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PubMed1998

A rapid novel derivatization of amphetamine and methamphetamine using 2,2,2-trichloroethyl chloroformate for gas chromatography electron ionization and chemical ionization mass spectrometric analysis.

Amphetamine and methamphetamine are commonly abused central nervous system stimulants. We describe a rapid new derivatization of amphetamine and methamphetamine using 2,2,2-trichloroethyl chloroformate for gas chromatography-mass spectrometric analysis. Amphetamine and methamphetamine, along with N-propyl amphetamine (internal standard), were extracted from urine using 1-chlorobutane. The derivatization with 2,2,2-trichloroethyl chloroformate can be achieved at room temperature in 10 minutes. The electron ionization mass spectrum of amphetamine 2,2,2-trichloroethyl carbamate showed two weak molecular ions at m/z 309 and 311, but showed diagnostic strong peaks at m/z 218, 220, and 222. In contrast, chemical ionization of the mass spectrum of amphetamine 2,2,2-trichloroethyl carbamate showed strong (M + 1) ions at m/z 310 and 312 and other strong diagnostic peaks at m/z 274 and 276. The major advantages of this derivative are the presence of a diagnostic cluster of peaks due to the isotopic effect of three chlorine atoms (isotopes 35 and 37) in the derivatized molecule and the relative ease of its preparation. We also observed strong molecular ions for derivatized methamphetamine in the chemical ionization mass spectrum, but the molecular ions were very weak in the electron ionization mass spectrum. We used the scan mode of mass spectrometry in all analyses. When using a urine standard containing 1,000 ng/mL of amphetamine (a 7.4-micromol/L concentration) and methamphetamine (a 6.7-micromol/L concentration), the within-run precisions were 4.8% for amphetamine and 3.6% for methamphetamine. The corresponding between-run precisions were 5.3% for amphetamine and 6.7% for methamphetamine. The assay was linear for amphetamine and methamphetamine concentrations of 250 to 5,000 ng/mL (amphetamine, 1.9-37.0 micromol/L; methamphetamine, 1.7-33.6 micromol/L). The detection limit was 100 ng/mL (amphetamine, 0.74 micromol/L; methamphetamine, 0.67 micromol/L) using the scan mode of electron ionization mass spectrometry. We observed good a correlation between the concentrations of amphetamine and methamphetamine in five urine specimens positive for amphetamines using the more conventional pentafluoropropionyl derivative and our new derivative using 2,2,2-trichloroethyl chloroformate.

Amphetamine↗
PubMed2003

Metabolic profile of amphetamine and methamphetamine following administration of the drug famprofazone.

There are a several drugs that lead to the production of methamphetamine and/or amphetamine in the body which are subsequently excreted in the urine. These drugs raise obvious concerns when interpreting positive amphetamine drug testing results. Famprofazone is an analgesic found in a multi-ingredient medication (Gewodin) used for pain relief. Two Gewodin tablets (50 mg of famprofazone) were administered orally to healthy volunteers with no history of amphetamine, methamphetamine, or famprofazone use. Following administration, urine samples were collected ad lib for up to six days, and pH, specific gravity, and creatinine values were determined. In order to determine the quantitative excretion profile of amphetamine and methamphetamine, samples were extracted using liquid-liquid extraction, derivatized with heptafluorobutyric anhydride, and analyzed by gas chromatography-mass spectrometry (GC-MS). The ions monitored were 91, 118, 240 for amphetamine and 254, 210, 118 for methamphetamine. Amphetamine-d(6) and methamphetamine-d(11) were used as internal standards. Peak concentrations for amphetamine ranged from 148 to 2271 ng/mL and for methamphetamine 615 to 7361 ng/mL. Concentrations of both compounds peaked between 3 and 7 h post-dose. Amphetamine and methamphetamine could be detected (limit of detection = 5 ng/mL) at 121 and 143 h post-dose, respectively. Using a cutoff of 500 ng/mL, all subjects had individual urine samples that tested positive. One subject had 14 samples above the cutoff with the last positive being detected over 48 h post-dose. The profile of methamphetamine and amphetamine enantiomers was also determined using liquid-liquid extraction, derivatization with N-trifluoroacetyl-l-prolyl chloride and analysis by GC-MS. Data showed the famprofazone metabolites amphetamine and methamphetamine to be both d- and l-enantiomers. The proportion of l-methamphetamine exceeded that of its d-enantiomer from the first sample collected. Initially, the proportion was approximately 70% l-methamphetamine and this proportion increased over time. Amphetamine results showed l- and d-amphetamine were virtually the same in the early samples with the proportion of l-amphetamine increasing as time progressed. Forensic interpretation of drug testing results is a challenging critical part of forensic drug testing area because of the potential repercussions the results found may have on an individual's life. The finding of each enantiomers by itself differentiates famprofazone use from the most commonly abused form of methamphetamine and all medicinal methamphetamine available in the U.S., which is either d-methamphetamine (prescription medication) or l-methamphetamine (Vicks inhaler). Coupling this information with the concentrations of amphetamine and methamphetamine helps to determine the potential for use of this drug.

