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PubMed1992

Ibogaine reduces amphetamine-induced locomotor stimulation in C57BL/6By mice, but stimulates locomotor activity in rats.

The effect of ibogaine hydrochloride on locomotor stimulation induced by d-amphetamine sulfate was tested in male C57BL/6By mice and in female Sprague-Dawley rats. In mice, locomotor stimulation induced by d-amphetamine at 1 or 5 mg/kg s.c. was reduced by prior administration of one or two injections of ibogaine (40 mg/kg), given 2 or 18 hours earlier. This reduction in locomotor activity persisted for two days. Locomotor stimulation induced by a higher dose (10 mg/kg) of d-amphetamine was not reduced by such prior administration of ibogaine. A lower dose of ibogaine (20 mg/kg) did not reduce the subsequent locomotor activity induced by d-amphetamine. Ibogaine decreased striatal dopamine levels, while d-amphetamine increased them. Ibogaine treatment (2 x 40 mg/kg, 18 hours apart) induced a decrease by 30% in the level of striatal dopamine and its metabolites measured in tissue extracts 3 hours after the second ibogaine injection. One hour after d-amphetamine (5 mg/kg) administration, the level of striatal dopamine increased by 26%. Although the level of striatal dopamine was initially lower in the ibogaine-pretreated mice, d-amphetamine (5 mg/kg) administration induced an increase in striatal dopamine and its metabolites. The effect of ibogaine seems to be species specific, since in rats pretreated with ibogaine 18 hours before d-amphetamine, locomotor stimulation induced by d-amphetamine was further increased. In addition, the in vitro electrical-evoked release of [3H]dopamine from striatal tissue was either unchanged or inhibited in the presence of d-amphetamine, and after ibogaine pretreatment in vivo, the release of tritium in the presence of d-amphetamine was inhibited or stimulated in mice and rats, respectively.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1982

Discriminative stimulus properties of d-amphetamine in pigeons.

Two out of four pigeons were successfully trained in an operant procedure to discriminate between the presence and absence of the effects induced by d-amphetamine (final dose: 1.6 mg/kg). The solvent (saline) or d-amphetamine was administered intramuscularly (IM) 30 min prior to training. Tests with other drugs and dosages indicated that l-amphetamine (ED50 = 0.55 mg/kg) and cocaine (ED50 = 1.05 mg/kg) fully generalized to d-amphetamine (ED50 = 0.35 mg/kg), whereas drugs such as p-hydroxy-amphetamine (1.6 and 3.2 mg/kg), morphine (1.5, 3.0 and, 6.0 mg/kg), and delta 9-THC (0.125, 0.25, and 0.50 mg/kg) failed to do so at the doses tested. Apomorphine (0.25 and 0.50 mg/kg) and LSD-25 (0.04 and 0.08 mg/kg) produced intermediate results. Pretreatment with haloperidol (dose range: 0.04 to 1.28 mg/kg), but not propranolol (10 and 20 mg/kg), attenuated significantly the d-amphetamine (1.6 mg/kg) stimulus effects. The two pigeons emitted predominantly d-amphetamine appropriate responses when the training dose (1.6 mg/kg) of d-amphetamine was tested on different occasions 15, 60, and 120 min after the administrations. One bird emitted mostly vehicle appropriate responses when tested 240 min after the d-amphetamine injection whereas the other bird performed d-amphetamine appropriate responses. Selection of the non-drug associated key occurred in the two birds when testing was carried out 480 min (8 hrs) after the administration of d-amphetamine.

Amphetamine↗
PubMed2001

The neurotensin receptor antagonist, SR48692, attenuates the expression of amphetamine-induced behavioural sensitisation in mice.

