Brain Amphetamine Research Articles

Elevated body fat increases amphetamine accumulation in brain: evidence from genetic and diet-induced forms of adiposity

Despite the high prevalence of obesity, little is known about its potential impact on the pharmacokinetics of psychotropic drugs. In the course of investigating the role of the microRNA system on neuronal signaling, we found that mice lacking the translin/trax microRNA-degrading enzyme display an exaggerated locomotor response to amphetamine. As these mice display robust adiposity in the context of normal body weight, we checked whether this phenotype might reflect elevated brain levels of amphetamine. To assess this hypothesis, we compared plasma and brain amphetamine levels of wild type and Tsn KO mice. Furthermore, we checked the effect of diet-induced increases in adiposity on plasma and brain amphetamine levels in wild type mice. Brain amphetamine levels were higher in Tsn KO mice than in wild type littermates and correlated with adiposity. Analysis of the effect of diet-induced increases in adiposity in wild type mice on brain amphetamine levels also demonstrated that brain amphetamine levels correlate with adiposity. Increased adiposity displayed by Tsn KO mice or by wild type mice fed a high-fat diet correlates with elevated brain amphetamine levels. As amphetamine and its analogues are widely used to treat attention deficit disorder, which is associated with obesity, further studies are warranted to assess the impact of adiposity on amphetamine levels in these patients.

Effect of neuroleptics on brain amphetamine concentrations in the rat.

Effect of neuroleptics on brain amphetamine concentrations in the rat.

Desipramine and amphetamine metabolism.

Abstract Desipramine (2.5–5 mg/kg) increases the urinary excretion of amphetamine given intraperitoneally at doses of 7.5–15 mg/kg and it decreases the excretion of p-hydroxyamphetamine. The rate of removal of brain amphetamine is decreased by desipramine (5 mg/kg, i.p.) when amphetamine is injected intraperitoneally but not when it is injected intracerebrally. It is suggested that desipramine impairs the hydroxylation of amphetamine in the liver thereby increasing the level of circulating amphetamine and eventually of brain amphetamine.

Caudate–putamen dopamine and stereotypy response profiles after intravenous and subcutaneous amphetamine

We compared the behavioral and caudate–putamen extracellular dopamine responses following intravenous (3.6 mg/kg) and subcutaneous (8 mg/kg) amphetamine administration using 2-min microdialysate sampling intervals, and doses of the drug selected to achieve comparable maximal brain concentrations. Following intravenous amphetamine, dopamine peaked within the first 2 min, then declined with a first-order decay rate of 0.018 ± 0.007 min−1. Following subcutaneous amphetamine, dopamine achieved maximum concentrations at 9 min and remained near peak levels for about 30 min before declining with a first-order decay rate of 0.019 ± 0.008 min−1. Maximal brain amphetamine levels and peak dopamine concentrations were equivalent following either route of drug administration. In contrast to the short latency to maximal extracellular dopamine, the onset of oral stereotypies was delayed until about 30 min following both routes of drug administration. Furthermore, in contrast to the behavioral response to amphetamine, apomorphine administration resulted in the rapid appearance of oral stereotypies within 5–10 min after drug administration. These results suggest that although caudate–putamen dopamine receptor activation may be a critical factor in the expression of focused oral stereotypies, other effects of amphetamine may interfere with the ability of animals to exhibit these behaviors. Synapse 31:125–133, 1999. © 1999 Wiley-Liss, Inc.

Caudate-putamen dopamine and stereotypy response profiles after intravenous and subcutaneous amphetamine.

We compared the behavioral and caudate-putamen extracellular dopamine responses following intravenous (3.6 mg/kg) and subcutaneous (8 mg/kg) amphetamine administration using 2-min microdialysate sampling intervals, and doses of the drug selected to achieve comparable maximal brain concentrations. Following intravenous amphetamine, dopamine peaked within the first 2 min, then declined with a first-order decay rate of 0.018+/-0.007 min(-1). Following subcutaneous amphetamine, dopamine achieved maximum concentrations at 9 min and remained near peak levels for about 30 min before declining with a first-order decay rate of 0.019+/-0.008 min(-1). Maximal brain amphetamine levels and peak dopamine concentrations were equivalent following either route of drug administration. In contrast to the short latency to maximal extracellular dopamine, the onset of oral stereotypies was delayed until about 30 min following both routes of drug administration. Furthermore, in contrast to the behavioral response to amphetamine, apomorphine administration resulted in the rapid appearance of oral stereotypies within 5-10 min after drug administration. These results suggest that although caudate-putamen dopamine receptor activation may be a critical factor in the expression of focused oral stereotypies, other effects of amphetamine may interfere with the ability of animals to exhibit these behaviors.

