Assessment of purine-dopamine interactions in 6-hydroxydopamine-lesioned rats: evidence for pre- and postsynaptic influences by adenosine.
Lesch-Nyhan syndrome involves disorders of both purine and dopamine metabolism. Neonatal lesioning of dopaminergic neurons with 6-hydroxydopamine (6-OHDA) has been proposed as a rodent model of the dopamine deficiency in this childhood disorder. In the present studies, the functional interaction between purines and dopamine was examined in adult rats which received 6-OHDA lesions either as neonates or as adults. Even though dopamine levels were decreased by at least 92%, both neonatal- and adult-6-OHDA-lesioned rats had normal hypoxanthine-guanine phosphoribosyltransferase function and purine nucleotide levels (adenosine, ADP, ATP and AMP), indicating that hypoxanthine-guanine phosphoribosyltransferase is not localized only to dopaminergic neurons in striatum. However, the 6-OHDA-lesioned animals were supersensitive to the locomotor activating effects of the adenosine antagonist, theophylline, with the response being greater in adult-6-OHDA-lesioned rats. This effect was presynaptic to dopaminergic neurons as indicated by alpha-methyltyrosine blockade of the theophylline response and its reinstatement by L-dopa. The presynaptic nature of this action of theophylline was supported further by a lack of interaction between theophylline and the direct acting D1- and D2-dopamine agonists, SKF-38393 and LY-171555, respectively. After systemic administration of SKF-38393 or L-dopa, central microinjection of the adenosine agonists, 2-chloroadenosine or 5'-N-ethylcarboxamide adenosine, were effective in preventing self mutilation induced by these dopamine agonists in neonatally lesioned rats. Relative potencies of the adenosine agonists for A1 and A2-adenosine receptors suggested involvement of an A2-adenosine receptor in this action.(ABSTRACT TRUNCATED AT 250 WORDS)
D000241:Adenosine / Q000494:pharmacology*; D000818:Animals; D005260:Female; D006892:Hydroxydopamines; D007041:Hypoxanthine Phosphoribosyltransferase / Q000032:analysis; D007926:Lesch-Nyhan Syndrome / Q000378:metabolism; D007980:Levodopa / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine; D011247:Pregnancy; D011687:Purines / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects*; D011983:Receptors, Purinergic / Q000187:drug effects; D013806:Theophylline / Q000494:pharmacology
D006892:Hydroxydopamines; D011687:Purines; D011954:Receptors, Dopamine; D011983:Receptors, Purinergic; D007980:Levodopa; D016627:Oxidopamine; D013806:Theophylline; D007041:Hypoxanthine Phosphoribosyltransferase; D000241:Adenosine; C030985:purine