Age-related changes in cerebellar noradrenergic pre- and postsynaptic mechanisms: intrinsic vs extrinsic determinants evaluated with brain grafts in oculo.
Intrinsic versus extrinsic determinants of changes in cerebellar noradrenergic transmission during senescence in the rat were measured using homologous cerebellar grafts in oculo. Postsynaptic sensitivity of Purkinje neurons to catecholamines was determined by perfusing the anterior eye chamber with known concentrations of norepinephrine (NE) dissolved in a balanced salt solution. NE elicited a dose-dependent slowing of spontaneous Purkinje neuron discharge in both young (3-6 months) and aged (20-22 months) cerebellar grafts. Hill plots demonstrated that the dose-response relationships in both age-groups were linear and parallel to one another. Aged transplant Purkinje neurons manifested a marked and highly significant subsensitivity to NE with an EC50 of 583 microM, as compared with an EC50 of only 15.9 microM in the young grafts. Young grafts in 15-21-month-old hosts manifested an EC50 of 20 microM for the depressant actions of NE. Collaterals of host iris sympathetic fibers innervate the grafts. Activity of these fibers can be reflexly altered by changing illumination of the retina. The dynamics of presynaptic NE release from these fibers was evaluated using in vivo electrochemistry with Nafion-coated graphite epoxy capillary electrodes, which are highly selective for the monoamine neurotransmitters. As illumination of the ipsilateral retina is increased, the release of catecholamine in the cerebellar graft decreases. A mean change in the extracellular electroactive species of 4.2 +/- 0.6 microM was found in young cerebellar grafts. Equivalent stimuli induced a mean change of 2.3 +/- 0.8 microM in aged grafts. However, this diminished release was not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)
Granholm
A C
AC
Department of Pharmacology, University of Colorado Health Sciences Center, Denver 80262.
Gerhardt
G A
GA
Eriksdotter-Nilsson
M
M
Bickford-Wimer
P C
PC
Palmer
M R
MR
Seiger
A
A
Olson
L
L
Hoffer
B J
BJ
D000200:Action Potentials / Q000187:drug effects; D000344:Afferent Pathways / Q000502:physiology; D000375:Aging; D000818:Animals; D002531:Cerebellum / Q000196:embryology / Q000502:physiology / Q000637:transplantation*; D004622:Embryo, Mammalian; D005123:Eye / Q000254:growth & development*; D005260:Female; D007700:Kinetics; D008027:Light; D009474:Neurons / Q000502:physiology; D009638:Norepinephrine / Q000494:pharmacology*; D011689:Purkinje Cells / Q000502:physiology*; D051381:Rats; D013569:Synapses / Q000187:drug effects / Q000502:physiology*
D009638:Norepinephrine