Biomedical subjects

Glen R Hanson

Publications and source records attributed to Glen R Hanson.

At least 19 recordsLinked to original sources

PubMed2007

New insights into the mechanism of action of amphetamines.

Amphetamine is a psychostimulant commonly used to treat several disorders, including attention deficit, narcolepsy, and obesity. Plasmalemmal and vesicular monoamine transporters, such as the neuronal dopamine transporter and the vesicular monoamine transporter-2, are two of its principal targets. This review focuses on new insights, obtained from both in vivo and in vitro studies, into the molecular mechanisms whereby amphetamine, and the closely related compounds methamphetamine and methylenedioxymethamphetamine, cause monoamine, and particularly dopamine, release. These mechanisms include amphetamine-induced exchange diffusion, reverse transport, and channel-like transport phenomena as well as the weak base properties of amphetamine. Additionally, amphetamine analogs may affect monoamine transporters through phosphorylation, transporter trafficking, and the production of reactive oxygen and nitrogen species. All of these mechanisms have potential implications for both amphetamine- and methamphetamine-induced neurotoxicity, as well as dopaminergic neurodegenerative diseases.

Amphetamines↗

PubMed2006

Multiple high doses of methamphetamine increase the number of preproneuropeptide Y mRNA-expressing neurons in the striatum of rat via a dopamine D1 receptor-dependent mechanism.

Neuropeptide Y (NPY) is a neuropeptide that may be involved with emotional regulation and drug addiction and may act as a neuroprotective agent during toxic insults, such as is associated with multiple, high doses of methamphetamine (METH). The purpose of the present study was to elucidate the nature of METH-induced changes in the NPY system by examining the effect of multiple, high doses of METH on preproNPY (ppNPY) mRNA expression in the striatum and the role that dopamine (DA) D1 and D2 receptors might play in these changes. Rats were administered five injections of 10 mg/kg METH at 6-h intervals, along with the D1 receptor antagonist 7-chloro-8-hydoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benazepine hydrochloride (SCH22390) or the D2 receptor antagonist eticlopride, and they were sacrificed 3 h after the last dose of METH. The number of neurons expressing ppNPY mRNA in striatum was examined using in situ hybridization histochemistry. An acute dose of METH as well as multiple, high doses of METH increased the number of neurons expressing ppNPY mRNA in all regions of striatum examined. There was no change in the number of prosomatostatin (pSOM) mRNA-containing neurons. The increase in the number of ppNPY mRNA-expressing neurons was abolished by pretreatment with SCH22390. Eticlopride alone increased the number of ppNPY mRNA-expressing neurons in striatum, and METH treatment did not further increase the number. These findings suggest that exposure to multiple, high doses of METH increases the number of neurons expressing detectable levels of ppNPY mRNA and that this phenomenon is dependent on DA D1-receptor activation.

Animals↗

PubMed2006

Methamphetamine administration reduces hippocampal vesicular monoamine transporter-2 uptake.

Repeated high-dose injections of methamphetamine (METH) rapidly decrease dopamine uptake by the vesicular monoamine transporter-2 (VMAT-2) associated with dopaminergic nerve terminals, as assessed in nonmembrane-associated vesicles purified from striata of treated rats. The purpose of this study was to determine whether METH similarly affects vesicular uptake in the hippocampus; a region innervated by both serotonergic and noradrenergic neurons and profoundly affected by METH treatment. Results revealed that repeated high-dose METH administrations rapidly (within 1 h) reduced hippocampal vesicular dopamine uptake, as assessed in vesicles purified from treated rats. This reduction was likely associated with serotonergic nerve terminals because METH did not further reduce vesicular monoamine uptake in para-chloroamphetamine-lesioned animals. Pretreatment with the serotonin transporter inhibitor fluoxetine blocked both this acute effect on VMAT-2 and the decrease in serotonin content observed 7 days after METH treatment. In contrast, there was no conclusive evidence that METH affected vesicular dopamine uptake in noradrenergic neurons or caused persistent noradrenergic deficits. These findings suggest a link between METH-induced alterations in serotonergic hippocampal vesicular uptake and the persistent hippocampal serotonergic deficits induced by the stimulant.

Animals↗

PubMed2006

Measurement of kinetically resolved vesicular dopamine uptake and efflux using rotating disk electrode voltammetry.

