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PubMed2002

Dizocilpine inhibits amphetamine-induced formation of nitric oxide and amphetamine-induced release of amino acids and acetylcholine in the rat brain.

Glutamate receptor activation participates in mediation of neurotoxic effects in the striatum induced by the psychomotor stimulant amphetamine. The effects of the non-competitive NMDA receptor antagonist dizocilpine (MK-801) on amphetamine-induced toxicity and formation of nitric oxide (NO) in both striatum and cortex and on induced transmitter release in the nucleus accumbens were investigated. Repeated, systemic application of amphetamine elevated striatal and cortical lipid peroxidation and NO production. Moreover, amphetamine caused an immediate release of acetylcholine and aspartate and a delayed release of GABA in the nucleus accumbens. Surprisingly, glutamate release was not affected. Dizocilpine abolished the amphetamine-induced lipid peroxidation and NO production in striatum and cortex and diminished the elevation of neurotransmitter release. These findings suggest that amphetamine evokes neurotoxic effects in both striatal and cortical brain areas that are prevented by inhibiting NMDA receptor activation. The amphetamine-induced acetylcholine, aspartate and GABA release in the nucleus accumbens is also mediated through NMDA receptor-dependent mechanisms. Interestingly, the enhanced aspartate release might contribute to NMDA receptor activation in the nucleus accumbens, while glutamate does not seem to mediate amphetamine-evoked transmitter release in this striatal brain area.

Acetylcholine↗
PubMed1983

Apparent hallucinations in monkeys during around-the-clock amphetamine for seven to fourteen days. Possible relevance to amphetamine psychosis.

Schizophrenia-like symptoms have been experimentally produced in humans by a single, large dose of amphetamine or by relatively low level, but continuous administration of the drug. In animal studies of the psychotomimetic properties of amphetamine, high doses and, in particular, repeated daily-injection drug schedules have often been used. However, amphetamine psychosis is not always a prominent effect of repeated intake drug schedules in humans and available clinical evidence suggests that psychosis develops more readily when the drug is taken in a continuous fashion over longer periods. The state produced by single large doses of amphetamine, although clearly abnormal, has been said to bear less resemblance to schizophrenia than the delayed paranoid symptoms developing after longer periods of continuous intake. In the present experiments we have studied the behavioral effects of 7 to 14 days of continuous administration of amphetamine to monkeys (Cercopithecus aethiops) using subcutaneously implanted silicone capsules releasing approximately .7 to 1.5 mg/kg/day of d-amphetamine base. Around-the-clock TV monitoring of the animals revealed a general biphasic sequence of drug effects, although considerable individual variation occurred: a) an "acute" phase dominated by stereotyped movements and/or prolonged staring, lasting for 2 to 5 days; b) a "late" phase peaking during days 5 to 10 after capsule implantation and characterized by highly individual, but striking sequences of: (1) Attack or sudden threat reactions directed at invisible objects; (2) rapid orienting and flight behavior without apparent cause; (3) sudden startle reactions; (4) prolonged vocalization; (5) visual tracking of invisible objects, sometimes involving coordinated patterns of "eating behavior" and (6) prolonged and rapid grooming directed at various parts of the body. These behaviors might be termed "hallucinatory" since no eliciting stimuli could be determined for their occurrence. Motor disturbances, including whole-body shakes, were often present at the same time. The animals were generally sleepless throughout the drug treatment period. Reimplantation of amphetamine capsules 2 to 8 months after the first capsule treatment produced the same effects in an individual-specific manner, but the "late phase" behaviors generally appeared sooner. The delayed occurrence of apparent hallucinatory behaviors and other abnormal "late" phase behaviors in the present experiment may be a close parallel to the delayed development of psychosis in humans induced by a similar drug regimen. Furthermore, the hallucinogenic nature of the late amphetamine state is consonant with other reports in the literature that hallucinogen-characteristic behaviors are present at this time.

Animals↗
PubMed1985

Effects of multiple pretreatment with apomorphine and amphetamine on amphetamine-induced locomotor activity and its inhibition by apomorphine.