The effects of acute administration of the neurotensin receptor antagonist, SR48692 (2-[[1-(7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-carbonyl]amino]adamantane-2-carboxylic acid), on amphetamine-induced behavioural sensitisation were studied with the locomotor activity of mice in an open-field as an experimental parameter. The animals were repeatedly pretreated with saline or amphetamine (2.0 mg/kg, i.p. once a day, every other day for 13 days) and 2, 9 and 16 days after the last injection they received an acute i.p. administration of saline or 0.3 mg/kg SR48692 15 min before a challenge i.p. injection of 2.0 mg/kg amphetamine. Locomotor activity of the amphetamine-challenged mice was significantly higher in amphetamine-pretreated animals than in saline-pretreated mice on days 9 and 16 after withdrawal. SR48692 prevented the expression of this behavioural sensitisation. In addition, in saline-pretreated mice, the first two challenge injections of amphetamine sufficed to induce a sensitized locomotor response to the third challenge injection of the drug. SR48692 administration before amphetamine challenge injections prevented the development of this challenge injection-induced sensitisation in saline-pretreated mice but not in amphetamine-pretreated animals. In order to determine the effects of SR48692 on the expression of amphetamine-induced behavioural sensitisation in the absence of this challenge injection-induced sensitisation, the experiment was redone with a single challenge test 9 days after pretreatment. Once again, SR48692 prevented the expression of amphetamine-induced behavioural sensitisation. These results suggest that neurotensinergic transmission has a critical role in both the initiation and expression of locomotor sensitisation to amphetamine.

Amphetamine↗
PubMed1999

Rapid effects of estrogen or progesterone on the amphetamine-induced increase in striatal dopamine are enhanced by estrogen priming: a microdialysis study.

There are estrous cycle-dependent differences in amphetamine-stimulated behaviors and striatal dopamine (DA) release; intact female rats exhibit a greater behavioral response to amphetamine on estrus than on other days of the cycle. Following ovariectomy amphetamine-induced behavior is attenuated, as is the striatal DA response to amphetamine in vitro. Repeated estrogen treatment in ovariectomized rats reinstates both of these responses to a level comparable to estrous females. In addition, 30 min after a single treatment with a physiological dose of estrogen there is enhanced amphetamine-induced behavior and increased amphetamine-induced striatal DA detected during microdialysis. This experiment was conducted to determine whether the acute effect of estradiol and the effect of repeated exposure to estrogen are functionally related. We report here that prior treatment with estrogen (three daily treatments of 5 microg estradiol benzoate) results in a significant enhancement of the effect of acute estrogen (5 microg estradiol benzoate) or progesterone (500 microg) on amphetamine-induced striatal DA release and stereotyped behaviors. Both the peak response and the duration of the response are greater in estrogen-primed animals treated with estrogen or progesterone 30 min prior to amphetamine, than in all other groups. Either prior treatment with estrogen (last dose 24 h before) or a single acute injection of estrogen result in an enhanced peak response to amphetamine, with no effect on the duration of amphetamine-induced striatal DA release. Treatment with progesterone in animals not primed with estrogen was not different from treatment with oil vehicle. These results demonstrate that there are both acute and long-term effects of estrogen on the striatum that underlie the dynamic changes in stimulated DA release and amphetamine-induced behaviors during the reproductive cycle.

Amphetamine↗
PubMed2000

Previous exposure to amphetamine increases incentive to obtain the drug: long-lasting effects revealed by the progressive ratio schedule.

The present experiment tested whether previous exposure to amphetamine would enhance rats' predisposition to self-administer a high dose of the drug under fixed (FR) and progressive ratio (PR) schedules of reinforcement. Rats in different groups were given five injections of either amphetamine (1.5 mg/kg, i.p.) or saline (1.0 ml/kg, i.p.), one injection administered every third day and, starting 10 days later, given the opportunity to lever press for amphetamine (200 microg/kg/infusion, i.v.) on each of several 4 h sessions. When allowed to self-administer up to 10 infusions under first an FR-1 and then an FR-2 schedule, amphetamine and saline pre-exposed rats were indistinguishable and readily acquired the lever press response. However, when tested under the PR schedule of reinforcement, rats previously exposed to amphetamine achieved higher break points than saline pre-exposed rats across six consecutive PR sessions. This difference between groups was long lasting and durable. When compared to saline pre-exposed rats on three separate tests conducted 10, 14 and 21 days following the last PR session, rats pre-exposed to amphetamine also showed (i) greater nucleus accumbens dopamine reactivity to amphetamine (1.0 mg/kg, i.p.), (ii) higher break points when retested on the PR schedule, and (iii) a greater locomotor response to amphetamine (1.0 mg/kg, i.p.). On the last test, both groups showed higher levels of locomotion than no drug control animals that received amphetamine for the first time on this test. These findings suggest that previous exposure to amphetamine produces a long lasting enhancement in the incentive motivation animals will exhibit in their effort to obtain the drug. This enhancement appears to parallel sensitization of the drug's locomotor and nucleus accumbens dopamine activating effects. It may very well be exacerbated by continued exposure to self-administered amphetamine.

