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PubMed1975

Amphetamine: evaluation of d- and l-isomers as releasing agents and uptake inhibitors for 3H-dopamine and 3H-norepinephrine in slices of rat neostriatum and cerebral cortex.

Release of 3H-doapamine or of 3H-norepinephrine and inhibition of accumulation of 3H-dopamine or 3H-norepinephrine by d- and l-amphetamine were studied in slices of rat neostriatum and in slices of rat cerebral cortex. The two stereoisomers of amphetamine were equally potent as inhibitors of accumulation in the cortex, whereas d-amphetamine was approximately 3-fold more potent than l-amphetamine in the neostriatum. A similar relationship was observed between the two stereoisomers in release experiments. Some spontaneous efflux of 3H-dopamine from tissue slices was evident in absence of added drug in release experiments. When cocaine (2 X 10(-5) M), a known inhibitor of biogenic amine uptake, was added to the medium, there was very little increment in spontaneous efflux of 3H-dopamine in neostriatal slices, but cocaine blocked the release caused by d-amphetamine. This showed that the apparent releasing action of d-amphetamine in the neostriatum was not due to blockade of reuptake of spontaneously released material and that d-amphetamine itself must be taken up to evoke a releasing action. Experiments were designed to compare directly the releasing and uptake inhibiting actions of d-amphetamine. In the cortex, uptake inhibition of 3H-norepinephrine was greater than release over a wide concentration range, while in the neostriatum the two actions were essentially identical in magnitude for 3H-dopamine. We conclude that in the cortex, d-amphetamine can act both to release and to block uptake of 3H-norepinephrine. In the neostriatum, on the other hand, there is releasing action of 3H-dopamine by d-amphetamine (which is stronger than that in the cortex), but the apparent blockade of "uptake" is of questionable significance and appears to result from the release of previously accumulated 3H-dopamine

Amphetamine↗
PubMedDate not supplied

Serotonin1B receptor ligands in the nucleus accumbens shell do not affect the discriminative stimulus effects of amphetamine in rats.

Enhanced dopamine neurotransmission particularly, in the target area of the mesolimbic system, i.e. the nucleus accumbens (NAc), seems to be critical for the behavioral effects of amphetamine in rodents. Nonetheless, recent findings have also demonstrated a modulatory role of 5-hydroxytryptamine (5-HT; serotonin) in these effects. In the present study, we examined whether 5-HT1B receptors in the NAc shell are engaged in the discriminative stimulus of amphetamine. To this end male Wistar rats were trained to discriminate amphetamine (1 mg/kg, ip) from saline (ip) in a two-lever, water reinforced fixed ratio (FR) 20 task. After acquiring the amphetamine-saline discrimination, rats were stereotaxically implanted with bilateral cannulae aimed at the NAc shell and then infused with selective 5-HT1B receptor ligands. The ability of these drugs to substitute for or to alter (enhance or antagonize) the discriminative stimulus effects of amphetamine was examined. When given systemically, amphetamine (0.125-1 mg/kg) produced a dose-dependent increase in drug-lever responding. In substitution studies, microinjection of the 5-HT1B receptor agonist CP 93129 (1-10 microg/side) or the 5-HTIB receptor antagonist GR 55562 (1-10 microg/side) into the NAc shell did not evoke amphetamine-lever responding. Combination tests of 5-HT1B receptor ligands demonstrated that local injection with fixed doses of CP 93129 (1 or 10 microg/side) or GR 55562 (1 or 10 microg/side) with the submaximal doses of amphetamine (0.125-0.5 mg/kg) did not modify dose-response curves of the psychostimulant, nor did it affect its ED50 value. Our results seem to exclude a role for the NAc shell 5-HT1B receptors in the control of the discriminative stimulus effects of amphetamine. These findings also show that pharmacological stimulation of those receptors does not affect the amphetamine discrimination in rats.

Amphetamine↗
PubMed2005

Single- and multiple-dose pharmacokinetics of an oral mixed amphetamine salts extended-release formulation in adults.

