Modulatory effects of testosterone on
Male; Animals; Mice; Species Specificity; Reference Values; Dopamine/*metabolism; Corpus Striatum/drug effects/*metabolism; Orchiectomy; Drug Implants; Testosterone/administration & dosage/*pharmacology; Neurotoxins/antagonists & inhibitors/*toxicity; *MPTP Poisoning; Levodopa/pharmacology; Inbred Strains; Inbred C57BL; 3; 1-Methyl-4-phenyl-1; 2; Parkinson Disease; 6-tetrahydropyridine/antagonists & inhibitors; Secondary/chemically induced/*physiopathology
In this experiment, we examined the modulatory effects of testosterone on the parkinsonism-inducing drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in two strains of mice. Orchidectomized male CD-1 and C57/B1 mice were implanted with either empty Silastic capsules or capsules containing testosterone and subsequently treated with MPTP. A small area of the corpus striatum was removed for determination of dopamine (DA) content, whereas the remainder was superfused and used to measure L-DOPA (5 microM)-evoked DA release. In animals treated with MPTP, L-DOPA-evoked DA release was reduced significantly in CD-1 mice, but not in C57/B1 mice, treated with testosterone. No differences in L-DOPA-stimulated DA release between MPTP-versus vehicle-treated mice was observed in either the CD-1 or C57/B1 mice receiving empty Silastic capsules. Corpus striatum DA contents were more severely depleted in the MPTP-sensitive C57/B1 versus the CD-1 mouse strain irrespective of hormone treatment. These results confirm previous results demonstrating differences in these two mouse strains in response to the neurotoxic effects of MPTP upon corpus striatum DA content. More interestingly, they show an important differential modulatory effect of testosterone upon
Dluzen D; Jain R; Liu B
Journal of neurochemistry
1994
1994-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
The effects of intranasal infusion of
Male; Animals; Mice; Corpus Striatum/drug effects/*metabolism; Dopamine/metabolism; Olfactory Bulb/drug effects/*metabolism; Norepinephrine/metabolism; Injections; Catecholamines/*metabolism; Dopamine Agents/administration & dosage/*pharmacology; Inbred C57BL; 3; Intraperitoneal; 1-Methyl-4-phenyl-1; 2; Administration; Intranasal; 6-tetrahydropyridine/administration & dosage/*pharmacology
Male C57/B1 mice received bilateral intranasal infusions of saline, MPTP or an intraperitoneal injection of MPTP. Infusions were performed using a peristaltic pump at a setting of 100 microliters/min. The MPTP, diluted in saline at concentrations of 2 mg/ml, was infused over 15 (0.1 mg) or 30 (0.2 mg) s, while the saline (control) infusions were of 30 s duration. In a separate group of mice, MPTP was injected via the intraperitoneal route at a dose equivalent to that of the 30-s intranasal concentration (0.2 mg). At 7 days post-treatment, catecholamine concentrations were determined from the olfactory bulbs and corpus striatum. Concentrations of norepinephrine within both the olfactory bulbs and corpus striatum of mice receiving the intranasal infusion of MPTP were significantly lower than those of the intranasal saline and intraperitoneal
Dluzen D E; Kefalas G
Brain research
1996
1996-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Tamoxifen diminishes methamphetamine-induced striatal dopamine depletion in intact female and male mice.
Animals; Catecholamines/metabolism; Corpus Striatum/drug effects/*metabolism; Dopamine Uptake Inhibitors/*pharmacology; Dopamine/*metabolism; Estrogen Antagonists/*pharmacology; Female; Humans; Hypothalamus/metabolism; Inbred Strains; Male; Methamphetamine/*pharmacology; Mice; Neurotoxins/*pharmacology; Olfactory Bulb/metabolism; Organ Size/drug effects; Pituitary Gland/anatomy & histology; Tamoxifen/*pharmacology
It has been demonstrated that the nigrostriatal dopaminergic system of male mice is more sensitive to the neurotoxic effects of methamphetamine (MA). The basis for this difference can be related to oestrogen, which has the capacity to function as a neuroprotectant against neurotoxins that target the nigrostriatal dopaminergic system. We examined the effects of the anti-oestrogen, tamoxifen (TMX), upon MA-induced neurotoxicity of the nigrostriatal dopaminergic system in intact female and male CD-1 mice. Striatal dopamine concentrations of TMX-treated female and male mice receiving MA were significantly greater than mice receiving MA alone. In female, but not male, mice, oestrogen treatment also resulted in greater striatal dopamine concentrations compared to mice receiving MA alone. Interestingly, male mice treated with oestrogen were particularly sensitive to the acute toxic effects of MA and displayed no evidence of nigrostriatal neuroprotection. The dihydroxyphenylacetic acid/dopamine ratios following MA for female and male mice treated with TMX or females treated with oestrogen were significantly reduced compared to MA-treated mice and oestrogen + MA-treated male mice. No differences among the treatment groups were obtained for dopamine in the hypothalamus or olfactory bulb. These data demonstrate that TMX treatment of intact female and male mice diminishes striatal dopamine depletions to the nigrostriatal dopaminergic neurotoxin, MA. Oestrogen also displayed this capacity when administered to female, but accentuated acute toxicity in male mice. These effects are relatively specific for the nigrostriatal dopaminergic system. Such data suggest that TMX can function as a nigrostriatal dopaminergic neuroprotectant against MA-induced neurotoxicity in intact female and male mice.