The vesicular monoamine transporter-2 (VMAT-2) sequesters cytoplasmic dopamine (DA) into vesicles for storage and subsequent release. VMAT-2 activity has traditionally been measured in small synaptic vesicles isolated from rat striatum by monitoring [3H] DA uptake and in cellular expression systems using fast scan cyclic voltammetry. This is the first report using rotating disk electrode (RDE) voltammetry to measure VMAT-2 DA uptake and efflux in small synaptic vesicles. DA uptake profiles followed mixed order kinetics with apparent zero order kinetics for the first 25 s and apparent first order kinetics thereafter. Vesicular DA uptake was temperature- and ATP-dependent and was blocked by the VMAT-2 inhibitor tetrabenazine. Initial velocities of DA uptake were kinetically resolved and displayed Michaelis-Menten kinetics with a Km and Vmax of 289 +/- 59 nM and 1.9 +/- 0.2 fmol/(s microg protein), respectively. Methamphetamine-induced DA efflux was blocked by tetrabenazine and kinetically resolved with an initial velocity of 0.54 +/- 0.08 fmol/(s microg protein). These results suggest that RDE voltammetry can be used to make kinetically resolved measurements of vesicular DA uptake and efflux and will allow the design of experiments that could reveal important information about the kinetics of VMAT-2 activity and its inhibition.

Adenosine Triphosphate↗

PubMed2006

Kinetic analysis of developmental changes in vesicular monoamine transporter-2 function.

The vesicular monoamine transporter-2 (VMAT-2) sequesters cytoplasmic dopamine (DA) into vesicles and may thus protect neurons from DA-associated oxidative damage. VMAT-2 function, as assessed by measuring [(3)H]DA uptake, is less in adolescent when compared with young adult rats and VMAT-2 susceptibility to methamphetamine also changes with age. Thus, developmental alterations in VMAT-2 function warrant further investigation. The current study extends these findings by showing that the initial velocities of both DA uptake and methamphetamine-induced DA efflux are less in adolescent postnatal day (PND 38-42) vs. young adult (PND 88-92) rats as assessed in nonmembrane associated (presumably cytoplasmic) vesicles purified from rat striatal synaptosomes. The decrease in DA uptake velocities is due to a decrease in the V(max) of DA uptake with no change in the K(m). The density of kinetically active VMAT-2 and VMAT-2 immunoreactivity are less in adolescent vs. young adult rats while both the turnover number (2.4-2.8 s(-) (1)) and rate constant for the association of DA with VMAT-2 ( 1 x 10(7) M(-) (1) s(-) (1)) are similar in these age groups. These results suggest that the kinetics of DA binding and translocation across the membrane are unaltered in the vesicles of PND 38-42 vs. PND 88-92 rats. However, decreased VMAT-2 density in PND 38-42 rats reduces V(max), which in turn lowers DA uptake.

Aging↗

PubMed2006

Mechanisms of methamphetamine-induced dopaminergic neurotoxicity.

Methamphetamine (METH) is a powerful stimulant of abuse with potent addictive and neurotoxic properties. More than 2.5 decades ago, METH-induced damage to dopaminergic neurons was described. Since then, numerous advancements have been made in the search for the underlying mechanisms whereby METH causes these persistent dopaminergic deficits. Although our understanding of these mechanisms remains incomplete, combinations of various complex processes have been described around a central theme involving reactive species, such as reactive oxygen and/or nitrogen species (ROS and RNS, respectively). For example, METH-induced hyperthermia, aberrant dopamine(DA), or glutamate transmission; or mitochondrial disruption leads to the generation of reactive species with neurotoxic consequences. This review will describe the current understanding of how high-dose METH administration leads to the production of these toxic reactive species and consequent permanent dopaminergic deficits.

Animals↗

PubMed2006

Age-dependent effects of methamphetamine on VMAT-2.

Abuse of methamphetamine (METH) among adolescents and young adults is concerning since studies have demonstrated that multiple administrations of high-dose METH induce persistent dopaminergic deficits. METH has also been shown to reduce dopamine (DA) uptake by the vesicular monoamine transporter-2 (VMAT-2) and to reduce the amount of VMAT-2 protein in a purified vesicular fraction. VMAT-2 plays a critical role in the sequestration of DA in dopaminergic nerve terminals. This function is important since DA can oxidize rapidly to form highly reactive species. It is likely that disruption of this normal intracellular processing of DA contributes to oxidative sequences ultimately leading to persistent deficits. Interestingly, METH appears to be less toxic in adolescent rats compared to young adult rats. VMAT-2 is proposed to play an important role in the age-dependent difference. Since the effect of METH on the function and quantity of VMAT-2 has primarily been studied in young adult rats and since developmental changes in the dopaminergic system are reported to occur between adolescence and adulthood, it is important to determine if there is an age-dependent difference in response of VMAT-2 to METH.

Age Factors↗

PubMed2005

Role of monoamine transporters in mediating psychostimulant effects.