Differential effects of ibogaine pretreatment on brain levels of morphine and (+)-amphetamine

Previous studies in rats have shown that ibogaine inhibits neurochemical and behavioral effects of morphine yet potentiates similar effects of (+)-amphetamine. To assess whether these different functional interactions have a metabolic basis, brain levels of morphine and (+)-amphetamine were measured by gas chromatography-mass spectrometry after ibogaine pretreatment (19 h before injection of morphine or (+)-amphetamine). Ibogaine pretreatment had no effect on brain morphine levels, either at 30 min or 2 h after morphine injection; however, ibogaine significantly increased brain amphetamine levels at 30 min and, to a greater extent, at 2 h after (+)-amphetamine injection. These and other data suggest that ibogaine irreversibly inhibits an amphetamine-metabolizing enzyme. The functional interactions between ibogaine and (+)-amphetamine, but not those between ibogaine and morphine, may result from a hepatic drug-drug interaction.

Effect of ascorbic acid on brain amphetamine concentrations in the rat

1. 1. Ascorbic acid is reported to have antiamphetamine effects in rodents. 2. 2. The effect of ascorbic acid (1 g/kg ip) on the half-life of amphetamine (10 mg/kg) in rat brain using 3H-amphetamine and on amphetamine—induced stereotyped behaviour was investigated. 3. 3. Ascorbic acid had no effect on amphetamine—induced stereotyped behaviour or on the half-life of amphetamine in brain. 4. 4. If ascorbic acid antagonizes amphetamine-induced behavioural responses this is unlikely to be a result of altering the pharmacokinetics of amphetamine.

Amphetamine Anorexia and Hypothalamic catecholamines in genetically obese mice ( obob)

Genetically obese mice ( obob) and their lean littermates were acclimated to a restricted food-access schedule of six hours and then treated with various doses of amphetamine (0, 3, 5 or 10 mg/kg). Saline-treated obob mice maintained on this schedule retained the primary characteristics of obob mice fed ad lib, i.e., hyperphagia, hyperglycemia, elevated hypothalamic norepinephrine (NE) levels. Both lean and obese mice treated with amphetamine showed a dose-dependent decrease in food intake and hypothalamic NE levels. In obob mice amphetamine treatment reduced food intake and hypothalamic NE levels to values which were not significantly different from those of similarly treated lean mice. When the drug dose was administered on a body weight basis, however, brain amphetamine levels were twice as high in obob as in lean mice. When the amphetamine dose was adjusted to produce approximately equivalent brain levels of amphetamine in obob and lean mice, the obob mice ate significantly more than lean mice. The results indicate that amphetamine is an effective anorectic agent capable of reducing food intake, body weight, and hypothalamic NE levels in obob mice.

Amphetamine actions in dorsolateral tegmental rats: Hypodipsia, anorexia, and central nervous system permeation to [ 14C]amphetamine

Electrolytic lesions of the dorsolateral tegmentum produced hyperdipsia, enhanced amphetamine-induced hypodipsia, yet attenuated amphetamine-induced anorexia. Central nervous system permeation by [ 14 C]amphetamine was comparable in control, operated control, and tegmental rats. These data suggest that (a) a common motivational process, such as malaise, cannot explain the anorexic and hypodipsic properties of amphetamine and (b) that the influence of tegmental damage on amphetamine actions did not result from differences in brain amphetamine levels.

Aging alters amphetamine-induced stereotyped gnawing and neostriatal elimination of amphetamine in mice

Amphetamine-induced compulsive gnawing was assessed in C57BL/6J male mice (4, 10 and 29 months old). The 29-month old mice displayed a longer latency before initiation of the compulsive-gnawing response and a longer duration of compulsive-gnawing response than either younger age group. Following administration of 10 mg/kg of 3H-amphetamine sulfate neostriatal amphetamine levels were equivalent for the first hour for all age groups, but the oldest group of mice has a longer amphetamine elimination half-life from the striatum despite no change in the elimination of amphetamine from the plasma. These changes suggest that in old mice there is an altered time course of stereotyped gnawing response to amphetamine. Also, plasma amphetamine levels may be less reliable as a measure of brain amphetamine levels in old age.

Amphetamine-induced hypersensitivity in guinea pigs.

Chronic administration of d-amphetamine to young guinea pigs results in an increased behavioral response to this drug. After 6 months of daily amphetamine exposure, animals demonstrated behavioral hypersensitivity and developed full amphetamine-induced stereotyped behavior with decreased latency. The data suggest that chronic agonism with amphetamine can produce dopaminergic hypersensitivity, a behavior that contrasts with the development of drug tolerance to other pharmacologic agents. The mechanism of this induced hypersensitivity was studied by comparing brain amphetamine levels after acute and chronic amphetamine treatment. The two groups of guinea pigs showed no significant difference in amphetamine levels or drug distribution. These results suggest that altered amphetamine metabolism cannot account for the hypersensitivity seen after amphetamine exposure. Guinea pigs chronically pretreated with d-amphetamine were hypersensitive to another dopaminergic agonist whose metabolic pathway is distinct from that of amphetamine. These results have therapeutic implications in the management of clinical conditions related to chronic agonist-induced hypersensitivity.

