Studies on Adenosine and Calcium Antagonists in Rat Brain

Adenosine is an endogenous neuromodulator that can impose an inhibitory action on synaptic transmission in the peripheral and central nervous system. In the central nervous system the mechanism by which adenosine acts is unclear. One proposed mechanism is by an action at presynaptic calcium channels to reduce calcium influx and subsequent neurotransmitter release. Three approaches were used to study interactions between adenosine and calcium related events. A neurochemical approach was used to determine the action of adenosine on presynaptic calcium uptake in central nervous tissue. Electrophysiological techniques were employed in the hippocampal slice preparation to study a) the interactions between calcium channel blockers and adenosine compounds and b) the effect of magnesium free ACSF on the inhibition of synaptic transmission by adenosine. Determination of the uptake of radiocalcium into rat brain synaptosomes across potassium activated voltage dependent calcium channels demonstrated that adenosine compounds could impose a small but significant inhibition on calcium uptake. A similar action was demonstrated on calcium uptake into hippocampal slices, an action that was effectively antagonized by the adenosine antagonist 8-phenyltheophylline The dihydropyridine class of calcium channel blockers do not affect synaptic transmission in the hippocampal slice, but they do affect the action of adenosine and adenosine analogues. Nifedipine and BayK 8644, a dihydropyridine calcium channel blocker and activator respectively, both act to increase the inhibition of synaptic transmission by adenosine while attenuating the inhibitory action of the adenosine analogues. This interaction appears to involve an effect at both the adenosine receptor and the nucleoside transport system. In the hippocampal slice the inhibitory action of adenosine on the synaptically evoked population potential was markedly attenuated, and in some cases totally abolished, when magnesium ions were omitted from the artificial cerebrospinal fluid bathing the slice. The proposed explanation for this effect is that activation of NMDA receptor associated channels directly reduces the inhibitory action of adenosine on synaptic transmission. The results of this study into the action of adenosine on calcium channel associated actions confirm the ability of adenosine to reduce presynaptic calcium influx. It also highlights an interaction between adenosine and the dihydropyridines and provides evidence for an interaction between adenosine inhibition of synaptic transmission and activation of NMDA receptor operated calcium channels

Changes in adenosine sensitivity in the hippocampus of rats with streptozotocin induced diabetes

1Hippocampal slices have been used to assess the sensitivity of the CNS to adenosine and γ-aminobutyric acid (GABA) in diabetes. The effects of adenosine, 2-chloroadenosine, GABA, muscimol and baclofen were studied on orthodromic synaptic potentials recorded in the CA1 region of slices taken from normal rats or animals made diabetic by the injection of streptozotocin.2In diabetic animals the sensitivity to adenosine was increased 4 fold compared with normal rats. The potency of 2-chloroadenosine was unchanged.3The nucleoside transport inhibitor, hydroxynitrobenzylthioinosine (HNBTI), increased the potency of adenosine in slices from normal rats but not in slices from diabetic rats.4No change was observed in the potency of GABA or muscimol, although a small but significant decrease was detected in the EC50 value for baclofen.5Treatment of diabetic animals with insulin restored the potency of adenosine to control levels.6It is concluded that the diabetic state is accompanied by substantial changes of adenosine sensitivity due to the loss of nucleoside uptake processes. Secondary neurochemical changes following from this in human diabetic patients may contribute to the reported behavioural changes