Amphetamine-induced stereotyped behaviour and brain concentrations of amphetamine and its hydroxylated metabolites in mice.
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Animals↗
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Consequent events as determinants of drug effects on schedule-controlled behavior: modification of effects of cocaine and d-amphetamine following chronic amphetamine administration.
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Animals↗
Nonstriatal dopaminergic neurons: Section X. Morphine, amphetamine, and noncataleptogenic neuroleptics: Introduction: morphine, amphetamine, and noncataleptogenic neuroleptics.
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Acetylcholine↗
Human d-amphetamine drug discrimination: testing with d-amphetamine and hydromorphone.
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Adult↗
Comparison of the locomotor stimulant mechanisms of action of d-amphetamine and d-amphetamine plus l-dopa: possible involvement of serotonin.
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Animals↗
Amphetamine elicited potential changes in vertebrate and invertebrate central neurons.
The effects of amphetamine on potential changes in both vertebrate and invertebrate central neurons and factors affecting the potential changes were tested. The animals studied included mice, newborn rat and African snail. Seizure was elicited after lethal doses of d-amphetamine (75 mg/kg, i.p.) administration in mice. Repetitive firing of the action potentials were elicited after d-amphetamine (1-30 microM) administration in thin thalamic brain slices of newborn rat. Bursting firing of action potentials in the giant African central RP4 neuron were also elicited after d-amphetamine or l-amphetamine (0.27 mM) administration. The amphetamine elicited bursting firing of action potentials was not blocked even after high concentrations of d-tubocurarine, atropine, haloperidol, hexamethonium administration. Therefore, the amphetamine elicited potential changes may not be directly related to the activation of the receptors of the neuron. The bursting firing of action potentials elicited by amphetamine occurred 20-30 min after amphetamine administration extracellularly, even after high concentrations of d-amphetamine administration (0.27, 1 mM). However, the bursting firing of potentials occurred immediately if amphetamine was administrated intracellularly at lower concentration. Extracellular application of ruthenium red, the calcium antagonist, abolished the amphetamine elicited bursting firing of action potentials. If intracellular injection of EGTA, a calcium ion chelator, or injection with high concentrations of magnesium, the bursting firing of potentials were immediately abolished. These results suggested that the active site of amphetamine may be inside of the neuron and the calcium ion in the neuron played an important role on the bursting of potentials. In two-electrode voltage clamped RP4 neuron, amphetamine, at 0.27 mM, decreased the total inward and steady outward currents of the RP4 neuron. d-Amphetamine also decreased the calcium, Ia and the steady-state outward currents of the RP4 neuron. Besides, amphetamine elicited a negative slope resistance (NSR) if membrane potential was in the range of -50 to -10 mV. The NSR was decreased in cobalt substituted calcium free and sodium free solution. The effects of secondary messengers on the amphetamine elicited potential changes were tested. The bursting firing of action potentials elicited by amphetamine in central snail neurons decreased following extracellular application of H8 (N-(2-methyl-amino) ethyl-3-isoquinoline sulphonamide dihydrochloride), a specific protein kinase A inhibitor and anisomycin, a protein synthesis inhibitor. However, the bursting firing of action potentials were not affected after extracellular application of H7 (1,(5-isoquinolinesulphonyl)-2-methylpiperasine dihydrochloride), a specific protein kinase C (PKC) inhibitor, or intracellular application of GDPbetaS, a G protein inhibitor. The oscillation of membrane potential of the bursting activity was blocked after intracellular injection of 3'-deoxyadenosine, an adenylyl-cyclase inhibitor. These results suggested that the bursting firing of action potentials elicited by d-amphetamine in snail neuron may be associated with the cyclic AMP second messenger system; on the other hand, it may not be associated with the G protein and protein kinase C activity. It is concluded that amphetamine elicited potential changes in both vertebrate and invertebrate central neurons. The changes are closely related to the ionic currents and second messengers of the neurons.
