Susceptibility of ascending dopamine projections to 6-hydroxydopamine in rats: effect of hypothermia.
The aims of this study were to determine (1) whether mesolimbic and nigrostriatal DA cell bodies degenerate to different extents after 6-hydroxydopamine (6-OHDA) is administered into their respective terminal fields and (2) whether hypothermia, associated with sodium pentobarbital anesthesia, protects DA neurons from the toxic effects of 6-OHDA. To address these questions, 6-OHDA or vehicle was infused into either the ventral or dorsal striatum or into the medial forebrain bundle, under conditions of brain normothermia or hypothermia. Two weeks post-surgery, tyrosine hydroxylase-positive cell bodies were counted in the ventral tegmental area (VTA) and substantia nigra. In addition, autoradiographic labeling of tyrosine hydroxylase protein and dopamine transporter was quantified in dopamine terminal fields and cell body areas. Overall, DA cell bodies in the VTA were substantially less susceptible than those in the substantia nigra to depletion of dopaminergic markers. Hypothermia provided two types of neuroprotection. The first occurred when 6-OHDA was administered into the dorsal striatum, and was associated with a 30-50% increase in residual dopaminergic markers in the lateral portion of the VTA. The second neuroprotective effect of hypothermia occurred when 6-OHDA was given into the medial forebrain bundle. This was associated with a 200-300% increase in residual dopaminergic markers in the mesolimbic and nigrostriatal terminal fields; no significant protection occurred in the cell body regions.Collectively, these findings show that (1) the dopaminergic somata in the substantia nigra are more susceptible than those in the VTA to 6-OHDA-induced denervation, and (2) hypothermia can provide anatomically selective neuroprotection within the substantia nigra-VTA cell population. The continued survival of mesolimbic dopamine cell bodies after a 6-OHDA lesion may have functional implications relating to drugs of abuse, as somatodendritic release of dopamine in the VTA has been shown to play a role in the effectiveness of cocaine reward.
Grant
R J
RJ
Department of Pharmacology and Therapeutics, McGill University, 3655 Promenade Sir William Osler, H3G 1Y6, Montreal, QC, Canada.
Clarke
P B S
PB
D000818:Animals; D001831:Body Temperature / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003042:Cocaine / Q000031:analogs & derivatives*; D004198:Disease Susceptibility / Q000473:pathology / Q000503:physiopathology / Q000628:therapy; D004298:Dopamine / Q000378:metabolism*; D004525:Efferent Pathways / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D007036:Hypothermia, Induced; D008297:Male; D008474:Medial Forebrain Bundle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration / Q000503:physiopathology / Q000517:prevention & control / Q000628:therapy*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D020258:Neurotoxicity Syndromes / Q000503:physiopathology / Q000517:prevention & control / Q000628:therapy*; D016627:Oxidopamine / Q000037:antagonists & inhibitors*; D010424:Pentobarbital / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology
D018696:Neuroprotective Agents; C069723:2beta-carbomethoxy-3beta-(4-iodophenyl)tropane; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D010424:Pentobarbital; D003042:Cocaine; D004298:Dopamine