Metabolism of amphetamine by rat brain tissue

The metabolism of amphetamine by rat brain tissue was investigated in vivo and in vitro with the use of [ 3H]amphetamine. After intracisternal administration of 0.53 nmole or 890 nmoles amphetamine, brain amphetamine content declined biphasically, with a T 1 2 of 6 min for the fast component and 60 min for the slow component. p-Hydroxyamphetamine (POHA), norephedrine (NOR) and p-hydroxynorephedrine (POHNOR) were isolated from brain tissue after either dose of amphetamine. Brain content of POHA and NOR declined quickly, while brain POHNOR content rose gradually to a maximum 1 hr after amphetamine administration and decreased only slightly between 1 and 4 hr. Metabolites could not be detected in brains of animals injected intraperitoneally with either dose. indicating that the metabolites found after intracisternal administration had not been formed peripherally. POHA and POHNOR but not NOR formation were decreased by pretreatment of rats with iprindole, an inhibitor of hepatic p-hydroxylation of amphetamine. Pretreatment of animals with U 14–624, an inhibitor of the enzyme dopmaine-β-hydroxylase, or with 6-hydroxydopamine, which destroys catecholamine nerve terminals, caused a reduction of POHNOR and NOR formation but did not affect brain AMPH content. All three hydroxylated metabolites were isolated from brain slices which had been incubated for 30 min in the presence of amphetamine. These findings indicate that amphetamine can be metabolized by brain tissue to the hydroxylated metabolites, POHA. NOR and POHNOR, although brain content of these metabolites represents a small fraction of the dose of amphetamine. The data also suggest that POHA is formed outside of catecholamine nerve terminals by a process which is inhibited by iprindole, while POHNOR and NOR are formed in noradrenergic nerve terminals by the enzyme dopamine-β-hydroxylase.

Effect of acute and chronic injections of amphetamine on intracranial self-stimulation: Amphetamine levels and effects upon some aryl alkyl amines in rat brain

1. 1. A relationship between brain amphetamine levels and amphetamine-induced effects of self-stimulation behavior was established. Doses of amphetamine sulfate which produced brain amphetamine levels in excess of 1000 ng/g resulted in reduced rates of self-stimulation while brain levels below 1000 ng/g caused rate enhancement. 2. 2. Chronic treatment with d-amphetamine sulfate produced animals which were tolerant to the rate-reducing effects of amphetamine. 3. 3. Characteristics of the temporal pattern of rate reduction were similar to those produced by drug induced motor deficit. 4. 4. Measurement of cerebral levels of meta-tyramine and para-tyramine showed changes which paralleled the effects on self-stimulation.

Effect of cortisone, aldosterone and nialamide on "amphetamine stereotypies" and brain methamphetamine levels of adrenalectomized rats.

Cortisone, aldosterone or nialamide was administered to adrenalectomized or sham-operated rats for 7 days, and methamphetamine was injected 24 hrs after the last injection of these compounds. Stereotyped head movement and licking activity were scored 5 min, 30 min and 60 min after methamphetamine injection and, in parallel brain methamphetamine levels in similarly treated rats were measured 5 min, 30 min and 60 min after the methamphetamine injection. Adrenalectomy depressed stereotyped head movements but enhanced the brain amphetamine accumulation. Nialamide but not the hormones further increased the amphetamine accumulation in adrenalectomized rats. No drugs had any effect on the amphetamine-induced head movement suppressed by adrenalectomy.

甲状腺機能の充進，減退がAmphetamineの中枢作用，特にラットの直腸温，脳Norepinephrine量への影響

Infleunce of hyper-and hypothyroidism on amphetamine activity was observed by measuring the effects on hyperthermia and brain amphetamine and norepinephrine levels. Hyperthyroidism was obtained in rats injected with tri-iodothyronine 0.2 mg/kg i.p. every day for 5 days. Controls were treated with the vehicle 1.0 ml/kg i.p. for the same period. On the 6th day, d-amphetamine (10 mg/kg i.p.) was administered to the two groups of animals and the body temperature and brain amphetamine and norepinephrine contents were measured at 0 min, 15 min, 30 min and 60 min. Hyperthyroid rats showed a more marked hyperthermia than did the control animals. On the other hand "amphetamine-induced release of norepinephrine" of hyperthyroid rats was not so marked as in the control rats, however amphetamine levels did not differ in the two groups. Hypothyroidism was evident in the thyroidectomized rats. Controls for this group underwent a sham-operation. All animals were injected with amphetamine 21 days later. Amphetamine did not cause a hyperthermia in thyroidectomized rats. On the other hand, amphetamine levels were considerably higher than in the control rats, but the degree of norepinephrine release was comparable in the two groups.

