Amphetamine and methamphetamine differentially affect dopamine transporters in vitro and in vivo.
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ABSTRACT:
SUBMITTER: Goodwin JS
PROVIDER: S-EPMC2631950 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Amphetamine maintenance is effective clinically to reduce the consumption of the monoamine uptake inhibitor cocaine but not of the monoamine releaser methamphetamine, and its effectiveness in treating the abuse of other psychostimulants is not known. The mechanisms for differential amphetamine-maintenance effectiveness to treat different types of psychostimulant abuse are also not known. Accordingly, the present study compared the effects of amphetamine maintenance on abuse-related behavioral and neurochemical effects of cocaine, methamphetamine, and the "bath salts" constituent 3,4-methylenedioxypyrovalerone (MDPV) in rats. In behavioral studies, rats were trained to lever press for electrical brain stimulation in an intracranial self-stimulation (ICSS) procedure. In neurochemical studies, nucleus accumbens (NAc) levels of dopamine (DA) and serotonin (5-HT) were monitored by in vivo microdialysis. Cocaine, methamphetamine, and MDPV each produced dose-dependent ICSS facilitation and increases in NAc DA; cocaine and methamphetamine also increased NAc 5-HT. Amphetamine maintenance (0.32 mg/kg/h × 7 days) produced (1) sustained increases in basal ICSS and NAc DA with no change in NAc 5-HT, (2) blockade of cocaine but not methamphetamine effects on ICSS and NAc DA, and (3) no blockade of cocaine- or methamphetamine-induced increases in NAc 5-HT. Amphetamine maintenance blocked the increases in NAc DA produced by the selective DA uptake inhibitor MDPV, but it did not block MDPV-induced ICSS facilitation. These results show different effects of amphetamine maintenance on behavioral and neurochemical effects of different psychostimulants. The selective effectiveness of amphetamine maintenance to treat cocaine abuse may reflect attenuation of cocaine-induced increases in NAc DA while preserving cocaine-induced increases in NAc 5-HT.
| S-EPMC6006258 | biostudies-literature
Project description:The psychostimulants amphetamine (AMPH) and methamphetamine (MA) are widely abused illicit drugs. Here we show that both psychostimulants acutely increase NMDA receptor (NMDAR)-mediated synaptic currents and decrease AMPA receptor (AMPAR)/NMDAR ratios in midbrain dopamine neurons. The potentiation depends on the transport of AMPH into the cell by the dopamine transporter. NMDAR-GluN2B receptor inhibitors, ifenprodil, RO 25-6981, and RO 04-5595, inhibit the potentiation without affecting basal-evoked NMDA currents, indicating that NMDAR-GluN2B receptors are activated by AMPH. A selective peptide inhibitor of AMPH-dependent trafficking of the neuronal excitatory amino acid transporter 3 (EAAT3) blocks potentiation, suggesting that EAAT3 internalization increases extracellular glutamate concentrations and activates GluN2B-containing NMDARs. Experiments with the use-dependent NMDAR blocker, MK-801, indicate that potentiated NMDARs reside on the plasma membrane and are not inserted de novo. In behavioral studies, GluN2B inhibitors reduce MA-mediated locomotor activity, without affecting basal activity. These results reveal an important interaction between dopamine and glutamatergic signaling in midbrain dopamine neurons in response to acute administration of psychostimulants.
| S-EPMC5436114 | biostudies-literature
Project description:Neuroimaging studies in stimulant use (eg, cocaine, methamphetamine) disorders show that diminished dopamine release by dopamine-elevating drugs is a potential marker of relapse and suggest that increasing dopamine at the D2/3 receptors may be therapeutically beneficial. In contrast, recent investigations indicate heightened D3 receptor levels in stimulant users prompting the view that D3 antagonism may help prevent relapse. Here we tested whether a 'blunted' response to amphetamine in methamphetamine (MA) users extends to D3-rich brain areas. Fourteen MA users and 15 healthy controls completed two positron emission tomographic scans with a D3-preferring probe [11C]-(+)-PHNO at baseline and after amphetamine (0.4?mg/kg). Relative to healthy controls, MA users had greater decreases in [11C]-(+)-PHNO binding (increased dopamine release) after amphetamine in D3-rich substantia nigra (36 vs 20%, p=0.03) and globus pallidus (30 vs 17%, p=0.06), which correlated with self-reported 'drug wanting'. We did not observe a 'blunted' dopamine response to amphetamine in D2-rich striatum; however, drug use severity was negatively associated with amphetamine-induced striatal changes in [11C]-(+)-PHNO binding. Our study provides evidence that dopamine transmission in extrastriatal 'D3-areas' is not blunted but rather increased in MA users. Together with our previous finding of elevated D3 receptor level in MA users, the current observation suggests that greater dopaminergic transmission at the D3 dopamine receptor may contribute to motivation to use drugs and argues in favor of D3 antagonism as a possible therapeutic tool to reduce craving and relapse in MA addiction.
