Effect of L-dopa and 6-hydroxydopamine lesioning on [11C]raclopride binding in rat striatum, quantified using PET.
A positron emission tomograph (PET) was used to image D2 dopamine receptor function in rat striata and to obtain regional time-radioactivity curves from individual rat brains following i.v. injection of carbon-11-labelled raclopride. Despite the limited resolution of the camera, together with associated spillover and partial volume effects, the kinetic data obtained from striata were such that specific binding of the radioligand could be quantified unilaterally, using a reference tissue compartmental model, with cerebellum data as an indirect input function. With the exception that the rat is anaesthetised, the experimental system is analogous to the acquisition and collection of clinical PET data and, by using animal models of disease, can be used to aid the interpretation of clinical studies. Using 6-hydroxydopamine (6-OHDA) lesioning of the substantia nigra pars compacta to produce a rat hemiparkinsonian model, the present results confirm that deafferentation causes a supersensitivity of post-synaptic D2 dopamine receptors. Saturation studies indicated that the measured 23% increase in [11C]raclopride binding potential reflected a change in receptor affinity. Modulation of extracellular dopamine concentration, monitored by in vivo microdialysis, demonstrated that the increased binding was unlikely to be due to a reduction in receptor occupancy by endogenous dopamine. Acute administration of L-3,4-dihydroxyphenylalanine (L-dopa) also caused an increase in [11C]raclopride binding potential, confirming the suggestion that L-dopa plays a more complex role than that of dopamine precursor in the nigrostriatal pathway.
PET Methodology and Neurosciences Groups, MRC Clinical Sciences Centre, Royal Postgraduate Medical School, Hammersmith Hospital, London, United Kingdom.
S P
SP
Hume
J
J
Opacka-Juffry
R
R
Myers
R G
RG
Ahier
S
S
Ashworth
D J
DJ
Brooks
A A
AA
Lammertsma
D000818:Animals; D001667:Binding, Competitive; D003342:Corpus Striatum / Q000187:drug effects*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D016627:Oxidopamine / Q000494:pharmacology*; D020891:Raclopride; D051381:Rats; D017207:Rats, Sprague-Dawley; D012457:Salicylamides / Q000494:pharmacology*; D013997:Time Factors
D018492:Dopamine Antagonists; D012457:Salicylamides; D020891:Raclopride; D007980:Levodopa; D016627:Oxidopamine