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At least 19 recordsLinked to original sources
PubMed1996

A simple HPLC method for the separation of amphetamine isomers in urine and its application in differentiating between 'street' amphetamine and prescribed D-amphetamine.

D-amphetamine has been increasingly prescribed to treat amphetamine abusers. Prescribing D-amphetamine requires laboratory evidence or confirmation of current use of 'street' amphetamine, using a method which should be capable of differentiating between 'street' amphetamine and prescribed D-amphetamine. We have developed a simple high-performance liquid chromatography (HPLC) method for the separation of the two isomers of amphetamine in urine and have assessed its use in differentiating between 'street' amphetamine and prescribed D-amphetamine. The method is reproducible, free from interference and has a detection limit of 0.1 microgram/mL for each isomer. Urine from patients prescribed D-amphetamine contained only a trace amount of L-amphetamine (less than 4%) whereas urine from those taking 'street' amphetamine contained more than 50% L-amphetamine. The method is applicable to confirmation of 'street' amphetamine misuse and for monitoring patient compliance with treatment. The presence of 4% or less L-amphetamine in urine would suggest that the patient is only taking prescribed D-amphetamine whereas the presence of L-amphetamine in higher concentrations suggests that the patient is taking 'street' amphetamine, with or without prescribed D-amphetamine.

Amphetamines↗
PubMedDate not supplied

Detection of D,L-amphetamine, D,L-methamphetamine, and illicit amphetamine analogs using diagnostic products corporation's amphetamine and methamphetamine radioimmunoassay.

Cross-reactivity with Diagnostic Products Corporation (DPC) amphetamine and methamphetamine radioimmunoassay (RIA) reagents was determined for amphetamine, methamphetamine, and a number of amphetamine analogs. Concentrations from 100 to 100,000 ng/mL were assayed. 3,4-Methylenedioxyamphetamine (MDA) and 3,4-methylenedioxymethamphetamine (MDMA) showed significant cross-reactivity for the amphetamine and methamphetamine reagents respectively. 4-Hydroxymethamphetamine, 3,4-methylenedioxyethylamphetamine (MDEA), and N,N-dimethyl-MDA also showed significant cross-reactivity with the methamphetamine reagents, but less than MDMA. None of the other analogs showed a positive result with the amphetamine or methamphetamine reagents at even the highest concentration, although several did show measurable cross-reactivity. The L isomers of amphetamine and methamphetamine showed substantially less cross-reactivity than the D forms to which the respective antibody systems are targeted.

3,4-Methylenedioxyamphetamine↗
PubMed1985

Effects of pGlu-His-Pro-amphetamine (TRH-amphetamine) on the isolated duodenum of the guinea-pig: antagonistic effect of amphetamine on TRH response.

pGlu-His-Pro-dexamphetamine (TRH-A) produced a contraction through the release of acetylcholine from postganglionic cholinergic neurons in the duodenum of the guinea-pig in the same manner as TRH. However, the affinity of TRH-A (pD2, 4.70) toward isolated duodenum was one thousandth that of TRH (pD2, 7.74). The effects of TRH-A (10(-4)M) were abolished by 10(-7) M TRH, but only partially (about 50%) inhibited by 10(-4) M d-amphetamine. D-Amphetamine showed no stimulatory effect on the myenteric nerves. However, the duodenal response to TRH (10(-6) M) was dose dependently inhibited by d-amphetamine (10(-6), 10(-5), 10(-4) M) while the phasic and tonic contractions caused by high K+ (40 mM) or the contractile responses to acetylcholine (10(-7) M) were not blocked by d-amphetamine. These results indicate that d-amphetamine may act as an antagonist to TRH without influencing the movement of calcium ions in smooth muscle or muscarinic receptors and that contractile responses to TRH-A are mediated through TRH receptors in the myenteric cholinergic nerves.