OBJECTIVES: Assess the bioavailability of mixed amphetamine salts extended-release (MAS XR) 30-mg capsules and the dose proportionality of pharmacokinetic measures for MAS XR 20, 40, and 60 mg. METHODS: Study A, an open-label single-period study, and Study B, a randomized, open-label, three-way crossover study, were conducted in healthy adults in a clinical research unit. In Study A, 20 subjects received a single MAS XR 30-mg capsule by mouth daily for 7 days. In Study B, 12 subjects received single oral doses of MAS XR 20, 40, and 60 mg separated by 7-14-day washout periods. FINDINGS: Plasma dextroamphetamine (d-amphetamine) and levoamphetamine (l-amphetamine) concentrations were measured using a validated LC-MS/MS method. In Study A, a 3:1 ratio of d-amphetamine to l-amphetamine was observed for AUC0-inf and Cmax. Tmax was 4.2 and 4.3 hours for d-amphetamine to l-amphetamine, respectively. In Study B, for d- and l-amphetamine, statistically significant differences were observed for AUC0-t, AUC0-inf, and Cmax between all doses; there was a linear relationship between pharmacokinetic variables and dose and Tmax was similar for each isomer (range: 4.5-5.3 hours) with all given MAS XR doses. CONCLUSION: The extent of exposure as assessed by mean AUC0-24 and Cmax reflected the 3:1 ratio of d-amphetamine to l-amphetamine in MAS XR 30-mg capsules. The pharmacokinetic profiles of MAS XR 20, 40, and 60 mg are dose proportional for the isomers.

Administration, Oral↗
PubMed2005

Perinatal effects of amphetamine and heroin use during pregnancy on the mother and infant.

OBJECTIVES: To determine the perinatal impacts of heroin and amphetamine on both mothers and infants. MATERIAL AND METHOD: This is a retrospective study on the influence of amphetamine and heroin on pregnant women and their newborn infants at King Chulalongkorn Memorial Hospital in Bangkok, Thailand, between January 1997 and December 2002. The medical and demographic data of both mothers and infants were evaluated. Comparison of the consistent drug effects of these 2 drugs on the mothers and infants were also performed RESULTS: Two hundred and eleven women were identified There were 178 (84.4%) and 33 (15.6%) women addicted to amphetamine and heroin respectively. Sixty one (28.9%) of them were polydrug users. There were more polydrug users among heroin addicts than amphetamine addicts, (43.7% vs 27.2%, p < 0.05). Poor obstetric history were noted in both groups of women including lack of prenatal care (74.9%), a high incidence of previous abortion (22.3%), positive HIV serology test (11.1%), pre-eclampsia (5.2%), infection (3.3%) and antepartum hemorrhage (1.9%). Drug intoxication was found in 11 amphetamine addicted mothers, whereas 2 heroin addicts developed withdrawal symptoms during intrapartum and postpartum periods. All infants were singleton. There was one stillbirth and 2 neonatal deaths. There was no statistical difference in terms of sex ratio, mean birth weight, gestational age, length, head circumference and Apgar score between the groups of amphetamine and heroin exposed infants. The incidence of prematurity, low birth weight, IUGR and microcephaly were not statistically different between both groups of infants. The overall incidence was 31.7%, 31.7%, 9.5% and 8.6% respectively. Congenital anomalies were found in 5 (2.8%) amphetamine exposed infants. Thirty one out of 33 heroin exposed infants (93.9%) and 4 out of 178 amphetamine exposed infants (2.2%) developed drug withdrawal symptoms with the mean onset of 21.5 +/- 16.5 hours and 10.3 +/- 7.5 hours respectively, p > 0.05. All heroin withdrawal infants were successfully treated with Phenobarbital with the mean duration of treatment of 23.7 +/- 11.5 days. None of the amphetamine withdrawal infants needed specific treatment. They recovered spontaneously within 6.0 +/- 5.3 days. Eighteen infants were left in an orphanage or under the custody of their relatives. CONCLUSION: Amphetamine or heroin use during pregnancy can cause many serious adverse effects on both mothers and infants. The findings in the present study are consistent with previous reports, although they seemed to be more common and severe. Increasing awareness and improving understanding of drug abuse in the medical, legal and social aspects are needed in order to reduce these impacts.