Action Potentials↗
[Schizophrenia and amphetamine dependence. A case report].
UNLABELLED: Whereas observations of psychotic disorders induced by amphetamines are common, few observations described the impact of chronic amphetamine abuse on schizophrenic patients. We report the case of a schizophrenic patient who presented with amphetamine dependence for several years, without other accompanying addiction. CASE REPORT: During his adolescence, Mr. X. gradually developed delusional beliefs of persecution and telepathy. He believed that the other pupils and teachers spoke about him in malicious terms. At the age of 23, Mr. X began to consume 60-100 mg/week of amphetamines orally. He consumed amphetamines during 7 years. The delusions, in particular the auditory hallucinations worsened after the use of amphetamines. Subsequently, he married and was declared unfit for national service due to the psychotic disorders. Mr. X received neuroleptic treatment with moderate effects on the psychotic symptoms. Between the age of 24 and 30, the patient presented persecutory, megalomanic and physical transformation beliefs, delusions of being controlled as well as auditory, somatic-tactile and visual hallucinations. At the age of 30, while he had stopped his consumption of amphetamines for 9 months, the patient, overwhelmed with the delusions, murdered his wife. He was sent in jail for 13 months, and subsequently hospitalized for one year in a high security psychiatric department and 7 years in our psychiatric department. The neuroleptic treatment was effective, particularly against the hallucinations. Following stabilisation, the symptomatology of the patient was marked by a disorganization syndrome, including prominent thought disorder, disorganized speech, associative loosening, frequent derailments and negative signs of schizophrenia, in particular affective flattening and blunting of emotional expression. When the patient was 43, a trial discharge was authorized owing to improvement of his condition. The neuroleptic treatment was switched with single-drug olanzapine therapy, 10 mg/day which improved the negative symptoms. Mr. X. resumed part-time professional activities and remarried. DISCUSSION: The patient fulfilled the DSM IV criteria for schizophrenia and for amphetamine dependence assessed using the Composite International Diagnostic Interview (CIDI). He presented, in particular, withdrawal syndrome when amphetamines were discontinued. The amphetamine consumption was followed by a marked deterioration in the delusions, particularly the hallucinations. Worsening of the positive symptoms in schizophrenic patients by amphetamines has been established in single dose studies, in particular characterized by persecutory delusions and hallucinations. On the other hand, amphetamines tend to transiently and moderately reduce the negative symptoms. Some stu-dies have shown that amphetamine consumption promoted violent acting out in non-schizophrenic subjects. In our observation, the acting out may be not related to the acute effects of these substances, since it occurred 9 months after stated discontinuation of amphetamine consumption. However, the cerebral toxicity and psycho-behavioural disturbances related to amphetamines might be prolonged after withdrawal. In non-schizophrenic patients, the existence of prolonged neurotoxicity of amphetamines and related psycho-behavioral disturbances has been suggested. The prolonged administration of amphetamines to animals produces neuro-axonal degeneration in the striatum, the frontal cortex, the nucleus accumbens and the amygdala. In human, there are some evidence of persistant deteriorations of the serotoninergic and dopaminergic systems in the caudate nucleus, the putamen and the nucleus accumbens following amphetamine consumption. CONCLUSION: The neurobiological and psycho-behavioural effects of amphetamines may be prolonged following withdrawal in both schizophrenic and non-schizophrenic patients.
Adult↗
Mossy cells and different subpopulations of pyramidal neurons are immunoreactive for cocaine- and amphetamine-regulated transcript peptide in the hippocampal formation of non-human primates and tree shrew (Tupaia belangeri).