| S-EPMC5101546 | biostudies-literature
Project description:BACKGROUND:Although hair testing is well established for the assessment of past drug exposure, uncertainties persist about mechanisms of drug incorporation into hair and interpretation of results. The aim of this study was to administer methamphetamine (MAMP) under controlled conditions as a model drug to investigate drug incorporation into human hair. MATERIAL AND METHODS:Seven volunteers with a history of stimulant use received 4×10 mg (low) doses of sustained release S-(+)-MAMP HCl within 1 week, with weekly head hair samples collected by shaving. 3 weeks later, 4 of them received 4×20 mg (high) doses. After extensive isopropanol/phosphate buffer washing of the hair, MAMP and its metabolite amphetamine (AMP) concentrations were determined in all weekly hair samples by LC-MS-MS in selected reaction monitoring mode with the undeca- and deca-deuterated drugs, respectively, as internal standards (LLOQ, 0.005 ng mg(-1)). RESULTS:MAMP T(max) occurred from 1 to 2 weeks after both doses, with C(max) ranging from 0.6 to 3.5 ng mg(-1) after the low and 1.2 to 5.3 ng mg(-1) after the high MAMP doses. AMP C(max) in hair was 0.1-0.3 ng mg(-1) and 0.2-0.5 ng mg(-1), respectively, for low and high doses. Highly dose-related concentrations within subjects, but large variability between subjects were observed. MAMP concentrations were above the 0.2 ng mg(-1) cut-off for at least 2 weeks following administration of both low and high doses. The overall AMP/MAMP ratio ranged from 0.07 to 0.37 with a mean value of 0.15 ± 0.07, and a median of 0.13. The percentage of MAMP and AMP removed with the washing procedure decreased with time after administration. A strong correlation was found between area under the curve of MAMP (r(2)=0.90, p=0.00) and AMP (r(2)=0.94, p=0.00) concentrations calculated for the 3-week period following administration and the total melanin concentration in hair. Significant correlations were observed also between C(max) and melanin. CONCLUSIONS:This study demonstrated that despite large inter-individual differences, the incorporation of MAMP and AMP into hair is dose-related with much of the observed scatter of MAMP and AMP concentrations explained by melanin concentration in hair.
| S-EPMC3391534 | biostudies-literature
Project description:Drugs of abuse, including cocaine, amphetamine (AMPH), and heroin, elevate extracellular dopamine (DA) levels in the brain, thereby altering the activity/plasticity of reward circuits and precipitating addiction. The physiological release of DA occurs through the calcium-dependent fusion of a synaptic vesicle with the plasma membrane. Extracellular DA is cleared by uptake through the Na+/Cl- -dependent DA transporter (DAT). In contrast, the substrate AMPH induces nonvesicular release of DA mediated by DAT. Extracellular AMPH is generally believed to trigger DA efflux through DAT by facilitating exchange for cytosolic DA. Here, in outside-out patches from heterologous cells stably expressing DAT or from dopaminergic neurons, by using ionic conditions in the patch pipette that mimic those produced by AMPH stimulation, we report that AMPH causes DAT-mediated DA efflux by two independent mechanisms: (i) a slow process consistent with an exchange mechanism and (ii) a process that results in rapid (millisecond) bursts of DA efflux through a channel-like mode of DAT. Because channel-like release of DA induced by AMPH is rapid and contains a large number of DA molecules, with a single burst of DA on par with a quantum of DA from exocytotic release of a vesicle, this burst mode of release may play a role in the synaptic actions and psychostimulant properties of AMPH and related compounds. Unlike AMPH, the endogenous substrate DA, when present on both sides of the plasma membrane, inhibits this channel-like activity, thereby suggesting that the DAT channel-like mode cannot accumulate DA against a concentration gradient.
