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Dean E Dluzen

Publications and source records attributed to Dean E Dluzen.

27 records · Page 2Linked to original sources
PubMed2004

Methamphetamine-induced loss of striatal dopamine innervation in BDNF heterozygote mice does not further reduce D3 receptor concentrations.

Depletion of dopamine (DA) reduces D(3) receptor number, but D(3) receptor expression is also regulated by brain-derived neurotrophic factor (BDNF). We took advantage of transgenic heterozygous BDNF mutant mice (+/-) to determine if reduced BDNF and loss of DA fibers produced by methamphetamine were additive in their impact on D(3) receptor number. We assessed selective markers of the dopaminergic system including caudate-putamen DA concentrations and quantitative autoradiographic measurement of tyrosine hydroxylase (TH) levels, DA transporter (DAT), and DA D(3) receptor binding between vehicle and methamphetamine-treated BDNF +/- and their wildtype (WT) littermate control mice. Caudate-putamen DA concentrations, TH and DAT levels were significantly reduced following methamphetamine treatment in both WT and BDNF +/- mice. The extent of methamphetamine-induced reduction in TH and DAT was greater for the WT than BDNF +/- mice and DAT levels were also decreased to a greater extent in nucleus accumbens of WT as compared to BDNF +/- mice. Lower D(3) receptor existed in caudate-putamen and nucleus accumbens in BDNF +/- mice and these differences were not affected by methamphetamine treatment. Taken together, these results not only substantiate the importance of BDNF in controlling D(3) receptor expression, but also indicate that a methamphetamine-induced depletion of DA fibers fails to produce an additive effect with lowered BDNF for control of D(3) receptor expression. In addition, the reduction of D(3) receptor expression is associated with a decreased neurotoxic response to methamphetamine in BDNF +/- mice.

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PubMed2004

Developmental and genetic influences upon gender differences in methamphetamine-induced nigrostriatal dopaminergic neurotoxicity.

The gonadal steroid hormone estrogen (E) may play an important role in sex differences in methamphetamine (MA)-induced neurotoxicity of the nigrostriatal dopaminergic (NSDA) system because E can serve as a neuroprotectant in female, but not male, mice. Gonadal steroid hormones also exert important organizational/developmental effects upon the brain at critical developmental periods. In Part 1 we assessed whether organizational (neonatal) or developmental (prepubertal) effects of gonadal steroids would alter gender/E-dependent neuroprotection of MA-induced NSDA neurotoxicity. Attempts to feminize male mice by gonadectomy at either the neonatal or prepubertal period failed to enable E to function as a neuroprotectant within the adult male mouse. Attempts to masculinize the female by testosterone administration at the neonatal period did not abolish the capacity for E to function as a neuroprotectant. However, prepubertal gonadectomy of female mice did disrupt E's capacity to serve as a neuroprotectant. These results suggest that genetic sex may prove the primary determinant for the sex differences observed in response to MA-induced NSDA neurotoxicity. In Part 2 we examined whether gender differences in response to MA-induced NSDA neurotoxicity would interact with a specific genetic alteration in a neurotrophic factor, brain-derived neurotrophic factor (BDNF). Female and male mice that were either deficient (+/- BDNF) or overexpressing (DBH:BDNF+) BDNF were treated with MA. Sex differences in MA-induced NSDA neurotoxicity remained present in +/- BDNF mice and were less severe as compared with their wild-type controls. A similar result was obtained in mice that overexpress BDNF, with female and mutant mice showing less NSDA neurotoxicity. In both BDNF-deficient mice and mice that overexpress BDNF, the relative degree of MA-induced NSDA neurotoxicity was lower in males. Taken together, these results suggest that a selective alteration in BDNF expression offers some neuroprotective potential against MA-induced NSDA neurotoxicity, and the relative degree of this neuroprotection may interact with the gender of the subject.

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PubMed2003

Gender differences in methamphetamine-induced mRNA associated with neurodegeneration in the mouse nigrostriatal dopaminergic system.