Abnormalities, Drug-Induced↗
PubMed1991

[The urinary screening and identification of amphetamines in clinical toxicology laboratory--VGH].

Amphetamines abuse has recently become a problem in this country. Four case identification, we used Emit-d.a.u. amphetamine assay to screen the amphetamines in human urine, and then confirmed them by gas chromatography-ion trap detector (GC-ITD). From January 1989 to August 1990, 267 urinary samples were requested by the physicians for amphetamine identification. Six samples were accompanied with drug powders used by the patients. Among the 267 samples, 79 were confirmed for the presence for both of methamphetamine and amphetamine. Neither the presence of amphetamine nor methamphetamine itself was detected. Among the six packs of drug powder tested, methamphetamine but not amphetamine was detected in four. We found that fenfluramine and diethylpropion would have false positive amphetamine reactions in Emit-d.a.u. assay. All the samples originated from 34 hospitals were widely distributed in the country. Other drugs concomitantly used included ethanol, morphine, flunitrazepam and ephedrine. Since methamphetamine can be metabolized to amphetamine but not vers versa, our study confirmed the abuse of methamphetamine not amphetamine in this country.

Amphetamines↗
PubMed1972

Cardiovascular effects of amphetamine in the horse.

Each of nine horses was treated with amphetamine alone, with atropine alone, and with amphetamine and atropine in combination. Cardiac effects of these drugs were studied by electrocardiography during resting and exercising states and immediately after exercise. Although each treatment increased heart rate significantly during the resting state, only the amphetamine plus atropine treatment increased heart rate significantly during exercise. Decrease in heart rate immediately after exercise differed significantly for each treatment; the most rapid decrease in heart rate was found after the amphetamine treatment. Amphetamine caused second-degree atrioventricular (AV) block in each horse during the postexercise period. Amphetamine also caused ectopic beats either during or immediately after exercise in six horses. Second-degree AV block was not found when atropine was used alone or when used in combination with amphetamine. Fewer ectopic beats were found when atropine was used with amphetamine. Heart rate responses indicated that the direct effect of amphetamine was greater than the reflex effect at rest and during exercise; the opposite was true during postexercise. Second-degree AV block during the postexercise period was attributed to vagotonia due to baroreceptor stimulation. Release of norepinephrine by amphetamine probably caused many of the ectopic beats by increasing automaticity of subordinate pacemakers.

Amphetamine↗
PubMed1993

Evaluation of the stereoisomers of deprenyl for amphetamine-like discriminative stimulus effects in rats.

The antiparkinsonian agent l-deprenyl, a selective monoamine oxidase (MAO)-B inhibitor, is a phenylalkylamine derivative which is metabolized in part to l-methamphetamine and l-amphetamine. As the clinical use of amphetamine-like psychostimulants is limited by their potential for abuse, we evaluated l-deprenyl for amphetamine-like discriminative stimulus effects over a range of experimental conditions. Male Fisher rats were trained under a 5-response, fixed-ratio schedule of stimulus-shock termination or a 10-response, fixed-ratio schedule of food-presentation to discriminate between d-amphetamine (1.0 mg/kg i.p.) and saline in a two-lever, operant conditioning procedure. Full generalization was obtained to l-amphetamine (1.0-2.0 mg/kg), d-deprenyl (10.0-17.0 mg/kg) and l-deprenyl (17.0 and 30.0 mg/kg) under both the food-presentation and stimulus-shock termination schedules, and increases in responding on the lever appropriate to d-amphetamine were dose-dependent. The dose-effect functions for l-amphetamine, l-deprenyl and d-deprenyl were shifted slightly to the left under the stimulus-shock termination schedule compared to the food-presentation schedule. When l-deprenyl (3.0 or 5.6 mg/kg i.p.) was given 30 min before d-amphetamine it produced a small shift to the left in the dose-effect function for d-amphetamine under the food-presentation schedule. l-Deprenyl produced clear generalization to the d-amphetamine stimulus only at very high doses of 17.0 to 30.0 mg/kg, doses about 10-fold higher than those that have a selective action on MAO-B vs. MAO-A and which start to have marked rate decreasing actions on food-reinforced responding.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamines↗
PubMed1996