Cocaine- and amphetamine-regulated transcript peptide mRNA was discovered in the rat striatum following cocaine and amphetamine administration. Since both psychostimulants elicit memory-related effects, localization of cocaine- and amphetamine-regulated transcript peptide in the hippocampal formation may have functional importance. Previous studies demonstrated different cellular localizations of cocaine- and amphetamine-regulated transcript peptide in humans and in rodents. Mossy cells were cocaine- and amphetamine-regulated transcript-positive in the human dentate gyrus, whereas granule cells contained this peptide in the rat. In the present study, the localization of cocaine- and amphetamine-regulated transcript peptide was examined using immunohistochemistry in the hippocampal formation of the rhesus monkey (Macaca mulatta), the common marmoset monkey (Callithrix jacchus) and in the tree shrew (Tupaia belangeri). In these species principal neurons of the hippocampal formation were cocaine- and amphetamine-regulated transcript-immunoreactive. In both monkeys and tree shrews, mossy cells of the hilus were cocaine- and amphetamine-regulated transcript-positive whereas granule cells of the dentate gyrus were cocaine- and amphetamine-regulated transcript-negative. The dense cocaine- and amphetamine-regulated transcript-immunoreactive axonal plexus of the associational pathway outlined the inner one-third of the dentate molecular layer. In the hippocampus of the tree shrew and marmoset monkey, a subset of CA3 pyramidal cells were cocaine- and amphetamine-regulated transcript-immunoreactive. In the marmoset monkey, cocaine- and amphetamine-regulated transcript labeling was found only in layer V pyramidal cells of the entorhinal cortex, while in the rhesus monkey, pyramidal cells of layers II and III were cocaine- and amphetamine-regulated transcript-immunopositive. Our results show that cocaine- and amphetamine-regulated transcript positive neurons in the dentate gyrus of non-human primates are similar to that of the human. Furthermore, in the hippocampal formation of the tree shrew similar cocaine- and amphetamine-regulated transcript-immunoreactive cell-types were observed as in monkeys, supporting their evolutionary relationship with primates. Mossy cells and granule cells are members of a mutual excitatory intrahippocampal circuitry, therefore cocaine- and amphetamine-regulated transcript-immunoreactivity of these neurons in primates and rodents suggests that psychostimulants cocaine and amphetamine may induce memory-related effects at different points of the same excitatory circuitry in the hippocampal formation.
Animals↗
Pentadecapeptide BPC 157 attenuates chronic amphetamine-induced behavior disturbances.
AIM: To investigate the effect of pentadecapeptide BPC 157 on chronic exposure to amphetamine in rats, particularly the changes commonly referred in chronic amphetamine studies as tolerance (lesser grade of stereotyped behavior, without increased excitability) and reverse tolerance (ie, prominent stereotyped behavior and heightened startle response upon late amphetamine challenges). METHODS: After initial application (initial single dose-regimen), amphetamine (10 mg/kg,ip) was given once daily till d 5 (continuous administration-regimen), and thereafter on d 8, 16, and 46 (intermittent administration regimen). Fo r stereotyped behavior and heightened startle response the observation period was 120 min after amphetamine application, and each animal was observed for 10 s in 5 min intervals. Pentadecapeptide BPC 157 (10 microg/kg or 10 ng/k g, ip) or saline (5.0 mL/kg, ip) were given only at the beginning of the experiment, simultaneously with the initial dose of amphetamine. RESULTS: In relation to applied initial-single/continuous/intermittent amphetamine applications regimen, the control amphetamine rats throughout the experiment showed the changes in stereotyped behavior and heightened startle response, increment or decrement, commonly explained in chronic amphetamine studies as tolerance and reverse tolerance. After t he initial application of the amphetamine, the higher BPC 157 dosage apparently attenuated the stereotyped behavior, while the lower dosage of BPC 157 did not reach a statistical significance. Considering the forthcoming amphetamine challenges, in the rats initially treated with pentadecapeptide BPC 157, either 10 microg- or 10 ng-dose, at the time of the first application of amphetamine, the stereotyped behavior remains to be attenuated after all additional amphetamine challenges (on d 2-5, 8, 16, and 46). This attenuation was not limited to stereotyped behavior only. After the initial application of the amphetamine the heighten ed startle response was also apparently mitigated in rats receiving the BPC 157 dosage, either higher or lower. Later, confronted with the forthcoming amphetamine challenges, they showed apparently less abnormal excitability at all tested points. CONCLUSION: In summary, gastric pentadecapeptide BPC 157 (ie, both microg- and ng-BPC 157 regimens) attenuated chronic amphetamine disturbances. This effect was present throughout the observation period at a statistically significant level. Therefore, it seems that this gastric pentadecapeptide BPC 157 has a modulatory effect on dopamine system, and it could be used in chronic amphetamine disturbances.