In this report female and male CD-1 mice were treated with a neurotoxic regimen of methamphetamine (MA) to compare gender differences in striatal dopamine depletion and concordant changes in mRNA markers of the transforming growth factor-beta injury response associated with neurodegeneration. Striatal dopamine concentrations of MA-treated female mice were less depleted and significantly greater than that of identically treated males. Associated with this gender difference in striatal dopamine depletion were significantly decreased mRNA levels of plasminogen activator inhibitor-1 and a trend for increased (p = 0.06) mRNA levels of glial fibrillary acidic protein within females. No statistically significant differences between MA-treated female and male mice were obtained in mRNA levels for transforming growth factor-beta, transforming growth factor-beta type 2 receptor, activin-like kinase-5 or fibronectin. These data demonstrate the presence of changes in two specific molecular markers of the transforming growth factor-beta injury response which are in accordance with gender differences in MA-induced striatal dopamine depletion. The results suggest that the neuroprotective advantage displayed by females may in part be related to reductions in the transforming growth factor-beta injury response as indicated by decreased mRNA plasminogen activator inhibitor-1 and an increased response of reactive astrocytes which promote neuronal survival as indicated by augmented glial fibrillary acidic protein mRNA levels.

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PubMed2002

Castration increases nisoxetine-evoked norepinephrine levels in vivo within the olfactory bulb of male rats.

In the present experiment we compared differences in extracellular norepinephrine levels in vivo within the olfactory bulb of intact and castrated male rats following infusion of the norepinephrine transport inhibitors, nisoxetine and tomoxetine. With this approach it was possible to assess whether dynamic changes in in vivo norepinephrine transporter function occur as a function of the gonadal state of the animal. Norepinephrine levels following infusion of nisoxetine were significantly increased in castrated compared with intact male rats. While a similar trend was present in response to tomoxetine infusion, these differences failed to achieve a statistically significant difference. These results demonstrate that castration of male rats alters norepinephrine transporter function within the olfactory bulbs. The increased extracellular levels of norepinephrine in response to agents which inhibit transporter function suggest that castration reduces transporter activity. Such effects have important implications not only with regard to processes involving the norepinephrine system in the olfactory bulb but also to the generalized sites and mechanisms by which gonadal steroid hormones modulate central nervous system functions.

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PubMed2002

Striatal dopamine output is compromised within +/- BDNF mice.

We reported previously that mice lacking one brain-derived neurotrophic factor (BDNF) allele demonstrate elevated striatal dopamine (DA) concentrations but impaired behavioral responses involving the nigrostriatal dopaminergic (NSDA) system. To test the hypothesis that these elevated striatal DA concentrations are associated with perturbed NSDA functioning, we compared striatal DA output between heterozygous mutant (+/-) and wild-type littermate control (+/+) BDNF mice under conditions of an intact NSDA system, as well as following methamphetamine (MA)-induced neurotoxicity. Basal DA output from superfused CS tissue fragments did not differ between +/+ and +/- BDNF mice. Potassium (K+) stimulated DA outputs from intact striatal fragments of +/+ mice were significantly greater than that of +/- BDNF mice. Following MA treatment, K+ stimulated DA output of +/+ mice was statistically equivalent to +/- BDNF mice. Striatal DA concentrations of +/- BDNF mice were elevated, albeit not significantly, in both intact and MA-treated mice relative to +/+ mice. Following MA treatment, striatal DA concentrations were significantly decreased for both genotypes; however, the degree of DA depletion was significantly greater in +/+ mice. Analyzed collectively, these data show the differential effects exerted by a BDNF mutation upon striatal DA concentrations and output. Notably, lower striatal DA concentrations of +/+ vs. +/- BDNF mice can be contrasted with the significantly greater K+ stimulated DA output from the former. This difference was abolished following MA treatment. These results suggest that processes involved with the dynamics of DA release within the NSDA system may be compromised in +/- BDNF mutant mice.

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PubMed2002

Modulation of olfactory bulb tyrosine hydroxylase and catecholamine transporter mRNA by estrogen.

Since estrogen exerts wide ranging effects within the central nervous system, it is important to investigate the sites and actions of this gonadal steroid hormone at extra-hypothalamic locations. In the present report, the effects of estrogen upon catecholaminergic function within the olfactory bulb were examined. To assess the role of estrogen at this site, ovariectomized mice received either no further hormonal treatment or were treated with estrogen, the anti-estrogen, tamoxifen, or a combination of estrogen and tamoxifen as administered in a 21-day release pellet. At 14 days post-hormonal treatment, the olfactory bulbs were assayed for mRNA levels of tyrosine hydroxylase, dopamine transporter and norepinephrine transporter using competitive-PCR. Tyrosine hydroxylase mRNA levels in either estrogen or estrogen+tamoxifen treated females were significantly decreased compared with non-hormonally treated controls. In addition, tyrosine hydroxylase mRNA levels of tamoxifen-treated mice were significantly greater than that of estrogen-treated mice. Dopamine transporter mRNA levels of tamoxifen-treated females were significantly greater than that of non-hormonally treated controls and estrogen treated mice. The combination of estrogen+tamoxifen significantly increased dopamine transporter mRNA levels compared to that of estrogen treated mice. No overall statistically significant differences in norepinephrine transporter mRNA levels were obtained among the four treatment groups. The data demonstrate that estrogen can exert significant modulatory effects upon olfactory bulb catecholaminergic function. Therefore, events which alter estrogen levels (menstrual/estrogen cycle, pregnancy/lactation, menopause, tamoxifen treatment) can modulate olfactory bulb catecholaminergic functions which may be involved with the detection and processing of olfactory stimuli.