Acetylcholine↗
PubMedDate not supplied

Comparison and evaluation of DRI methamphetamine, DRI ecstasy, Abuscreen ONLINE amphetamine, and a modified Abuscreen ONLINE amphetamine screening immunoassays for the detection of amphetamine (AMP), methamphetamine (MTH), 3,4-methylenedioxyamphetamine (MDA), and 3,4-methylenedioxymethamphetamine (MDMA) in human urine.

The performances of four immunoassays (DRI amphetamines, DRI ecstasy, Abuscreen ONLINE amphetamines, and a modified Abuscreen ONLINE amphetamines) were evaluated for control failure rates, sensitivity, and specificity for amphetamine (AMP), methamphetamine (MTH), 3,4-methylenedioxyamphetamine (MDA), and 3,4-methylenedioxymethamphetamine (MDMA). The two DRI reagents and the ONLINE reagents were run according to manufacturer specifications using a Roche Hitachi Modular DDP system. The modified ONLINE reagent was calibrated with MDMA and had 16mM sodium periodate added to the R2 reagent. These assays were run on approximately 27,500 human urine samples and 7000 control urine samples prepared at 350 and 674 ng/mL over the course of 8 days. All assays were calibrated using a single point, qualitative cutoff standard with the manufacturer-recommended compound at the Department of Defense cutoff (500 ng/mL). Gas chromatography-mass spectrometry (GC-MS) confirmation was conducted on screened-positive samples. Control performance for the manufacturer recommended assays was excellent, with a maximum qualitative control failure rate of 2.03%. The modified ONLINE reagent demonstrated poor control performance with a maximum failure rate of 38.3% and showed no improved MDMA sensitivity when compared with the ONLINE reagent; the confirmation rate (20%) was improved when compared with the production ONLINE reagent (8%). The DRI ecstasy reagent provided improved sensitivity for MDMA as compared with the ONLINE reagent, with approximately 23% more samples screening and confirming positive for MDMA and a confirmation rate of approximately 90%. The DRI methamphetamine reagent had a low confirmation rate (6% or less) and produced numerous positives for samples with only ephedrine or pseudoephedrine present.

3,4-Methylenedioxyamphetamine↗
PubMed1989

Effect of pretreatment with amphetamine on the interaction between amphetamine and dopamine neurons in the nucleus accumbens.

The present study was designed to examine the effect of pretreatment with amphetamine on the ability of amphetamine to release dopamine from slices of the nucleus accumbens and striatum and to stimulate locomotor activity or stereotyped behavior, after direct injection into either the nucleus accumbens or the striatum. Rats were injected twice daily for 5 days with either amphetamine (5 mg/kg, i.p.) or saline. At 33 days after this pretreatment, the release of endogenous dopamine from both regions of the brain in vitro by amphetamine and the changes in behavioral responses to the direct injection of amphetamine into either region were examined. Amphetamine at both 1 and 10 microM stimulated the release of endogenous dopamine from slices prepared from both of the brain areas. The release of dopamine by amphetamine was increased in rats pretreated with amphetamine. Consistent with its ability to stimulate endogenous release of dopamine, amphetamine, when injected into the nucleus accumbens, stimulated locomotor activity, while stereotyped behavior was enhanced when amphetamine was injected into the striatum. However, the locomotor activity and stereotyped behavioral responses to small doses of amphetamine (5, 10 or 25 micrograms) were not significantly greater in amphetamine-pretreated rats, compared to saline-pretreated animals. A greater stimulation of both responses in amphetamine-pretreated rats was only observed when a large dose (50 micrograms) of amphetamine was administered into either the nucleus accumbens or striatum.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamine↗
PubMed1981

The regional distribution of d-amphetamine and local glucose utilization in rat brain during continuous amphetamine administration.