Dluzen D E; McDermott J L; Anderson L I
Journal of neuroendocrinology
2001
2001-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1046/j.1365-2826.2001.00675.x" target="_blank" rel="noreferrer noopener">10.1046/j.1365-2826.2001.00675.x</a>
Estrogen differentially modulates nicotine-evoked dopamine release from the striatum of male and female rats.
Animals; Corpus Striatum/drug effects/*metabolism; Dopamine/*metabolism; Estradiol/*pharmacology; Female; In Vitro Techniques; Kinetics; Male; Nicotine/*pharmacology; Orchiectomy; Ovariectomy; Rats; Sex Characteristics; Sprague-Dawley
In the present experiment we examined the effects of an in vitro infusion of nicotine (10 microM) upon dopamine release from superfused striatum of castrated male and female rats treated or not treated with estrogen. Estrogen exerted bidirectional effects on nicotine-evoked dopamine release as a function of the sex of the animal. Nicotine-evoked dopamine release was increased in estrogen treated females and decreased in estrogen treated males. Peak nicotine-evoked dopamine output from estrogen treated females was significantly greater than that of estrogen treated males. These results may be related to the gender differences in response to nicotine and smoking behavior.
Dluzen D E; Anderson L I
Neuroscience letters
1997
1997-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0304-3940(97)00487-4" target="_blank" rel="noreferrer noopener">10.1016/s0304-3940(97)00487-4</a>
The effect of testosterone upon methamphetamine neurotoxicity of the nigrostriatal dopaminergic system.
Animals; Corpus Striatum/drug effects/*metabolism; Dopamine/*metabolism; Drug Implants; Female; Male; Methamphetamine/*toxicity; Mice; Neuroprotective Agents/pharmacology; Neurotoxins/*toxicity; Orchiectomy; Ovariectomy; Potassium/pharmacology; Substantia Nigra/drug effects/*metabolism; Testosterone/administration & dosage/*pharmacology
The gonadal steroid hormone estrogen (E) can function as a neuroprotectant of nigrostriatal dopaminergic (NSDA) neurotoxicity, however, there exists very limited information on the role of testosterone (T) in this capacity. In the present report, the effects of T on methamphetamine (MA) induced neurotoxicity of the NSDA system were examined in gonadectomized female and male CD-1 mice. In Experiment 1, striatal dopamine (DA) concentrations and output from T-treated ovariectomized mice were not significantly different from that of non-T-treated mice following MA. These results suggest that T is not functioning as a modulator of MA-induced NSDA neurotoxicity in ovariectomized CD-1 mice. In Experiment 2, there were no significant differences in DA concentrations or output among
Gao X; Dluzen D E
Brain research
2001
2001-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/s0006-8993(00)03221-2" target="_blank" rel="noreferrer noopener">10.1016/s0006-8993(00)03221-2</a>
Differences in reserpine-induced striatal dopamine output and content between female and male mice: implications for sex differences in vesicular monoamine transporter 2 function.
