The prevalence, age of onset, and clinical symptoms for virtually all neuropsychiatric disorders differ between men and women. Among the disorders with pronounced sex bias are Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD), where the ratio of males/females diagnosed is approximately 4 to 1. Whether this skewed ratio arises from roles played in brain development by sex-specific DNA sequences or hormones or reflects the way that biological mechanisms and environmental influences elicit behavioral patterns differently in males and females, remains an area of open investigation.
Regardless of origin, side effects of compazine iv altered behavior in these disorders signals a change in the function of key brain circuits wired up during development, refined throughout life, and coordinated through the actions of brain chemicals called neurotransmitters. One vital neurotransmitter that plays a key role in the behaviors altered by both ADHD and ASD is dopamine, whose powerful actions support motor initiation and coordination, motivation, reward and social behavior, as well as attention and higher cognitive function. Although dopamine-sensitive brain circuits engaged in these processes have been under scrutiny for decades, and in the case of ADHD, are the target of medications such as Adderall® and Ritalin®, the intrinsic sex-dependent differences in these pathways that could guide more precise diagnoses and treatments have only recently begun to be elucidated.
To better understand how dopamine levels at brain synapses are managed, neuroscientists from Florida Atlantic University, along with collaborators at the University of North Dakota School of Medicine and Health Sciences, have now added a significant piece to this puzzle by establishing key differences in the molecular dopamine disposal machinery in the brains of male and female mice.
The new research published in the journal Molecular Psychiatry and led by Randy Blakely, Ph.D., professor of biomedical science in FAU’s Schmidt College of Medicine and executive director of the FAU Stiles-Nicholson Brain Institute, provides new insight into how sex determines the mechanisms by which distinct synapses monitor and regulate dopamine signaling. Moreover, the impact the sex differences described is particularly pronounced when the mice express a human genetic variant found in boys with either ADHD or ASD.
“Often, due to assumptions that sex hormone variation will cloud data interpretations, and that use of one sex will cut animal use and costs in half without a loss of key insights, many researchers using animal models to study brain disorders work chiefly with males, even more reasonable when modeling disorders that exhibit male bias,” said Blakely.
In a prior study, looking for genetic changes in dopamine regulatory genes in children with ADHD, Blakely and his team identified a gene variant that alters the function of the dopamine transporter (DAT) in a peculiar way. Normally DAT acts to remove dopamine from synapses, acting like a nanoscale dopamine vacuum cleaner. When the DAT variant was expressed in cells, however, it “ran backward,” spitting out dopamine rather than efficiently removing it. After engineering the variant into the genome of mice, Blakely’s team found changes in behavior and drug responses predicted by this anomalous DAT behavior, with an emphasis on traits linked to pathways related to locomotor activation, habitual behavior and impulsivity. Notably, these studies were performed exclusively with male mutant mice.
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