The distribution of radioactivity following administration of either [3H]d-ampetamine or [3H]2-deoxy-d-glucose was examined by scintillation counting of 22 microdissected brain regions from rats pretreated with either acute or continuous amphetamine, or continuously administered labeled d-amphetamine. Animals continuously administered drug were sacrificed in behaviorally distinct stages of the continuous amphetamine syndrome, a potential animal model of amphetamine psychosis. Both isotopes were heterogeneously distributed within brain, and their distributions were differentially affected by acute or continuous amphetamine regimens. While the distribution of either isotope in naive rats was characterized by greatest concentrations of counts in rostral rather than caudal regions, and grey-matter rather than white-matter structures, continuous amphetamine administration resulted in progressively increased retention of amphetamine by mesolimbic but not nigrostriatal brain regions; this was accompanied by locally enhanced levels of glucose utilization. This effect was predominantly localized in the nucleus accumbens, which exhibited the greatest retention of amphetamine and greatest relative increase in glucose utilization of any region studied during that stage of the continuous amphetamine syndrome thought to best model amphetamine psychosis. Alterations in amphetamine distribution and local levels of neural activity may reflect a change in the principal locus of control of amphetamine effects within brain as animals progress through the stages of the continuous amphetamine syndrome.

Amphetamine↗
PubMed1985

Time course of the development of the enhanced behavioral and biochemical responses to amphetamine after pretreatment with amphetamine.

These experiments were designed to examine the time course of development of the enhanced stereotyped behavioral response to amphetamine after withdrawal from chronic pretreatment with amphetamine and to determine whether this time course correlates with that of the enhancement in the amphetamine-induced stimulation of the release of dopamine (DA) from striatal slices. Rats were pretreated with amphetamine (5 mg/kg, i.p.) or saline, twice daily for 5 consecutive days. At 3, 15 and 30 days after withdrawal of the drug the stereotyped behavioral response and the release of endogenous DA from slices of striatum in response to a challenge dose of amphetamine were measured. At all 3 times tested, the stereotyped behavioral response to the challenge dose of amphetamine was enhanced in the rats pretreated with amphetamine, with the greatest degree of enhancement seen at 15 and 30 days after withdrawal of the drug. At these times, the responses were associated with a significant attenuation in the stimulation of locomotor activity produced by the challenge dose of amphetamine, which was probably related to the enhanced stereotyped behavioral response. Amphetamine stimulated the release of endogenous DA from slices of striatum in rats pretreated with saline and amphetamine. However, the release of endogenous DA from slices of rats pretreated with amphetamine was significantly greater than that of saline-pretreated rats at 15 and 30 days after withdrawal of the drug, but not at 3 days after withdrawal. Thus, pretreatment with amphetamine resulted in enhanced behavioral and biochemical responses to amphetamine which increased over time after withdrawal of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamine↗
PubMed2000

Urinary excretion of 4-hydroxyamphetamine and amphetamine in male and female Sprague-Dawley and Dark Agouti rats following multiple doses of amphetamine.

Previous studies have demonstrated that the cytochrome P450 2D subfamily is involved in the 4-hydroxylation of amphetamine in the rat. These studies followed urinary levels of 4-hydroxyamphetamine and amphetamine after a single dose of amphetamine given with the P450 2D inhibitor quinidine or in P450 2D-deficient Dark Agouti (DA) rats. Multiple doses of amphetamine are used by humans and in experimental neurotoxicity studies of amphetamine. We hypothesized that the elimination of amphetamine (as opposed to 4-hydroxyamphetamine) will remain elevated in the DA rat after multiple doses, implying that no alternative pathway is induced to compensate for reduced 4-hydroxylation. Male and female Sprague-Dawley (SD) and DA rats were given daily i.p. injections of 5 mg/kg amphetamine for 5 days. Urine was collected at 12-h intervals and analyzed by HPLC for the presence of amphetamine and 4-hydroxyamphetamine. The amount of amphetamine detected in the urine remained elevated with a corresponding reduction of 4-hydroxyamphetamine in the DA rats when compared to SD rats over the entire time course. This reduction in 4-hydroxyamphetamine was greater in female than male DA rats; no difference was found between male and female SD rats. At the dose used, amphetamine did not increase with time and total amphetamine and 4-hydroxyamphetamine excreted by all rats was not different, implying no accumulation of amphetamine. These results suggest that no alternative pathway is induced following multiple doses of amphetamine in normal SD or P450 2D deficient DA rats.