Monoamine transporters such as the dopamine (DA) transporter (DAT) and the vesicular monoamine transporter-2 (VMAT-2) are critical regulators of DA disposition within the brain. Alterations in DA disposition can lead to conditions such as drug addiction, Parkinson's disease, and schizophrenia, a fact that underscores the importance of understanding DAergic signaling. Psychostimulants alter DAergic signaling by influencing both DAT and VMAT-2, and although the effects of these drugs result in increased levels of synaptic DA, the mechanisms by which this occurs and the effects that these drugs exert on DAT and VMAT-2 vary. Many psychostimulants can be classified as releasers (ie, amphetamine analogs) or uptake blockers (ie, cocaine-like drugs) based on the mechanism of their acute effects on neurotransmitter flux through the DAT. Releasers and uptake blockers differentially modulate the activity and subcellular distribution of monoamine transporters, a phenomenon likely related to the neurotoxic potential of these drugs to DAergic neurons. This article will review some of the recent findings whereby releasers and uptake blockers alter DAT and VMAT-2 activity and how these alterations may be involved in neurotoxicity, thus providing insight on the neurodegeneration observed in Parkinson's disease.

Animals↗

PubMed2005

Differential neurotensin responses to low and high doses of methamphetamine in the terminal regions of striatal efferents.

Neurotensin is a neuropeptide associated with basal ganglia dopaminergic neurons. Because levels of neurotensin in striatal tissue are differentially affected by low or high doses of methamphetamine, we employed microdialysis to assess the dose-dependent effects of methamphetamine on neurotensin release from the terminals of striatonigral and striatopallidal neurons. A low (0.5 mg/kg), but not high (10 mg/kg), dose of methamphetamine significantly increased nigral extracellular levels of neurotensin. The low-dose effect on extracellular nigral neurotensin levels was blocked by pretreatment with either a dopamine D1 or D2 receptor antagonist. In the globus pallidus, only half of the animals demonstrated increased neurotensin release after the low dose of methamphetamine. These findings suggest that low and high doses of methamphetamine differentially affect the release of neurotensin from the terminals of striatonigral neurons and that both dopamine D1 and D2 receptor activation contributes to the low-dose methamphetamine effects in the substantia nigra.

Analysis of Variance↗

PubMed2005

Bupropion increases striatal vesicular monoamine transport.

The vesicular monoamine transporter-2 (VMAT-2) is principally involved in regulating cytoplasmic dopamine (DA) concentrations within terminals by sequestering free DA into synaptic vesicles. This laboratory previously identified a correlation between striatal vesicular DA uptake through VMAT-2 and inhibition of the DA transporter (DAT). For example, administration of methylphenidate (MPD), a DAT inhibitor, increases vesicular DA uptake through VMAT-2 in a purified vesicular preparation; an effect associated with a redistribution of VMAT-2 protein within DA terminals. The purpose of this study was to determine if other DAT inhibitors, including bupropion, similarly affect VMAT-2. Results revealed bupropion rapidly, reversibly, and dose-dependently increased vesicular DA uptake; an effect also associated with VMAT-2 protein redistribution. The bupropion-induced increase in vesicular DA uptake was prevented by pretreatment with eticlopride, a DA D2 receptor antagonist, but not by SCH23390, a DA D1 receptor antagonist. We previously reported that MPD post-treatment prevents persistent DA deficits associated with multiple methamphetamine (METH) administrations. Although bupropion attenuated the METH-induced reduction in VMAT-2 activity acutely, it did not prevent the long-term dopaminergic toxicity or the METH-induced redistribution of VMAT-2 protein. The findings from this study demonstrate similarities and differences in the mechanism by which MPD and bupropion affect striatal dopaminergic nerve terminals.

Analysis of Variance↗

PubMed2005

Age-dependent methamphetamine-induced alterations in vesicular monoamine transporter-2 function: implications for neurotoxicity.