Administration, Oral↗
PubMed1987

Inhibitory effects of amphetamine on potassium-stimulated release of [3H]dopamine from striatal slices and synaptosomes.

Amphetamine, 10(-7) M or greater, evoked the release of [3H]dopamine ([3H]DA) and inhibited subsequent K+-evoked [3H]DA release from striatal synaptosomes superfused at a flow rate (1 ml/min) that prevented reuptake. Amphetamine inhibited the K+-evoked release of [3H]DA to a lesser extent in striatal slices or in synaptosomes superfused at a flow rate (0.35 ml/min) that allowed reuptake. The observed decrease in amphetamine inhibition of K+-evoked release was primarily due to amphetamine blocking [3H]DA reuptake. Interneuronal interactions may account for some of the inhibitory effects of amphetamine on K+-evoked release in the slice. Inhibition of K+-evoked release from either slices or synaptosomes was still evident when 10(-6) M amphetamine was removed from the superfusion buffer and the spontaneous release had returned to control levels. The presence of Ca++ during amphetamine exposure was required for subsequent inhibition of K+-evoked release in synaptosomes. Amphetamine in the presence of Ca++ did not affect the subsequent release of [3H]DA evoked by the Ca++ ionophore, A23187. Therefore, amphetamine inhibition of the K+-evoked release of [3H]DA cannot be explained by prior depletion of Ca++-releasable pools. Nifedipine, 1 microM, failed to block either the Ca++-dependent release of [3H]DA or the inhibition of K+-evoked release by amphetamine. However, 1 mM cobalt inhibited the Ca++-dependent release of [3H]DA by amphetamine and antagonized the inhibition of K+-evoked release after amphetamine exposure. This suggests that amphetamine may open voltage-dependent Ca++ channels sensitive to cobalt but not nifedipine. Amphetamine may desensitize these voltage-dependent Ca++ channels and inhibit their activation by K+ depolarization.

Amphetamine↗
PubMed1999

Depletion of brain serotonin following intra-raphe injections of 5,7-dihydroxytryptamine does not alter d-amphetamine self-administration across different schedule and access conditions.

OBJECTIVES: These experiments investigated the effects of selective serotonin (5-HT) depletion on intravenous self-administration of d-amphetamine. METHODS: Depletion of brain 5-HT levels was induced by injecting the serotonergic neurotoxin 5,7-dihydroxytryptamine (5, 7-DHT) into the dorsal and median raphe nuclei. Rats were then trained to self-administer d-amphetamine according to various schedule and access conditions via chronically indwelling intravenous catheters. RESULTS: Large reductions of brain 5-HT did not alter responding for a training dose of 120 microgram/kg d-amphetamine delivered according to a fixed ratio 1 schedule during 3-h sessions. When the dose of d-amphetamine was altered (0, 3.75, 7. 5, 15, 30, 60 microgram/kg per infusion) a characteristic inverted U-shaped dose response function was obtained. The 5-HT depleted rats showed increased responding for the lower doses of d-amphetamine, with a large significant increase in responding for the 7.5 microgram/kg dose. In these same rats, the suppressive effect of 10 mg/kg fluoxetine on d-amphetamine (60 microgram/kg) self-administration was prevented. The 5,7-DHT lesion also did not alter responding for d-amphetamine (120 microgram/kg) in longer (8 h) daily access sessions. Responding for d-amphetamine delivered on a progressive ratio schedule, in which response requirements increased for each successive infusion of d-amphetamine, was also determined in 5-HT depleted rats. The number of d-amphetamine infusions was not different from the number of infusions earned by sham-lesioned rats across a range of doses of d-amphetamine (7.5-60 microgram/kg). In a final experiment, spontaneous acquisition of self-administration of low doses of d-amphetamine (10 and 30 microgram/kg) was measured in 5-HT depleted and control rats. Again, self-administration behaviour in the 5-HT depleted rats did not differ from controls. CONCLUSIONS: These results provide no evidence that reducing 5-HT function alters the primary reinforcing effects of self-administered amphetamine. The increase in self-administration of a low dose of amphetamine observed in experiment 1 probably involves some other process such as increased resistance to extinction.

5,7-Dihydroxytryptamine↗
PubMed1999

RGS mRNA expression in rat striatum: modulation by dopamine receptors and effects of repeated amphetamine administration.