Amphetamine↗
Effects of d-amphetamine on the frequency of the spontaneous contraction of the portal vein in rat.
1. Effects of d-amphetamine on the frequency of spontaneous contraction of the longitudinal muscle of the portal vein were studied in Wistar rats. Its effects on the circular muscles of the pulmonary artery and stomach also were tested. 2. d-Amphetamine increased the frequency of the spontaneous contraction of the portal vein. The ratio of the frequency of the spontaneous contraction of the portal vein before and after d-amphetamine treatment also was increased. The effect was not affected in the presence of prazocin, (+)-lysergic acid diethylamide, atropine and haloperidol. These results that the d-amphetamine-elicited response was not due mainly to the activation of adrenergic, serotoninergic (5-HT), cholinergic or dopaminergic receptors. 3. Increasing extracellular calcium or sodium ion concentrations decreased the frequency of the spontaneous contraction of the portal vein. However, the ratios of the frequency of the spontaneous contraction of the rat portal vein before and after d-amphetamine treatment in media containing different extracellular calcium or sodium concentrations were not significantly altered. Tetrodotoxin did not alter the effect of d-amphetamine on the frequency of spontaneous contractions. It appeared that calcium and sodium ions may not take part in the effects of d-amphetamine on the frequency of the portal vein. 4. An increase in extracellular potassium ion concentrations increased the frequency of the spontaneous contractions of the portal vein. In addition, the ratios of the frequency of the spontaneous contractions of the rat portal vein before and after d-amphetamine treatment in media containing different extracellular potassium ion concentrations were significantly altered. Tetraethylammonium chloride (TEA) and 4-aminopyridine (4-AP) increased the spontaneous contractions of the portal vein. However, TEA and 4-AP did not increase the d-amphetamine-elicited increasing effect on the frequency of spontaneous muscle contractions. 5. Levochromakalim, a potassium channel opener, decreased the frequency of the spontaneous contractions of the portal vein. Levochromakalim also decreased the effect of d-amphetamine on the frequency of spontaneous contractions of the muscle. It appeared that potassium ion may be associated with the effects of d-amphetamine on the activity of the portal vein. 6. d-Amphetamine potentiated, whereas prazosin decreased, the noradrenaline-elicited contracture of the rat pulmonary artery in a dose-dependent manner. 7. d-Amphetamine elicited contracture of the circular muscle of rat stomach, whereas it did not alter the frequency of the spontaneous contraction of the muscle. 8. Both 5-HT and d-amphetamine elicited the contracture of the circular muscle of rat stomach. Ketanserin decreased the 5-HT-elicited response, whereas it did not alter the d-amphetamine-elicited response in the muscle. d-Amphetamine did not alter the frequency of the spontaneous contraction of the stomach. 9. It is concluded that d-amphetamine has different effects on the frequency of spontaneous smooth muscle contractions. It increased the frequency in the portal vein, but it did not alter the frequency in stomach circular muscle.
Adrenergic Agents↗
Differential effects of amphetamine isomers on dopamine release in the rat striatum and nucleus accumbens core.
