6 to 11 years, with ADHD treated for 15 months in a randomized, double-blind, placebo-controlled study at the Child and Adolescent Psychiatry University departments in Goteborg, Uppsala, Malmo-Lund, and Umea, Sweden.

Effects of the administration of amphetamine, either alone or in combination with reserpine or cocaine, on regional brain beta-phenylethylamine and dopamine release.

The effect of amphetamine sulfate (AMPH) on beta-phenylethylamine (PEA) and 3-methoxytyramine (3MT) levels in the rat frontal and cingulate cortices, the nucleus accumbens, and the striatum were evaluated after the administration of either cocaine or reserpine alone and in combination with AMPH. The purpose of this study was to evaluate the neuromodulator properties of PEA on dopamine (DA) release as reflected by 3MT steady-state concentrations. The highest concentration of PEA was found in the nucleus accumbens, followed by the cingulate and frontal cortices, and then the striatum. Time-course effects of the intraperitoneal administration of 5 mg/kg AMPH on PEA and 3MT concentrations were similar but not identical. AMPH at a dosage of 1 mg/kg significantly increased PEA concentration only in the striatum. A dosage of 2.5 mg/kg reserpine, which markedly depressed 3MT levels in all brain regions studied except the striatum, significantly reduced PEA concentrations only in the nucleus accumbens. This dosage of reserpine reduced DA concentrations by more than 80% in all regions examined, but its effects on norepinephrine were less marked. Pretreatment with cocaine (10 mg/kg) or reserpine (2.5 mg/kg) potentiated the effects of 1 mg/kg AMPH on PEA and 3MT levels in the frontal cortex and of 3MT in the striatum. Pretreatment with either 1 mg/kg reserpine (specifically used to partially mobilize DA storage) or cocaine (10 mg/kg) produced quantitative changes in the effects of 5 mg/kg AMPH on PEA and 3MT levels that were region-specific. For example, in contrast to the cortical regions and the nucleus accumbens, the AMPH-induced increase in 3MT was potentiated in the striatum. On the other hand, the increase in brain PEA produced by AMPH (5 mg/kg) was not influenced by either increased cytoplasmic DA (as deduced from the effects of 1 mg/kg reserpine pretreatment) or DA uptake inhibition (as deduced from the effect of cocaine pretreatment) in the frontal cortex or the nucleus accumbens. Furthermore, the increase in PEA produced by AMPH (5 mg/kg) in the cingulate cortex and the striatum were abolished and potentiated, respectively, by these drug pretreatments. Our results suggest that although DA release and PEA formation are stimulated by AMPH, these effects appear to involve mechanisms that are not directly related and hence suggest a dissociation between 3MT and PEA formation in the brain. Our work also suggests that PEA is most likely not to be co-released with DA following the administration of AMPH. Therefore, it is concluded that whatever physiological role PEA may play in central synaptic transmission, its effects do not appear to be dependent on DA release.

Repeated amphetamine administration alters the expression of mRNA for AMPA receptor subunits in rat nucleus accumbens and prefrontal cortex.

Recent evidence suggests that behavioral sensitization to amphetamine is associated with alterations in excitatory amino acid (EAA) transmission in perikarya (ventral tegmental area) and terminal regions (nucleus accumbens [NAc]) of the mesoaccumbens dopamine system. The present study determined whether repeated amphetamine administration alters expression of mRNAs for AMPA receptor subunits. We studied the NAc, because it is the site of expression of amphetamine sensitization, and the prefrontal cortex (PFC), because it is the origin of EAA projections that regulate the mesoaccumbens dopamine system. Rats were treated for 5 days with 5 mg/kg/day amphetamine sulfate or vehicle (controls) and perfused 3 or 14 days after the last injection. We used a novel in situ hybridization method that allows quantification of mRNA levels [Lu et al. (1996) J. Neurosci. Methods, 65:69-76]. Repeated amphetamine administration decreased levels of GluR1 and GluR2 but not GluR3 mRNAs in both core and shell subregions of the NAc at the 14 day withdrawal time; no changes were observed after 3 days of withdrawal. In contrast, levels of GluR1 mRNA in the PFC were increased at 3 but not 14 days of withdrawal, while GluR2 and 3 mRNAs were unchanged. Levels of GluR4 mRNA were very low in both NAc and PFC. Functional properties of heteromeric AMPA receptors are determined by subunit composition. Thus, the observed changes in mRNAs for AMPA receptor subunits may result in altered AMPA transmission in NAc and PFC. This, in turn, may influence the responsiveness of the mesoaccumbens DA system to psychomotor stimulants and potentially contribute to behavioral sensitization.

