In vivo imaging of disturbed pre- and post-synaptic dopaminergic signaling via arachidonic acid in a rat model of Parkinson's disease.
BACKGROUND
Parkinson's disease involves loss of dopamine (DA)-producing neurons in the substantia nigra, associated with fewer pre-synaptic DA transporters (DATs) but more post-synaptic dopaminergic D2 receptors in terminal areas of these neurons.


OBJECTIVE
Arachidonic acid (AA) signaling via post-synaptic D2 receptors coupled to cytosolic phospholipase A2 (cPLA2) will be reduced in terminal areas ipsilateral to a chronic unilateral substantia nigra lesion in rats given D-amphetamine, which reverses the direction of the DAT, but will be increased in rats given quinpirole, a D2-receptor agonist.


METHODS
D-amphetamine (5.0 mg/kg i.p.), quinpirole (1.0 mg/kg i.v.), or saline was administered to unanesthetized rats having a chronic unilateral lesion of the substantia nigra. AA incorporation coefficients, k* (radioactivity/integrated plasma radioactivity), markers of AA signaling, were measured using quantitative autoradiography in 62 bilateral brain regions following intravenous [1-(14)C]AA.


RESULTS
In rats given saline (baseline), k* was elevated in 13 regions in the lesioned compared with intact hemisphere. Quinpirole increased k* in frontal cortical and basal ganglia regions bilaterally, more so in the lesioned than intact hemisphere. D-amphetamine increased k* bilaterally but less so in the lesioned hemisphere.


CONCLUSIONS
Increased baseline elevations of k* and increased responsiveness to quinpirole in the lesioned hemisphere are consistent with their higher D2-receptor and cPLA2 activity levels, whereas reduced responsiveness to D-amphetamine is consistent with dropout of pre-synaptic elements containing the DAT. In vivo imaging of AA signaling using dopaminergic drugs can identify pre- and post-synaptic DA changes in animal models of Parkinson's disease.
Bhattacharjee
Abesh Kumar
AK
Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bldg. 9, Room 1S126, Bethesda, MD 20892, USA. abesh@mail.nih.gov
Meister
Lindsey M
LM
Chang
Lisa
L
Bazinet
Richard P
RP
White
Laura
L
Rapoport
Stanley I
SI
D000465:Algorithms; D000818:Animals; D016718:Arachidonic Acid / Q000008:administration & dosage / Q000502:physiology*; D001345:Autoradiography; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D003913:Dextroamphetamine / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology*; D018491:Dopamine Agonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006892:Hydroxydopamines; D007261:Infusions, Intra-Arterial; D007262:Infusions, Intravenous; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D019257:Quinpirole / Q000494:pharmacology; D019275:Radiopharmaceuticals; D051381:Rats; D017661:Receptors, Presynaptic / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction; D013565:Sympatholytics; D013569:Synapses / Q000187:drug effects / Q000502:physiology*
D018491:Dopamine Agonists; D018765:Dopamine Uptake Inhibitors; D006892:Hydroxydopamines; D019275:Radiopharmaceuticals; D017661:Receptors, Presynaptic; D013565:Sympatholytics; D019257:Quinpirole; D016718:Arachidonic Acid; D003913:Dextroamphetamine; D004298:Dopamine