Amphetamine↗
PubMed2000

Implication of dopaminergic mechanisms in the wake-promoting effects of amphetamine: a study of D- and L-derivatives in canine narcolepsy.

Using a canine model of narcolepsy and selective DA and NE uptake inhibitors, we have recently shown that DA uptake inhibition promotes wakefulness, while NE uptake inhibition inhibits rapid eye movement sleep and cataplexy. In order to further delineate the respective roles of the dopaminergic and noradrenergic systems in the pharmacological control of symptoms of narcolepsy, we compared the potency of amphetamine isomers (D- and L-amphetamines) and a derivative (L-methamphetamine) on wakefulness and cataplexy. Their respective effects on these narcolepsy symptoms were then compared with their in vivo effects on extracellular DA levels in the caudate and NE levels in the frontal cortex during local drug perfusion in narcoleptic dogs. Polygraphic recordings demonstrated that D-amphetamine was about twice as potent as L-amphetamine, and was six times more potent than L-methamphetamine in increasing wakefulness and reducing slow-wave sleep. D-Amphetamine and L-amphetamine were equipotent in reducing rapid eye movement sleep and cataplexy, and L-methamphetamine was about half as potent as L- and D-amphetamines. D-Amphetamine was found to be more potent in increasing DA efflux than L-amphetamine, and L-methamphetamine was found to have little effect on DA efflux; there was no significant difference in the potencies of the three derivatives on NE efflux. The potencies of these amphetamines on wakefulness correlated well with DA, but not NE, efflux in the brain of narcoleptic dogs during local drug perfusion. Our current results further exemplify the importance of the DA system for the pharmacological control of electroencephalogram arousal and suggest that increased DA transmission mediates the wake-promoting effects of amphetamine-like stimulants.

Amphetamine↗
PubMed1999

Amphetamine dose dependently disrupts prepulse inhibition of the acoustic startle response in rats within a narrow time window.

Prepulse inhibition (PPI) of the acoustic startle response refers to the reduction in startle amplitude when a weak prepulse precedes a startle-inducing pulse. Prepulse inhibition has been shown to be disrupted by amphetamine at doses that also stimulate locomotor activity, and it has been suggested that the same neuroanatomical substrate, mesolimbic dopamine activation, mediates the effects of amphetamine on locomotor activity and PPI. Amphetamine stimulates locomotor activity and mesolimbic dopamine release over a 1- to 3-h period, whereas PPI is typically measured within the first 30 min following amphetamine treatment. The present study therefore determined whether delays in testing would alter the PPI-disruptive effect of amphetamine in male Wistar rats. Amphetamine dose dependently disrupted PPI when the test session occurred 10 min following amphetamine treatment and only when the prepulse intensity was 5-10 dB above background. Delays of 40 and 60 min post-amphetamine injection, however, resulted in a loss of the ability of amphetamine to disrupt PPI although locomotor activity was significantly stimulated by amphetamine at these time points. The data from the present study therefore do not readily fit with the notion that the effects of amphetamine on locomotion and PPI are mediated by the same substrate.

Acoustic Stimulation↗
PubMed1996

Acute and repeated systemic amphetamine administration: effects on extracellular glutamate, aspartate, and serine levels in rat ventral tegmental area and nucleus accumbens.

Recent work indicates an important role for excitatory amino acids in behavioral sensitization to amphetamine. We therefore examined, using in vivo microdialysis in awake rats, the effects of amphetamine on efflux of glutamate, aspartate, and serine in the ventral tegmental area and nucleus accumbens, brain regions important for the initiation and expression of amphetamine sensitization, respectively. Water-pretreated and amphetamine-pretreated rats were compared to determine if sensitization altered such effects. In both brain regions, Ca2+-dependent efflux of glutamate accounted for approximately 20% of basal glutamate efflux. A challenge injection of water or 2.5 mg/kg of amphetamine did not significantly alter glutamate, aspartate, or serine efflux in the ventral tegmental area or nucleus accumbens of water- or amphetamine-pretreated rats. However, 5 mg/kg of amphetamine produced a gradual increase in glutamate efflux in both regions that did not reverse, was observed in both water- and amphetamine-pretreated rats, and was prevented by haloperidol. Although increased glutamate efflux occurred with too great a delay to mediate acute behavioral responses to amphetamine, it is possible that repeated augmentation of glutamate efflux during repeated amphetamine administration results in compensatory changes in levels of excitatory amino acid receptors in the ventral tegmental area and nucleus accumbens that contribute to development of expression of amphetamine sensitization.

