Effects of adenosine analogs on rat cerebral cortical neurons

Abstract

Adenosine and the adenosine 5'-phosphates (5'-AMP, 5'-ADP and 5'-ATP) depress the spontaneous firing of cerebral cortical neurons. In this study adenosine analogs, adenosine transport blockers and adenosine deaminase inhibitors have been used to gain further insight into the nature of the adenosine receptor and the likely routes of metabolism of extracellularly released adenosine. The firing rate of cortical neurons, including identified corticospinal neurons, was depressed by 2-substituted derivatives of adenosine. 2-Halogenated derivatives of adenosine were potent depressors while 2-aminoadenosine and 2-hydroxyadenosine (crotonoside) were slightly less potent than adenosine. The α,β-methylene isosteres of 5'-ADP and 5'-ATP were almost devoid of agonist activity while the β,γ-methylene analog was an active agonist. This suggests that ADP and ATP must be converted to AMP or possibly adenosine before they can activate the adenosine receptor. 2'-, 3'- and 5'- deoxyadenosine depressed spontaneous firing without antagonizing the effect of adenosine. Adenosine deaminase inhibitors, deoxycoformycin and erythro -9-(2-hydroxy-3-nonyl) adenine had potent, long lasting depressant actions on the spontaneous firing of cortical neurons and concurrently potentiated the actions of adenosine or 5'-AMP. Inhibitors of adenosine transport, papaverine and 2-hydroxy-5-nitrobenzylthioguanosine, prolonged the duration of action of adenosine and 5'-AMP. Intracellular recordings show that 5'-AMP hyperpolarizes cerebral cortical neurons and suppresses spontaneous and evoked excitatory postsynaptic potentials, in the absense of any pronounced alterations in membrane resistance.