THE MOLECULAR AND BEHAVIORAL CONSEQUENCES OF ABNORMAL NORADRENERGIC NEUROTRANSMISSION IN THE HYPERACTIVE SNAP-25 DEFICIENT MOUSE MUTANT COLOBOMA
Open Access
- Author:
- Jones, Michelle Denise
- Graduate Program:
- Neuroscience
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- July 02, 2001
- Committee Members:
- Melvin Lee Billingsley, Committee Member
Andrew Ewing, Committee Member
Robert J Milner, Committee Chair/Co-Chair
Ellen Hess, Committee Chair/Co-Chair - Keywords:
- catecholamines
Tourette's syndrome
ADHD
SNAP-25 - Abstract:
- ABSTRACT Attention Deficit Hyperactivity Disorder (ADHD) is the most common pediatric neuropsychiatric disorder. The disorder has a genetic component and affects nearly 2 million American children. An imbalance between dopaminergic and noradrenergic systems has been implicated in ADHD and Tourette's syndrome, a common comorbid condition. Indeed, many drugs used to treat hyperactivity act on both dopaminergic and noradrenergic systems. However, the mechanism(s) through which these two transmitters interact is not well understood. The subsequent doctoral work examines the role of norepinephrine in the regulation of locomotor hyperactivity. The research is on the forefront of expanding our knowledge of catecholaminergic regulation of motor activity, which may lead to development of better pharmacological treatments for hyperactivity disorders. We have identified the mouse mutant coloboma as an animal model for examining the neurological basis of hyperactivity with a well-defined genetic abnormality; these mice carry a mutation that includes the Snap gene. The mouse mutant exhibits spontaneous locomotor hyperactivity that is on average 3 times greater than control mice; this hyperactivity is a direct result of a reduction in SNAP-25 protein and occurs naturally without physical or chemical induction. Administration of amphetamine produces a paradoxical reduction in locomotor activity in coloboma mice that is similar to the ameliorative response seen in ADHD children taking psychostimulants. The reduced SNAP-25 expression contributes to a region and neurotransmitter-specific deficiency in coloboma mice. The regional concentrations of dopamine, norepinephrine, serotonin and their metabolites were determined using HPLC analysis. In striatum and nucleus accumbens it was revealed that dopamine was slightly, but not significantly reduced in coloboma, while HVA and DOPAC (dopamine metabolites) concentrations in coloboma mice were significantly decreased. This suggests a reduction in dopamine turnover, consistent with a reduction in dopamine release observed by others. By contrast, the norepinephrine concentration was significantly increased in coloboma mice in both striatum and nucleus accumbens but unchanged in other brain regions. Also, norepinephrine release was increased as assayed by superfusion in striatum and nucleus accumbens slices. Further molecular characterization of the increased norepinephrine in this mutant mouse has shown an upregulation in the tyrosine hydroxylase and a2A adrenergic receptor mRNA expression in the locus coeruelus. The norepinephrine reuptake transporter receptor density and maximal velocity were unchanged. Thus, the elevated release and concentration of norepinephrine are most likely the products of increased synthesis. The functional role of norepinephrine in the expression of locomotor hyperactivity in adult coloboma mice was examined by specifically depleting noradrenergic innervation using the neurotoxin DSP-4. Depletion of norepinephrine by DSP-4 either through systemic or intracerebroventricular administration significantly reduced the aberrant locomotor activity of the coloboma mouse by 50%, suggesting that norepinephrine plays an important role in the expression of hyperactivity. Experiments examining the interaction between norepinephrine and dopamine traditionally use gross pharmacological or surgical manipulations to alter catecholamine levels, whereas the catecholaminergic imbalance in coloboma mice occurs endogenously. Thus, the coloboma mutant mouse is an unprecedented model for understanding the biochemical and behavioral relationship of norepinephrine and dopamine, which may shed a more realistic light on human dysfunction. Ultimately, by examining the role of norepinephrine in locomotor hyperactivity in a murine model we hope to identify novel approaches to the treatment of hyperactivity disorders in humans.