Amino Acids↗
PubMed2004

Drug use patterns and mental health of regular amphetamine users during a reported 'heroin drought'.

AIMS: The present study extends the findings of a pilot study conducted among regular amphetamine users in Newcastle, NSW, in 1998. It compares key features between current participants in a state capital city (Brisbane) and a regional city (Newcastle) and between the 1998 and current Newcastle sample. DESIGN: Cross-sectional survey. Setting Brisbane and Newcastle, Australia. PARTICIPANTS: The survey was conducted among 214 regular amphetamine users within the context of a randomized controlled trial of brief interventions for amphetamine use. MEASUREMENTS: Demographic characteristics, past and present alcohol and other drug use and mental health, treatment, amphetamine-related harms and severity of dependence. FINDINGS: The main findings were as follows: (i). the rate of mental health problems was high among regular amphetamine users and these problems commonly emerged after commencement of regular amphetamine use; (ii). there were regional differences in drug use with greater accessibility to a wider range of drugs in a state capital city and greater levels of injecting risk-taking behaviour outside the capital city environment; and (iii). there was a significant increase in level of amphetamine use and percentage of alcohol users, a trend for a higher level of amphetamine dependence and a significant reduction in the percentage of people using heroin and benzodiazepines among the 2002 Newcastle cohort compared to the 1998 cohort. CONCLUSIONS: Further longitudinal research is needed to elucidate transitions from one drug type to another and from recreational to injecting and regular use and the relationship between drug use and mental health in prospective studies among users. IMPLICATIONS: Intervention research should evaluate the effectiveness of interventions aimed at: preventing transition to injecting and regular use of amphetamines; toward reducing levels of depression among amphetamine users and interventions among people with severe psychopathology and personality disorders; and toward reducing the prevalence of tobacco dependence among amphetamine users.

Adolescent↗
PubMed1986

Dose response for amphetamine-induced changes in dopamine levels in push-pull perfusates of rat striatum.

Levels of dopamine were determined in push-pull perfusates of striatum in chloral hydrate-anesthetized rats as a function of increasing systemic doses of amphetamine over the range 0.5-5.0 mg/kg. In the absence of amphetamine administration, basal dopamine levels remained stable for at least 6 h. Perfusate levels of dopamine responded in a quantitatively predictable fashion to increasing doses of amphetamine: (1) the maximal increase in perfusate levels of dopamine after amphetamine, relative to predrug levels, was directly proportional to the dose of the drug up to 3 mg/kg (fivefold after 0.5 mg/kg to 30-fold after 3 mg/kg); (2) the duration over which perfusate levels of dopamine were significantly elevated, with respect to preamphetamine levels, was proportional to the dose of amphetamine up to 5 mg/kg; and (3) each successively higher dose of amphetamine significantly increased the perfusate level of dopamine over that observed at the next lower dose up to 3 mg/kg amphetamine. However, maximal levels of dopamine in striatal perfusates were achieved following 3 mg/kg amphetamine and were not increased further at higher doses of the drug. The data suggest that, at higher doses of amphetamine, extraneuronal metabolism of dopamine may be of sufficient capacity to limit increases in synaptic levels of dopamine. The absence of further increases in perfusate levels of dopamine as the dose of amphetamine is increased beyond 3 mg/kg is discussed in terms of potential relevance to mechanisms of amphetamine-induced stereotyped behaviors.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2007

Evidence for D2 receptor mediation of amphetamine-induced normalization of locomotion and dopamine transporter function in hypoinsulinemic rats.