Single injections of cocaine, amphetamine, or methamphetamine increased RGS2 mRNA levels in rat striatum by two- to fourfold. The D1 dopamine receptor-selective antagonist SCH-23390 had no effect by itself but strongly attenuated RGS2 mRNA induction by amphetamine. In contrast, the D2 receptor-selective antagonist raclopride induced RGS2 mRNA when administered alone and greatly enhanced stimulation by amphetamine. To examine the effects of repeated amphetamine on RGS2 expression, rats were treated with escalating doses of amphetamine (1.0-7.5 mg/kg) for 4 days, followed by 8 days of multiple daily injections (7.5 mg/kg/2 h x four injections). Twenty hours after the last injection the animals were challenged with amphetamine (7.5 mg/kg) or vehicle and killed 1 h later. In drug-naive animals, acute amphetamine induced the expression of RGS2, 3, and 5 and the immediate early genes c-fos and zif/268. RGS4 mRNA levels were not affected. Prior repeated treatment with amphetamine strongly suppressed induction of immediate early genes and RGS5 to a challenge dose of amphetamine. In sharp contrast, prior exposure to amphetamine did not reduce the induction of RGS2 and RGS3 mRNAs to a challenge dose of amphetamine, indicating that control of these genes is resistant to amphetamine-induced tolerance. These data establish a role for dopamine receptors in the regulation of RGS2 expression and suggest that RGS2 and 3 might mediate some aspects of amphetamine-induced tolerance.

Amphetamine↗
PubMed2003

Amphetamine enantiomer excretion profile following administration of Adderall.

Amphetamine remains a widely abused drug throughout the world. It is also used therapeutically for weight loss, narcolepsy, and attention deficit disorder with hyperactivity (ADHD). ADHD has grown dramatically recently both in terms of diagnosis and treatment. Increasingly, older individuals are diagnosed and treated for ADHD, and treatment often continues into adulthood. Of the available treatments for ADHD, Adderall is widely prescribed. Despite its widespread use, there are no published data regarding the expected amphetamine excretion profile following its use. This is problematic because, in this case, medical review officers (MRO) and forensic toxicologists are asked to assess results in terms of use pursuant to valid medical prescription without specific data on which to base a sound decision. To address this situation, a study to determine the concentration and enantiomer composition of amphetamine excretion following administration of Adderall was undertaken. Adderall (20 mg) was administered to five healthy subjects with all subsequent ad lib urine samples (total urine void) collected for seven days. Adderall is a 3:1 mixture of d- and l-enantiomers of amphetamine salts. Peak amphetamine concentrations ranged from 2645 to 5948 ng/mL. Samples containing > or = 500 ng/mL of amphetamine (the administrative cutoff for a positive result by gas chromatography-mass spectrometry) were seen up to 47:30 h post dose. The number of samples that contained amphetamine concentrations of > or = 500 ng/mL ranged among individuals from 7 to 13. As anticipated, analysis showed the d-enantiomer to be in excess of the l-enantiomer, with the proportion of l-enantiomer increasing over time. Because of the mixture of enantiomers, not all samples that contained > or = 500 ng/mL of amphetamine were positive when tested by immunoassay. The drug concentration profiles were quite variable within and between subjects because of dilution and fluctuations in pH of the samples. These results are the first to describe the excretion of amphetamine following administration of Adderall. The presence of the l-enantiomer separates this drug from other preparations of the drug that are composed of only the d-enantiomer (i.e., dexedrine and much illicit amphetamine), thus readily differentiating them from Adderall use. Some illicit and medicinal amphetamine is, however, a mixture of amphetamine enantiomers. Because the enantiomers are metabolized at different rates, their proportion offers the opportunity to describe excretion versus time. Coupling this data with drug concentration makes it possible for forensic toxicologists and MROs to come to an informed decision about the involvement of this drug in a positive drug test result. Using the combination of enantiomer composition and quantitative data will allow MROs and forensic toxicologists to better assess the use of this drug from abuse of amphetamine.

Administration, Oral↗
PubMed2006

Amphetamines as potential inducers of fatalities: a review in the district of Ghent from 1976-2004.

Abuse of amphetamine (AMP) and its derivatives, such as 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy'), 3,4-methylenedioxyethylamphetamine (MDEA, MDE), and 3,4-methylenedioxyamphetamine (MDA) is an important public issue. Fatalities following ingestion of these substances are not infrequent in current forensic practice. The aim of this study was twofold. Firstly, considering the wide range of blood levels reported in fatalities, to provide insight into the interpretation of a quantified blood level and, secondly, to examine and discuss possible causes, mechanisms and manners of death. All the medico-legal files between January 1976 and December 2004 were skimmed through to investigate whether amphetamine and/or derivatives were involved in the fatal outcome. Particularly, in addition to overdose cases due to or including amphetamines, all amphetamines-related fatalities were examined. In addition to AMP, MDMA, MDEA, and MDA, two other amphetamine derivatives, namely 4-methylthioamphetamine (4-MTA) and para-methoxyamphetamine (PMA) were considered. In 34 fatalities, amphetamines were involved and the majority were men, under the age of 25 years. A wide range of blood levels was found: e.g. MDMA blood concentrations in cases of 'pure' intoxication were found between 0.27 and 13.51 microg/ml. The age and sex distribution as well as the broad range of quantified amphetamines blood levels were in line with those reported in the literature. In our study group, 'pure' intoxications with amphetamines, polydrug overdoses, and the combination of amphetamines use and polytrauma were the most prominent causes of death. Considering the manner of death in these fatalities, unintentional overdoses were most frequent, though suicides, traffic accidents, and criminal offences associated with amphetamines use also accounted for significant percentages. Acute to subacute cardiopulmonary failure was the most frequent mechanism of death, followed by (poly)trauma, mechanical asphyxia, and hyperthermia, respectively. In conclusion, although amphetamines-related fatalities are only a fraction of the total number of fatalities studied at our Department, their contribution to current forensic practice has been increasing during the last few years. As there is still considerable debate as to what level of amphetamines can be toxic or even potentially lethal, it is strongly advisable to interpret the anatomo-pathological findings and the toxicological results together in arriving at a conclusion. This guideline is important in view of the different possible mechanisms of death which implicate quite different survival times following intake of amphetamine and/or its derivatives (e.g. cardiopulmonary complications, hyperthermia).