Haloperidol and MK-801 block increases in striatal calmodulin resulting from repeated amphetamine treatment.

Repeated, intermittent treatment with amphetamine leads to a behavioral sensitization characterized in rats by an increase in locomotor activity and a more rapid onset of stereotyped behaviors. Induction of amphetamine sensitization is blocked by dopamine and N-methyl-D-aspartate (NMDA) antagonists. We have reported an increase in the content of the Ca2(+)-binding protein, calmodulin, in striatum and limbic forebrains from rats given repeated, intermittent amphetamine. To determine whether the increase was related to development of amphetamine sensitization, we examined whether the increase in calmodulin would be blocked by the dopamine antagonist, haloperidol, or the NMDA antagonist, MK-801. Rats were given amphetamine or saline twice weekly for 5 weeks. Thirty min prior to the amphetamine, rats were pretreated with 0.25 mg/kg haloperidol s.c., 0.1 mg/kg MK-801 i.p. or saline. Twice weekly amphetamine treatment increased calmodulin in the cytosol fraction of striatum and limbic forebrain and the increase was blocked by pretreatment with either haloperidol or MK-801. Neither antagonist alone affected cytosolic calmodulin. Haloperidol pretreatment, but not amphetamine or MK-801, increased calmodulin in striatal but not limbic forebrain membranes. Calmodulin-binding proteins were examined by biotinylated calmodulin blotting to determine if repeated, intermittent amphetamine altered the content of calmodulin-binding proteins in striatal cytosol or membranes. A band of 73 kDa was increased in striatal membranes. Immunoblotting with antisera to caldesmon, a cytoskeletal calmodulin-binding protein of 77 kDa, demonstrated increases in immunoreactivity in striatal membranes and cytosol. These data suggest that dopaminergic and glutamatergic components are required for the increases in striatal and limbic forebrain calmodulin and that the rise in calmodulin is related to the development of amphetamine sensitization. In addition, the content of select calmodulin-binding proteins can be coordinately regulated with increases in calmodulin.

Amphetamine↗
PubMed1997

Striatal acetylcholine release correlates with behavioral sensitization in rats withdrawn from chronic amphetamine.

Stimulant sensitization is defined as an enhancement of the behavioral response to drug after repeated drug exposure. We have examined the relation between the expression of behavioral sensitization and the release of the striatal neurotransmitters acetylcholine (ACh) and dopamine (DA). Rats were treated with amphetamine (4 mg/kg i.p., b.i.d.) for 12 days. The behavioral response to amphetamine challenge was assessed during the chronic treatment, at short withdrawal (2 days) and at long withdrawal (2-3 wk) from the drug. Neurochemical responses to amphetamine challenge were assessed in separate groups of rats at the two withdrawal timepoints using in vivo microdialysis. The expression of behavioral sensitization in response to a low challenge dose of amphetamine (0.5 mg/kg) was only observed after long withdrawal; indeed, tolerance was observed at the short withdrawal timepoint. In contrast, sensitization of the behavioral response to challenge with 4 mg/kg amphetamine developed progressively over the course of drug treatment and continued to increase throughout withdrawal. Striatal ACh release was enhanced by amphetamine challenge (4 mg/kg) in the chronically treated animals and this response also was greater at long withdrawal vs. short withdrawal. However, amphetamine administration had no net effect on striatal ACh release in animals previously given chronic saline injections. Amphetamine challenge increased striatal DA release but this response did not differ between drug- or saline-treated animals at either withdrawal timepoint. Thus, an enhancement of the drug-induced stimulation of striatal ACh release correlates with the temporal profile of the expression of behavioral sensitization to amphetamine. In contrast, amphetamine-induced DA release does not appear to correlate with the expression of behavioral sensitization in the same manner.

