[H-3]acetycholine release in rat striatal slices is not subject to dopamine heteroreceptor supersensitivity 30 months after 6-hydroxydopamine lesion of the substantia nigra

Using the rat model of Parkinson's disease described by Ungerstedt the rele ase of [H-3]acetylcholine ([H-3]ACh) in the caudatoputamen was investigated to assess possible long-term effects of unilateral dopaminergic denervatio n on the modulation of cholinergic interneurons. This seemed of interest si nce rats with 6-hydroxy-dopamine (6-OHDA) lesions of the left substantia ni gra showed an increase in the behavioural susceptibility to small doses of dopamine (DA) D-2 receptor agonists 30 months after the lesion. Electrical field stimulation with 3 Hz elicited release of [H-3]ACh in slices of both the lesioned and the intact striatum. The DA reuptake blocker nomifensine w as ineffective on the lesioned side but diminished the release of [H-3]ACh in the intact striatum. This inhibition was reversed by the D-2 receptor an tagonist domperidone and hence probably due to the effect of endogenously r eleased DA. Single electrical pulses at 0.05 Hz, which neither induced auto inhibition of [H-3]ACh release nor heteroinhibition by endogenous DA, elici ted a higher release of [H-3]ACh on the intact side. Under this stimulation paradigm activation of the D-2 heteroreceptor with quinpirole depressed th e release of [H-3]ACh to a similar extent on both sides, irrespective of th e absence or presence of the competitive NMDA receptor antagonist D-CPPene. Also blockade of the NMDA receptor channel by dizocilpine, or of AMPA rece ptors by NBQX, was ineffective on either side. The NMDA-evoked release of [ H-3]ACh was higher on the lesioned side. It was equally depressed by quinpi role and by ethanol on both sides. Thus, single electrical pulses and NMDA stimulation per se had opposite effects on the lesioned and the intact side , whereas the modulation of release was similar. Since the lesioned striata were considerably smaller, measurements of mRNA levels of choline acetyltr ansferase (ChAT) were used to assess the density of cholinergic interneuron s and their content of ChAT mRNA. This analysis did not reveal any side dif ference. In conclusion, the function of D-2 heteroreceptors on, and the den sity and ChAT mRNA content of, cholinergic interneurons are not or no longe r altered after long-term DA denervation. Most probably, cholinergic intern eurons are not involved in the increased behavioural susceptibility of 6-OH DA-lesioned rats to DA agonists.