Browsing by Subject "dopamine"
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Item Dopamine Signaling in Substantia Nigra and Its Impact on Locomotor Function-Not a New Concept, but Neglected Reality(MDPI, 2024-01-23) Salvatore, Michael F.The mechanistic influences of dopamine (DA) signaling and impact on motor function are nearly always interpreted from changes in nigrostriatal neuron terminals in striatum. This is a standard practice in studies of human Parkinson's disease (PD) and aging and related animal models of PD and aging-related parkinsonism. However, despite dozens of studies indicating an ambiguous relationship between changes in striatal DA signaling and motor phenotype, this perseverating focus on striatum continues. Although DA release in substantia nigra (SN) was first reported almost 50 years ago, assessment of nigral DA signaling changes in relation to motor function is rarely considered. Whereas DA signaling has been well-characterized in striatum at all five steps of neurotransmission (biosynthesis and turnover, storage, release, reuptake, and post-synaptic binding) in the nigrostriatal pathway, the depth of such interrogations in the SN, outside of cell counts, is sparse. However, there is sufficient evidence that these steps in DA neurotransmission in the SN are operational and regulated autonomously from striatum and are present in human PD and aging and related animal models. To complete our understanding of how nigrostriatal DA signaling affects motor function, it is past time to include interrogation of nigral DA signaling. This brief review highlights evidence that changes in nigral DA signaling at each step in DA neurotransmission are autonomous from those in striatum and changes in the SN alone can influence locomotor function. Accordingly, for full characterization of how nigrostriatal DA signaling affects locomotor activity, interrogation of DA signaling in SN is essential.Item Probing the Role of Transmembrane Segments Two and Three in the Activation State of the D2 Dopamine Receptor(2009-08-01) Cummings, David F.; Schetz, John A.This work examines the contribution of transmembrane segments two and three to the activation state of the D2 dopamine receptor by using ligand probes which are highly sensitive to substitutions at specific amino acid positions within this microdomain. Specifically, D2 receptors were modified by substitution of one to three specific amino acids with the corresponding amino acids of the D4 receptor to enhance the binding of D4 selective 1,4-disubstituted aromatic piperidines/piperazines. The ability of these ligands to elicit G protein mediated inhibition of cyclic adenosine monophosphate was then tested. Modification of all three amino acid residues was found to modify ligand function at the D2 receptor to match the function elicited at the D4 receptor. Additionally, the modification of specific ligand interactions with the D2-V2.61F receptor in the presence of sodium provides evidence for transmembrane segment repositioning in the inactive state of G protein coupled receptors.Item The Interaction of Psychostimulant Intake With Brain Aging: Effects On Behavioral Capacity, Oxidative Damage and Dopaminergic Markers(2009-05-01) Hilburn, Craig R.; Forster, Michael J.Frequent abuse of psychostimulants is known to induce changes in brain neurochemistry that are most profound in dopaminergic neurons. These changes could both impair dopamine neurotransmission and adversely affect psychomotor and cognitive functions. One hypothesized cause of these impairments is the adverse effects of psychostimulant-induced increases in oxidative stress. The current studies addressed the general hypothesis that chronic administration of cocaine and methamphetamine would create a change in neurochemistry in dopaminergic neurons and, as a consequence, increase oxidative damage. This would result in decreases in dopaminergic functions specifically in the nigrostriatal region and cause impairments in psychomotor functions. To test this hypothesis we utilized an in vivo rodent model involving continuous chronic administration of cocaine or methamphetamine. Separate groups of mice were exposed to a 30-day treatment, involving continuous infusion of saline, 40 mg/kg of cocaine, or 2 mg/kg of methamphetamine. After discontinuation of the drug treatment, separate groups of the mice were tested for cognitive and psychomotor function at 11, 14, or 16 months of age i.e., 1 week, 3 months, or 5 months after treatment. The test used in this study included spatial learning and memory (swim maze), coordinated running ability (accelerating rotorod), muscle and grip strength (wire suspension) and balance and coordination (bridge walking). Following completion of the behavioral tests brain regions were dissected. The regions we analyzed were the cortex, striatum, cerebellum, hippocampus, midbrain, and hindbrain. These regions were analyzed for carbonyl and thiobarbituric acid reactive substances concentrations to measure levels of protein and lipid oxidation, and Western blotting procedures to address dopaminergic protein expression. Overall, both chronic administration of cocaine and methamphetamine resulted in significant impairments to psychomotor functions. These impairments were evident for both groups on wire hanging tests, bridge walking, and rotating rod tests, both initially following the treatment phase and throughout the age ranges that were analyzed. In addition, the cocaine treatment administered led to profound impairments on cognitive function in the 14-month-old age groups. This impairment was most evident on the reversal phase of the spatial swim maze tests. The biochemical tests revealed that chronic cocaine and methamphetamine administration induced significant increases in protein oxidative damage in the striatum initially following the treatment phase. Psychostimulant-induced lipid oxidative damage was evident in the striatum in both the 14 and 16 month old age groups. Age related declines were evident in the midbrain, cortex and striatum. Overall neither treatment had any effect on the expression of the dopaminergic proteins that were analyzed. The results from these studies warrant the conclusion that chronic cocaine and methamphetamine administration causes an increase in intracellular oxidative damage in the nigrostriatal neurons which decrease dopamine-mediated psychomotor functions. Overall there was not enough evidence to conclude that chronic abuse of these drugs induce impairments that would increase during senescence.