RATIONALE: Current medications for attention-deficit/hyperactivity disorder (ADHD) include some single isomer compounds [dextroamphetamine (D: -amphetamine, dexedrine) and dexmethylphenidate (Focalin)] and some racemic compounds [methylphenidate and mixed-salts amphetamine (Adderall)]. Adderall, which contains approximately 25% L: -amphetamine, has been successfully marketed as a first-line medication for ADHD. Although different clinical effects have been observed for D: -amphetamine, Adderall, and benzedrine; potential psychopharmacological differences on the level of neurotransmission between D: -amphetamine and L: -amphetamine have not been well characterized. OBJECTIVES: To evaluate potential differences in the isomers, we used the technique of high-speed chronoamperometry with Nafion-coated single carbon-fiber microelectrodes to measure amphetamine-induced release of dopamine (DA) in the striatum and nucleus accumbens core of anesthetized male Fischer 344 rats. Amphetamine solutions were locally applied by pressure ejection using micropipettes. RESULTS: The presence of L: -amphetamine in the D: ,L: -amphetamine solutions did not cause increased release of DA but did change DA release kinetics. The D: ,L: -amphetamine-evoked signals exhibited significantly faster rise times and shorter signal decay times. This difference was also observed in the nucleus accumbens core. When L: -amphetamine was locally applied, DA release was not significantly different in amplitude, and it exhibited the same rapid kinetics of D: ,L: -amphetamine. CONCLUSIONS: These data support the hypothesis that amphetamine isomers have different effects on release of DA from nerve endings. It is possible that L: -amphetamine may have unique actions on the DA transporter, which is required for the effects of amphetamine on DA release from nerve terminals.
Amphetamines↗
Treatment for amphetamine dependence and abuse.
BACKGROUND: The ease of synthesis from inexpensive and readily available chemicals makes possible the wide spread of amphetamine dependence and abuse. Amphetamine use is of concern because it causes a variety of devastating health consequences, including physical and neurological disorders due to amphetamines, amphetamine-induced mental disorders, health consequences of amphetamine use and social consequences of amphetamine use. OBJECTIVES: To search and determine risks, benefits and costs of a variety treatments for amphetamine dependence or abuse. 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 clinical controlled trials (CCTs) were included. Participants were people with amphetamine dependence or abuse, diagnosed by any set of criteria. Any kinds of biological and psychological treatment 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: Fluoxetine, amlodipine, imipramine and desipramine have been investigated in four randomised-controlled trials. In comparison to placebo, short-term treatment of fluoxetine (40 mg/day) significantly decreased craving. In comparison to imipramine 10 mg/day, medium-term treatment of imipramine 150 mg/day significantly increased the duration of adherence to treatment. All four drugs had no benefits on a variety of outcomes, including amphetamine use. REVIEWER'S CONCLUSIONS: The evidence about the treatment for amphetamine dependence and abuse is very limited. It shows that fluoxetine, amlodipine, imipramine and desipramine have very limited benefits for amphetamine dependence and abuse. Fluoxetine may decrease craving in short-term treatment. Imipramine may increase duration of adherence to treatment in medium-term treatment. Apart from these, no other benefits, in particular proximal benefits, can be found. This limited evidence suggests that no treatment has been demonstrated to be effective for the treatment of amphetamine dependence and abuse. Although there is a large number of people with amphetamine dependence and abuse worldwide, very few controlled trials in this issue have been conducted. As the previous treatment trials show no promising result, other treatments, both biological and psychosocial, should be further investigated. However, the results of neurotoxic studies of amphetamines are also crucial for the study designs appropriate for further treatment studies for amphetamine dependence and abuse.
Amphetamine-Related Disorders↗
Evidence of a complete independence of the neurobiological substrates for the induction and expression of behavioral sensitization to amphetamine.