Amphetamine-Related Disorders↗
PubMed2005

Comparative and interactive human psychopharmacologic effects of ketamine and amphetamine: implications for glutamatergic and dopaminergic model psychoses and cognitive function.

BACKGROUND: In healthy individuals, ketamine hydrochloride and amphetamine sulfate produce cognitive, behavioral, and subjective effects resembling endogenous psychoses. Studying the comparative and interactive effects of these agents may provide insights into the roles of the glutamate and monoamine systems in psychosis and cognition. OBJECTIVES: To directly compare the effects of ketamine and amphetamine and to explore their interactive effects within individuals. DESIGN: Placebo-controlled, randomized, double-blind psychopharmacologic trial. SETTING AND PARTICIPANTS: Forty-one healthy individuals recruited from the community who completed up to 4 test days. MAIN OUTCOME MEASURES: On each test day, participants received amphetamine (a 1-minute infusion of amphetamine sulfate, 0.25 mg/kg, or saline) and ketamine (a 1-minute intravenous infusion of ketamine, 0.23 mg/kg, followed by a 1-hour infusion of 0.5 mg/kg or an identical saline bolus and infusion). The order of amphetamine and ketamine infusions was randomized. RESULTS: At the doses studied, ketamine and amphetamine produced positive symptoms and euphoria. However, perceptual changes were produced only by ketamine, and hostility, grandiosity, and somatic concern were stimulated only by amphetamine. Amphetamine and ketamine produced conceptual disorganization, but only ketamine produced concrete ideation and unusual mannerisms. Ketamine produced negative symptoms and disrupted delayed recall. Ketamine and amphetamine showed 3 types of interactive effects: (1) amphetamine attenuated the impairment of working memory produced by ketamine; (2) amphetamine and ketamine had additive effects on thought disorder, arousal, and euphoria; and (3) amphetamine and ketamine had less-than-additive effects on psychosis. CONCLUSIONS: These findings implicate N-methyl-D-aspartate glutamate receptors and dopamine systems in psychosis. However, glutamate and dopamine may differentially contribute to psychosis, thought disorder, and euphoria. Regarding medication development for cognitive dysfunction, the pattern of the interactive effects of ketamine and amphetamine is consistent with the hypothesis that facilitation of prefrontal cortical dopamine levels would attenuate some cognitive impairments associated with deficits in N-methyl-D-aspartate receptor function.

Amphetamine↗
PubMed2001

Treatment for amphetamine withdrawal.

BACKGROUND: Amphetamine withdrawal has been less studied although it is a common problem with a prevalent rate of 87% among amphetamine users. Its symptoms, in particular intense craving, may be a critical factor leading to relapse of amphetamine use. In clinical practice, treatment for cocaine withdrawal has been recommended for the management of amphetamine withdrawal although the pharmacodynamic and pharmacokinetic properties of these two substances are not the same. OBJECTIVES: To search and determine risks, benefits, and costs of a variety of treatments for the management of amphetamine withdrawal. SEARCH STRATEGY: Electronic searches of MEDLINE (1966 - December 2000), EMBASE (1980 - February 2001), CINAHL (1982 - January 2001) and Cochrane Controlled Trials Register (Cochrane Library 2000 issue 4) were undertaken. References to the articles obtained by any means were searched. SELECTION CRITERIA: All relevant randomised controlled trials (RCTs) and controlled clinical trials (CCTs) were included. Participants were people with amphetamine withdrawal, diagnosed by any set of criteria. Any kinds of biological and psychological treatments both alone and combined were examined. A variety of outcomes, for example, number of treatment responders, score changes, were considered. DATA COLLECTION AND ANALYSIS: Two reviewers evaluated and extracted the data independently. The dichotomous data were extracted on an intention-to-treat basis in which the dropouts were assigned as participants with the worst outcomes. The Relative Risk (RR) with the 95% confidence interval (95% CI) was used to assess the dichotomous data. The Weighted Mean Difference (WMD) with 95% CI was used to assessed the continuous data. MAIN RESULTS: The results of two studies have shown some benefits of amineptine in the treatment of amphetamine withdrawal. Those benefits can be seen in the respects of discontinuation rate and global state, as measured by Clinical Global Impression Scale. However, no direct benefit of amineptine on amphetamine withdrawal symptoms or craving was shown. REVIEWER'S CONCLUSIONS: The evidence about the treatment for amphetamine withdrawal is very limited. Amineptine has limited benefits on some amphetamine withdrawal symptoms. Due to a number of reports of amineptine abuse, it has been withdrawn from the market for a few years. At present, no available treatment has been demonstrated to be effective in the treatment of amphetamine withdrawal. The medications that should be considered for further treatment studies may be those with the propensities to increase dopamine, norepinephrine and/or serotonin activities of the brain. Naturalistic studies of amphetamine withdrawal symptoms and course are also crucial for the development of study designs appropriate for further treatment studies of amphetamine withdrawal.