Amphetamine↗
PubMed1999

Enhanced amphetamine- and K+-mediated dopamine release in rat striatum after repeated amphetamine: differential requirements for Ca2+- and calmodulin-dependent phosphorylation and synaptic vesicles.

After cessation of repeated, intermittent amphetamine, we detected an emergent Ca2+-dependent component of amphetamine-induced dopamine release and an increase in calmodulin and Ca2+- and calmodulin-dependent protein kinase activity in rat striatum. This study examined the involvement of calmodulin-dependent protein kinase II (CaM kinase II) and synaptic vesicles in the enhanced Ca2+-dependent dopamine release in response to amphetamine or K+ in rat striatum. Rats were pretreated for 5 d with 2.5 mg/kg amphetamine or saline and withdrawn from drug for 10 d. The selective CaM kinase II inhibitor KN-93 (1 microM), but not the inactive analog KN-92, attenuated the Ca2+-dependent amphetamine-mediated dopamine release from amphetamine-pretreated rats but had no effect in saline-pretreated controls. [3H]Dopamine uptake was unaltered by repeated amphetamine or KN-93 and was Ca2+ independent. Striatal dopamine release stimulated by 50 mM KCl was enhanced twofold after repeated amphetamine compared with that in saline controls but was unaffected by KN-93. To examine the requirement for dopaminergic vesicles in the Ca2+-dependent dopamine release, we administered reserpine to saline- and amphetamine-pretreated rats 1 d before killing. Reserpine pretreatment did not affect amphetamine-mediated dopamine release from either pretreatment group but completely ablated K+-mediated dopamine release. Reserpine did not disrupt the ability of 1 microM KN-93 to block the Ca2+-dependent amphetamine-mediated dopamine release from amphetamine-pretreated rats. The results indicate that the enhanced dopamine release elicited by amphetamine from chronically treated rats is dependent on Ca2+- and calmodulin-dependent phosphorylation and is independent of vesicular dopamine storage. On the contrary, the enhanced depolarization-mediated vesicular dopamine release is independent of Ca2+- and calmodulin-dependent phosphorylation.

Amphetamine↗
PubMed1977

Comparative effects of d-amphetamine, l-amphetamine, and methylphenidate on mood in man.

The comparative effects of d-amphetamine, l-amphetamine, and methylphenidate were assessed in 16 normal subjects, using a double-blind, crossover placebo-controlled design. Within the dose range tested, the efficacy ratio of d-amphetamine:l-amphetamine was about 2:1, and graphic presentation of dose response scores indicated a relatively small difference in potency between the amphetamine isomers. Methylphenidate was intermediate in efficacy between d-amphetamine and l-amphetamine. The efficacy ratios for d-amphetamine:l-amphetamine on increasing euphoric mood in man were similar to the previously reported ratios of there two isomers in inducing or exacerbating psychosis in humans. These findings do not support the suggestion, made by Snyder and others, that the differential effects of d-amphetamine vs. l-amphetamine on a specific type of behavior in man could be utilized to infer the predominance of noradrenergic vs. dopaminergic mediation of amphetamine's effects on this behavior.

Adult↗
PubMed2002

Enhanced amphetamine-mediated dopamine release develops in PC12 cells after repeated amphetamine treatment.

