Biomedical subjects

Kamisha L Johnson-Davis

Publications and source records attributed to Kamisha L Johnson-Davis.

6 recordsLinked to original sources

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↗

PubMed2004

Alterations in vesicular dopamine uptake contribute to tolerance to the neurotoxic effects of methamphetamine.

Previous studies demonstrated that tolerance to the long-term neurotoxic effects of methamphetamine on dopamine neurons could be induced by pretreating with multiple injections of escalating doses of methamphetamine. The mechanism(s) underlying this tolerance phenomenon is unknown. Some recent studies suggested that aberrant vesicular monoamine transporter-2 (VMAT-2) and dopamine transporter function contribute to neurotoxic effects of methamphetamine. Hence, the purpose of this study was to explore the role of the VMAT-2 and dopamine transporter in the induction of tolerance to the longterm persistent dopaminergic deficits caused by methamphetamine. A second purpose was to investigate the potential role of hyperthermia and alterations in brain methamphetamine distribution in this tolerance. Results revealed that the methamphetamine pretreatment regimen attenuated both the acute methamphetamine-induced decrease in VMAT-2 function 2 h after the methamphetamine challenge administration and its resulting persistent dopamine deficits without attenuating the acute methamphetamine-induced decreases in dopamine transporter uptake. Furthermore, pretreatment with methamphetamine prior to a high-dose methamphetamine challenge administration also attenuated the acute methamphetamine-induced redistribution of VMAT-2 immunoreactivity within the nerve terminal. This protection was not due to alterations in concentration of methamphetamine in the brain because both the methamphetamine- and saline-pretreated rats had similar amounts of methamphetamine and amphetamine at 30 min to 2 h after the last methamphetamine challenge injection. In summary, these data are the first to demonstrate an association between the prevention of acute alterations in vesicular dopamine uptake and the development of tolerance to the neurotoxic effects of methamphetamine.

Adrenergic Uptake Inhibitors↗

PubMed2003

The role of hyperthermia and metabolism as mechanisms of tolerance to methamphetamine neurotoxicity.

Pretreatment with multiple methamphetamine injections prior to a high-dose methamphetamine challenge administration can attenuate long-term deficits in striatal and hippocampal serotonin content caused by the stimulant. The present data extend previous findings by demonstrating that rats pretreated with escalating doses methamphetamine did not exhibit dopamine deficits in the striatum, nor serotonin deficits in striatal, frontal cortical, or hippocampal tissues, 7 days after a challenge methamphetamine administration. This protection was not due to attenuation of methamphetamine-induced hyperthermia or altered brain methamphetamine concentrations. These data differ from previous findings thereby highlighting that different mechanisms contribute to the tolerance of the neurotoxic effects.

Animals↗

PubMed2003

Lack of effect of kappa-opioid receptor agonism on long-term methamphetamine-induced neurotoxicity in rats.

High-dose methamphetamine treatment induces long-term deficits in central monoamine systems. However, the mechanisms underlying these effects are unknown. Previous work has shown that the Kappa-opioid receptor agonist U-69593 [(+)-(5alpha,7alpha,8b)-(+)-N-methyl-N[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl] benzeneacetamide] attenuates the neurotoxic effects of methamphetamine on extracellular dopamine levels in mice, suggesting that endogenous Kappa-opioid receptor ligands, such as dynorphin, may protect against methamphetamine-induced toxicity and play a role in mediating the long-term consequences of methamphetamine. To further examine the role that dynorphin systems play in methamphetamine-induced neurotoxicity, we administered to male rats a total of four injections of methamphetamine (7.5 mg/kg, s.c.), with a 2-h interval between each dose. Rats were pretreated with either the Kappa-agonist U-69593 (0.32 mg/kg, s.c.) or vehicle, 15 min prior to the first and third methamphetamine injection. Furthermore, cages containing the U-69593 + methamphetamine-treated rats were placed on heating pads for 30 min after the first U-69593 injection to prevent the drug from blocking methamphetamine-induced hyperthermia. Rats were sacrificed 7 days after treatment. Striatal dopamine and serotonin contents were decreased approximately 75% and 55%, respectively, in the methamphetamine-treated rats and approximately 88% and 65%, respectively, in rats receiving the U-69593 + methamphetamine combination. There was a approximately 20% mortality rate in the rats treated with methamphetamine compared to approximately 75% mortality rate in rats treated with both U-69593 and methamphetamine. A similar rate of mortality was observed when combining a different Kappa-agonist, U-50488 [trans-(-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamine], with methamphetamine. These data suggest that Kappa-agonists do not protect against methamphetamine-induced toxicity to monoamines in rats, and may potentiate mortality when co-administered with methamphetamine.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed2002

Long-term post-synaptic consequences of methamphetamine on preprotachykinin mRNA expression.

Exposure to repeated high doses of methamphetamine produces long-term toxicity to central monoamine systems and alters striatonigral pathway function 3 weeks after exposure. To determine whether these changes in the striatonigral pathway persist for longer we examined neuropeptide mRNA expression in the striatum and cytochrome oxidase activity in the output nuclei of the basal ganglia after treatment with multiple high doses of methamphetamine. Rats exposed to multiple high doses of methamphetamine had significant depletion in dopamine and serotonin content, decreases in tyrosine hydroxylase immunoreactivity, and decreases in preprotachykinin mRNA expression, 6 and 12 weeks after methamphetamine treatment. Preprotachykinin mRNA expression was significantly reduced by approximately 20% in the middle striatum and approximately 32% in the caudal striatum, 6 weeks after treatment. Twelve weeks after treatment, preprotachykinin mRNA expression continued to be significantly reduced by approximately 20% in the middle striatum and approximately 14% in the caudal striatum. Cytochrome oxidase histochemical staining in the entopeduncular nucleus and substantia nigra pars reticulata was not significantly different from that in controls at either time point. These data suggest that neurotoxic regimens of methamphetamine induce changes in striatonigral neurons that persist for up to 3 months, although there is some recovery.

Animals↗