Tens of thousands of adolescents and young adults have used illicit methamphetamine. This is of concern since its high-dose administration causes persistent dopaminergic deficits in adult animal models. The effects in adolescents are less studied. In adult rodents, toxic effects of methamphetamine may result partly from aberrant cytosolic dopamine accumulation and subsequent reactive oxygen species formation. The vesicular monoamine transporter-2 (VMAT-2) sequesters cytoplasmic dopamine into synaptic vesicles for storage and perhaps protection against dopamine-associated oxidative consequences. Accordingly, aberrant VMAT-2 function may contribute to the methamphetamine-induced persistent dopaminergic deficits. Hence, this study examined effects of methamphetamine on VMAT-2 in adolescent (postnatal day 40) and young adult (postnatal day 90) rats. Results revealed that high-dose methamphetamine treatment caused greater acute (within 1 h) decreases in vesicular dopamine uptake in postnatal day 90 versus 40 rats, as determined in a nonmembrane-associated subcellular fraction. Greater basal levels of VMAT-2 at postnatal day 90 versus 40 in this purified fraction seemed to contribute to the larger effect. Basal tissue dopamine content was also greater in postnatal day 90 versus 40 rats. In addition, postnatal day 90 rats were more susceptible to methamphetamine-induced persistent dopaminergic deficits as assessed by measuring VMAT-2 activity and dopamine content 7 days after treatment, even if drug doses were adjusted for age-related pharmacokinetic differences. Together, these data demonstrate dynamic changes in VMAT-2 susceptibility to methamphetamine as a function of development. Implications with regard to methamphetamine-induced dopaminergic deficits, as well as dopamine-associated neurodegenerative disorders such as Parkinson's disease, are discussed.

Age Factors↗

PubMed2005

3,4-Methylenedioxymethamphetamine increases neuropeptide messenger RNA expression in rat striatum.

The amphetamine analog 3,4-methylenedioxymethamphetamine (MDMA) is also known as the recreational drug of abuse, Ecstasy. Several neuropeptides are found in striatal neurons postsynaptic to dopamine and serotonin nerve terminals, and changes in neuropeptide neurotransmission may be important for behavioral effects of 3,4-methylenedioxymethamphetamine. This study used in situ hybridization to characterize the effects of 3,4-methylenedioxymethamphetamine on four neuropeptide mRNAs: preprodynorphin, preprotachykinin, neurotensin/neuromedin N, and preproenkephalin. Male, Sprague-Dawley rats received a single administration of 10 mg/kg 3,4-methylenedioxymethamphetamine and were sacrificed 30 min or 3 h later. Three hours after administration, 3,4-methylenedioxymethamphetamine increased preprodynorphin, preprotachykinin, and neurotensin/neuromedin N mRNAs. These increases were most prominent in ventral and medial aspects of the rostral-middle striatum, and then became more dorsally restricted in the caudal striatum. At the 30-minute time point, MDMA significantly decreased the signal for preproenkephalin mRNA in a general manner but did not affect the signal for the other neuropeptide precursors. These data suggest that 3,4-methylenedioxymethamphetamine has a generalized, transient, inhibitory effect on striatopallidal neuron gene expression, and then preferentially influences striatonigral neuropeptide systems at the later time point in a regionally selective manner.

3,4-Methylenedioxyamphetamine↗

PubMed2004

Dopamine D2 receptor activation increases vesicular dopamine uptake and redistributes vesicular monoamine transporter-2 protein.

Recent studies demonstrate that multiple dopamine receptor subtypes contribute to the regulation of vesicular monoamine transporter-2 (VMAT-2) activity. The present studies extend these findings by demonstrating that administration of the nonselective dopamine D2 receptor family agonist, quinpirole, rapidly increased vesicular dopamine uptake in purified rat striatal vesicles. This effect occurred in both postnatal day 40 and 90 rats, and was associated with redistribution of the vesicular monoamine transporter-2 (VMAT-2) within nerve terminals. Neither a full nor a partial dopamine D1 receptor family agonist (SKF81297 nor SKF38393, respectively) affected vesicular dopamine uptake per se, nor the effect of quinpirole. Neither the dopamine D3 nor the D4 receptor antagonists, NGB2904 and clozapine, respectively, altered the quinpirole-mediated increase in uptake. However, the nonselective dopamine D2 receptor family antagonist, eticlopride, prevented the quinpirole-induced increase. Taken together, these data demonstrate that dopamine D2 receptor subtype activation increases vesicular dopamine uptake. Implications of this phenomenon with regard to the treatment of Parkinson's disease will be discussed.

Animals↗

PubMed2004

Apomorphine increases vesicular monoamine transporter-2 function: implications for neurodegeneration.

Apomorphine is a nonselective dopamine D1/D2 receptor agonist used in Europe to treat symptoms resulting from the dopaminergic degeneration associated with Parkinson's disease. In addition, neuroprotective effects of this agent in rodent models have been reported. Recent studies indicate that treatments that alter vesicular monoamine transporter-2 (VMAT-2) function may be protective in models of dopaminergic degeneration. Hence, the purpose of the present study was to examine the effect of apomorphine on VMAT-2 function. Results revealed that apomorphine rapidly and reversibly increased vesicular dopamine uptake, as determined in purified striatal vesicles obtained from treated rats. This increase occurred in both postnatal day 40 and postnatal day 90 rats, and was associated with a redistribution of VMAT-2 protein within nerve terminals. This effect of apomorphine on vesicular dopamine uptake was blocked by pretreating with eticlopride, a dopamine D2 receptor antagonist. The implications of these findings relevant to the treatment of neurodegeneration are discussed.