Dopamine (DA) D2 receptors regulate DA transporter (DAT) activity, and mediate some behavioral effects of amphetamine. DA clearance and amphetamine-stimulated locomotion are reduced in hypoinsulinemic [streptozotocin (STZ)-treated] rats, and these deficits are normalized by repeated treatment with amphetamine. Here, a role for D2 receptors in mediating amphetamine-induced normalization of these parameters was investigated. One week after a saline or STZ injection (50 mg/kg), rats were treated with amphetamine (1.78 mg/kg), raclopride (0.056 mg/kg), saline, or combinations thereof, every-other-day for 8 days with locomotor activity measured following each treatment. Conditioned place preference (CPP) for amphetamine and in vivo chronoamperometry to measure DA clearance were carried out on days 17 and 18, respectively, after STZ or saline. Baseline locomotion and DA clearance were significantly reduced in STZ-treated rats compared with control rats. In STZ-treated rats, amphetamine treatment normalized DA clearance, and restored the locomotor-stimulating effects of amphetamine. Raclopride prevented normalization of these parameters. Amphetamine produced CPP in both STZ-treated and control rats; raclopride significantly attenuated amphetamine-induced CPP in control and not in STZ-treated rats. These results support a role for D2 receptors in regulating DA transporter activity, and further demonstrate that D2 receptors contribute to changes in sensitivity to amphetamine in hypoinsulinemic rats.

Amphetamine↗
PubMed1989

Prenatal amphetamine effects on behavior: possible mediation by brain monoamines.

The present analysis indicates that the literature is currently too limited to draw anything but very tentative conclusions about whether amphetamine during pregnancy is detrimental to the offspring. However, exposure to very high doses of the drug appears to be teratogenic; and studies in which animals were exposed to lower doses of either amphetamine or methamphetamine throughout pregnancy indicate that this class of drugs can have long-term neurochemical and behavioral consequences for rodent offspring. The commonly reported behavioral effects include abnormal responding on aversively motivated tasks, and heightened motor activity which might be associated with slower habituation. Neurochemical studies have focused on various aspects of the monoamine neurotransmitter systems and suggest that prenatal amphetamine exposure can increase the synthesis and turnover of DA and NE and reduce the number of adrenergic receptors in adult offspring. In addition, concentrations of NE appear to be reduced at birth suggesting prenatal depletion and are sometimes found to be altered at later times. Although these studies are provocative, the absence of pair-fed controls and cross-fostering prevent ruling out the possible confounding effects of undernutrition and altered maternal care. In addition to the above limited empirical support, the effects of amphetamines on adult brain provide a logical rationale for anticipating that prenatal exposure to the drug could be detrimental. This rationale is essentially that amphetamine can have long-term effects of monoaminergic systems in the brains of adults, including neural degeneration; and, since the drug can cross the placenta, it should also have long-lasting consequences for the developing fetus. It is proposed that the later stages of gestation might be particularly sensitive to the long-term behavioral effects of amphetamine. Although there are no systematic studies on critical periods for the effects of prenatal amphetamine exposure, several reports indicate that exposure restricted to GD 12-15 has little effect. Since amphetamine predominantly affects the neuron terminals and terminals develop later than GD 15, it is proposed that amphetamine exposure later in gestation, after the monoaminergic systems are more mature, will have a greater effect. The rationale for the long-term behavioral effects of prenatal amphetamine is based on studies indicating that 1) rapidly developing systems are very sensitive to insult from external agents; 2) the monoaminergic systems and pituitary-adrenal organization are developing rapidly during the later gestation and early neonatal periods; 3) amphetamine influences each of these systems in adults and the monoamine systems in fetuses; and, 4) alterations in the systems cause predictable behavioral changes.(ABSTRACT TRUNCATED AT 400 WORDS)

Amphetamine↗
PubMed2003

Selective decreases in amphetamine self-administration and regulation of dopamine transporter function in diabetic rats.