Amphetamine↗
PubMed1994

Relationship between asymmetries in striatal dopamine release and the direction of amphetamine-induced rotation during the first week following a unilateral 6-OHDA lesion of the substantia nigra.

In animals with a large unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal dopamine (DA) system the traditional "rotational behavior model" states that amphetamine will induce circling behavior towards the denervated striatum (ipsiversive), that is, away from the side where there is greater amphetamine-stimulated DA release and greater DA receptor stimulation. It is puzzling, therefore, why amphetamine induces contraversive rotation in rats tested 4 days after a unilateral 6-OHDA lesion, despite a 90-95% loss of the dopaminergic input to the striatum by this time. Rats reverse their direction of amphetamine-induced rotation by 8 days post-lesion and turn in the ipsiversive direction thereafter. To try and resolve this paradox, bilateral striatal microdialysis was used to estimate the effects of amphetamine on DA neurotransmission on Day 4 and Day 8 following a large unilateral 6-OHDA lesion of the substantia nigra. On Day 4 post-lesion, amphetamine produced a moderate (around 50% of control) increase in the extracellular concentration of DA in the denervated striatum. This amphetamine-releasable pool of DA was exhausted by a single amphetamine-challenge, because a second injection of amphetamine given 3 h after the first did not produce a comparable increase in DA. It is suggested that on Day 4 post-lesion the amount of DA released by amphetamine in the denervated striatum is sufficient to produce greater DA receptor stimulation on that side, because of DA receptor supersensitivity, and this leads to contraversive rotation. On Day 8 post-lesion, amphetamine induced DA release in the intact striatum but had no effect on extracellular DA in the denervated striatum (DA was nondetectable). On Day 8, therefore, DA receptor stimulation would be greatest in the intact striatum, leading to ipsiversive rotation. In conclusion, it is suggested that the seemingly paradoxical reversal in the direction of amphetamine-induced rotation that occurs over the first week following a unilateral 6-OHDA lesion is consistent with the traditional rotational model, and is due to time-dependent changes in the ability of amphetamine to release DA in the denervated striatum.

Amphetamine↗
PubMed2001

Effects of amphetamine on the plus-maze discriminative avoidance task in mice.

RATIONALE: The contradictory amphetamine effects on memory could be due to different protocols of amphetamine administration or the well-known anxiogenic effect of the drug. OBJECTIVE: The effects of different protocols of administration of amphetamine were investigated on mice tested in the plus-maze discriminative avoidance task (DAT), which provides simultaneous information about memory and anxiety. METHODS: Acutely pre- or post-training, 0.3, 1.0, or 3.0 mg/kg amphetamine-treated, 10-day chronically 3.0 mg/kg amphetamine-treated, 0.3 mg/kg amphetamine plus 0.25 mg/kg scopolamine and 3.0 mg/kg amphetamine plus 3.0 mg/kg tacrine-treated mice were conditioned to choose between two enclosed arms (one of which was aversive) while avoiding two open arms. Learning/memory was evaluated by the percentage time in the aversive enclosed arm (PTAV), and anxiety by the percentage time in the open arms (PTO). RESULTS: Given acutely before conditioning, amphetamine significantly decreased PTO in training, suggesting an anxiogenic effect, and significantly increased PTAV in the test, suggesting an amnestic action. Given acutely after the conditioning, no action of this drug on memory was found. After repeated treatment, the anxiogenic effect disappeared, while the amnestic effect remained. While no effects of subeffective doses of amphetamine and scopolamine co-administration were detected, tacrine attenuated the amnestic effect of amphetamine. CONCLUSIONS: Amphetamine has different effects on DAT when given pre- or post-training. While acute pre-training amnestic action is temporally correlated with an anxiogenic effect, there is tolerance to the anxiogenic but not to the amnestic effect after repeated administration. Because this acute amnestic effect of amphetamine is attenuated by tacrine, a possible relationship with cholinergic system cannot be discarded as a mechanism to amphetamine-induced amnesia in DAT.