*Sex Characteristics; Adrenergic Uptake Inhibitors/*pharmacology; Animals; Chromatography; Corpus Striatum/drug effects/*metabolism; Dopamine/*metabolism; Female; High Pressure Liquid; Male; Mice; Orchiectomy; Ovariectomy; Reserpine/*pharmacology; Vesicular Monoamine Transport Proteins/*metabolism
In this report a series of six in vitro experiments in which reserpine-evoked dopamine output and two in vivo experiments in which the effects of reserpine injections upon dopamine content from striatal tissue of female and male mice were performed as a means to assess possible sex differences in vesicular monoamine transporter 2 (VMAT2) function. Significantly greater amounts of dopamine were obtained from striatal tissue of female mice in response to either a brief (experiment 1) or continuous (experiment 2) infusion of reserpine. Similarly, reserpine-evoked dopamine output from striatal tissue of gonadectomized females was significantly greater that that of gonadectomized males (experiment 3). When reserpine-evoked dopamine responses were compared directly between intact versus gonadectomized females (experiment 4) or males (experiment 5) no statistically significant differences were obtained. Finally, comparisons of gonadectomized females treated or not with estrogen revealed no statistically significant differences in reserpine-evoked dopamine output (experiment 6). Injections of reserpine produced significantly greater depletions of striatal dopamine content within intact female versus male mice (experiment 7). Dopamine contents of gonadectomized females treated or not with estrogen did not differ following treatment with reserpine, but were significantly greater than that of gonadectomized males (experiment 8). Taken together, these results show that female striatal tissue is more responsive to reserpine-evoked dopamine output, and this sex difference appears to be estrogen independent. Similarly, the dopamine depleting effects of reserpine are greater in intact female mice, however, gonadectomy reverses this effect in an estrogen independent manner. The data suggest that female mice may have a greater amount/activity of VMAT2 function as revealed by the increased responsiveness to the VMAT2 blocking drug, reserpine. Such differences in VMAT2 function may be related to the gender differences observed in conditions like Parkinson's disease and drug addiction.
Dluzen D E; Bhatt S; McDermott J L
Neuroscience
2008
2008-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.neuroscience.2008.04.051" target="_blank" rel="noreferrer noopener">10.1016/j.neuroscience.2008.04.051</a>
MPTP neurotoxicity is highly concordant between the sexes among BXD recombinant inbred mouse strains.
*QTL; *Recombinant inbred mice; *Sex Characteristics; *Sex differences; 1-Methyl-4-phenyl-1; 2; 3; 4-Dihydroxyphenylacetic Acid/metabolism; 6-tetrahydropyridine/pharmacology; Animal; Animals; Corpus Striatum/drug effects/*metabolism; Disease Models; Dopamine/metabolism; Female; Gene Expression Regulation/drug effects/*genetics; Glial Fibrillary Acidic Protein/*metabolism; Homovanillic Acid/metabolism; Inbred Strains; Male; Mice; MPTP Poisoning/chemically induced/*pathology; Serotonin/metabolism; Species Specificity; Tyrosine 3-Monooxygenase/metabolism
Continuing our previous work in which we showed wide-ranging strain differences in MPTP neurotoxicity in male mice among ten BXD recombinant inbred strains, we replicated our work in females from nine of the same strains. Mice received a single s.c. injection of 12.5mg/kg MPTP or saline. Forty-eight hours later the striatum was dissected for neurochemical analysis. Striatal dopamine (DA) and its metabolites, DOPAC and HVA, striatal serotonin (5-HT) and its metabolite, 5-HIAA, were analyzed using HPLC. Tyrosine hydroxylase (TH) and glial fibrillary acidic protein (GFAP), an astrocytic protein that increases during the astroglial response to neural injury, were measured using ELISA. There were wide genetic variations in the DA, DOPAC, HVA, TH and GFAP responses to MPTP. We also performed principal component analysis (PCA) on the difference values, saline minus MPTP, for DA, DOPAC, HVA and TH and mapped the dominant principal component to a suggestive QTL on chromosome 1 at the same location that we observed previously for males. Moreover, there were significant correlations between the sexes for the effect of MPTP on DA, HVA, and TH. Our findings suggest that the systems genetic approach as utilized here can help researchers understand the role of sex in individual differences. The same approach can pave the way to understand and pinpoint the genetic bases for individual differences in pathology attributable to toxicants. Such systems genetics approach has broad implications for elucidating gene-environment contributions to neurodegenerative diseases.
Alam Gelareh; Miller Diane B; O'Callaghan James P; Lu Lu; Williams Robert W; Jones Byron C
Neurotoxicology
2016
2016-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.neuro.2016.04.008" target="_blank" rel="noreferrer noopener">10.1016/j.neuro.2016.04.008</a>
Sex differences in striatal dopaminergic function within heterozygous mutant dopamine transporter knock-out mice.
