Dopamine efflux from striatal slices after intracerebral 6-hydroxydopamine: evidence for compensatory hyperactivity of residual terminals.
In this study, we have examined the spontaneous efflux and stimulation-induced overflow of endogenous dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) from striatal slices prepared from adult rats. Partial destruction of striatal DA terminals with 6-hydroxydopamine reduced the electrically evoked overflow of DA and DOPAC, but by less than the DA content of the tissue slices. This resulted in an increase in the fractional overflow of DA and DOPAC, a measure of overflow from residual dopaminergic terminals. The increase in fractional DA overflow was related to the lesion size, reaching 7-fold with DA depletions of greater than 90%. Inhibition of DA re-uptake with nomifensine (10 microM) increased DA overflow and reduced DOPAC overflow by an equivalent amount, indicating that a portion of the DA released by electrical stimulation is recaptured and metabolized before appearing as DOPAC in the superfusate. However, 6-hydroxydopamine lesions further elevated fractional DA overflow above control even in the presence of nomifensine, suggesting that slices prepared from lesioned animals exhibit an increase in DA release from residual dopaminergic terminals. DA overflow was enhanced by the DA receptor antagonist sulpiride (1 microM) in control tissue but not in slices prepared from lesioned animals, suggesting that increased efflux per terminal was accompanied by reduced autoinhibition of release. Over a range of firing frequencies typical of nigrostriatal neurons in vivo (2-8 Hz), fractional DA overflow per pulse from lesioned slices was 3-fold higher than control overflow; however, fractional overflow per pulse was reduced from lesioned but not control slices when slices were exposed to a higher frequency (12 Hz). Thus, the lesion appeared to have increased DA release at moderate frequencies, but had reduced the effective range of frequencies over which the DA terminals could operate. Finally, 3-iodotyrosine (2 mM), an inhibitor of tyrosine hydroxylase, reduced DA overflow from intact slices, but completely abolished overflow from lesioned slices, suggesting that 6-hydroxydopamine had increased the dependence of DA efflux on a sustained rate of DA synthesis. Taken together, these data suggest that after lesioning with 6-hydroxydopamine, DA released per pulse from residual terminals is increased relative to control, so long as the stimulation frequency is within the physiological range. This increase in release may serve a compensatory function, maintaining dopaminergic control over striatal function despite extensive loss of DA neurons.
Snyder
G L
GL
Department of Behavioral Neuroscience, University of Pittsburgh, Pennsylvania.
Keller
R W
RW
Zigmond
M J
MJ
D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis / Q000378:metabolism; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000032:analysis / Q000378:metabolism*; D004558:Electric Stimulation; D005071:Evoked Potentials; D006892:Hydroxydopamines / Q000494:pharmacology*; D008297:Male; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism; D009627:Nomifensine / Q000494:pharmacology; D016627:Oxidopamine; D051381:Rats; D011919:Rats, Inbred Strains
D006892:Hydroxydopamines; D015102:3,4-Dihydroxyphenylacetic Acid; D009627:Nomifensine; D016627:Oxidopamine; D004298:Dopamine