The dopamine transporter (DAT) regulates extracellular dopamine DA levels and is an important site of action for amphetamine and cocaine. Amphetamine and cocaine increase extracellular levels of DA by acting on the DAT; thus, variations in DAT binding sites or activity might influence the action of some drugs of abuse. It was hypothesized that streptozotocin-induced diabetes decreases amphetamine self-administration and that this behavioral change is accompanied by changes in DAT function. Separate groups of male rats responded to receive either amphetamine (0.03 mg/kg/infusion), cocaine (0.25 mg/kg/infusion), or food before and for 7 days after receiving streptozotocin. Rats were sacrificed and [(3)H]DA uptake and [(3)H]WIN 35,428 binding were measured in the striatum. In a second study, rats could self-administer one of several different doses of amphetamine (0.01-0.178 mg/kg/infusion) before and after receiving streptozotocin. In streptozotocin-treated rats, a marked decrease in staining for insulin in pancreatic sections was paralleled by a more than doubling in blood glucose levels. Streptozotocin significantly decreased the number of amphetamine infusions without changing the number of cocaine infusions or food pellets received. Streptozotocin increased DA uptake (V(max)) 1.6- or 2.4-fold in rats that responded for food or amphetamine and increased 3-fold the K(m) for DA only in rats that responded for food; however, [(3)H]WIN 35,428 binding was not changed in any rat. In the second study, streptozotocin only decreased amphetamine self-administration thereby supporting the view that streptozotocin does not simply decrease the potency of amphetamine. These results demonstrate a selective decrease in amphetamine self-administration in diabetic rats that was associated with increased DAT function in the striatum. Collectively, these studies suggest that insulin pathways in the brain may play an important role in regulating DAT activity and amphetamine action.

Amphetamine↗
PubMed1968

Fat-mobilizing action of amphetamine.

The effects of amphetamine and methamphetamine on plasma free fatty acid (FFA), blood glucose, serum total fat, and triglyceride concentrations were investigated in 21 subjects; the effect of epinephrine were studied in an identical manner in 14 subjects. The administration of amphetamine and methamphetamine led to an increase in the plasma FFA concentration. No significant changes were found in the blood glucose, serum total fat, and triglyceride concentrations. Kinetic studies of FFA were also made in some of the subjects receiving amphetamine, methamphetamine, and epinephrine. It was shown that amphetamine and methamphetamine lead to an augmentation of plasma FFA pool due to a primary increase of FFA production rate. Catecholamine depletion, by prolonged parenteral adminstration of reserpine, nearly completely abolished the adipokinetic action of amphetamine whereas the effect of epinephrine was greatly potentiated. This was interpreted as evidence for the dependence of the adipokinetic action of amphetamine on endogenous catecholamines. ESTIMATED FROM A DOSE RATIO (AMPHETAMINE: epinephrine) of 352:1, the relative adipokinetic potency of amphetamine, expressed as peak DeltaFFA rise, +DeltaFFA area, and DeltaFFA production rate, respectively, was found to be 55, 84, and 39% in comparison with the same effects of epinephrine. The more pronounced changes in +DeltaFFA area reflect the longer duration of action of amphetamine viz. epinephrine. This study demonstrates that amphetamine is an adipokinetic agent causing an increase in the plasma FFA pool of a lesser extent but of longer duration than equipressor doses of epinephrine. The mechanism of fat-mobilizing action of amphetamine is indirect i.e., dependent on endogenous catecholamine release.

Amphetamines↗
PubMed1979

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.

Amphetamine↗
PubMed1987

Amphetamine detection during toxicology screening of a university medical center patient population.

The frequency of detection of "amphetamines" (amphetamine and/or methamphetamine) in the toxicology tests of a university medical center patient population was evaluated by retrospective review of the results of 2,900 toxicology test profiles performed on urine during the year 1986-87. Ten percent of these (291 cases) were positive for either amphetamine alone or amphetamine in conjunction with methamphetamine--a substantial increase from the 3% noted in 1978 at this medical center. Amphetamines were detected predominantly in males (164 cases). The most common age range for the entire series was 21 to 30 years (61% of cases). The typical user was a 27 year old Caucasian man who used amphetamines alone or in combination with at least one other drug with about equal frequency. The sympathomimetic amines (ephedrine, phenylpropanolamine, and pseudoephedrine) were the most frequently associated category of other drugs, perhaps reflecting either adulteration of the amphetamines with these compounds or concurrent ingestion of over-the-counter preparations containing these agents. Requests for those toxicology tests which subsequently revealed amphetamines mostly originated in the emergency room (30% of cases) although 25% originated on the trauma service and 17% on the obstetrics service. Twelve percent of cases occurred in neonates, presumably reflecting transplacental transmission of amphetamines detected in mothers that were studied simultaneously. Amphetamine and methamphetamine were detected together 84% of the time. Analysis of amphetamines should be an integral part of toxicology testing performed on a university medical center patient population.