We previously demonstrated that rats treated with repeated, intermittent amphetamine displayed enhanced amphetamine-mediated dopamine release in the striatum. In this study, we examined whether amphetamine pretreatment would elicit enhanced amphetamine-mediated dopamine release in a cultured cell line in the absence of intact synaptic connections. PC12 cells pretreated with 1 microM amphetamine produced over twofold increase in amphetamine-mediated dopamine release upon challenge with 1 microM amphetamine as compared with vehicle-treated cells. No change in norepinephrine transporter density or [3H]dopamine uptake was detected. A withdrawal time of 6 days was required to observe the enhanced amphetamine-mediated dopamine release. Differentiation of the cells with nerve growth factor did not alter the amphetamine-mediated dopamine release in control cells or the development of enhanced release in amphetamine-treated cells. Our results demonstrate that repeated, intermittent amphetamine leads to a neuroadaptation resulting in enhanced amphetamine-induced dopamine release in catecholaminergic cells without the need of an intact neuroanatomy.

Amphetamine↗
PubMed1992

Sensitization and individual differences to IP amphetamine, cocaine, or caffeine following repeated intracranial amphetamine infusions.

Rats that have a high locomotor response to novelty (HR) sensitize more readily to IP-administered amphetamine than rats with a low locomotor response (LR) to novelty. This experiment compared sensitization in HR and LR rats following amphetamine (3.0 micrograms/side for 5 days) infused bilaterally into either the nucleus accumbens (NACC), ventral tegmental area (VTA), or the medial frontal cortex (MFC). The subsequent locomotor response to IP-administered d-amphetamine sulfate (1 mg/kg), cocaine HCl (15 mg/kg), and caffeine benzoate (20 mg/kg) was also examined. No differences were observed between HR and LR rats following amphetamine infusion into either the MFC, NACC, or VTA. However, HR rats showed greater locomotor activity compared to LR rats following either IP amphetamine, cocaine, or caffeine for subjects cannulated in the NACC, MFC, or the VTA. Repeated infusions of amphetamine into the VTA increased the locomotor response to both IP amphetamine and cocaine, but not to IP caffeine, while repeated infusions of amphetamine into the NACC or MFC had no effect on locomotor response to any drug subsequently administered IP. The results support previous findings that changes induced by intra-VTA infusions, but not intra-NACC or MFC infusions, of amphetamine induce sensitization to IP-administered amphetamine and cocaine. Findings from the present experiment indicate the ability of the dopamine cell body region, but not the dopamine terminal fields, to produce locomotor sensitization to amphetamine and cocaine. The results from the present experiment also indicate the lack of localization to one of studied regions of individual differences.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamine↗
PubMed1987

Repeated amphetamine pretreatment alters the responsiveness of striatal dopamine-stimulated adenylate cyclase to amphetamine-induced desensitization.

The repeated daily administration of moderate doses of amphetamine results in an augmentation of the behavioral response to subsequent amphetamine challenge. One feature of the augmentation is a shift in the type of perseverative behaviors to those generally associated with higher acute doses of the drug. Consistent with these observations, rats pretreated with six daily injections of amphetamine (3 mg/kg) exhibited primarily oral stereotypies to a challenge dose of 2.5 mg/kg of amphetamine, whereas control animals exhibited focused sniffing and repetitive head movements. Previously we found that the acute administration of amphetamine or methylphenidate only at doses which induce oral stereotypies promotes a rapid desensitization of striatal dopamine-stimulated adenylate cyclase. We therefore examined the effects of repeated amphetamine pretreatment on this index of D1 dopamine receptors. The administration of 2.5 mg/kg of amphetamine produced a 2-fold shift to the right in the concentration-response curve for dopamine-stimulated adenylate cyclase in animals pretreated with amphetamine, but not in saline pretreated controls. No effect of the chronic amphetamine pretreatment on dopamine stimulated cyclase in the absence of amphetamine challenge was observed. The binding of [3H]cis-flupenthixol to striatal D1 dopamine receptors was not affected by acute or chronic amphetamine. These results suggest a relationship between stimulant-induced desensitization of striatal D1 dopamine receptors and the induction of oral stereotypies.