Mice were given a saline preinjection and habituation to the testing environment followed by injection of amphetamine (0.675-5.0 mg/kg IP) and apomorphine (AP, 15-80 micrograms/kg SC) 15 min later. AP produced a dose-dependent inhibition of the amphetamine-induced locomotor activity. A dose of 40 micrograms/kg AP increased approximately threefold the amphetamine dose required to induce the same increase in activity. Repeated administration of AP (30 mg/kg IP once daily for 14 days) resulted in an enhanced response (in the early portion of the time response) to amphetamine challenge, while the ability of subsequent microgram challenge doses of AP to reduce the response were unaffected. Similarly, repeated administration (twice-daily IP injections for 5 days) of amphetamine (5.0 mg/kg) resulted in an enhanced locomotor response to amphetamine challenge and no change in the ability of AP to inhibit the response. These results suggest that repeated administrations of dopamine agonists, although acting through different mechanisms (i.e., indirect versus direct), increase the initial release of neurotransmitter. However, the repeated administration of these agonists does not attenuate the ability of AP to inhibit the release of the neurotransmitter induced by amphetamine. The regulatory functions (i.e., presynaptic receptor control) of release appears to remain intact, but the level of neuronal activity has been increased.

Amphetamine↗
PubMed1993

Amphetamine injected into the ventral tegmental area sensitizes the nucleus accumbens dopaminergic response to systemic amphetamine: an in vivo microdialysis study in the rat.

Different groups of rats received three injections of either D-amphetamine (2.5 micrograms/0.5 microliters/side) or saline into the ventral tegmental area (VTA), one injection every third day. Two weeks following the last injection, dopamine (DA) neurotransmission in the nucleus accumbens (N. Acc.) was assessed with in vivo microdialysis before and after a challenge with systemic D-amphetamine (1.0 mg/kg, i.p.). Prior to challenge, basal extracellular concentrations of DA in the N.Acc. did not differ in VTA amphetamine- and saline-preexposed animals. Following challenge, however, both groups showed an increase in N.Acc. DA but this was significantly greater (2-fold) in VTA amphetamine-preexposed animals. These latter animals also showed significantly higher DA metabolite levels in comparison to saline-preexposed animals prior to (DOPAC) as well as after challenge (HVA). These findings extend those of behavioral experiments showing that intra-VTA amphetamine produces sensitized locomotor responding to drug challenge (J. Pharmacol. Exp. Ther., 245 (1988) 1095-1102; Brain Res., 516 (1990) 99-106; Ann. NY Acad. Sci., 654 (1992) 444-447) and demonstrate that amphetamine applied to the somatodendritic region of mesolimbic DA neurons sensitizes these neurons as evidenced by their enhanced N.Acc. DA response to a systemic amphetamine challenge.

Amphetamine↗
PubMed1987

Interactions between radiation and amphetamine in taste aversion learning and the role of the area postrema in amphetamine-induced conditioned taste aversions.

Three experiments were run to assess the role of the area postrema in taste aversion learning resulting from combined treatment with subthreshold unconditioned stimuli and in the acquisition of an amphetamine-induced taste aversion. In the first experiment, it was shown that combined treatment with subthreshold radiation (15 rad) and subthreshold amphetamine (0.5 mg/kg, IP) resulted in the acquisition of a taste aversion. The second experiment showed that lesions of the area postrema blocked taste aversion learning produced by two subthreshold doses of amphetamine. In the third experiment, which looked at the dose-response curve for amphetamine-induced taste aversion learning in intact rats and rats with area postrema lesions, it was shown that both groups of rats acquired taste aversions following injection of amphetamine, although the rats with lesions showed a less severe aversion than the intact rats. The results are interpreted as indicating that amphetamine-induced taste aversion learning may involve area postrema-mediated mechanisms, particularly at the lower doses, but that an intact area postrema is not a necessary condition for the acquisition of an amphetamine-induced taste aversion.