Acetylcholine↗
PubMed1976

In vitro metabolism of amphetamine: an apparent enantiomeric interaction.

The stereoselective formation of the major metabolites N-hydroxyamphetamine and 1-phenyl-2-propanol in incubations of amphetamine with 9,000 X g supernatant fractions of rabbit liver has been studied using deuterium labelling in conjunction with selected-ion-monitoring gas chromatography/mass spectrometry. Comparison of separate incubations of (R)-amphetamine with those of (S)-amphetamine-d3 and of (S)-amphetamine with those of (R)-amphetamine-d3 showed that larger amounts of the two metabolites were formed from the (R) enantiomer. When "pseudoracemic" mixture (R)-amphetamine/(S)-amphetamine-d3 or (R)-amphetamine-d3/(S)-amphetamine were incubated the two metabolites were preferentially formed from the (S) enantiomer. Studies on the disappearance of substrate during incubation gave results in agreement with the findings on stereoselective metabolite formation. It was concluded that (S)-amphetamine or one of its metabolites inhibits the metabolism of the (R) enantiomer.

Amphetamine↗
PubMed1997

Robust sensitization to amphetamine following intra-VTA cholera toxin administration.

Studies were conducted regarding the hypothesis that enhanced cAMP formation in the ventral tegmental area (VTA) affects the magnitude of the behavioral responses elicited by psychostimulant drugs. In the first paradigm, spontaneous and amphetamine-elicited locomotor activity was measured at various times following injection of cholera toxin (CTX), a known activator of adenylate cyclase, into the VTA. Adult male rats showed enhanced amphetamine-stimulated locomotor activity when tested 1 or 3 days after treatment with 0.5 microgram CTX into the VTA. Spontaneous activity was markedly increased 1 and 3 days following treatment with the higher dose of 1.0 microgram CTX into the VTA, and amphetamine was still capable of eliciting an increased level of locomotor activity above this high baseline. Using a paradigm in which repeated amphetamine injections were given on an intermittent schedule following injection of CTX into the VTA, it was observed that a single low dose of amphetamine (0.5 mg/kg) given 1 day after CTX (0.5 microgram) injection into the VTA led to a markedly potentiated locomotor activity response to subsequent treatment with amphetamine. Evaluation of this protocol (initial amphetamine dose 24 h after CTX injection, and challenge treatment of amphetamine at various times thereafter) showed that the sensitization was long-lasting and could be observed after an initial dose of amphetamine as low as 0.1 mg/kg. A sensitized response was also expressed when the challenge dose was given directly into the nucleus accumbens. These data suggest that injection of CTX into the VTA enhances the induction of locomotor sensitization to amphetamine.

Adenylyl Cyclases↗
PubMed2003

D-amphetamine responses in catechol-O-methyltransferase (COMT) disrupted mice.

