Micaela Morelli

Adenosine–dopamine receptor–receptor interactions as an integrative mechanism in the basal ganglia

Increasing evidence suggests that antagonistic interactions between specific subtypes of adenosine and dopamine receptors in the basal ganglia are involved in the motor depressant effects of adenosine receptor agonists and the motor stimulant effects of adenosine receptor antagonists, such as caffeine. The GABAergic striatopallidal neurons are regulated by interacting adenosine A2A and dopamine D2 receptors. On the other hand, the GABAergic striatonigral and striatoentopeduncular neurons seem to be regulated by interacting adenosine A1 and dopamine D1 receptors. Furthermore, behavioural studies have revealed interactions between adenosine A2A and dopamine D1 receptors that occur at the network level. These adenosine-dopamine receptor-receptor interactions might offer new therapeutic leads for basal ganglia disorders.

Modulatory functions of neurotransmitters in the striatum: ACh/dopamine/NMDA interactions

The striatum is viewed as a structure performing fast neurotransmitter-mediated operations through somatotopically organized projections to medium-size spiny neurons. This view is contrasted with another view that depicts the striatum as a site of diffuse modulatory influences mediated by cholinergic interneurons and by dopamine and N-methyl-D-aspartate receptors. These two operational and organizational modes both contribute, through their mutual interaction, to the function of basal ganglia. Detailed knowledge of the neural mechanisms by which such interactions take place and are expressed into behaviour, can provide new insight into the physiopathology and new clues for therapy of disorders of basal ganglia.

Evidence for a GABAergic projection from the substantia nigra to the ventromedial thalamus and to the superior colliculus of the rat.

Unilateral intranigral infusion of kainic acid (1.5 microgram) produced neuronal loss in the lateral two-thirds of the nigra while sparing axons en passage. Fink-Heimer silver impregnation revealed dense terminal degeneration in the nigra itself (both in the compacta and in the reticulata) and in areas of non-dopaminergic nigral projection such as the ventromedial (VM) nucleus of the thalamus, the superior colliculus and the reticular formation; only spare terminal degeneration was found in areas of dopaminergic projection such as the caudate and septum. In order to clarify the nature of the transmitter of the nigrothalamic and nigrocollicular neurons, the activity of glutamic decarboxylase (GAD), the marker of cholinergic neurons, was measured in the VM and ventrobasal (VB) thalamus and in the nigra of each side, 7 days after unilateral intranigral injection of kainic acid. GAD activity was reduced significantly in the VM-thalamus (-33%), in the superior colliculus (-40%) and in the substantia nigra (-18%) but not in the VB-thalamus of the lesioned side. CAT remained unchanged in these areas. Similar results were obtained in the thalamus and in the superior colliculus after electrocoagulative lesions of the nigra. The results indicate the existence of a nigrothalamic and of a nigrocollicular GABAergic pathway. This projection might play an important role in motor coordination and gaze control.

The 6-hydroxydopamine model of Parkinson's disease.

The neurotoxin 6-hydroxydopamine (6-OHDA) continues to constitute a valuable topical tool used chiefly in modeling Parkinson’s disease in the rat. The classical method of intracerebral infusion of 6-OHDA, involving a massive destruction of nigrostriatal dopaminergic neurons, is largely used to investigate motor and biochemical dysfunctions in Parkinson’s disease. Subsequently, more subtle models of partial dopaminergic degeneration have been developed with the aim of revealing finer motor deficits. The present review will examine the main features of 6-OHDA models, namely the mechanisms of neurotoxin-induced neurodegeneration as well as several behavioural deficits and motor dysfunctions, including the priming model, modeled by this means. An overview of the most recent morphological and biochemical findings obtained with the 6-OHDA model will also be provided, particular attention being focused on the newly investigated intracellular mechanisms at the striatal level (e.g., A2A and NMDA receptors, PKA, CaMKII, ERK kinases, as well as immediate early genes, GAD67 and peptides). Thanks to studies performed in the 6-OHDA model, all these mechanisms have now been hypothesised to represent the site of pathological dysfunction at cellular level in Parkinson’s disease.