Amifostine↗
PubMed2004

Long-term voluntary D-amphetamine consumption and behavioral predictors for subsequent D-amphetamine addiction in rats.

Flexibility of drug taking is characteristic for "controlled" drug consumption whereas addiction is reflected by inflexibility and persistent high risk to relapse. Male Wistar rats (N = 12) that were given a continuous free choice between water and D-amphetamine solutions for 16 weeks, revealed a moderate and flexible pattern of D-amphetamine intake when tested again after 36 weeks of drug deprivation. A second group of rats had the same choice between water and D-amphetamine for 42 weeks. In the retest after abstinence, six out of 12 rats showed a moderate and flexible pattern of intake whereas the other animals revealed an excessively high and inflexible D-amphetamine consumption. They took high doses despite an adverse bitter taste of the drug solutions caused by addition of quinine. After 39 weeks of moderate D-amphetamine intake in the long-term period exactly the same animals had spontaneously and suddenly increased their D-amphetamine consumption. In a retrospective view, the later inflexible D-amphetamine consumers had already shown differences to their flexible conspecifics before their first drug access. During "tetradic" encounter tests the later "inflexible" animals were more interested in non-social stimuli than the later "flexible" ones. The results are discussed in respect to predisposition factors that might facilitate or inhibit the development of loss of control over drug intake.

Aggression↗
PubMed1997

Amphetamine-related harms and treatment preferences of regular amphetamine users in Sydney, Australia.

Amphetamines remain a popular illicit drug among young adults in Australia and a number of other countries, particularly by injection. A significant increase in the number of people presenting to drug treatment services with a primary amphetamine problem in Australia and the US has occurred in recent years. A survey of 200 regular amphetamine users was conducted in Sydney to determine the treatment issues and preferences of this population. Substantial harm associated with the use of this drug was found, most notably psychological problems, physical health problems, dependence and financial problems. A perceived need for amphetamine-specific treatment was evident. Popular treatment options requested by users included pharmacotherapies, natural therapies and counselling. While regular amphetamine users can attend existing treatment services, the efficacy of these treatments for amphetamine problems has not been evaluated. There is also a need to develop and evaluate amphetamine-specific interventions in order to attract this population into treatment.

Adolescent↗
PubMed1997

VMAT2 knockout mice: heterozygotes display reduced amphetamine-conditioned reward, enhanced amphetamine locomotion, and enhanced MPTP toxicity.

The brain vesicular monoamine transporter (VMAT2) pumps monoamine neurotransmitters and Parkinsonism-inducing dopamine neurotoxins such as 1-methyl-4-phenyl-phenypyridinium (MPP+) from neuronal cytoplasm into synaptic vesicles, from which amphetamines cause their release. Amphetamines and MPP+ each also act at nonvesicular sites, providing current uncertainties about the contributions of vesicular actions to their in vivo effects. To assess vesicular contributions to amphetamine-induced locomotion, amphetamine-induced reward, and sequestration and resistance to dopaminergic neurotoxins, we have constructed transgenic VMAT2 knockout mice. Heterozygous VMAT2 knockouts are viable into adult life and display VMAT2 levels one-half that of wild-type values, accompanied by smaller changes in monoaminergic markers, heart rate, and blood pressure. Weight gain, fertility, habituation, passive avoidance, and locomotor activities are similar to wild-type littermates. In these heterozygotes, amphetamine produces enhanced locomotion but diminished behavioral reward, as measured by conditioned place preference. Administration of the MPP+ precursor N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to heterozygotes produces more than twice the dopamine cell losses found in wild-type mice. These mice provide novel information about the contributions of synaptic vesicular actions of monoaminergic drugs and neurotoxins and suggest that intact synaptic vesicle function may contribute more to amphetamine-conditioned reward than to amphetamine-induced locomotion.

Amphetamine↗
PubMed1995

Preference for sex on amphetamine: a marker for HIV risk behaviour among male intravenous amphetamine users in Stockholm.