RATIONALE: We have earlier found that 1). COMT inhibitors did not enhance amphetamine-induced dopamine efflux into striatal extracellular, that 2). they did not increase dopamine levels in striatal tissue and that 3). they did not potentiate amphetamine-induced turning behavior of hemiparkinsonian rats. Further, when COMT knockout mice were challenged with l-dopa or a dopamine transporter (DAT) inhibitor, an accumulation of dopamine occurred and the neurochemical and locomotor effects of l-dopa and GBR 12909 were modified accordingly. OBJECTIVE: Since DAT inhibitors and amphetamine apparently have different mechanisms of action, we were interested to see how COMT knockout mice would react to d-amphetamine treatment. METHODS: We measured the effects of d-amphetamine on locomotor activity and on the levels of catecholamines and their metabolites in striatal microdialysis fluid and in striatal, hypothalamic and cortical brain regions of COMT gene disrupted mice. Striatal dopamine receptor binding was also determined. RESULTS. After d-amphetamine administration, the DOPAC content in homozygous mice was 3-fold in the striatum, 17- to 18-fold in the cortex and 7- to 8-fold in the hypothalamus higher than in wild-type control mice, and there were no indications of genotypexsex interactions. However, the lack of COMT did not potentiate d-amphetamine-induced dopamine levels in brain tissue or in striatal extracellular fluid. D-amphetamine-induced (10 mg/kg) hyperlocomotion was less suppressed in male COMT knockout mice than in their wild-type counterparts. Striatal dopamine D(1) and D(2) receptor levels in male mice were not altered by COMT gene disruption. CONCLUSIONS: Changes in COMT activity modulates dopamine metabolism but the behavioral effects of d-amphetamine in male mice only to a small extent, and this action does not seem to depend on the actual extracellular dopamine concentration. Nor is it mediated through compensatory changes in dopamine D(1) and D(2) receptor levels. In dopaminergic neurons, the contribution of intracellular COMT remains secondary in conditions when dopamine is released by d-amphetamine.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2001

Acute doses of d-amphetamine and bupropion increase cigarette smoking.

RATIONALE: Bupropion is used clinically as a treatment for smoking cessation, but the processes by which it reduces smoking are poorly understood. Bupropion shares some neurochemical actions and behavioral effects with the psychostimulant amphetamine, and it has been shown that amphetamine increases smoking when administered acutely. The effects of single doses of bupropion on smoking have not been studied but, based on its similarities to amphetamine, we postulated that acute bupropion would also increase smoking. OBJECTIVE: To measure the effects of single doses of amphetamine and bupropion on smoking and craving for cigarettes in smokers. METHODS: Cigarette smokers who were not trying to quit participated in a three-session study in which they received placebo and a single dose of either d-amphetamine sulfate (10 and 20 mg; n=10) or bupropion hydrochloride (150 and 300 mg; n=12) after overnight abstinence. The three outcome measures were: i) subjective and behavioral effects of amphetamine and bupropion after a period of acute abstinence, ii) effects of amphetamine and bupropion on subjective responses to a single, smoked cigarette, and iii) effects of the drugs on number of cigarettes smoked during an ad libitum smoking period. RESULTS: After the acute abstinence and before smoking, both amphetamine and bupropion increased self-reported mood and euphoria, but did not change ratings of craving or withdrawal. After subjects smoked a single smoked cigarette, they reported that bupropion reduced ratings of "buzzed" and "intensity". During the period of ad libitum smoking both amphetamine and bupropion increased the number of cigarettes smoked. CONCLUSION: Acute doses of both bupropion and amphetamine increase smoking in non-treatment-seeking smokers without altering ratings of craving or withdrawal. Bupropion reduced some of the sensory responses to the smoked cigarette. It remains to be determined why bupropion increases smoking when administered acutely under controlled conditions, while it helps to reduce smoking in patients trying to quit.

Adult↗
PubMed1976

Mechanism of D-amphetamine inhibition of protein synthesis.

