Changes in somatodendritic but not terminal dopamine
regulation in aged rhesus monkeys

Abstract

For these studies, young (8±9 years), middle-aged (14± 17 years) and aged (23±28 years) rhesus monkeys were used as a model of normal aging in humans to investigate changes in dopamine (DA)-containing neurons in senescence. Aged monkeys exhibited signi®cant age-related motoric declines as compared to the young animals. In vivo microdialysis studies showed that basal levels of the DA metabolites, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were diminished by 44% and 79%, respectively, in the substantia nigra (SN) of aged monkeys. In addition, D-amphetamine-evoked over¯ow of DA in the SN was diminished by 30% in the middle-aged animals and 67% in the aged monkeys. Post-mortem measures of DA and DA metabolites showed signi®cant decreases in DA (20%), DOPAC (47%) and HVA (22%) levels in the putamen and a 25% decline in HVA tissue levels in the SN of the aged monkeys as compared to the young animals. Unbiased stereological cell counting of tyrosine hydroxylase (TH)-immunoreactive neurons in the SN showed a small (15±20%) but signi®cant agerelated decline in TH-positive neurons. In addition, there was a small (15±20%) but signi®cant decline in TH-positive ®ber density and TH-positive cell size. In comparison to the massive loss of DA neurons responsible for the movement dysfunctions seen in Parkinson's disease, pronounced functional changes in DA release in the SN and putamen may signi®-cantly contribute to the motoric dysfunctions characterizing normal aging in rhesus monkeys.

Occupancy of Striatal and Extrastriatal Dopamine D2/D3 Receptors by Olanzapine and Haloperidol

“…Studies in animals have demonstrated that a number of motor behaviors require normal nigral as well as normal striatal dopaminergic function. Motor dysfunction in middle-aged and elderly monkeys compared to young monkeys was most closely correlated with declines in DA release in the substantia nigra as opposed to putamen (Gerhardt et al, 2002). In unilaterally MPTP-lesioned rhesus monkeys, a single intraventricular injection of GDNF produced improvement in motor function, which was correlated with DOPAC and HVA levels in the lesioned nigra but not in the striatum (Gerhardt et al, 1999).…”

“…These include the ability of olanzapine (Stockton and Rasmussen, 1996), like clozapine (Chiodo and Bunney, 1983), but unlike haloperidol (Chiodo and Bunney, 1983), to produce a selective depolarization of DA neurons in the VTA, but not in the substantia nigra, and the role of dopaminergic neurotransmission in the substantia nigra in motor behaviors (Gerhardt et al, 1999(Gerhardt et al, , 2002Robertson and Robertson, 1989). Studies in animals have demonstrated that a number of motor behaviors require normal nigral as well as normal striatal dopaminergic function.…”

Amphetamine-Induced Displacement of [18F] Fallypride in Striatum and Extrastriatal Regions in Humans

“…This is surprisingly high taking into consideration that extracellular DA levels at baseline and following D-AMPH administration are approximately 10% of that seen in the striatum (Gerhardt et al, 2002). In the substantia nigra, DA D 2 receptors are autoreceptors which are localized on the dendrites of dopaminergic neurons (Sesack et al, 1994) and are in the high-affinity agonist state, while in the striatum they are in both the high-and low-affinity state.…”

Mitochondrial ATP-sensitive potassium channels enhance angiotensin-induced oxidative damage and dopaminergic neuron degeneration. Relevance for aging-associated susceptibility to Parkinson’s disease

“…Recent evidence suggests that dopaminergic and renin-angiotensin systems directly counterregulate each other in renal cells (Gildea 2009) and also in the nigrostriatal system (Villar-Cheda et al 2010a), and that abnormal counterregulation between dopamine and angiotensin II plays an important role in degenerative changes Li et al 2008;Rodriguez-Pallares et al 2008). Interestingly, several studies have shown that there is an agingrelated decrease in dopamine release, which results in a progressive decrease in motor activity (Collier et al 2007;Gerhardt et al 2002), and may be responsible for the above mentioned aging-related increase in angiotensin activity (Villar-Cheda et al 2010a,b).…”