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PubMed2002

Estrogen, anti-estrogen, and gender: differences in methamphetamine neurotoxicity.

In Part 1 of this report, we review data on the effects of estrogen (E), the anti-E tamoxifen (TMX), and testosterone (T) on methamphetamine (METH)-induced neurotoxicity in female and male CD-1 mice. Treatment of gonadectomized females with a physiological regimen of E significantly diminished the amount of striatal dopamine (DA) depletion to METH compared with non-E-treated mice. If these E-treated mice received coadministered TMX, the neuroprotective effects of E were abolished. However, TMX administration to either intact female or male mice appeared to exhibit a neuroprotective effect. Whereas E administration one week before METH treatment serves as a neuroprotectant, reversing the treatment order (METH-->one week-->E) failed to indicate any neurorestorative effects for E. This striatal DA-preserving effect of E was gender specific, because males receiving an identical treatment of E followed by METH failed to show any evidence of neuroprotection, nor did the predominantly male gonadal steroid hormone T afford any neuroprotection in gonadectomized male or female mice. In the second part of the report, we direct our attention toward examining some of the means by which E can exert this neuroprotective effect. The findings that gonadectomized female, but not intact male, mice treated with E show a significant reduction in body temperature can contribute to the gender-specific METH neuroprotection. E also diminishes the initial amounts of DA evoked by METH, as observed when E is co-infused with METH into superfused striatal tissue fragments of gonadectomized female and male mice. By contrast, T tends to increase METH-evoked DA responses. Finally, differences in mRNA levels were obtained between male and female mice treated with METH. Intact female mice tend to show greater levels of striatal glial fibrillary acidic protein and decreased levels of plasminogen activator inhibitor-1 compared with males. Each of these factors, combined with our previous findings that E can inhibit DA transporter function, represent significant events contributing to E/gender-dependent effects on METH neurotoxicity.

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PubMedDate not supplied

Methamphetamine-gonadal steroid hormonal interactions: effects upon acute toxicity and striatal dopamine concentrations.

Methamphetamine (MA)-related deaths and nigrostriatal dopaminergic (NSDA) neurotoxicity are greater in males. The exact basis for this gender difference is not known, but data, which show that estrogen (E) can function as a protectant of both the cardiovascular and NSDA systems, suggest an important role for gonadal steroids in modulating toxicity to this psychostimulant. In the present report, we examined the effects of treatment with the gonadal steroid hormones E and testosterone (T) upon MA-induced toxicity within intact and castrated female and male CD-1 mice. Treatment of intact males with E produced a severe acute toxicity to MA, with only 41% (7/17) males surviving at 24-h post-MA. This incidence of mortality was significantly different from that of nonhormonally treated mice receiving an identical regimen of MA [94% survival (16/17)]. None of the other treatment groups showed mortality rates, which differed significantly from the nonhormonally treated mice. Striatal dopamine (DA) concentrations of E-treated female mice (intact or castrated) were significantly greater than that of the nonhormonally treated mice, which failed to differ statistically among each other. In an attempt to understand some of the bases for the mortality rates in E-treated intact males, body temperatures, heart rates and heart catecholamine concentrations were measured from an additional group of intact male mice treated or not treated with E. Heart rates of E-treated intact males were significantly decreased compared with non-E-treated males. No statistically significant differences were obtained for body temperatures or heart catecholamine concentrations. These data demonstrate that MA induces an exacting, acute toxicity, which is specific for E-treated intact male mice and is associated with a reduction in heart rate. In addition, E can function as a neuroprotectant of NSDA system within female, but not male, mice. These data suggest that acute MA toxicity observed with E in intact male mice may result from a change in cardiac function. Accordingly, gonadal steroid hormones can function as critical modulators of both central and peripheral toxicological effects of MA.

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