Animals↗

PubMed2004

Methamphetamine increases dopamine transporter higher molecular weight complex formation via a dopamine- and hyperthermia-associated mechanism.

Multiple high-dose administrations of methamphetamine (METH) both rapidly (within hours) decrease plasmalemmal dopamine (DA) uptake and cause long-term deficits in DA transporter (DAT) levels and other dopaminergic parameters persisting weeks to months in rat striatum. In contrast, either a single administration of METH or multiple administrations of methylenedioxymethamphetamine (MDMA) cause less of an acute reduction in DA uptake and little or no persistent dopaminergic deficits. The long-term dopaminergic deficits caused by METH have been suggested, in part, to involve the DAT. Hence, this study assessed the impact of METH and MDMA administration on the DAT protein per se. Results revealed that multiple administrations of METH promoted formation of higher molecular weight (>170 kDa) DAT-associated protein complexes 24-48 hr after treatment. This increase was attenuated by either preventing hyperthermia or pretreatment with the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine; notably, each of these manipulations has also been demonstrated previously to prevent the persistent deficits in dopaminergic function caused by METH treatment. In contrast, either a single injection of METH or multiple injections of MDMA caused little or no formation of these DAT complexes. The addition of the reducing agent beta-mercaptoethanol to samples prepared from METH-treated rats diminished the intensity of these complexes. Taken together, these data are the first to demonstrate higher molecular weight DAT complex formation in vivo and that such formation can be altered by both pharmacological and physiological manipulations. The implications of this phenomenon with regard to the neurotoxic potential of these stimulants are discussed.

Adrenergic Uptake Inhibitors↗

PubMed2004

The methamphetamine experience: a NIDA partnership.

The neurotoxic properties of the amphetamines such as methamphetamine (METH) were originally described about the time of the National Institute on Drug Abuse's organization, in the early 1970s. It required more than 20 years to confirm these neurotoxic properties in humans. Much like Parkinson's disease, multiple high-dose administration of METH somewhat selectively damages the nigrostriatal dopamine (DA) projection of the brain. This effect appears to be related to the intracellular accumulation of cytosolic DA and its ability to oxidize into reactive oxygen species. Both the dopamine plasmalemmal transporter and the vesicular monoamine transporter-2 seem to play critical roles in this neurotoxicity. METH and related analogs such as methylenedioxymethamphetamine (MDMA) can also damage selective CNS serotonin neurons. The mechanism of the serotonergic neurotoxicity is not as well characterized, but also appears to be related to the formation of reactive oxygen species and monoamine transporters. Studies examining the pharmacological and neurotoxicological properties of the amphetamines have helped to elucidate some critical features of monoamine regulations as well as helped to improve our understanding of the processes associated with degenerative disorders such as Parkinson's disease.

Amphetamine-Related Disorders↗

PubMed2004

Psychostimulants and vesicle trafficking: a novel mechanism and therapeutic implications.

The monoamine vesicular transporter 2 (VMAT-2) has been associated with dopamine (DA) sequestration and protection against neurodegeneration caused by the intracellular oxidation of this monoamine. The data presented herein suggest that methylphenidate treatment enhances the amount of VMAT-2 protein and possibly its activity in the presynaptic cytosol, where it is able to increase the sequestration of DA and likely protect against its instability. In contrast, methamphetamine (METH) has an opposite effect on cytosolic VMAT-2 resulting in degradation of DA terminals. The fact that posttreatment of methylphenidate after a neurotoxic regimen of METH protects against resulting loss of DA parameters suggests that treatment with methylphenidate, or other DA transporter blockers, may be protective against degenerative disorders of DA pathways, such as Parkinson's disease.

Animals↗

PubMed2003

Impact of psychostimulants on vesicular monoamine transporter function.

The vesicular monoamine transporter-2 (VMAT-2) facilitates the sequestration of catecholamines and serotonin into synaptic vesicles, and is therefore an essential regulator of monoaminergic neuronal function. VMAT-2 proteins may also play a role in neuroprotection, since these transporters have the capacity to sequester neurotoxins within vesicles. Recent studies have demonstrated that psychostimulants, particularly dopamine "releasers" and "reuptake inhibitors", differentially alter VMAT-2 function. As described in this review, these studies not only provide insight into the pharmacological actions of stimulants, but also mechanisms underlying neurodegenerative disorders, including Parkinson's disease.

Animals↗