Evidence that a behavioral augmentation following repeated amphetamine administration does not involve peripheral mechanisms

doi:10.1016/0091-3057(82)90317-3

Pharmacology Biochemistry and Behavior

Volume 17, Issue 3, September 1982, Pages 547-553

https://doi.org/10.1016/0091-3057(82)90317-3 Get rights and content

Abstract

Repeated administration of amphetamine (AMPH) to rats results in an augmentation of the drug-induced locomotion and stereotypy. The studies reported below were directed at examining the potential role for some dispositional and peripheral sympathomimetic factors in mediating the enhanced stereotypy response. These included three factors associated with repeated AMPH administration: (1) the possible accumulation of AMPH in a peripheral mobilizable pool; (2) repeated sympathetic activation; and (3) AMPH metabolite induced depletion of peripheral stores of norepinephrine. The approach utilized was to selectively reduce or mimic the peripheral actions of AMPH through the use of non-pharmacological or pharmacological manipulations which are relatively lacking in AMPH-like central stimulant effects. The results indicate that these factors cannot account for the augmentation of the behavioral response to AMPH and suggest that these behavioral alterations reflect changes in the responsiveness of brain mechanisms which mediate the behavioral effects of the drug.

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Cited by (21)

Dexamethasone pretreatment reduces the psychomotor stimulant effects induced by cocaine and amphetamine in mice
1995, Progress in Neuropsychopharmacology and Biological Psychiatry
- 1.
  1. The present study examined a comparison of the effect of DEX on psychomotor stimulant effects of cocaine and amphetamine in mice by using the locomotor activity test.
- 2.
  2. Cocaine (10 mg/kg/i.p.) and amphetamine (5 mg/kg/i.p.) increased markedly locomotor activity of mice whereas DEX $per se$ (0.1-1.0–10 mg/kg/i.p.) did not modify the activity of control mice.
- 3.
  3. DEX pretreatment decreased the stimulating effects induced both by cocaine and amphetamine but no consistent dose-related effects were observed.
- 4.
  4. The results suggest that DEX may play an important role on the stimulating effects of cocaine and amphetamine and that it may be of some utility in the clinical management of psychostimulants abuse.
In vivo microdialysis reveals a diminished amphetamine-induced DA response corresponding to behavioral sensitization produced by repeated amphetamine pretreatment
1992, Brain Research
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.
Acute and subchronic effects of methylenedioxymethamphetamine [(±)MDMA] on locomotion and serotonin syndrome behavior in the rat
1989, Pharmacology, Biochemistry and Behavior
Specific behaviors comprising the serotonin syndrome (low body posture, forepaw treading, headweaving) and the automatic signs of piloerection and salivation were determined and analyzed with locomotor activity in response to MDMA at three doses (2.5, 5.0, and 7.5 mg/kg). All behaviors were dose-responsive. Serotonin syndrome behaviors increased in both intensity and duration of response with increasing doses. In contrast, locomotion varied only in intensity. Subchronic injections, in the same group of animals, permitted an analysis of acute vs. subchronic effects on these same behaviors. Both the serotonin syndrome and locomotor behaviors were augmented on subsequent testing, indicating that, (±)MDMA, like amphetamine, is capable of producing behavioral sensitization.
How metabolites may augment some psychostimulant actions of amphetamine
1987, Trends in Pharmacological Sciences
The release of dopamine in the CNS by repeated doses of amphetamine is thought to underlie amphetamine-induced psychosis in humans and behavioural augmentation in experimental animals, although the mechanisms involved are incompletely understood. Donald Dougan, Denis Wade and Patricia Duffield discuss recent data on the long-term accumulation of metabolites of amphetamine in the brain. One of these compounds, α-methyltyramine, the para-hydroxylated metabolite of amphetamine, enhances the stereotype response to the acute administration of the drug and also causes augmentation of the amphetamine-induced decrease in dopamine metabolism in the striatum. These observations are consistent with the hypothesis that behavioural augmentation, seen after repeated doses of amphetamine, is due to the accumulation of α-methyltyramine in dopaminergic nerve terminals. Subsequent doses of amphetamine then release α-methyltyramine which blocks dopamine uptake with an apparent increase in the amphetamine-releasable pool of dopamine without change in receptor sensitivity. The close structural and metabolic similarities between amphetamine and its metabolites, and naturally occurring monoamines, again raises the question of the possible role of these amines in some forms of schizophrenia.
Evidence that alpha-methyl-p-tyramine is implicated in behavioural augmentation to amphetamine
1986, General Pharmacology
- 1.
  1. Behavioural studies showed that administration of α-methyl-p-tyramine (AMT; 10 mg/kg i.p.) to rats 24 hr before treatment with d-amphetamine (AMPHET; 4 mg/kg i.p.) resulted in augmentation of AMPHET-induced stereotype activity.
- 2.
  2. Parallel experiments involving electro-chemical estimation of dopamine metabolites in the striatum showed that the decrease in the concentration of homovanillic acid (HVA) produced by AMPHET (4 mg/kg) was enhanced in AMT (10 mg/kg) pretreated animals.
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  3. These findings suggest that AMT derived from previous doses of AMPHET may play a role in the phenomena of behavioural augmentation observed after chronic administration of AMPHET.
Biochemical and behavioral changes in rats during and after chronic d-amphetamine exposure
1985, Drug and Alcohol Dependence
Two groups of rats were implanted with ALZET^® minipumps to deliver vehicle or a theoretical amount of 1 mg/kg per h of d-amphetamine (A) for 12 days. After 3 days of A-exposure, motor movements and stereotypic behavior were markedly increased. Subsequent testing during A-exposure showed that motor movements and stereotypic behavior remained significantly increased but declined. After removal of the pumps, these effects disappeared and no differences at rest, during stress or A challenge, were apparent in either group. Animals sacrificed after 3 days of drug exposure, showed a drastic decrease in cardiac, but not adrenal, catecholamine levels. In the brain, norepinephrine (NE) levels were markedly decreased in the frontal cortex, hypothalamus, caudate, pons-medulla and cerebellum. Epinephrine (E) levels were unaffected and dopamine (DA) levels were decreased in most areas without reaching statistical significance. Plasma corticosterone levels were similar in both groups. Animals in both groups sacrificed about 25 days after pump removal were biochemically similar. Under our conditions, A-exposure produced marked behavioral and biochemical changes but there was no evidence of residual abnormalities after cessation of drug treatment.

