Postsynaptic Supersensitivity after 6‐Hydroxy‐dopamine Induced Degeneration of the Nigro‐striatal Dopamine System

Abstract

The effect of L-DOPA and the dopamine (DA) receptor stimulating drug apomorphine was studied in rats after unilateral degeneration of the nigrostriatal DA system by intracerebral injection of 6-hydroxydopamine. Both apomorphine and L-DOPA induced a strong rotational behaviour which was registered in a specially designed "rotometer". The direction of the rotation indicated that the denervated striatum was more sensitive to DA receptor stimulating drugs than the innervated striatum. This supersensitivity probably corresponded to the decentralisation type of supersensitivity in the peripheral nervous system although it developed faster. The action of L-DOPA was inhibited by pretreatment with the DOPA-decarboxylase inhibitor R04-4602 which indicated that L-DOPA must be converted to DA in order to stimulate the supersensitive postsynaptic cells. Pretreatment with a single dose of reserpine also induced supersentitivity to apomorphine which reached its maximum on the 3rd day and then decreased on the 4th day. Postsynaptic supersensitivity after degeneration of the nigro-striatal DA system is probably an important reason for the effectiveness of the L-DOPA therapy against Parkinson's disease.

Stimulation of acetylcholine or dopamine receptors in the nucleus accumbens differentially alters dopamine release in the striatum of freely moving rats

“…The finding that both the cholinergic and the dopaminergic treatment of the nucleus accumbens produced the greatest increase in dopamine release in the striatum ipsilateral to the drug injection site in the nucleus accumbens provides an unequivocal expla nation for the observation that both treatments resulted in contralateral turning, since rats with a functional imbalance between the left and right striatum are known to turn away from the side with the higher dopamine activity (Ungerstedt, 1971). Still, the carbachoi-treated rats stopped their contralateral turning long before the increased dopamine release returned to baseline levels.…”

Behavioural effects and supersensitivity in the rat following intranigral MPTP and MPP+ administration

“…away from the hemisphere with the higher striatal dopaminergic activity. Behavioural supersensitivity is manifested by the animal rotating in a direction contralateral to the side of the lesion after the systemic administration of dopamine agonists, and appears to be due to supersensitivity of the denervated striatal dopamine receptors (Ungerstedt, 1971;Creese et al, 1977).…”

“…Ungerstedt, 1971;Creese et al, 1977). A possible explanation for this difference is the ratio between the number of striatal dopamine receptors in the injected and intact hemispheres.…”

In vivo transgene expression from an adenoviral vector is altered following a 6-OHDA lesion of the dopamine system

“…Rotation was assessed using an automated rotometer system modeled after the design of Ungerstedt and Arbuthnot [30]. Rotation test scores were accumulated over a 90-min testing session following an intraperitoneal injection of methamphetamine hydrochloride (dissolved in 0.9% sterile saline) at a dose of 2.5 mg/kg of body weight.…”

“…Such technology allows the direct transfer of genetic material into post-mitotic cells in the adult brain. In theory, it should be possible to deliver genes of interest such as growth factor genes, or the genes necessary for the synthesis of dopamine, directly into the Parkinsonian brain and in this way to halt or even reverse the deficits induced by the loss of dopamine in this condition [5,30].…”