Two hundred injecting drug users at the Remand Prison in Stockholm participated in an interview study of sexual behaviour in parallel to an ongoing HIV epidemiological study. Fifty-four subjects were women and 146 were men. Amphetamine was the main drug used by 115 and heroin by 85. Twenty-six were HIV seropositive. Sexual activity was reported as the preferred activity on amphetamine by 51% of the male and 20% of the female amphetamine injectors. Among the 74 men who mainly injected amphetamine the characteristic of preferring sex on amphetamine was strongly associated with positive HIV serostatus in bivariate analysis, but was not independently predictive of HIV serostatus when injection frequency was controlled for. The results suggest that preferring sex on amphetamine may be viewed as a marker of high risk behaviour, both sexually and with needles, for HIV among male but not among female amphetamine injectors.

Adult↗
PubMed2000

Using amphetamine isomer ratios to determine the compliance of amphetamine abusers prescribed dexedrine.

The amphetamine isomer ratios (l-amphetamine/d-amphetamine) in 373 urine specimens submitted for analysis over a two-year period have been determined using a chiral derivatizing agent in conjunction with a gas chromatograph fitted with a nitrogen-specific detector. All of the specimens were collected from known or suspected amphetamine abusers, some of which were prescribed dexedrine for maintenance and detoxification. The mean (+/- 1 standard deviation [SD]) l/d-amphetamine isomer ratio for 147 specimens from compliant subjects prescribed dexedrine was 15.0% (+/- 4.9%). The mean (+/- 1 SD) l/d-amphetamine isomer ratio from 165 subjects abusing illicit amphetamine was 98.5 (+/- 27.5%). The calculation of l/d-amphetamine isomer ratios in urine has been found to be a rapid method for determining the compliance of subjects prescribed dexedrine and is therefore a useful technique for the continued management of amphetamine abusers. In addition, 17 specimens of illicit amphetamine powder (assumed to be a racemic mixture) were submitted to the laboratory for analysis. Using a combination of gas chromatography with and without chiral derivatization, the powders were found to have a mean l/d-amphetamine isomer ratio of 89.2% (range 72.2% to 98.3%) and mean purity (w/w) of 21.5% (range 3.4% to 71.0%) relative to pure dl-amphetamine substance.

Amphetamine-Related Disorders↗
PubMed2006

Simultaneous determination of amphetamines and amphetamine-derived designer drugs in human urine by GC-MS.

OBJECTIVES: The purpose of this study is to evaluate the gas chromatographicmass spectrometric method (GC-MS) for assay of stimulants of amphetamine type: amphetamine (AMP), methamphetamine (MAMP), ephedrine (EPH), norephedrine (NOREPH), and the amphetamine-derived designer drugs 3,4-methylenedioxyamphetamine (MDA), 3,4-methylenedioxymethamphetamine (MDMA, ecstasy), 3,4-methylenedioxy-N-ethylamphetamine (MDEA) and N-methyl-benzodioxolylbutanamine (MBDB) in urine. These drugs are often encountered in forensic and clinical toxicological analysis. METHODS: GC-MS method after mixed-mode solid-phase extraction (SPE) and derivatization with heptafluorobutyric anhydride (HFBA) is presented for quick and reliable screening as well as identification and quantification of amphetamines and amphetamine derived designer drugs in urine. RESULTS: The measurement of calibration dependence allowed to determine the extent of linearity in the concentration range from 10 to 2,000 ng/ml for all amphetamines except AMP and for all amphetamine-derived designer drugs with correlation coefficients exceeding 0.98. Detection limits were established at 5 ng/ml and quantification limits at 10 ng/ml for all analytes, except AMP. LOD for AMP was established at 20 ng/ml and LOQ at 50 ng/ml. Extraction efficiency for all analytes at concentration levels 50 and 500 ng/ml (n=6) was established in the range 60-99%. Repeatability was measured at concentration levels 50 and 500 ng/ml (n=6), relative standard deviations (RSDs) were under 10% for all analytes. CONCLUSIONS: The GC-MS method after mix-mode solid-phase extraction and derivatization with heptafluorobutyric anhydride is presented for screening followed by identification and quantification of AMP, MAMP, EPH, NOREPH, MDA, MDMA, MDEA, and MBDB. The applicability of the GC-MS method was proven by analyzing authentic urine samples.