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^☆: This research was supported in part by USPHS Grant DA-01568-06; R.K. and D. S. S. are recipients of Research Scientist Development Awards KO2-MH00091 and KO2-MH70183, respectively.

²: These studies were performed while on leave from the Pharmacology Department, Vanderbilt University, Nashville, TN 37217.

³: Present address: Pharmacology Department, Chas. Pfizer Inc., Groton, CT 06340.

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Pharmacology Biochemistry and Behavior

Abstract

References (28)

Tolerance to the discriminative stimulus properties of d-amphetamine

Neuropharmacology

Metabolic and experiential factors in the behavioral response to repeated amphetamine

Pharmac. Biochem. Behav.

The conversion in vivo of d-amphetamine to (+)p-hydroxynorephedrine

Biochim. biophys. Acta

Chronic administration of d-amphetamine and chlorpromazine in rats

Eur. J. Pharmac.

Apparent tolerance to some aspects of amphetamine stereotypy with long-term treatment

Pharmac. Biochem. Behav.

Long-term administration of d-amphetamine: Progressive augmentation of motor activity and stereotypy

Pharmac. Biochem. Behav.

Conditioned drug effects and absence of tolerance to d-amphetamine-induced activity

Pharmac. Biochem. Behav.

Cardiovascular effects of pressor amines

Anesthesiology

Studies on sympathetic amines. II. The biotransformation and physical disposition of d-amphetamine, d-p-hydroxy-amphetamine and d-amphetamine

J. Pharmac. exp. Ther.

Possible role of p-hydroxynorephedrine in the depletion of norepinephrine induced by d-amphetamine and in tolerance to this drug

An evaluation of the vasodilation produced by mephentermine and certain other sympathomimetic amines

J. Pharmac. exp. Ther.

Biosynthesis and storage of catecholamines in tissues of rats injected with various doses of d-amphetamine

Monoaminergic drugs: General pharmacology

Pharmac. Ther.

Tolerance of rats toward amphetamine methamphetamine

J. Am. pharm. Ass.

Cited by (21)

Dexamethasone pretreatment reduces the psychomotor stimulant effects induced by cocaine and amphetamine in mice

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

Acute and subchronic effects of methylenedioxymethamphetamine [(±)MDMA] on locomotion and serotonin syndrome behavior in the rat

How metabolites may augment some psychostimulant actions of amphetamine

Evidence that alpha-methyl-p-tyramine is implicated in behavioural augmentation to amphetamine

Biochemical and behavioral changes in rats during and after chronic d-amphetamine exposure

Evidence that a behavioral augmentation following repeated amphetamine administration does not involve peripheral mechanisms☆

Abstract

Neuropharmacology

Pharmac. Biochem. Behav.

Biochim. biophys. Acta

Eur. J. Pharmac.

Pharmac. Biochem. Behav.

Pharmac. Biochem. Behav.

Pharmac. Biochem. Behav.

Cardiovascular effects of pressor amines

Anesthesiology

Studies on sympathetic amines. II. The biotransformation and physical disposition of d-amphetamine, d-p-hydroxy-amphetamine and d-amphetamine

J. Pharmac. exp. Ther.

Possible role of p-hydroxynorephedrine in the depletion of norepinephrine induced by d-amphetamine and in tolerance to this drug

An evaluation of the vasodilation produced by mephentermine and certain other sympathomimetic amines

J. Pharmac. exp. Ther.

Biosynthesis and storage of catecholamines in tissues of rats injected with various doses of d-amphetamine

Monoaminergic drugs: General pharmacology

Pharmac. Ther.

Tolerance of rats toward amphetamine methamphetamine

J. Am. pharm. Ass.