Amphetamine↗
PubMed2004

Transient disruption of attentional performance following escalating amphetamine administration in rats.

RATIONALE: Attentional deficits are thought to be critically involved in the development of positive symptoms in schizophrenia. The present experiment tests the general hypothesis that sensitization of the mesolimbic dopaminergic system contributes to the attentional deficits in schizophrenia. OBJECTIVES: The present study assessed attentional performance following administration of an escalating amphetamine regimen and subsequent "challenge" amphetamine administration in rats. METHODS: Rats were trained to perform a two-lever sustained attention task that involved discrimination of visual signals and no signal presentation. After reaching criterion, subjects were assigned to receive escalating amphetamine or saline. Attentional performance was assessed immediately following escalating amphetamine, following "challenge" amphetamine administration (1.0 mg/kg) to amphetamine-pretreated rats, and for 3 days after the challenge session. At the end of this experiment, a dose-response study was conducted with saline-pretreated rats to confirm the appropriateness of the challenge dose. RESULTS: Amphetamine-pretreated animals demonstrated a transient increase in errors on nonsignal trials following escalating amphetamine administration. The latency to press a lever was decreased during and after challenge amphetamine administration. Administration of 1.0 mg/kg amphetamine did not alter accuracy of amphetamine-pretreated animals or of saline-pretreated animals in the dose-response experiment. CONCLUSIONS: Prior escalating amphetamine administration transiently disrupted attention, increasing incorrect "claims" for a signal on trials when no signal was presented. The present data support the existing literature that escalating amphetamine regimens may be useful to model the attentional deficits that contribute to the psychotic symptoms in schizophrenia.

Amphetamine↗
PubMed2006

Differences in the cellular mechanism underlying the effects of amphetamine on prepulse inhibition in apomorphine-susceptible and apomorphine-unsusceptible rats.

BACKGROUND: Amphetamine is often used to mimic certain aspects of schizophrenia in laboratory animals, such as a decreased prepulse inhibition. MATERIALS AND METHODS: Apomorphine-susceptible and apomorphine-unsusceptible rats represent a well-characterized animal model for individual differences in the sensitivity to dopaminergic drugs. Moreover, apomorphine-susceptible rats show a wide variety of schizophrenia-like abnormalities. The differential response to administration of amphetamine (1-4 mg/kg, i.p.) was investigated in these two rat lines using the prepulse inhibition paradigm. Because amphetamine promotes dopamine release, the cellular mechanism underlying the line-specific effects of amphetamine was investigated by administration of alpha-methyl-para-tyrosine (aMpT) and reserpine, substances that are known to deplete the cytosolic dopamine pool and the vesicular dopamine pool, respectively, the former being primarily implicated in mediating the effects of amphetamine. RESULTS: All doses of amphetamine decreased prepulse inhibition in apomorphine-susceptible rats, whereas only the highest doses (2 and 4 mg/kg, i.p.) of amphetamine decreased prepulse inhibition in apomorphine-unsusceptible rats. Alpha-methyl-para-tyrosine, but not reserpine, blocked the amphetamine-induced disruption in prepulse inhibition in apomorphine-unsusceptible rats, whereas both substances alone had no effect in apomorphine-susceptible rats. However, the combination of alpha-methyl-para-tyrosine and reserpine did block the amphetamine-induced effects in the latter rat line. DISCUSSION: The present study suggests that apomorphine-susceptible rats are more sensitive to systemic administration of amphetamine than apomorphine-unsusceptible rats. In addition, the data show that the cellular mechanism underlying the effects of amphetamine differs between apomorphine-susceptible and apomorphine-unsusceptible rats. Whereas the effects of amphetamine on prepulse inhibition in apomorphine-unsusceptible rats just require the alpha-methyl-para-tyrosine sensitive dopamine pool, the effects in apomorphine-susceptible rats require both the alpha-methyl-para-tyrosine sensitive and the reserpine sensitive dopamine pool. Because apomorphine-susceptible rats share many features with schizophrenic patients, these data open the perspective that in these patients amphetamine may induce dopamine release from both types of dopamine pool. This might provide an explanation for the increased dopamine release after this psychostimulant drug in patients vs controls.

Amphetamine↗
PubMed1987

The effects of footshock stress on regional brain dopamine metabolism and pituitary beta-endorphin release in rats previously sensitized to amphetamine.