Barbiturates and Analgesics in Calliphora vicina Larvae

Abstract Calliphora vicina larvae were reared on artificial foodstuffs spiked with a range of concentrations of aspirin (acetylsalicylic acid), sodium salicylate, paracetamol, sodium aminohippurate, amphetamine sulfate, and the barbiturates thiopentone, phenobarbitone, amylobarbitone, barbitone, and brallobarbitone. Larvae were harvested at either day 6, 7, or 8 for analysis of drug content. Paracetamol, aspirin, amylobarbitone, and thiopentone were not detected in larvae fed on foodstuff containing drug concentrations equivalent to those expected in skeletal muscle from fatal human overdoses. Drug concentrations in larvae (expressed as larva: Foodstuff drug ratio) were 12–14% for phenobarbitone, 9–11% for sodium salicylate, 10% for aminohippurate, 18–19% for brallobarbitone, 41% for amphetamine, and 50–67% for barbitone. Amylobarbitone became detectable in larvae fed on higher drug concentrations (larva: Foodstuff drug ratio 2.6–21%). Higher levels of thiopentone and phenobarbitone were lethal to the larvae. Despite sharing similar basic structures, related drugs were each handled very differently by the larvae. We found it impossible to predict, on the basis of chemical structure, which drugs are likely to be detectable in Calliphora vicina larvae and in what ratio to the drug-spiked foodstuff. Drug concentrations in larvae are significantly lower than in their food source and the absence of a drug from feeding larvae does not necessarily imply its absence from the food source.

Novelty-associated locomotion: correlation with cortical and sub-cortical GABA A receptor binding

The present study was designed to determine whether variability in GABA (η-aminobutyric acid) A receptor binding in cortical and subcortical brain regions was correlated with locomotor activity in a novel environment. Twenty four animals were rated for locomotor activity in a novel circular runway. Eight days later, locomotor activity was assessed following 1.5 mg/kg amphetamine sulfate (i.p.). After four to six days, animals were killed and samples were pooled in groups of four animals ranked according to novely locomotor score, and specific binding of the GABA A receptor antagonist [2-(3′-carboxy-2′-propyl)-3-amino-6- p-methoxy phenylpyridazinium bromide] ([ 3H]SR95531) was determined. Significant negative correlations were seen between specific ([ 3H]SR95531) binding and novelty induced locomotion in the cingulate and prefrontal cortices, and in the ventral pallidum. A near-significant negative correlation was seen in the striatum. Correlation coefficients between locomotion scores in the novel environment and specific [ 3H]SR95531 binding were: cingulate cortex, R = −0.91, P = 0.012; prefrontal cortex, R = −0.85, P = 0.032; ventral pallidum, R = −0.85, P = 0.030; striatum, R = −0.73, P = 0.097; and nucleus accumbens, R = −0.09, P = 0.85. The positive correlation between novelty- and amphetamine-induced locomotion was also quite high ( R = 0.95, P = 0.004). These results are discussed in terms of their relevance to potential biochemmical correlates of drug abuse vulnerability.

Intake of dietary sucrose or fat reduces amphetamine drinking in rats

The effects of intake of a palatable food source on oral amphetamine intake were assessed in adult male Long-Evans rats. In Experiment 1, six rats were given an amphetamine sulfate solution (0.1 mg/ml) and four rats were given water as their sole source of fluid. Rats were given a choice of chow and granulated sucrose for a week, alternated with weeks when only chow was fed. In Experiment 2, eight rats were given the amphetamine solution, and four rats water to drink. Rats were fed chow and hydrogenated vegetable fat for a week alternated with weeks when only chow was available. In both experiments, rats drank significantly less of the amphetamine solution when the palatable food choice was available than when given only chow to eat. Intake of palatable foods had a significantly smaller effect on water intake. In both experiments, rats drinking the amphetamine solution took in less fluid and less calories and gained less weight than rats drinking water. However, in Experiment 1, when sucrose was available, rats drinking amphetamine consumed a significantly greater proportion of their calories as sucrose than rats drinking water. Similarly, in Experiment 2, rats drinking the amphetamine solution chose a significantly greater percentage of their calories as fat than rats drinking water. These results demonstrate that intake of sucrose or fat leads to a significant reduction in amphetamine intake, and that the anorectic effects of amphetamine are not equivalent for different types of foods.