Adenosine A2A receptor antagonism potentiates L-DOPA-induced turning behaviour and c-fos expression in 6-hydroxydopamine-lesioned rats

In order to investigate the role of adenosine A2A receptor blockade on dopamine-mediated motor responses, contralateral turning behaviour and expression of the early-gene c-fos was evaluated in rats with a unilateral 6-hydroxydopamine lesion of the dopaminergic nigrostriatal pathway. SCH 58261, (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1 , 5-c]pyrimidine) a potent and selective antagonist of adenosine A2A receptors (5 mg/kg i.p.), induced a 70-fold increase in the contralateral turning behaviour induced by a low dose (2 mg/kg i.p.) of the dopamine precursor L-DOPA (L-3, 4-dihydroxyphenylalanine). Expression of c-fos as measured by Fos-like immunoreactivity after SCH 58261 plus L-DOPA was also potentiated as compared with L-DOPA alone, both in striatum and globus pallidus of the 6-hydroxydopamine-lesioned side of the brain. SCH 58261 induced a less marked potentiation (7-fold) of turning behaviour induced by dopamine D2 receptor stimulation with quinpirole, while Fos-like immunoreactivity in the striatum and globus pallidus was not affected. Previous studies have shown that SCH 58261 strongly potentiated dopamine D1 receptor-mediated responses. The results of the present study therefore indicate that the positive interaction between SCH 58261 and L-DOPA, in 6-hydroxydopamine-lesioned rats, is mainly due to an interaction with dopamine D1 receptors. The data also suggest that adenosine A2A receptor antagonists might be useful for potentiating the effects of L-DOPA in Parkinsons disease.

Adenosine, adenosine A2A antagonists, and Parkinson's disease

Adenosine derived from the degradation of ATP/AMP functions as a signalling molecule in the nervous system through the occupation of A1, A2, and A3 adenosine receptors. Adenosine A(2A) receptors have a selective localization to the basal ganglia and specifically to the indirect output pathway, and as a consequence offer a unique opportunity to modulate the output from the striatum that is believed critical to the occurrence of motor components of PD. Indeed, the ability of A(2A) antagonists to modulate basal ganglia neurotransmission has been shown to be associated with improved motor function in experimental models of PD. This suggests that A(2A) antagonists would be effective as a symptomatic treatment in humans without provoking marked dyskinesia. Indeed, the A(2A) antagonist istradefylline reduces OFF time in moderate- to late-stage patients with PD already receiving dopaminergic therapy, with an increase in non-troublesome dyskinesia. Adenosine and adenosine receptors also exert actions relevant to pathogenesis in PD, raising the possibility of their use as neuroprotective agents. Both epidemiologic evidence and the current preclinical data strongly support a role for A(2A) antagonists in protecting dopaminergic neurons and influencing the onset and progression of PD.

Pathophysiology of L-dopa-induced motor and non-motor complications in Parkinson's disease.

Involuntary movements, or dyskinesia, represent a debilitating complication of levodopa (L-dopa) therapy for Parkinsons disease (PD). L-dopa-induced dyskinesia (LID) are ultimately experienced by the vast majority of patients. In addition, psychiatric conditions often manifested as compulsive behaviours, are emerging as a serious problem in the management of L-dopa therapy. The present review attempts to provide an overview of our current understanding of dyskinesia and other L-dopa-induced dysfunctions, a field that dramatically evolved in the past twenty years. In view of the extensive literature on LID, there appeared a critical need to re-frame the concepts, to highlight the most suitable models, to review the central nervous system (CNS) circuitry that may be involved, and to propose a pathophysiological framework was timely and necessary. An updated review to clarify our understanding of LID and other L-dopa-related side effects was therefore timely and necessary. This review should help in the development of novel therapeutic strategies aimed at preventing the generation of dyskinetic symptoms.