Adenylyl Cyclases↗
PubMed1994

Amphetamine administered to the ventral tegmental area sensitizes rats to the locomotor effects of nucleus accumbens amphetamine.

This experiment investigated whether pre-exposure to injections of amphetamine into the ventral tegmental area (VTA) sensitizes the locomotor response to a subsequent test injection of amphetamine given into the nucleus accumbens (N.Acc.). Different groups of rats received three intra-VTA injections of amphetamine (2.5 micrograms/0.5 microliters/side) or saline (0.5 microliters/side), one injection given every 3rd day, and locomotor activity was measured for 60 min. Seven to 10 days later, all animals were tested with an intra-N.Acc. challenge injection of amphetamine (0, 1.5, 2.5 or 5.0 micrograms/0.5 microliter/side) and locomotor activity was again measured. In agreement with previous reports, intra-VTA amphetamine produced no behavioral effects acutely. However, when animals were subsequently challenged with an injection of amphetamine into the N.Acc., animals pre-exposed to intra-VTA amphetamine showed significantly and dose-dependently greater levels of locomotor activity than saline pre-exposed rats. Animals pre-exposed to amphetamine in sites outside the VTA did not show sensitized responding when subsequently tested with intra-N.Acc. amphetamine. These findings support the view that the induction of behavioral sensitization to amphetamine results from an action of this drug in the cell body region of mesolimbic dopamine neurons (VTA), whereas its expression reflects an enhanced reactivity in the terminals of these neurons in the N.Acc. Implications of such findings for the molecular neurobiological basis of behavioral sensitization to amphetamine are discussed.

Amphetamine↗
PubMed1997

Extracellular dopamine and amphetamine after systemic amphetamine administration: comparison to the behavioral response.

To further delineate amphetamine-dopamine pharmacokinetic-pharmacodynamic relationships, we examined extracellular levels of dopamine and amphetamine in caudate-putamen after the s.c. administration of 8 mg/kg amphetamine. In a parallel group of animals, we also assessed caudate-putamen tissue levels of the drug. Extracellular concentrations of the transmitter and the drug exhibited similar temporal profiles, each achieving maximum concentrations within 30 min of drug administration. Tissue levels of amphetamine exhibited a similar, although slightly earlier time to maximum levels. The concentrations of amphetamine and dopamine in the extracellular fluid and amphetamine in tissue rapidly declined with similar rates of elimination. In contrast to the temporal profiles for both dopamine and amphetamine, stereotyped behaviors achieved maximum intensity at about 60 min. In addition, although transmitter and drug declined almost 10-fold from maximum values over the 4-hr interval after amphetamine administration, stereotyped behaviors persisted for at least 3 hr before abating. The results of these studies confirm our previous observation that the temporal profiles for stereotyped behaviors and extracellular dopamine are dissociated, and also extend this dissociation to extracellular amphetamine. In addition, although there was a close correspondence between dopamine and amphetamine within each experimental animal, individual animals exhibited a broad range of maximal dopamine responses, suggesting a differential responsiveness to amphetamine.

Amphetamine↗
PubMed1979

Paradoxical effect of amphetamine in an endogenous model of the hyperkinetic syndrome in a hybrid dog: correlation with amphetamine and p-hydroxyamphetamine blood levels.

A telomian-beagle hybrid has been studied as a possible model for the hyperkinetic syndrome in children. Behavior tests showed that hybrids, like children, exhibit hyperactivity, impulsiveness, and impaired learning. Two groups of hybrid could be differentiated; the behaviour of one improved after amphetamine (responders) while that of the other did not (nonresponders). Moreover hybrids were less responsive than beagles to other effects of amphetamine such as stereotyped behaviour and hyperthermia. Measurement of blood levels of amphetamine and its active metabolite p-hydroxyamphetamine (pOA) showed that hybrids form less pOA. We propose that the lesser response of hybrids to toxic effects of amphetamine is due to this difference in amphetamine metabolism. Responders showed higher peak blood levels of amphetamine than nonresponders and their improvement on amphetamine correlated with blood levels of amphetamine. Therefore high levels of amphetamine appear to be necessary for its 'paradoxical' effect in this model. This suggests that amphetamine acts by activating both noradrenergic and dopaminergic neuronal systems in the CNS.