At 1 h after intraperitoneal administration of D-amphetamine sulphate (15 mg/kg), rat brain polyribosomes show disaggregation accompanied by reduced capacity for in vitro peptide chain elongation. The direct action of amphetamine on cell-fine protein-synthesizing systems was therefore explored. When brain or liver polyribosomes from untreated rats were incubated with pH 5 enzyme, peptide chain elongation was not inhibited by the addition 4 mM amphetamine to the medium. On the other hand, an initiation-dependent system consisting of rat liver of brain mRNA and wheat germ S-30 fraction showed inhibition of [3H]leucine incorporation by 50% when 4 mM amphetamine were added. The metabolites of amphetamine, p-hydroxyamphetamine and p-hydroxynorephedrine, had no inhibitory action in either system, but the potent neurotoxin p-chloroamphetamine was a more powerful inhibitor of initiation than amphetamine. By using [3H]amphetamine, it was shown that amphetamine binds to the 80-S ribosomes of the wheat germ system. This binding depended on the presence in the system of natural liver or brain mRNA or several synthetic mRNAs, but was not promoted by polyuridylic acid as the messenger. Significantly, polyuridylic acid-dependent polyphenylalanine synthesis by the wheat germ system was not inhibited by amphetamine or p-chloroamphetamine. Therefore, it was concluded that amphetamine inhibits protein synthesis by interfering with initiation through a step related to formation of the mRNA ribosome complex.

Animals↗
PubMed1976

Differential effects of para-chlorophenylalanine on amphetamine-induced locomotion and stereotypy.

Amphetamine-induced locomotion and stereotypy were concurrently evaluated in order to determine if pretreatment with para-chlorophenylalanine (PCPA) (which is reported to facilitate some of the effects of amphetamine) results in a behavioral pattern similar to the augmentation previously reported to occur with repeated amphetamine administration. In the present study the behavioral response of rats was characterized after administration of saline or various doses of D-amphetamine (0.5, 2.5 and 4.0 mg/kg) for 48 h following PCPA (300 mg/kg) or vehicle injection. The predominant effects produced by the low dose of D-amphetamine (0.5 mg/kg), i.e., enhanced crossovers and rearings, were found to be significantly elevated after PCPA administration. This effect persisted (relative to PCPA controls) when the response of non-PCPA pretreated animals returned to corresponding control levels, thus indicating that the two drugs acted synergistically. However, while the locomotor component of the amphetamine response was potentiated by PCPA pretreatment, the more focused stereotypies produced by higher doses of amphetamine (2.5 and 4.0 mg/kg) were significantly displaced by enhanced crossovers and rearings. These differential effects of PCPA on amphetamine-induced locomotion and stereotypy are in contrast to the uniform pattern of behavioral augmentation resulting from repeated amphetamine administration. The relationship between the various behavioral components of the amphetamine response and the possible neurochemical mechanisms subserving their interaction are discussed.

Animals↗
PubMed1992

Effect of desipramine and amphetamine on noradrenergic neurotransmission: electrophysiological studies in the rat brain.

The present electrophysiological experiments were undertaken to investigate the effect of desipramine and d-amphetamine on noradrenergic neurotransmission in the rat central nervous system. The effectiveness of electrical stimulation of the locus coeruleus and of microiontophoretic application of norepinephrine (NE) in suppressing the firing activity of CA3 pyramidal neurons was studied in the dorsal hippocampus. Desipramine (0.5 and 5 mg/kg i.v.) and d-amphetamine (0.25 and 5 mg/kg i.v.) decreased the effectiveness of locus coeruleus stimulation and prolonged the effect of microiontophoretically applied NE on the same pyramidal neurons. Subsequent i.v. administration of idazoxan, an alpha 2-adrenoceptor antagonist, reversed the effects of desipramine and d-amphetamine on the effectiveness of locus coeruleus stimulation and decreased that of microiontophoretically applied NE. In addition, idazoxan prevented the effect of subsequent administration of desipramine (5 mg/kg i.v.) on the effectiveness of locus coeruleus stimulation. High doses of d-amphetamine (5 and 10 mg/kg i.v.) decreased the firing activity of hippocampus pyramidal neurons by 70 and 98%, respectively, whereas low doses of desipramine (0.5 mg/kg i.v.) or of d-amphetamine (0.25 mg/kg i.v.) were without effect. After lesioning of NE projections with 6-hydroxydopamine, the effect of the 5 mg/kg dose of d-amphetamine on the firing activity of hippocampus pyramidal neurons was markedly reduced, whereas the cumulative 10 mg/kg dose of d-amphetamine completely suppressed, as in control rats, the firing activity of these neurons. This effect of d-amphetamine in 6-hydroxydopamine-pretreated rats was reversed by the administration of the 5-HT1A receptor antagonist BMY 7378. These data provide evidence that acute administration of desipramine and d-amphetamine decreases the effectiveness of locus coeruleus stimulation by increasing the activation of terminal alpha 2-adrenoceptor autoreceptors. In addition, acute administration of high doses of d-amphetamine decreases the firing rate of hippocampus pyramidal neurons by increasing NE and serotonin release.