Structural Elucidation of Unusual Police Exhibits. II. Identification and Spectral Characterization of N-(2-Hydroxyethyl)amphetamine Hydrochloride

Abstract An unusual police exhibit having the physical appearance, color, and odor of methamphetamine hydrochloride was identified unequivocally on the basis of combined evidence from 1H- and 13C-NMR, mass, and infrared spectroscopic examination as N-(2-hydroxyethyl)amphetamine hydrochloride (HEA·HCl). A minor contaminant of the exhibit was similarly identified as ethanolamine hydrochloride (HE·HCl), suggesting synthesis via reductive amination of phenylacetone. Relevant spectroscopic data (1H-, 13C-NMR, mass, and FT-IR) and spectra are presented.

Etiologies and sequelae of excessive daytime sleepiness

Excessive dynamic sleepiness (EDS), the primary complaint of patients seen in sleep clinics, affects up to 12% of the general population. The effects of EDS can be debilitating and even life threatening. Patients with EDS may exhibit psychosocial distress, decreased work or school performance, and increased risk for accidents. The differential diagnosis of EDS requires objective assessments, such as polysomnography and the Multiple Sleep Latency Test. There are four major causes of EDS: (1) central nervous system (CNS) pathologic abnormalities, such as narcolepsy and idiopathic CNS hypersomnia; (2) qualitative or quantitative sleep deficiencies, such as sleep apnea and insufficient nocturnal sleep; (3) misalignments of the body's circadian pacemaker with the environment (eg, jet lag or shift work); and (4) drugs, which can increase sleepiness either therapeutically or as a side effect. Depending on etiology, management strategies for EDS include extension of time in bed, naps, surgery, various medical devices (eg, oral appliances, continuous positive airway pressure), and pharmacotherapy. Pharmacotherapy is generally achieved with stimulants, such as amphetamine sulfate, methylphenidate, and pemoline or newer, safer compounds like modafinil.

Foetal nigral cell suspension grafts influence dopamine release in the non-grafted side in the 6-hydroxydopamine rat model of Parkinson's disease: in vivo voltammetric data.

The present study employed differential-pulse voltammetry to assess the influence of foetal ventral mesencephalic grafts on dopamine overflow in the contralateral caudate putamen of the 6-hydroxydopamine rat model of Parkinson's disease. The experimental design involved measurements of dopamine overflow in the grafted and contralateral striatum. Control measurements of dopamine overflow were performed in 6-hydroxydopamine-lesioned rats only and the caudate putamen of normal control rats. Cell suspensions of foetal rat ventral mesencephalic tissue were grafted into the dopamine-depleted caudate putamen of unilaterally 6-hydroxydopamine-lesioned rats. At 6 weeks, animals with functional, mature grafts (as assessed by amphetamine-amplified behavioural asymmetry), were pretreated with pargyline (75 mg/kg i.p.), and both striatal sides were monitored for dopamine overflow for 90 min following amphetamine sulphate administration (5 mg/kg i.p.). The time course of dopamine overflow inside the graft was similar to that in the contralateral caudate putamen of the same animal, the normal control animal and the contralateral caudate putamen of 6-hydroxydopamine-lesioned animals. However, in grafted animals the mean dopamine overflow detected in the contralateral caudate putamen was approximately 34% lower than the concentration of dopamine detected in the contralateral caudate putamen of 6-hydroxydopamine-lesioned control animals and approximately 39% lower than the concentration of dopamine detected in the caudate putamen of the normal control animal. There was no statistical difference in the concentration of amphetamine-induced dopamine overflow between the caudate putamen contralateral to the 6-hydroxydopamine lesion and the caudate putamen of the normal control animal. These data suggest that intrastriatal foetal ventral mesencephalic suspension grafts reduce amphetamine-induced dopamine release in the contralateral non-grafted caudate putamen.