Amphetamine↗
PubMed1996

Amphetamine-induced changes in nigrostriatal terminal excitability are modified following repeated amphetamine pretreatment.

To investigate neural mechanisms associated with behavioral sensitization to amphetamine, we studied the effect of an intrastriatal infusion of amphetamine on nigrostriatal axon terminal electrical excitability in rats following withdrawal from repeated systemic treatment. Rats were injected with amphetamine 2.5 mg/kg s.c. or saline daily for 4 days. Either 24 h or 14 days after the last injection, extracellular recordings were obtained from dopaminergic neurons of the substantia nigra, in a blind design in which the experimenter did not know the pretreatment regime. In order to assess the electrical excitability of the nigrostriatal axonal field, neurons were activated antidromically by stimulating their terminal fields in the striatum. As previously reported, striatal infusion of amphetamine (1 microM/0.3 microliter) in control animals resulted in a significant reduction in excitability as indicated by an increase in striatal stimulus current necessary to evoke antidromic activity. In contrast, intrastriatal amphetamine administration to amphetamine-pretreated animals did not decrease excitability. Spontaneous firing rates and patterns of cell discharge did not differ between saline- and amphetamine-treated animals. The chronic amphetamine-induced change in the effect of an acute intrastriatal amphetamine infusion on nigrostriatal terminal excitability may be due to enduring alterations in the amphetamine-induced release of dopamine and other striatal neurotransmitters or to changes in the sensitivity of presynaptic hetero- and/or autoreceptors on the dopaminergic axons.

Amphetamine↗
PubMed2001

The purinergic P2 receptor antagonist pyridoxalphosphate-6-azophenyl-2'4'-disulphonic acid prevents both the acute locomotor effects of amphetamine and the behavioural sensitization caused by repeated amphetamine injections in rats.

Repeated administration of amphetamine-like psychostimulants produce a progressive and long-lasting hypersensitivity to their behavioural effects known as behavioural sensitization. Previous studies have shown that administration of the purinergic P2 receptor agonist 2-methylthio ATP into the nucleus accumbens of rats raises the extracellular level of dopamine accompanied with enhanced locomotion in a similar manner. Furthermore, the quantitative EEG after application of 2-methylthio ATP or amphetamine was characterized by an elevation of the alpha1-power. However, purinergic P2 receptor antagonists decreased the basal level of dopamine in the NAc and in addition prevented the effects of 2-methylthio ATP. The purpose of the present study was to investigate, whether endogenous ATP acting via purinergic P2 receptors is involved in the process of amphetamine-induced sensitization. Rats were treated systemically for five successive days with d-amphetamine (1.5 mg/kg) and tested in an open field with respect to their locomotor response. The enhanced locomotor activity after the first injection of amphetamine was diminished by the previous intracerebroventricular application of the purinergic P2 receptor antagonist pyridoxalphosphate-6-azophenyl-2'4'-disulphonic acid (PPADS; 0.6 nmol) (P<0.05). The challenge with a lower dose of amphetamine (0.75 mg/kg) produced an increased locomotion in comparison to the response after the first amphetamine application indicating the expression of a behavioural sensitization. Pretreatment with PPADS prior to each amphetamine administration prevented the increase of locomotor activity after the challenge with amphetamine (P<0.05). In summary, the present study demonstrates that PPADS blocks both the acute locomotor effects of amphetamine and the development of behavioural sensitization to the psychostimulant. We suggest that the activation of purinergic P2 receptors by endogenous ATP is necessary for the expression of these effects.

Adenosine Triphosphate↗