The repeated intermittent administration of amphetamine (AMP) produces an enduring enhancement in the response of dopamine (DA) systems in the brain to a subsequent "challenge" with amphetamine. However, former amphetamine addicts are not only hypersensitive to amphetamine, but also to "physical or psychological stress". This suggests that sensitization to amphetamine may change the response of DA neurons in brain to subsequent stress. To explore this idea, the effects of footshock stress on regional metabolism of DA in brain, and on the concentrations of plasma beta-endorphin and N-acetylated beta-endorphin, were studied in rats previously exposed to amphetamine or saline. It was found that: Prior treatment with amphetamine produced enduring (at least 7 days) changes in the dopaminergic response to footshock in the medial frontal cortex, hypothalamus, dorsolateral striatum and nucleus accumbens. Generally, rats pretreated with amphetamine showed a greater initial reduction in concentrations of DA in response to footshock, and a greater elevation in concentrations of metabolites of DA and/or metabolite/transmitter ratios, compared to nonhandled control rats. In some regions of the brain repeated injections of saline produced changes in the response to subsequent footshock that were comparable to those produced by amphetamine. Prior treatment with amphetamine enhanced the release of beta-endorphin and N-acetylated beta-endorphin from the pituitary elicited by footshock stress. It is concluded that repeated intermittent treatment with amphetamine or stress (injections of saline) produce enduring changes in the response of DA neurons and the pituitary to subsequent stress. These changes may be responsible for the hypersensitivity to stress reported in former amphetamine addicts, and in rats previously sensitized to amphetamine.

Amphetamine↗
PubMed1995

Acute and chronic amphetamine treatments differently regulate neuropeptide messenger RNA levels and Fos immunoreactivity in rat striatal neurons.

Repeated administration of amphetamine results in the well known phenomenon of reverse tolerance or sensitization. However, little is known about cellular and molecular mechanisms underlying acute versus chronic response to amphetamine. In this paper, we investigated the effects of acute (1.5 or 5 mg/kg) and chronic (5 mg/kg/day for 14 days) amphetamine treatment on locomotor activity, stereotypy, Fos immunoreactivity and messenger RNA levels of molecules implicated in dopamine transmission in the rat striatum and substantia nigra. In agreement with other studies, acute amphetamine induced a dose dependent increase in locomotor activity and stereotypy. Also, a comparison between the behavior observed after the first injection and the last injection of amphetamine in chronically treated rats showed sensitization as demonstrated by a higher rating of stereotypy. We have found that acute and chronic amphetamine treatments differently modulate the activity of several output neurons. A double labeling procedure with Fos immunohistochemistry coupled with in situ hybridization demonstrated that acute amphetamine treatment induces Fos immunoreactivity predominantly in striatal neurons expressing substance P messenger RNA (77.07 +/- 1.42%). Only 32.6 +/- 2.07% of Fos immunoreactive neurons expressed preproenkephalin A messenger RNA. In chronic amphetamine treated rats, 56.21 +/- 1.32% of the Fos immunoreactive neurons expressed substance P messenger RNA while 52.12 +/- 1.84% expressed preproenkephalin A messenger RNA. Statistical analysis revealed that this difference is mainly due to a decrease in the density of substance P immunoreactive neurons in chronically treated rats in comparison to acute. Amphetamine treatments induced Fos immunoreactivity in the substantia nigra in non-dopamine neurons. As measured by quantitative in situ hybridization, acute amphetamine induced an increase in substance P, preproenkephalin A and dynorphin messenger RNA levels (+23 +/- 0.05%, +45 +/- 0.07% and +24 +/- 0.05%, respectively). No difference in these increases was observed in relation with the dose injected (1.5 or 5 mg/kg). Chronic amphetamine treatment enhanced only substance P and dynorphin messenger RNA levels (+23 +/- 0.04% and +42 +/- 0.04%, respectively). Neither acute nor chronic amphetamine treatment had any effects on D1 or D2 dopamine receptor messenger RNA levels. Our main conclusions are: (1) in acutely treated rats Fos is essentially expressed by substance P neurons; (2) in chronically treated rats, Fos immunoreactivity is expressed by the two efferent striatal populations (i.e. preproenkephalin A and substance P neurons) and the number of Fos immunoreactive neurons is reduced as compared with acute; (3) neuropeptide messenger RNA levels, but not dopamine receptor messenger RNAs, are affected in the response to acute or chronic treatment with amphetamine.

Amphetamine↗
PubMed2004

Amphetamine activates connexin43 gene expression in cultured neonatal rat cardiomyocytes through JNK and AP-1 pathway.