The repeated administration of amphetamine in rats produces behavioral sensitization which is characterized either by a progressive enhancement of the locomotor activity induced by the drug or by an enduring behavioral hypersensitivity to the drug after the cessation of the treatment. Some authors have suggested that the action of amphetamine at the level of the nucleus accumbens is responsible for the expression of behavioral sensitization, whereas the action of amphetamine at the level of the dopamine cell bodies in the ventral tegmental area induces some changes responsible for the initiation of the phenomenon. The present study fully tested this hypothesis. In two separate experiments, the effects of different doses of amphetamine repeatedly administered in the ventral tegmental area or in the nucleus accumbens were tested on the later behavioral reactivity to the administration of amphetamine in the nucleus accumbens. Independent groups of rats received five repeated administrations (one injection every other day) of different doses of amphetamine either in the ventral tegmental area (0, 1, 2.5, 5 micrograms/0.5 microliters per side) or in the nucleus accumbens (0, 1, 3, 10 micrograms/l microliters per side). Two days following the last intracerebral amphetamine injection, each group received a phosphate buffer solution challenge directly into the nucleus accumbens followed two days later by an amphetamine challenge (1 microgram/l microliters per side) in the nucleus accumbens and two days later by a peripheral challenge with amphetamine (0.5 mg/kg, s.c.). Locomotor responses were recorded following each injection. Results showed that injections of amphetamine into the nucleus accumbens induced a dose-dependent increase in locomotor activity which remained identical with the repetition of the injections. No difference between the different intra-accumbens pretreated groups was observed following the diverse phosphate-buffered saline solution and amphetamine challenges. In contrast, intra-ventral tegmental area administration of amphetamine did not produce any modification of locomotor activity. However, whereas no difference between the differently pretreated groups was observed following phosphate-buffered saline administration into the nucleus accumbens, a potentiation of the locomotor response to a challenge dose of amphetamine into the nucleus accumbens was observed which was dependent on the dose of amphetamine pretreatment into the ventral tegmental area. Similar potentiation was observed following peripheral challenge with amphetamine. Finally, cross-sensitization was observed when a challenge dose of cocaine (10 micrograms/1 microliter per side) was injected into the nucleus accumbens, as well as when a peripheral challenge dose of morphine (2.5 mg/kg, s.c.) was administered to the ventral tegmental area-pretreated groups.(ABSTRACT TRUNCATED AT 400 WORDS)
Amphetamine↗
Brain and plasma concentrations of amphetamine isomers in mice.
Brain and plasma concentrations of (+)- and (-)-amphetamine were compared as a function of dose and time after administration to mice. Doses of an amphetamine isomer contained 12 muCi of [14C]-(+) or (-)-amphetamine. Thirty minutes after administration of 2.5, 5 or 10 mg/kg i.p., (+)-amphetamine/(-)-amphetamine concentration ratios in the brain were significantly greater than 1; this ratio was less than 1 for the 15 mg/kg dose. Plasma concentration ratios were significantly greater than 1 for all doses. The ratios of +/-isomers were consistently greater than 1 in brain and plasma when determined at various times (7.5--120 min) after 2.5 and 10 mg/kg i.p. By contrast, i.v. administration of these doses resulted in no isomeric differences in brain amphetamine, alhough plasma (+)-amphetamine/(-)-amphetamine ratios remained somewhat elevated. After SKF 525-A pretreatment, the i.p. and i.v. routes resulted in similar (+)-amphetamince/(-)-amphetamine concentration ratios. These results suggest that (-)-amphetamine has a higher apparent volume of distribution (Vd) than (+)-amphetamine [Vd for (+)- and (-)-amphetamine, 2.5 mg/kg i.v. = 3.35 and 4.61 liters/kg, respectively; Vd for (+)- and (-)-amphetamine 10 mg/kg i.v. = 2.36 and 4.61 liters/kg, respectively] and that the (-)-isomer may be extracted more efficiently by the liver [plasma clearance (V) for (+)- and (-)-amphetamine 2.5 mg/kg i.v. = 6.91 and 9.09 liters/hr/kg respectively; V for (+)- and (-)-amphetamine 10 mg/kg i.v. = 2.85 and 4.33 liters/hr/kg, respectively] resulting in lower plasma and brain concentrations after i.p. administration.
Amphetamine↗
Enhanced dopamine release and phosphorylation of synapsin I and neuromodulin in striatal synaptosomes after repeated amphetamine.
