Assessment of purine-dopamine interactions in 6-hydroxydopamine-lesioned rats: evidence for pre- and postsynaptic influences by adenosine.

Abstract

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)

• Authors: H Criswell, R A Mueller, G R Breese
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 244 Issue 2 Pg. 493-500 (Feb 1988) ISSN: 0022-3565 [Print] United States
• PMID: 3126293 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Hydroxydopamines
• Purines
• Receptors, Dopamine
• Receptors, Purinergic
• Levodopa
• Oxidopamine
• Theophylline
• Hypoxanthine Phosphoribosyltransferase
• Adenosine
• purine

Topics

• Adenosine (pharmacology)
• Animals
• Female
• Hydroxydopamines
• Hypoxanthine Phosphoribosyltransferase (analysis)
• Lesch-Nyhan Syndrome (metabolism)
• Levodopa (pharmacology)
• Motor Activity (drug effects)
• Oxidopamine
• Pregnancy
• Purines (metabolism)
• Rats
• Rats, Inbred Strains
• Receptors, Dopamine (drug effects)
• Receptors, Purinergic (drug effects)
• Theophylline (pharmacology)