POTENTIAL OF ADENOSINE A(2A) RECEPTOR ANTAGONISTS IN THE TREATMENT OFMOVEMENT-DISORDERS

The current pharmacological treatment of Parkinson's disease, based la rgely on levodopa and directly acting dopamine receptor agonists, rema ins unsatisfactory for many patients if long term treatment is require d. An alternative strategy may be to reduce the activity of endogenous pathways that antagonise dopaminergic systems. One such pathway is th e adenosine pathway. Adenosine receptors are present throughout the CN S, but with the A(2A) receptor subtype being highly localised to the b asal ganglia, especially intrinsic cholinergic neurons and the enkepha lin-containing gamma-aminobutyric acid (GABA) striopallidal projection neurons. A subtype of A(2A) receptors may exist in extrastriatal area s. Agonists at these receptors increase neuronal excitability and faci litate neurotransmitter release, but they also interact with dopamine receptors to suppress the effects of dopamine. Conversely, A(2A) recep tor antagonists in general stimulate locomotor behaviour in a wide var iety of experimental paradigms and show related behavioural properties consistent with their preventing the activation of adenosine receptor s by the endogenous agonist purine, thereby facilitating the activatio n of dopamine receptors. Preliminary studies in humans with nonselecti ve adenosine receptor antagonists have indicated that this motor stimu lant activity may extend to a reduction of the hypokinesia and tremor associated with Parkinson's disease. The development of selective anta gonists of A(2A) receptors, recently reported by several pharmaceutica l companies, may therefore herald the advent of a new pharmacological approach to the treatment of Parkinson's disease.