Effect of adenosine kinase, adenosine deaminase and transport inhibitors on striatal dopamine and stereotypy after methamphetamine administration

Abstract

The effect of adenosine kinase (AKA), adenosine deaminase (ADA) and transport inhibitors on the release of dopamine (DA) induced by methamphetamine (MTH) in rat striatum was assessed using in vivo microdialysis in freely moving rats. MTH injected in a dose of 3×5 mg/kg i.p. at 2-hour intervals produced a massive release of DA. This excessive release of DA was inhibited by the ADA inhibitor 2′-deoxycoformycin (DCF), the AKA inhibitor 5′-iodotubercidin (IOT) and the adenosine uptake inhibitor dilazep (DIL), each of them given locally to the striatum via a microdialysis probe at a concentration of 100 μM. Perfusion with the same concentrations of erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and 5′-amino-5′-deoxyadenosine (NH 2dAD), ADA and AKA inhibitors, respectively, induced a considerably weaker effect on DA release. The non-selective antagonist of adenosine A 1/A 2A receptor caffeine (75 μM) significantly prevented the inhibitory effect of DCF, IOT and DIL on the MTH-induced DA release. Intrastriatal administration of DCF, IOT and DIL (5 nmol/μl before each injection of MTH) inhibited the stereotypy induced by MTH. The striatal content of DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), decreased by MTH administration and measured 5 days after treatment with the toxin, was reversed by all the inhibitors at the order of potency as follows: IOT>DCF>DIL. Direct agonists of adenosine A 1 and A 1/A 2A receptors, N 6-cyclopentyladenosine (CPA) and 5′- N-ethylcarboxamidoadenosine (NECA), respectively, given intrastriatally (5 nmol/μl) completely abolished the MTH-induced stereotypy and the fall in the striatal content of DA, DOPAC and HVA. The above results show that augmentation of endogenous adenosine in rat striatum by inhibition of its metabolism or uptake—despite the differences in the efficacy of various inhibitors—may provide neuroprotection against a toxic action of MTH.