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>
Genetic alteration in the dopamine transporter differentially affects male and female nigrostriatal transporter systems.
Animals; Corpus Striatum/*metabolism; Dopamine Plasma Membrane Transport Proteins/*genetics; Female; Male; Messenger/biosynthesis; Mice; Mutant Strains; Protein Binding; Reserpine/pharmacology; RNA; Sex Characteristics; Substantia Nigra/*metabolism; Vesicular Monoamine Transport Proteins/antagonists & inhibitors/biosynthesis/*physiology
Female mice with a heterozygous mutation of their dopamine transporter (+/- DAT) showed relatively robust reductions in striatal DAT specific binding (38-50%), while +/- DAT males showed modest reductions (24-32%). Significant decreases in substantia nigra DAT specific binding (42%) and mRNA (24%) were obtained in +/- DAT females, but not +/- DAT males (19% and 5%, respectively). The effects of this DAT perturbation upon vesicular monoamine transporter-2 (VMAT-2) function revealed significantly greater reserpine-evoked DA output from +/+ and +/- DAT female as compared to male mice and the DA output profile differed markedly between +/+ and +/- DAT females, but not males. No changes in VMAT-2 protein or mRNA levels were present among these conditions. On the basis of these data, we propose: (1) a genetic mutation of the DAT does not exert equivalent effects upon the DAT in female and male mice, with females being more affected; (2) an alteration in the DAT may also affect VMAT-2 function; (3) this interaction between DAT and VMAT-2 function is more prevalent in female mice; and (4) the +/- DAT mutation affects VMAT-2 function through an indirect mechanism, that does not involve an alteration in VMAT-2 protein or mRNA. Such DAT/VMAT-2 interactions can be of significance to the gender differences observed in drug addiction and Parkinson's disease.
Ji Jing; Bourque Melanie; Di Paolo Therese; Dluzen Dean E
Biochemical pharmacology
2009
2009-12
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.bcp.2009.07.004" target="_blank" rel="noreferrer noopener">10.1016/j.bcp.2009.07.004</a>
Age-related changes in nigrostriatal dopaminergic function in heterozygous mutant dopamine transporter knock-out mice.
3; 4-Dihydroxyphenylacetic Acid/*metabolism; Aging/*physiology; Animals; Corpus Striatum/*metabolism; Dopamine Plasma Membrane Transport Proteins/*genetics; Dopamine/*metabolism; Heterozygote; Inbred C57BL; Knockout; Male; Mice; Motor Activity; Mutation; Substantia Nigra/*metabolism
In this report we compared three different parameters of nigrostriatal dopaminergic (NSDA) function - locomotor activity, striatal dopamine (DA) levels and 3,4-dihydroxyphenylacetic acid (DOPAC)/DA ratios between heterozygous mutant dopamine transporter mice (+/- DAT) and their wild type controls (+/+ DAT) at three different age range periods: 4-10, 11-17 and 18-24 months of age. Locomotor activity of the +/- DAT mice failed to differ over the three age periods sampled. In +/+ DAT mice a significant decrease in locomotor activity was obtained at the
Dluzen Dean E; Ji Jing; McDermott Janet L
Neuroscience letters
2010
2010-05
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.neulet.2010.04.004" target="_blank" rel="noreferrer noopener">10.1016/j.neulet.2010.04.004</a>