Animals↗
PubMed1982

Implications for multiple transmitter mediation of amphetamine-induced stereotypies.

Gerbils were pretreated with the dopamine (DA) receptor blocker, pimozide, prior to stereotypy-inducing injections of d-amphetamine. Some of the stereotypies induced with amphetamine were blocked, but some were not, supporting the hypothesis that multiple neurotransmitters are involved in the mediation of amphetamine-induced stereotypy. In addition, when apomorphine hydrochloride was injected, different stereotypic motor behaviors were induced than were induced with amphetamine. The behavioral changes following amphetamine treatment could be classified into four groups: (1) those that are probably DA related, based on the fact that they were induced with either amphetamine or apomorphine, and amphetamine induction was blocked with pimozide; (2) those that are probably not DA related because they were not induced by apomorphine, and amphetamine induction was not blocked by pimozide; (3) those behaviors that may be incompatible with stereotypic behaviors, were reduced with either amphetamine or apomorphine, but were not maintained with pimozide; and (4) circling, which was induced with amphetamine, blocked with pimozide, but not induced with apomorphine.

Animals↗
PubMed1995

Effects of D-amphetamine and phencyclidine on behavior and extracellular concentrations of neurotensin and dopamine in the ventral striatum and the medial prefrontal cortex of the rat.

The effects of systemically administered phencyclidine (PCP; 2.5 mg/kg, s.c.) and D-amphetamine (1.5 mg/kg, s.c.) on the extracellular concentrations of neurotensin-like immunoreactivity (NT-LI) and dopamine (DA) in the ventral striatum (vSTR) and the medial prefrontal cortex (mPFC) were studied in freely moving rats using microdialysis. In separate animals, the effects of PCP and D-amphetamine on open field activity were also analyzed. PCP, but not D-amphetamine, caused a significant increase (156% over baseline) of NT-LI levels in the vSTR which was relatively short lasting, i.e., of less than 2 h duration. In contrast, both drugs significantly increased NT-LI concentrations in the mPFC by almost 100% during the same period. PCP and D-amphetamine also significantly increased extracellular levels of DA in the vSTR by 83 and 364%, respectively. However, the peak effect of PCP on DA appeared later than that of D-amphetamine, i.e., at 150 and 60 min, respectively, after drug administration. Also in the mPFC, both PCP and D-amphetamine significantly increased DA concentrations by 98 and 284%, respectively. Generally, effects on DA levels of both PCP and D-amphetamine were, in contrast to their effects on NT-LI levels, clearly more long-lasting, i.e., of 3-4 h duration. Behaviorally, D-amphetamine produced a more pronounced, general activation than PCP, with a faster onset of activation, i.e. within 30 vs 90 min after administration. However, both drugs produced long-lasting effects on the spatial organization of behavioral activity, which lasted for 3-4 h. In conclusion, the more pronounced behavioral stimulation by D-amphetamine (1.5 mg/kg, s.c.) vs PCP (2.5 mg/kg, s.c.) in the rat may largely be explained by its more potent DA-releasing effect in the brain. Initial behavioral suppression by PCP, e.g., of rearing, as well as its rather poor locomotor stimulant action in general, might relate to release of NT in the vSTR. The long-lasting, behavioral disorganization by both PCP and D-amphetamine may, however, be related to increased release of DA rather than NT in the mesolimbocortical areas.

Animals↗