| S-EPMC549289 | biostudies-literature
Project description:BackgroundStimulant drugs are second only to cannabis as the most widely used class of illicit drug globally, accounting for 68 million past-year consumers. Dependence on amphetamines (AMPH) or methamphetamine (MA) is a growing global concern. Yet, there is no established pharmacotherapy for AMPH/MA dependence. A comprehensive assessment of the research literature on pharmacotherapy for AMPH/MA dependence may inform treatment guidelines and future research directions.MethodsWe systematically reviewed the peer-reviewed literature via the electronic databases PubMed, EMBASE, CINAHL and SCOPUS for randomised controlled trials reported in the English language examining a pharmacological treatment for AMPH/MA dependence or use disorder. We included all studies published to 19 June 2019. The selected studies were evaluated for design; methodology; inclusion and exclusion criteria; sample size; pharmacological and (if included) psychosocial interventions; length of follow-up and follow-up schedules; outcome variables and measures; results; overall conclusions and risk of bias. Outcome measures were any reported impact of treatment related to AMPH/MA use.ResultsOur search returned 43 studies that met our criteria, collectively enrolling 4065 participants and reporting on 23 individual pharmacotherapies, alone or in combination. Disparate outcomes and measures (n = 55 for the primary outcomes) across studies did not allow for meta-analyses. Some studies demonstrated mixed or weak positive signals (often in defined populations, e.g. men who have sex with men), with some variation in efficacy signals dependent on baseline frequency of AMPH/MA use. The most consistent positive findings have been demonstrated with stimulant agonist treatment (dexamphetamine and methylphenidate), naltrexone and topiramate. Less consistent benefits have been shown with the antidepressants bupropion and mirtazapine, the glutamatergic agent riluzole and the corticotropin releasing factor (CRF-1) antagonist pexacerfont; whilst in general, antidepressant medications (e.g. selective serotonin reuptake inhibitors [SSRIs], tricyclic antidepressants [TCAs]) have not been effective in reducing AMPH/MA use.ConclusionsNo pharmacotherapy yielded convincing results for the treatment of AMPH/MA dependence; mostly studies were underpowered and had low treatment completion rates. However, there were positive signals from several agents that warrant further investigation in larger scale studies; agonist therapies show promise. Common outcome measures should include change in use days. Future research must address the heterogeneity of AMPH/MA dependence (e.g. coexisting conditions, severity of disorder, differences between MA and AMPH dependence) and the role of psychosocial intervention.
| S-EPMC7125061 | biostudies-literature
Project description:RationaleExtracellular signal-regulated kinase (ERK), cAMP response element binding protein (CREB), and protein kinase B (PKB or Akt) in the striatum are differentially activated by acute and repeated amphetamine (AMPH) administration. However, the dopamine receptor subtypes that mediate transient vs. prolonged phosphorylation changes in these proteins induced by AMPH challenge in AMPH-sensitized rats are unknown.ObjectivesThe role of the D1 and D2 class of dopamine receptors in the differential phosphorylation of striatal ERK, CREB, Thr308-Akt and Ser473-Akt and the expression of behavioral sensitization induced by AMPH challenge in AMPH-pretreated rats were determined.MethodsD1 or D2 dopamine receptor antagonists were injected before an AMPH challenge in AMPH-sensitized rats. After behavioral activity was recorded, rats were euthanized either 15 min or 2 h after AMPH challenge and striatal phosphoprotein status was analyzed by Western blotting.ResultsThe D1 receptor antagonist (SCH23390) decreased stereotypical behavior whereas the D2 receptor antagonist (eticlopride) decreased all behavioral activity induced by an AMPH challenge in AMPH-sensitized rats. SCH23390, but not eticlopride, significantly decreased ERK, CREB, and Thr308-Akt phosphorylation in the striatum 15 min, and ERK and CREB phosphorylation 2 h, after AMPH challenge in AMPH-sensitized rats. In contrast, eticlopride, but not SCH23390, prevented a decrease in Akt phosphorylation 2 h after AMPH challenge.ConclusionsThese data indicate that the time course of phosphoprotein signaling is differentially regulated by D1 and D2 receptors in the striatum of AMPH-sensitized rats, suggesting that complex regulatory interactions are activated by repeated AMPH exposure.