Attitudes and Experience of Drug Use Amongst a Group of London Teenagers

Data are provided from the experiences of 23 young drug users recruited from the London area. Respondents reported a wide range of illicit drug use, centred on the so-called 'dance' drugs of MDMA, LSD and amphetamine sulphate. Friendship networks were important in the initiation and maintenance of drug use. Heroin and injecting were viewed negatively by the majority of respondents. Cocaine was seen in a more positive light, though many felt that it had damaging addictive properties. In the broader context of the young people's lifestyles, drugs were not viewed as a priority. Most stated that being with friends and family was the main priority in their lives. Most reported good levels of communication with parents, most of whom either approved or did not overtly object to some forms of illicit drug use by their children. The data suggest implications for health promotion and drug prevention. Peer education should be encouraged amongst networks of young drug users (where possible involving parents) and musi...

Amphetamine use (part II)

Amphetamine sulphate is a drug that is used widely throughout the UK. It can cause many physical and psychological problems and yet amphetamine users are under represented numerically in terms of referral to drugs agencies. A sample of 506 amphetamine users in South Glamorgan was interviewed in June 1993 regarding their drug use patterns and reported associated problems. The ratio of males to females was approximately 2:1 with an age range of 10–54 years. Of the sample 18.6% were currently injecting and 7 people in the sample reported that they were still sharing injecting equipment. High levels of both physical and psychological problems were reported, particularly from the injecting group, although only 11% of the whole sample reported seeking help from drug agencies. The findings highlight the need for drugs agencies in the UK to try to work more closely and appropriately with amphetamine users.

Exercise attenuates oral intake of amphetamine in rats

The effects of wheel running on oral intake of amphetamine were examined in six male Sprague-Dawley rats given a 0.075-mg/ml amphetamine sulfate solution as their sole source of liquid, six rats given a 0.15-mg/ml amphetamine solution, and four rats given water as their sole source of liquid. All animals were housed in Wahmann running wheels and adjoining cages, and had ad lib access to ground Purina Chow. For the first 7 days of the experiment, the doors to the running wheels were closed; the wheels were then opened for 6 days. This cycle was repeated a second time. Animals drinking the 0.15-mg/ml amphetamine solution consumed significantly less food and gained less weight than animals in the other two groups. Although there was no difference in food intake between rats drinking water and rats drinking the 0.075-mg/ml amphetamine solution, rats in the water group gained significantly more weight than rats in the 0.075-mg/ml amphetamine group. With respect to drug intake, rats consumed significantly less amphetamine when running in the wheels than when access to the wheels was prohibited. Access to running wheels did not alter water intake. These latter results suggest that drug intake can be reduced by the provision of an alternate behavior.

Potentiometric, enantioselective sensors for alkyl and aryl ammonium ions of pharmaceutical significance, based on lipophilic cyclodextrins.

Lipophilic alpha, beta and gamma cyclodextrins (CDs) have been systematically analysed in order to establish their selective binding to onium ions. They have been identified as excellent ionophores for a range of ions of vital importance in clinical, pharmaceutical and forensic analysis. From the results obtained we found the following. A peroctylated cyclodextrin provides a size-selective cavity for the binding and detection of onium ions. Potentiometric alpha, beta and gamma cyclodextrin-based electrodes selectively sense NH4+, NMe4+ and NEt4+ ions respectively. These experiments were performed in order to enable us to understand the nature of analyte recognition by the lipophilic cyclodextrins. Peroctylated alpha CD is a suitable ionophore for dopamine hydrochloride, -log[C] = 5.4, -log K = 2.0 (in serum level of Na+, K+, Ca2+) whereas peroctylated and 2,6 didodecyl beta CD sense acetylcholine chloride, -log[C] = 5.0, -log K = 4.2 (in serum level of Na+, K+, Ca2+) and creatinine hydrochloride, -log K = 2.7 (in serum level of Na+, K+, Ca2+), respectively. The 2,6 didodecyl beta CD responds to more bulky aryl ammonium ions such as the anaesthetics procaine, prilocaine and lignocaine hydrochlorides, -log K = 4.2 (in serum level of Na+, K+, Ca2+). Partially octylated alpha CD has been identified as an enantioselective sensor for ephedrine hydrochloride, -log K = 4.5 (in serum level of Na+, K+, Ca2+), -log Kpot+/- = 2.6, and related compounds such as amphetamine hydrochloride. The 2,6 didodecyl beta CD is enantioselective for propranalol hydrochloride, -log K = 4.2 (in serum level of Na+, K+, Ca2+), -log Kpot+/- = 2.7. Complexation has also been studied by electrospray mass spectrometry (ESMS).