Amphetamines↗
PubMed1980

Blood pressure and heart rate response evoked by p-hydroxyamphetamine and by p-hydroxynorephedrine II. A quantitative assessment of the role of amphetamine metabolites in acute responses evoked by d-amphetamine.

At postganglionic sympathetic sites, p-hydroxyamphetamine is neither a receptor agonist nor a receptor antagonist; in addition the drug does not act presynaptically to antagonize or synergize d-amphetamine. p-Hydroxyamphetamine is an indirectly acting sympathomimetic amine with a potency approximately twice that of d-amphetamine. In the rat, a large fraction (approximately 0.5) of d-amphetamine is biotransformed to p-hydroxyamphetamine. However, the rate of biotransformation to p-hydroxyamphetamine (approximately 0.0099 . min-1) is slow compared to the rate of elimination of p-hydroxyamphetamine (0.049 . min-1). As a result, plasma levels of d-amphetamine exceed those of p-hydroxyamphetamine. The kinetic data suggest that: 1) p-hydroxyamphetamine plays little role in immediate responses to single injections of d-amphetamine; 2) p-hydroxyamphetamine is not involved in tachyphylactic responses to repeated injections of d-amphetamine; and 3) p-hydroxynorephedrine plays no role in immediate or tachyphylactic responses to d-amphetamine.

Amphetamines↗
PubMed1988

Enhancement of conditioned preference for a place paired with amphetamine produced by blocking the association between place and amphetamine-induced sickness.

Rats learn to prefer a place that has been paired with the rewarding effect of amphetamine. Since amphetamine is also known to produce an aversive effect, called here sickness, pairings of a place with amphetamine should produce a place-sickness association as well as the place-reward association that underlies the conditioned place preference. The purpose of the present experiments was to enhance the conditioned place preference produced by place-amphetamine pairings by blocking the place-sickness association. In Experiments 1 and 2, the taste of saccharin was paired with sickness induced by amphetamine or by lithium, respectively. The saccharin taste was presented prior to each pairing of a white chamber with amphetamine to block the place-sickness association. In Experiment 3, a brief placement in a distinctive cage that had previously been paired with lithium-induced sickness preceded each pairing of the white chamber with amphetamine. Blocking of the place-sickness association occurred as evidenced by the reliable enhancement of conditioned place preference obtained in each of the three experiments.

Animals↗
PubMed1986

Differences in spontaneous and amphetamine-induced rotational behavior, and in sensitization to amphetamine, among Sprague-Dawley derived rats from different sources.

Nocturnal rotational behavior was found to vary severalfold among Sprague-Dawley derived rats obtained from seven different breeders; net rotations per night (18 hours) varied from 5.0 to 31.0 in males and from 6.2 to 42.4 in females. Rats from three sources were tested twice (a week between tests) for rotation induced by d-amphetamine. Rats from two sources showed evidence of sensitization to d-amphetamine, there being significantly greater rotation in response to the second dose than in response to the first dose; the d-amphetamine-induced rotational behavior of rats from the third source did not significantly change from one week to the next. However, the latter rats had a greater initial response to the first dose of d-amphetamine than did rats from the other two breeders. Further analysis revealed that, among rats from all three breeders, rats rotating weakly in response to d-amphetamine on the first test tended to rotate more on the second test whereas rats rotating strongly in response to d-amphetamine on the first test tended to rotate less on the second test. This relationship was found to apply to previously collected data as well and was discussed with reference to a proposed mechanism involving asymmetry in sensitization to d-amphetamine-induced release of striatal dopamine. Interindividual differences among seemingly similar experimental subjects appear to contribute importantly to reported differences in results among laboratories.

Animals↗
PubMed1998

Amphetamine infusions into the prefrontal cortex attenuate the sensitization to amphetamine.