Repeated, intermittent treatment of rats with amphetamine followed by a withdrawal period leads to an enhancement in amphetamine-induced dopamine release. We previously reported an increased stoichiometry of site 3-phospho-synapsin I and increased levels of phospho-Ser41-neuromodulin in striatum after repeated amphetamine. In this study, we examined whether the enhanced amphetamine-induced dopamine release and increased levels of these phosphoproteins would be detected in synaptosomes from rats pretreated and withdrawn from repeated amphetamine. Enhanced amphetamine-induced dopamine release was detected in striatal synaptosomes from rats treated with repeated amphetamine compared with controls. The enhanced dopamine release was Ca++ dependent. State-specific antibodies were used to measure the levels of site 3-phospho-synapsin I, phosphorylated by CaM kinase II, and phospho-Ser41-neuromodulin, phosphorylated by protein kinase C, in incubated striatal S1 fractions and synaptosomes. The levels of site 3-phospho-synapsin I and phospho-Ser41-neuromodulin were increased by 40% and 30%, respectively, in amphetamine-pretreated rats compared with controls. Total neuromodulin and synapsin I was not altered. There was a significant 26% increase in CaM kinase II activity in the synaptosomes from amphetamine-pretreated rats but no change in content. No change in protein kinase C activity or content of the alpha-isozyme was detected after repeated amphetamine. Our results demonstrate that the enhanced amphetamine-induced dopamine release and occurring after repeated amphetamine can be detected in synaptosome preparations. Repeated amphetamine leads to alterations in phosphorylation/dephosphorylation activities that can be detected in the incubated synaptosomes. Because the enhanced amphetamine-induced dopamine release after repeated amphetamine appears to be Ca++ sensitive, it is possible that the altered phosphorylation systems, and perhaps site 3-phospho-synapsin I and phospho-Ser41-neuromodulin, play a role in the enhanced dopamine release.
Amphetamine↗
Evidence for presynaptic dopamine mechanisms underlying amphetamine-conditioned locomotion.
Rats with a history of receiving (+)-amphetamine in a specific environment exhibit a conditioned psychomotor response when subsequently placed in that environment without drug treatment. Previous work has shown that while the unconditioned effects of amphetamine can be blocked by dopamine D1 or D2 receptor antagonists or with alpha-methyl-p-tyrosine, conditioned locomotion is not influenced by these treatments. In the present experiment, alpha-methyl-p-tyrosine (50 mg/kg, s.c.) was given in conjunction with amphetamine (1.5 mg/kg, s.c.) for 8 days before testing for conditioned locomotion. alpha-Methyl-p-tyrosine completely blocked amphetamine-induced locomotion but only attenuated amphetamine-conditioned locomotion. Reserpine (reduced over the 8 days from 2.5 to 1.25 mg/kg, i.p.) did not block amphetamine-induced locomotion; indeed, potentiation of amphetamine-induced locomotor activity was observed on the last 3 days of treatment. Reserpine treatment in conjunction with alpha-methyl-p-tyrosine treatment blocked amphetamine-induced locomotion for the first 4 days only, with full recovery of amphetamine-induced unconditioned locomotion by the last treatment day. Reserpine alone had no effect on amphetamine-conditioned locomotion, but completely blocked amphetamine-conditioned locomotion when given with alpha-methyl-p-tyrosine. It is concluded that the alpha-methyl-p-tyrosine-sensitive pool of dopamine mediates the immediate psychomotor effects of amphetamine, but that both the alpha-methyl-p-tyrosine- and reserpine-sensitive pools of dopamine are involved in the establishment of amphetamine-conditioned locomotion. In addition, the occurrence of amphetamine-conditioned locomotion is independent of the direct effects of amphetamine on locomotion.
Animals↗
Treatment for amphetamine psychosis.