Modification by L-DOPA methylester (H 19-61) of amphetamine-induced brain catecholamine changes, thermal responses and toxicity in developing mice.

Abstract: The effect of 150 mg/kg of L‐DOPA methylester on brain catecholamines was studied in adult and developing mice aged 3‐5 days and 13‐15 days. Noradrenaline was moderately increased in the developing brain but dopamine showed a manyfold increase. The increase of dopamine was less pronounced in adult brain. High doses of dl‐amphetamine (50‐160 mg/kg) injected to L‐DOPA pretreated mice further increased the dopamine levels in the developing brain. The adult brain catecholamines were remarkably depleted, provided the observation period was 4 hours after amphetamine. Amphetamine lowered the body temperature in mice aged 13‐15 days; the fall was dose‐dependent and potentiated by pretreatment with L‐DOPA. In adult mice amphetamine caused hyperthermia which was not modified by L‐DOPA. L‐DOPA did not change the mortality rates induced by amphetamine in developing mice, but infant mice pretreated with L‐DOPA showed a lower brain amphetamine concentration after death than the mice given amphetamine only. In adult mice GDOPA enhanced amphetamine toxicity. Special attention is paid to the importance of different turnover rates of catecholamines during development as well as to the complex action of amphetamine on enzymes regulating catecholamine turnover. It is assumed that the hypothermia of developing mice after amphetamine might result from the primary effect of amphetamine on dopaminergic mechanisms.

Influence of adrenalectomy on emotional behavior and brain methamphetamine concentration in rats--effect of chronic administrations of ACTH

The authors studied, in two experimental periods (spring and summer), the influence of adrenalectomy or chronic administrations of ACTH on methamphetamine-induced stereotyped behavior (sniffing, biting and licking) and increase of brain amphetamine level in rats. In both spring and summer, the brain amphetamine levels were markedly increased in adrenalectomized rats. Within the limits of the spring experiment, the biting hehavior was not observed in rats which had been treated with ACTH, while the frequent appearance of sniffing behavior in adrenalectomized rats was inhibited by ACTH. Within the limits of the summer experiment, the licking behavior was not seen in rats treated with ACTH, while the lack of biting in adrenalectomized rats was restored with administration of the drug.

Effect of ammonium chloride on the potentiation of amphetamine by psychotropic drugs in the rat

The effect of acidification of the urine on the potentiation of amphetamine by imipramine, butriptyline and chlorpromazine was investigated in the rat. Urine was acidified by administering ammonium chloride (500 mg/kg p.o.). Amphetamine, imipramine, butriptyline and chlorpromazine were injected i.p. CNS stimulation was measured in jiggle cages. Amphetamine and p-hydroxyamphetamine excretion in the urine were determined 4 hr after administration of the drugs. Ammonium chloride increased the rate of urinary excretion of amphetamine and shortened the intensity and the duration of amphetamine hypermotility. These findings correlated with lower levels of brain amphetamine. In rats treated with the combinations of amphetamine with (1) imipramine, (2) butriptyline and (3) chlorpromazine, ammonium chloride abolished the potentiation and prolongation of amphetamine effects. The effect of ammonium chloride on amphetamine excretion and brain levels in these groups was similar to that observed in animals treated with amphetamine alone. It is suggested that ammonium chloride blocked the potentiation of amphetamine stimulation by the psychotropic agents by promoting a more rapid excretion of amphetamine.

Further studies on the interaction between desipramine and amphetamine

Desipramine given to rats induced a higher level of brain amphetamine when given before amphetamine than in animals receiving only amphetamine. The hyperthermic effect was initially inhibited by desipramine but was prolonged at later times. The effect of desipramine on brain amphetamine was evident both in isolated and grouped rats; it was present when amphetamine was given intravenously and it was also clear when amphetamine was measured in selected parts of the brain. Mice, in contrast to rats, were not sensitive to this interaction between d esipramine and amphetamine possibly because in mice amphetamine is not hydroxylated and desipramine has a very short half-life.

Studies with amphetamine in hyper- and hypothyroid rats

Amphetamine has a greater hyperthermic effect in hyperthyroid rats than in hypthyroid animals. The brain amphetamine levels are increased in hypothyroidism. Therefore a change in the metabolism of amphetamine cannot explain the observed change in the pharmacological activity.