OBJECTIVE: Amphetamine has been known to induce cardiac dysrhythmia and sudden death. However, the molecular mechanism for the induction of dysrhythmia is not known. Connexin43 (Cx43) plays an important role for arrhythmogenesis. This study was undertaken to test the hypothesis that amphetamine could induce Cx43 expression in cardiac myocytes. METHODS: Neonatal Wistar rat cardiac myocytes were cultured under the stimulation of amphetamine. Cx43 mRNA and protein expression were examined by Northern and Western blots, respectively. We used c-Jun N-terminal kinase (JNK) inhibitor, SP600125, and JNK1 dsRNAi to investigate the signal pathway of amphetamine-induced expression of Cx43. RESULTS: The level of Cx43 protein significantly increased from 4 to 24 h after addition of amphetamine (10 microM). The Cx43 mRNA increased maximally to 4.2-fold at 6 h after addition of amphetamine and returned to the baseline level at 48 h. These increases of Cx43 protein at 24 h were completely attenuated (P<0.001) by SP600125 (20 microM) and JNK1 dsRNAi. Amphetamine increased and SP600125 decreased the immunohistochemical labeling of Cx43. Amphetamine increased and SP600125 decreased the phosphorylated JNK and c-Jun proteins. Gel-shifting assay showed that DNA-binding activity of AP-1 increased after addition of amphetamine and SP600125 and JNK1 dsRNAi abolished the binding activity induced by amphetamine. CONCLUSIONS: These findings indicate that amphetamine activates Cx43 gene expression in cultured rat neonatal cardiac myocytes. Amphetamine mediates the Cx43 gene expression, at least in part, through the JNK pathway. These findings from our study suggest that Cx43 plays a role for the molecular mechanism of amphetamine-induced cardiac dysrhythmias.

Amphetamine↗
PubMed2003

Environmental context and drug history modulate amphetamine-induced c-fos mRNA expression in the basal ganglia, central extended amygdala, and associated limbic forebrain.

The context in which amphetamine is administered modulates its ability to induce both behavioral sensitization and immediate early gene expression. When given in a novel test environment amphetamine produces greater levels of c-fos and arc mRNA expression in many brain regions relative to when it is given in the home cage. The purpose of the current study was to determine if environment and drug history interact to influence amphetamine-induced c-fos mRNA expression. Rats with a unilateral 6-hydroxydopamine lesion were treated for 7 days with saline or 0.5 mg/kg of d-amphetamine (i.v.) in a distinct and relatively novel test environment (Novel), or in their home cage (Home). Following a 10-12-day withdrawal period, a challenge injection of either saline or 0.5 mg/kg d-amphetamine was administered. In situ hybridization histochemistry was used to examine c-fos mRNA expression in several regions of the basal ganglia, the central extended amygdala, and limbic forebrain. In most brain regions amphetamine given in the Novel environment produced greater c-fos mRNA expression than when given it was given at Home, and drug history had no effect on amphetamine-induced c-fos mRNA expression. However, within the subthalamic nucleus, substantia nigra reticulata, and central nucleus of the amygdala prior experience with amphetamine in the Novel but not Home environment enhanced the effect of an amphetamine challenge injection on c-fos mRNA expression. In contrast, there was a decrease in c-fos mRNA expression in amphetamine-pretreated animals, regardless of environmental context, in the ventral portion of the far caudal striatum. Reexposure to an environment previously paired with amphetamine produced a conditioned increase in c-fos mRNA expression in portions of the caudate-putamen, the subthalamic nucleus, the nucleus accumbens shell and a conditioned decrease in c-fos mRNA expression in the central nucleus of the amygdala. We conclude that environmental context and drug history interact to alter the basal ganglia and central extended amygdala circuitry engaged by subsequent exposure to amphetamine, or exposure to an environment previously paired with amphetamine.

AIDS-Related Complex↗
PubMed2004

Repeated amphetamine couples norepinephrine transporter and calcium channel activities in PC12 cells.

Repeated intermittent amphetamine enhances efflux of dopamine through the dopamine transporter in rat basal ganglia and through the norepinephrine transporter in rat pheochromocytoma PC12 cells. Extracellular Ca2+ is required for the detection of this enhancement in the rat. In this study, we examined the role of Ca2+ and Ca2+ channels in the enhanced amphetamine-induced dopamine efflux that develops in PC12 cells following repeated intermittent amphetamine. Repeated pretreatment of PC12 cells with 1 microM amphetamine followed by a drug-free period increased amphetamine-induced efflux of dopamine compared with controls. The enhancement in amphetamine-induced dopamine efflux depended upon the presence of extracellular Ca2+ and was inhibited by the blockade of N-type and L-type Ca2+ channels. The enhanced dopamine efflux was not altered by tetanus toxin or reserpine, treatments that abrogate synaptic vesicle-mediated, exocytotic dopamine efflux. Measurement of intracellular Ca2+ concentrations using fura-2/acetoxymethyl ester revealed that amphetamine increased intracellular Ca2+ by a transporter-dependent mechanism. In amphetamine-pretreated cells, amphetamine elicited a greater increase in intracellular Ca2+; this increase depended upon the presence of extracellular Ca2+ and N- and L-type Ca2+ channel activity. The enhanced amphetamine-induced dopamine efflux requires Ca2+/calmodulin kinase activity. In vehicle-treated cells, 1 microM amphetamine inhibited the calmodulin kinase activity although it did not in amphetamine-pretreated cells. This study suggests that repeated intermittent amphetamine couples norepinephrine transporter activity and Ca2+ signaling.

Adrenergic Agents↗