*Sex Characteristics; 3; 4-Dihydroxyphenylacetic Acid/metabolism; Animals; Brain/drug effects/*metabolism; Corpus Striatum/drug effects/*metabolism; Dopamine Plasma Membrane Transport Proteins/*genetics; Dopamine Uptake Inhibitors/pharmacology; Dopamine/*metabolism; Down-Regulation/drug effects/genetics; Female; Gene Expression Regulation/drug effects/genetics; Heterozygote; Knockout; Male; Methamphetamine/pharmacology; Mice; Mutation/*genetics; Neural Pathways/drug effects/metabolism; Potassium Chloride/metabolism/pharmacology; Substantia Nigra/drug effects/metabolism; Synaptic Transmission/drug effects/genetics; Up-Regulation/drug effects/genetics
The issue of whether a deletion of the dopamine transporter (DAT) allele (+/- DAT) would differentially alter striatal dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) concentrations and DA release upon potassium and methamphetamine (MA) stimulation between male and female mice was examined. Striatal DA and DOPAC concentrations of female +/- DAT mice were significantly decreased as compared with wild type (+/+) controls and male +/- DAT mice. No such changes were obtained from the olfactory tubercle suggesting that these effects might be specific for the striatum. Potassium-stimulated DA was increased in male and female +/- DAT mice and maximally stimulated DA was obtained from +/- DAT females, although these mice showed the lowest DA concentrations. MA-evoked DA was increased in male and female +/- mice. While MA-evoked DA was significantly increased in +/+ males versus +/+ females, the +/- females showed the highest DA responses, thereby showing a reversal in the results seen in wild-type conditions. These findings indicate: (1) that a deficiency in the DAT interacts with the sex of the subject, (2)+/- DAT females show more extreme changes in dopaminergic responses, and (3) the importance for considering such variables such as sex when examining differences among knock-out conditions.
Ji Jing; Dluzen Dean E
Journal of neural transmission (Vienna, Austria : 1996)
2008
2008-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1007/s00702-007-0017-0" target="_blank" rel="noreferrer noopener">10.1007/s00702-007-0017-0</a>
L-DOPA modulation of corpus striatal dopamine and dihydroxyphenylacetic acid output from intact and 6-OHDA lesioned rats.
*Sympathectomy; 3; 4-Dihydroxyphenylacetic Acid/*metabolism; Animals; Antiparkinson Agents/*pharmacology; Chemical; Corpus Striatum/drug effects/*metabolism; Dopamine/*metabolism; Levodopa/*pharmacology; Male; Oxidopamine; Rats; Sprague-Dawley; Substantia Nigra/drug effects/metabolism
In the present report we examined the differences in in vitro dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) efflux from the corpus striatum (CS) of intact versus 6-hydroxydopamine (6-OHDA) lesioned (in substantia nigra) male rats in response to different doses of two pulse infusions of L-dihydroxyphenylalanine (L-DOPA). In the first experiment, we tested the effects of two 20-min infusions of 5 uM L-DOPA. In the second experiment we repeated this protocol using 50 uM
Xu K; Dluzen D E
Journal of neural transmission (Vienna, Austria : 1996)
1996
1905-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1007/BF01271190" target="_blank" rel="noreferrer noopener">10.1007/BF01271190</a>
Testosterone modulation of striatal dopamine output in orchidectomized mice.
Adrenergic Uptake Inhibitors/pharmacology; Animals; Corpus Striatum/drug effects/*metabolism; Dopamine/*metabolism/pharmacology; Male; Mice; Neural Pathways/drug effects/*metabolism; Orchiectomy; Potassium Chloride/pharmacology; Presynaptic Terminals/drug effects/metabolism; Reserpine/pharmacology; Sex Characteristics; Substantia Nigra/drug effects/*metabolism; Synaptic Transmission/drug effects/physiology; Synaptic Vesicles/drug effects/metabolism; Testosterone/*metabolism; Vesicular Monoamine Transport Proteins/drug effects/metabolism
Three experiments are presented in which dopamine (DA) responses from superfused striatal tissue of orchidectomized (ORCH) mice treated or not with testosterone (T) are compared. In experiment 1, potassium-stimulated DA output was significantly greater in ORCH vs. ORCH+T mice. This profile was reversed when reserpine was infused in experiment 2, with DA output being significantly greater in ORCH+T vs. ORCH mice. In experiment 3, the amount of DA recovered following infusion of DA indicated no statistically significant differences in DA recoveries between ORCH and ORCH+T mice as tested in this paradigm. The findings that both potassium- and reserpine-induced DA responses are altered significantly by T suggests that one potential site of T action might involve the storage/uptake of DA within the vesicles of these neurons. Such results have important implications with regard to understanding the sex differences that are present in nigrostriatal dopaminergic function within health and diseased states.
Shemisa Kamal; Kunnathur Vidhya; Liu Bin; Salvaterra Ty J; Dluzen Dean E
Synapse (New York, N.Y.)
2006
2006-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/syn.20309" target="_blank" rel="noreferrer noopener">10.1002/syn.20309</a>