Adenosine receptor antagonists such as caffeine cause dopamine-dependent behavioral arousal and hyperlocomotion in rodents. In the present study, we used the whole-cell recording technique in the rat brain slice to investigate effects of adenosine on dopamine neurons and their synaptic inputs in the substantia nigra zona compacta and ventral tegmental area. Adenosine was most potent for inhibiting the amplitude of the inhibitory postsynaptic current (IPSC) mediated by γ-aminobutyric acid (GABA)(B) receptors (EC50 = 47 ± 3 μM) compared with inhibition of the GABA(A)-mediated IPSC (117 ± 51 μM) and the excitatory amino acid-mediated excitatory postsynaptic current (119 ± 38 μM). Adenosine failed to inhibit current evoked by exogenous GABA or baclofen, suggesting that adenosine acted presynaptically to reduce GABA release from nerve terminals. Adenosine inhibited the GABA(B)-mediated IPSC by acting at the adenosine A1 receptor, because its effect was blocked by the selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3- dipropylxanthine (100 nM), as well as by the methylxanthines caffeine (1 mM) and theophylline (300 μM). The rank-order of potency of adenosine agonists [N6-cyclo hexyladenosine > R-(-)-N6-(2-phenylisopropyl)-adenosine N6- cyclohexyladenosine > 5'-N-ethylcarboxamidoadenosine > 2-chloroadenosine] also was consistent with activation of the adenosine A1 receptor, whereas the selective adenosine A(2A) agonist CGS 21680 [2-p-(2- carboxyethyl)phenethylamino-5'-N-ethylcarboxamido adenosine] had no effect on the GABA(B) IPSC. None of the adenosine agonists or antagonists affected holding current or membrane conductance. We conclude that adenosine acts at presynaptic adenosine A1 receptors to reduce release of GABA onto GABA(B) receptors on dopamine neurons. By blocking the inhibition/effect of adenosine on the GABA(B) IPSC, caffeine would be expected to increase GABA-dependent inhibition of dopamine neuronal firing rate in vivo. Suppression of dopamine neuronal firing might contribute to toxic effects of caffeine.
|Original language||English (US)|
|Number of pages||6|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - Jan 1 1995|
ASJC Scopus subject areas
- Molecular Medicine