BACKGROUND: During the phase of chronic, high-dose consumption of amphetamines, many amphetamine users may have the experience of paranoia and hallucination. It has long been believed that dopamine antagonists, such as chlorpromazine, haloperidol, and thioridazine, are effective for the treatment of amphetamine psychosis. OBJECTIVES: To search and determine risks, benefits, and costs of a variety treatments for amphetamine psychosis. SEARCH STRATEGY: Electronic searches of MEDLINE (1966-2000), EMBASE (1980-2000), 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 clinical trials (CCTs) were included. Participants were people with amphetamine psychosis, 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 assess the continuous data. MAIN RESULTS: The comprehensive searches found no controlled trials of treatment for amphetamine psychosis meeting the criteria for considering studies. REVIEWER'S CONCLUSIONS: The evidence about the treatment for amphetamine psychosis is very limited. To our knowledge, no controlled trials of treatment for amphetamine psychosis have been carried out. The results of two studies in amphetamine users show that agitation and some psychotic symptoms may be abated within an hour after antipsychotic injection. Whether this limited evidence can be applied for amphetamine psychotic patients is not yet known. The risks and benefits of giving an antipsychotic injection should be further investigated in amphetamine psychotic patients. Medications that have been used for the treatment of acute exacerbation of schizophrenia should be studied in amphetamine psychotic patients. The medications that may be of interest are conventional antipsychotics, newer antipsychotics and benzodiazepines. However, naturalistic studies of amphetamine psychotic symptoms and course are also crucial for the development of study designs appropriate for further treatment studies of amphetamine psychosis.
Amphetamine-Related Disorders↗
Phosphorylation of neuromodulin in rat striatum after acute and repeated, intermittent amphetamine.
Repeated, intermittent treatment of rats with amphetamine results in a sensitization of locomotor and stereotyped behaviors that is accompanied by an enhancement in stimulus-induced dopamine release. Increased phosphorylation of the neural specific calmodulin-binding protein, neuromodulin (GAP-43, B-50, F1) has been demonstrated in other forms of synaptic plasticity and plays a role in neurotransmitter release. To determine whether neuromodulin phosphorylation was altered during amphetamine sensitization, the in vivo phosphorylated state of neuromodulin was examined in rat striatum in a post hoc phosphorylation assay. Female, Holtzman rats received saline or 2.5 mg/kg amphetamine twice weekly for 5 weeks. One week after the last dose of amphetamine, rats were challenged with either 1 mg/kg or 2.5 mg/kg amphetamine or saline and the rats were sacrificed 30 min later. Purified synaptic plasma membranes were prepared in the presence of EGTA and okadaic acid to inhibit dephosphorylation, and were subsequently phosphorylated in the presence of purified protein kinase C and [gamma-32P]ATP. The protein kinase C-mediated post hoc phosphorylation of neuromodulin was significantly reduced in groups that received either acute or repeated amphetamine suggesting that neuromodulin in those groups contained more endogenous phosphate. The acute, challenge dose of amphetamine increased neuromodulin phosphorylation in the saline-treated controls but not in the repeated amphetamine-pretreated group. Anti-neuromodulin immunoblots showed no change in neuromodulin levels in any group. There was no significant change in protein kinase C activity in any treatment group. To further investigate the effect of acute amphetamine, the ability of amphetamine to alter neuromodulin phosphorylation in 32Pi-preincubated Percoll-purified rat striatal synaptosomes was examined. Amphetamine (10 microM) significantly increased phosphorylation of a 53 kDa band that migrated with authentic neuromodulin in the synaptosomes by 22% while 500 nM 12-O-tetradecanoylphorbol 13-acetate (TPA) increased neuromodulin phosphorylation by 45%. These data suggest that one injection of amphetamine can increase neuromodulin phosphorylation in rat striatum and that this increase is maintained for at least 1 week following a repeated, sensitizing regimen of amphetamine. Since sensitization can be induced with one dose of amphetamine, it is possible that enhanced neuromodulin phosphorylation could contribute to neurochemical events leading to enhanced release of dopamine and/or behavioral sensitization.
Amphetamine↗