| S-EPMC3065836 | biostudies-literature
Project description:This laboratory has demonstrated that a single methamphetamine (METH) injection rapidly and reversibly decreases the activity of the dopamine transporter (DAT), as assessed ex vivo in synaptosomes prepared from treated rats. This decrease does not occur because of residual drug introduced by the original injection or nor is it associated with a change in binding of the DAT ligand WIN35428. The purpose of this study was to elucidate the mechanism or mechanisms of this METH effect by determining whether direct application of this stimulant to synaptosomes causes changes in DAT similar to those observed ex vivo. Similar to the ex vivo effect, incubation of striatal synaptosomes with METH decreased DAT activity, but not WIN35428 binding: the effect on activity was not eliminated by repeated washing of synaptosomes. Also, as observed ex vivo, incubation with 3,4-methylenedioxymethamphetamine, but not cocaine or methylphenidate, caused a METH-like reduction in DAT function. The rapid and reversible METH-induced diminution in DAT activity did not occur because of a change in membrane potential, as assessed in vitro and ex vivo by [(3)H]tetraphenylphosphonium accumulation. However, the METH-related decline in DAT function may be attributed to phosphorylation because NPC15437, a protein kinase C inhibitor, attenuated the METH-induced decline in DAT function. Similarities between previously reported effects ex vivo of a single METH injection on serotonin and norepinephrine transporter function and effects of direct METH application in vitro were also found. Together, these data demonstrate that the in vitro incubation model mimics the rapid and reversible effects observed after a single METH injection.
| S-EPMC6762246 | biostudies-literature
Project description:Amphetamine abuse afflicts over 13 million people, and there is currently no universally accepted treatment for amphetamine addiction. Amphetamine serves as a substrate for the dopamine transporter and reverses the transporter to cause an increase in extracellular dopamine. Activation of the beta subunit of protein kinase C (PKC?) enhances extracellular dopamine in the presence of amphetamine by facilitating the reverse transport of dopamine and internalizing the D2 autoreceptor. We previously demonstrated that PKC? inhibitors block amphetamine-stimulated dopamine efflux in synaptosomes from rat striatum in vitro. In this study, we utilized in vivo microdialysis in live, behaving rats to assess the effect of the PKC? inhibitors, enzastaurin and ruboxistaurin, on amphetamine-stimulated locomotion and increases in monoamines and their metabolites. A 30 min perfusion of the nucleus accumbens core with 1 ?M enzastaurin or 1 ?M ruboxistaurin reduced efflux of dopamine and its metabolite 3-methoxytyramine induced by amphetamine by approximately 50%. The inhibitors also significantly reduced amphetamine-stimulated extracellular levels of norepinephrine. The stimulation of locomotor behavior by amphetamine, measured simultaneously with the analytes, was comparably reduced by the PKC? inhibitors. Using a stable isotope label retrodialysis procedure, we determined that ruboxistaurin had no effect on basal levels of dopamine, norepinephrine, glutamate, or GABA. In addition, normal uptake function through the dopamine transporter was unaltered by the PKC? inhibitors, as measured in rat synaptosomes. Our results support the utility of using PKC? inhibitors to reduce the effects of amphetamine.
| S-EPMC4909528 | biostudies-literature
Project description:1. (14)C-labelled amphetamine and methamphetamine were injected into rats cannulated at the bile duct under thiopentone anaesthesia and the output of their metabolites in urine and bile was determined. 2. With amphetamine, 69% of the (14)C was excreted in the urine and 16% in the bile in 24h. The main metabolite in bile was the glucuronide of 4-hydroxyamphetamine. The output of unchanged amphetamine was much greater in cannulated rats than in intact rats. 3. With methamphetamine, 54% of the (14)C appeared in the urine and 18% in the bile. The main metabolite in the bile was the glucuronide of 4-hydroxynorephedrine. The output of amphetamine, a metabolite of methamphetamine, was much greater in cannulated rats than in intact rats. 4. Evidence has been obtained for the enterohepatic circulation of certain amphetamine and methamphetamine metabolites in the rat. 5. Thiopentone anaesthesia appeared to inhibit the ring hydroxylation of amphetamine administered as such or formed as a metabolite of methamphetamine.
| S-EPMC1174038 | biostudies-other