Figure 13.3 Whole-cell patch-clamp recordings of excitatory postsynaptic currents (EPSCs) from dorsal horn neurons of rat (prenatal P2-13) spinal cord slices. The normal evoked EPSC of about 160 pA obtained by focal stimulation of nearby tissue was dramatically reduced by addition of a cocktail (CABS) of CNQX 10 ^M, D-APV 50 ^M, bicuculline 10 ^M and strychnine 5 ^M to block glutamate, GABAa and glycine receptors. The small residual EPSC shown was blocked by the ATP P2 receptor antagonist suramin and is therefore probably mediated by released ATP. (From Bardoni et al. 1997 and reproduced by permission of the Journal of Neuroscience)
to reduce the release of a number of NTs it has a strong inhibitory effect on central neurons, enhancing neuronal after-hyperpolarisation through a Ca2+-dependent change in K+ conductance probably through A2 receptors. The Aj receptor appears to be negatively linked to adenylate cyclase through Gi and may mediate the presynaptic inhibition of NT release, with the A2 acting positively through Gs.
Adenosine comes from the breakdown of ATP. This may occur either extracellularly (Fig. 13.2) or intraneuronally followed by evoked release or transport. Its basal extracellular level is 2 ^M but this can increase rapidly when neuronal firing increases and can rise some twentyfold during seizures. The two enzymes responsible for its breakdown are adenosine kinase (Km = 2 ^M) and adenosine deaminase (Km = 50 ^M). It will be clear that as more adenosine is released during seizures, it will quickly saturate the kinase and its concentration can therefore only be controlled by deaminase. In fact deaminase but not kinase inhibitors are anticonvulsant as is adenosine and its analogues, while its antagonist theophylline is proconvulsant and a central stimulant. Adenosine has even been promoted as an endogenous 'anticonvulsant' (see Dragunow 1986). While that may not be realistic, the antiepileptic benzodiazepine drugs, in addition to their effects on GABA receptors, have been shown to increase the efflux of [~3H] adenosine from the rat cortex probably by blocking its uptake and adenosine is often considered to be an endogenous limiter of neuronal activity. Despite this it has also been shown to reduce fast inhibitory postsynaptic potentials (IPSPs) in the rat lateral amygdala probably by presynaptic A1 inhibitory effect on GABA release (Henbockel and Pap 1999). Adenosine has also been considered to play a role in sleep induction (Chapter 22).
Recently much interest has been shown in the possible neuroproctive effects of adenosine but the responses are complex. Thus A3 agonists can offer some protection given chronically before ischaemic challenge but given acutely post-challenge they can be neurotoxic (see Jacobsen 1998).
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