Adolescent↗
PubMed1990

Repeated amphetamine administration alters the interaction between D1-stimulated adenylyl cyclase activity and calmodulin in rat striatum.

The effect of repeated intermittent treatment with amphetamine on the responses of rat striatal adenylyl cyclase to the D1 dopamine receptor agonist, SKF38393 [(+-)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride], and potentiative interactions with the endogenous Ca(++)-binding protein, calmodulin, were investigated. Female Sprague-Dawley rats were treated with saline or an escalating dose regimen of amphetamine for 4 weeks and withdrawn from treatment for either 2 or 4 weeks. Thirty minutes before sacrifice, rats in both groups were given a challenge dose of either saline or 1.0 mg/kg of amphetamine. In striatal membranes from rats chronically treated with saline and withdrawn 4 weeks, calmodulin increased SKF38393-stimulated adenylyl cyclase activity by 195% over that seen in the presence of GTP alone. In contrast, this pronounced potentiative interaction was absent in rats chronically treated with amphetamine. The lack of potentiation by calmodulin was independent of length of withdrawal from the drug or amphetamine challenge. Although the repeated amphetamine treatment abolished the potentiative response to calmodulin, this treatment significantly increased the calmodulin content in the striatal cytosol by 40%. Heightened responsiveness of several dopamine-related neurochemical activities was evident after an amphetamine challenge to rats that had been treated repeatedly with amphetamine. A challenge dose of 1 mg/kg of amphetamine decreased SKF38393-stimulated adenylyl cyclase activity in amphetamine-treated but not saline-treated rats. The degree of desensitization induced by amphetamine challenge was heightened with increased length of withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

Acute in vivo amphetamine produces a homologous desensitization of dopamine receptor-coupled adenylate cyclase activities and decreases agonist binding to the D1 site.

We have previously reported that, 30 min after a single injection of 7.5 mg/kg d-amphetamine sulfate, there was a significant 25% decrease in the apparent Vmax for stimulation of adenylate cyclase activity by the D1 receptor-selective partial agonist SKF 38393 in rat striatal membranes, as compared with saline-injected controls. This desensitization was seen in the striatal but not the mesolimbic forebrain. In the present study this desensitization was further characterized by using various ligands that interact with the three components of the D1 receptor-coupled adenylate cyclase complex to determine the site of modification that resulted in the desensitization. The desensitization was not associated with a change in the stimulation of adenylate cyclase at the level of the catalytic subunit or the guanyl nucleotide-regulatory protein Ns. Receptor number, as assessed by the binding of the D1 selective antagonist [3H]SCH 23390, was unaltered in the desensitized state. In contrast, the number of high affinity binding sites, as measured with the agonist [3H]dopamine was decreased 30% by acute amphetamine exposure. This suggests that the amphetamine-induced desensitization may be the result of an uncoupling of the receptor from Ns. In order to further assess the effects of amphetamine on receptor/Ns coupling, we measured the ability of the guanyl nucleotide guanosine-5'-(beta,gamma-imido)triphosphate [Gpp(NH)p] to decrease high affinity [3H]dopamine binding to striatal membranes. The inclusion of 100 microM Gpp(NH)p in the assay decreased the number of receptors in the high affinity state by 40% and 52% in membranes from saline- and amphetamine-pretreated rats, respectively. These results imply that amphetamine treatment does not modify the ability of Gpp(NH)p to decrease high affinity agonist binding. It is possible that amphetamine treatment decreases the number of receptors that can couple to Ns but the remaining receptors can still form a high affinity complex and are sensitive to the effects of Gpp(NH)p. We also report that maximal D2 dopamine receptor-mediated inhibition of forskolin-stimulated adenylate cyclase activity was decreased in striatal membranes prepared from amphetamine-treated rats as compared with saline-injected controls, implying that the D2 pathway was desensitized by amphetamine treatment. Conversely, acute amphetamine injection did not alter the ability of either the adenosine A2 receptor to stimulate or the muscarinic cholinergic receptor to inhibit adenylate cyclase activity in the rat striatum. These results suggest that acute amphetamine treatment produces a dopamine receptor-specific or homologous desensitization.

Adenylyl Cyclases↗