Blockade of A2a adenosine receptors positively modulates turning behaviour and c-Fos expression induced by D1 agonists in dopamine-denervated rats.

In rats with unilateral 6‐hydroxydopamine lesions of the dopaminergic nigrostriatal pathway, administration of the A2a adenosine antagonist SCH 58261 alone did not induce any motor asymmetry but strongly potentiated the contralateral turning behaviour induced by the dopamine D1 agonist SKF 38393. SCH 58261 also increased the number of Fos‐like positive nuclei induced by SKF 38393 in the 6‐hydroxydopamine‐lesioned striatum. Intense potentiation of D1‐dependent turning behaviour and c‐Fos expression was also observed after administration of the A2a/A1 antagonist CGS 15943. Administration of the A1 adenosine receptor antagonist DPCPX induced a small potentiation of D1‐mediated contralateral turning while c‐Fos expression induced by SKF 38393 was not modified. The results suggest that endogenous adenosine acting on A2a receptors can exert an inhibitory influence on the functional expression of D1‐mediated responses in dopamine‐denervated rats, and propose new possible therapeutic approaches in the treatment of Parkinsons disease.

Caffeine and the dopaminergic system.

Caffeine is the most widely consumed psychostimulant substance, being self-administered throughout a wide range of conditions and present in numerous dietary products. Due to its widespread use and low abuse potential, caffeine is considered an atypical drug of abuse. The main mechanism of action of caffeine occurs via the blockade of adenosine A1 and A2A receptors. Adenosine is a modulator of CNS neurotransmission and its modulation of dopamine transmission through A2A receptors has been implicated in the effects of caffeine. This review provides an updated summary of the results reported in the literature concerning the behavioural pharmacology of caffeine and the neurochemical mechanisms underlying the psychostimulant effects elicited by caffeine. The review focuses on the effects of caffeine mediated by adenosine A2A receptors and on the influence that pre-exposure to caffeine may exert on the effects of classical drugs of abuse.

Motor stimulant effects of the adenosine A2A receptor antagonist SCH 58261 do not develop tolerance after repeated treatments in 6-hydroxydopamine-lesioned rats.

Several evidences indicate that the selective blockade of adenosine A2A receptors counteracts the motor activity impairment in experimental models of Parkinsons disease. In the present study, the effects of the adenosine A2A receptor antagonist, SCH 58261 (5‐amino‐7‐(β‐phenylethyl)‐2‐(8‐furyl)pyrazolo(4,3‐e)‐1,2,4‐triazolo(1,5‐c)pyrimidine, were assessed following a repeated treatment schedule in the contralateral turning behavior rat model of Parkinsons disease. Unilateral lesions of the nigrostriatal pathway were induced by injecting 6‐hydroxydopamine (6‐OHDA) in medial forebrain bundle. Repeated administration of SCH 58261 was performed either alone (7 and 14 days repeated SCH 58261) or together with L‐dopa (19 days repeated SCH 58261 plus L‐dopa or L‐dopa alone). After a 7‐ and 14‐day repeated administration schedule, SCH 58261 (5 mg/kg) maintained its ability to potentiate the contralateral turning behavior induced by a subthreshold dose of L‐dopa (2 mg/kg i.p.), showing no tolerance to its stimulant effects. SCH 58261 (5 mg/kg) plus L‐dopa (3 mg/kg) or L‐dopa (6 mg/kg) alone induced, at these dosages, the same number of contralateral turnings after the first administration. While chronic intermittent SCH 58261 plus L‐dopa did not lead to a modified turning behavior during treatment, L‐dopa alone produced a progressive increase in turning behavior intensity and duration. These results provide evidence that SCH 58261 retains its ability to potentiate L‐dopa effects in a validated rat model of Parkinsons disease even after repeated treatments. Moreover, these results suggest that adenosine A2A blockade prevents the appearance of motor response alterations in L‐dopa‐treated rats, supporting the concept that A2A receptor antagonists have a therapeutic potential for the treatment of Parkinsons disease. Synapse 39:233–238, 2001.