Dopamine depletion abolishes apomorphine- and amphetamine-induced increases in extracellular serotonin levels in the striatum of conscious rats: a microdialysis study.
We investigated how serotonergic neurotransmission was affected by 6-hydroxydopamine (6-OHDA) lesioning of the adult rat brain dopamine (DA) system. In this animal model for Parkinson's disease (PD), the effect of destroying ascending DA pathways on extracellular levels of serotonin (5-HT) and 5-HT innervation in rat striatum were examined. Profound unilateral lesions of the nigrostriatal DA pathways were made by infusing 6-OHDA unilaterally into either the right medial forebrain bundle or the right substantia nigra. At 5 weeks after lesioning extracellular levels of DA and 5-HT were determined with microdialysis and high-pressure liquid chromatography under basal conditions and after systemic injections of apomorphine or amphetamine. DA nerve-terminal destruction and 5-HT innervation were determined with quantitative autoradiography. 6-OHDA lesioning reduced extracellular levels of DA below detection limits and led to statistically significant increases in extracellular 5-HT. Apomorphine, and amphetamine, respectively increased extracellular 5-HT to 8.2- and 2.2-fold above baseline levels in intact animals; these effects were absent in 6-OHDA-lesioned animals. Basal levels of [(3)H]paroxetine binding to 5-HT transporters in caudate-putamen increased by 41% in 6-OHDA-lesioned animals. These results suggest that 6-OHDA lesioning led to hyperinnervation of 5-HT nerve terminals and increases in basal extracellular 5-HT levels, but also to an unexplained loss of apomorphine and amphetamine-induced release of 5-HT. Addressing whether this impairment has significance in the onset of PD might lead to development of new strategies to manage parkinsonian symptoms.
Balcioglu
A
A
Neuroregeneration Laboratories, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, USA. abalcioglu@partners.org
Zhang
K
K
Tarazi
F I
FI
D000344:Afferent Pathways / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D003714:Denervation; D004195:Disease Models, Animal; D004298:Dopamine / Q000172:deficiency*; D018491:Dopamine Agonists / Q000494:pharmacology; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism; D026901:Membrane Transport Proteins; D017551:Microdialysis; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D009419:Nerve Tissue Proteins; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D017374:Paroxetine / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
D002352:Carrier Proteins; D018491:Dopamine Agonists; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D012701:Serotonin; D017374:Paroxetine; D016627:Oxidopamine; D000661:Amphetamine; D001058:Apomorphine; D004298:Dopamine