1. Adult male rats were implanted with chronic medial prefrontal cortex cannulae. 2. On each of 5 consecutive days, rats received bilateral 0.5 ml intra-prefrontal cortex injections of either 5 mg d-amphetamine or saline, followed by a subcutaneous injection of either 1 mg/kg d-amphetamine or saline. 3. Immediately after the drug treatments each rat was placed into a photocell equipped locomotor activity chamber for 60 min. 4. Administration of d-amphetamine into the prefrontal cortex did not block the acute locomotor response to subcutaneous d-amphetamine nor did it in itself produce an increase in locomotor activity. However, prefrontal cortex amphetamine treatments did attenuate the sensitized locomotor effects of subcutaneous amphetamine that developed over trials/days. 5. Dopamine in the prefrontal cortex may be involved in the development of amphetamine-induced behavioral sensitization.

Animals↗
PubMed1992

In vivo microdialysis reveals a diminished amphetamine-induced DA response corresponding to behavioral sensitization produced by repeated amphetamine pretreatment.

In vivo microdialysis procedures were used to assess the effects of repeated amphetamine administration on behavior and regional brain DA dynamics in freely moving rats. Pretreatment with amphetamine (2.5 or 3.0 mg/kg) for 4-6 days did not alter baseline DA or its metabolites in caudate or accumbens 48 h or 6 days after the last injection. However, whereas this dosage regimen revealed a profound behavioral sensitization in response to challenge with amphetamine (2.5 mg/kg), including a more rapid onset and intensification of stereotypy, the DA response was significantly diminished in both brain regions. In addition, the ratio of caudate to accumbens DA, either before or after amphetamine challenge, was not altered by the pretreatment regimen. These results are consistent with our previous suggestion that there is a dissociation between the DA and behavioral responses to amphetamine, and therefore that other neurotransmitter systems and/or mechanisms significantly contribute to the amphetamine response profile. Furthermore, DA effects may represent only one, albeit critical, aspect in a time-dependent sequence of changes underlying stimulant sensitization.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

The effects of conditioning with amphetamine on the thermic effects of amphetamine and pentobarbital.

1. Rats were injected with amphetamine (1.5 mg/kg) in the presence of a distinctive set of environmental stimuli (CS1) and saline in the presence of a different set of environmental stimuli (CS2) on different days for a total of 10 amphetamine and 20 saline injections. 2. The hyperthermic effect of amphetamine first increased but then declined to levels seen during the very first drug administration. 3. Following the conditioning phase, half the rats were injected with amphetamine in CS1 and half in CS2. Although there was little thermic effect of amphetamine injected in CS1, there was pronounced hyperthermia following amphetamine in CS2. 4. Next, pentobarbital (30 mg/kg) was administered to half the rats in CS1 and half in CS2. The hypothermic effect of pentobarbital was attenuated in CS2.

Amphetamine↗
PubMed2004

Differential interactions of desipramine with amphetamine and methamphetamine: evidence that amphetamine releases dopamine from noradrenergic neurons in the medial prefrontal cortex.

Amphetamine is more effective than methamphetamine at raising dopamine levels in the prefrontal cortex. The current study tested the hypothesis that norepinephrine transporters are involved in this difference. Using microdialysis, dopamine, norepinephrine, and serotonin were measured in the rat prefrontal cortex after administration of methamphetamine or amphetamine, with and without perfusion of desipramine. Amphetamine raised norepinephrine levels more than methamphetamine did. Desipramine raised dopamine and serotonin levels but did not alter metabolite levels. Desipramine attenuated the increase in dopamine by amphetamine while increasing the dopamine released by methamphetamine. These data suggest that methamphetamine and amphetamine differ in altering prefrontal cortical dopamine levels and in interacting with norepinephrine transporters. It is proposed that amphetamine releases dopamine in the prefrontal cortex primarily through norepinephrine transporters, whereas methamphetamine interacts minimally with norepinephrine transporters.

Amphetamine↗