Human Autonomic Pharmacology XVI. Benzedrine Sulfate as an Aid in the Treatment of Obesity

Human Autonomic Pharmacology <b>XVI. Benzedrine Sulfate as an Aid in the Treatment of Obesity</b>

Comparison of immune functional parameters following in vitro exposure to natural and synthetic amphetamines.

The potential of synthetic and natural amphetamines to modulate cellular immune effector and regulatory mechanisms was evaluated in an in vitro exposure system. Murine splenic lymphocytes and elicited peritoneal macrophages were cultured with 0.0001-100 microM of amphetamine sulfate, methamphetamine hydrochloride, or the (S) or (R) isomers of cathione hydrochloride. T-lymphocyte regulatory function was assessed by quantitating the production of cytokines, and T-lymphocyte effector function was assessed by the induction of cytotoxic T-lymphocytes (CTL). B-lymphocyte function was measured by proliferation, and natural immunity was assessed by quantitating basal and IL-2 augmented natural killer (NK) cell activity. None of the compounds tested had any direct effect on cellular viability. Exposure to amphetamine resulted in a significant suppression of IL-2, but not IL-4, production by T-lymphocytes, as well as a suppression of B-lymphocyte proliferation only at the highest amphetamine concentration examined. NK cell function was slightly suppressed by amphetamine exposure, but was enhanced by methamphetamine exposure. Conversely, exposure to either (S) or (R) isomers of cathinone resulted in stimulation of IL-2 production, B-lymphocyte proliferation, and CTL induction. No significant effect of cathione was noted on NK cell function. These data suggest that natural and synthetic amphetamines exhibit differential immunomodulatory activity following in vitro exposure.

An efficient synthesis of S-(+)-amphetamine

Optically active ( S)-(+)-amphetamine hydrochloride ( 5·HCl) was prepared from ( 1S,2S)-2-amino-1-phenyl-1,3-propanediol ( 1) via its 3-iodo intermediate ( 3). A phthaloyl group was used for protecting the amine function.

Effects of amphetamine on the release of excitatory amino acid neurotransmitters in the basal ganglia of the conscious rat.

The effects of systemic injections of amphetamine sulfate on the release of aspartic acid, glutamic acid, and glutamine were studied using a push-pull perfusion system in the conscious rat. Amphetamine produced a dose-related increase of the extracellular levels of aspartic acid and glutamic acid. The mean time effect of amphetamine was 40 min, followed by a recovery to baseline levels. The mean percentage increase in amino acids released by the highest dose of amphetamine (5 mg/kg) was as follows: Asp, 334.6%; Glu, 224.5%; and Gln, 317.6%. All these effects were blocked by the dopamine D1-D2 receptor blocker haloperidol. It is suggested that dopamine, released by amphetamine, induces the release of amino acid neurotransmitters in the neostriatum. In addition, it is proposed that dopamine could mediate the neurotoxic effects produced by amphetamines through their secondary action on the release of excitatory amino acids.

Effects of psychoactive drugs or stress on learning, memory, and performance as assessed using a novel water maze task

A novel water maze was used to assess the potential performance-disrupting effects of psychoactive drugs and stressors (4 mg/kg amphetamine sulfate; 1,2, or 4 mg/kg diazepam; 30 mg/kg caffeine; 5 or 30 mg/kg atropine sulfate; 15 min of either intermittent foot-shock, forced running, or immobilization). The task utilized a traditional type of maze with walls and doorways set inside a pool. The apparatus could easily be reconfigured to present different mazes of approximately equal difficulty by opening or closing multiple doorways. Performance was measured by number of errors and time required to swim from the “start” to “finish” (a raised platform not in the rat's line of sight). After initial maze training, rats were divided into two groups. One group ran three daily trials through the same maze each day; this group was used to assess memory. The second group was challenged to swim three consecutive trials in a new maze configuration each day as a measure of learning. On any given day, rats from both groups received the same treatment. Drug or stress treatments were interspersed with vehicle or no-treatment trial days. The new maze task was more sensitive than the well-learned maze to the performance-disrupting effects of amphetamine, caffeine, and diazepam, while atropine had no significant effect on performance on either maze. Foot-shock stress impaired performance on both mazes, while the other stressors had no significant effect.