ABSTRACT
Adenosine A(1) receptors are inhibitory G-protein coupled receptors that presynaptically regulate neurotransmitter release, but their role in self-regulating adenosine release is not known. In this study, we examined the modulation of evoked adenosine and dopamine efflux by A(1) receptors and studied whether D(1) receptors mediate these effects. Fast-scan cyclic voltammetry at carbon-fiber microelectrodes was used for the simultaneous detection of adenosine and dopamine efflux on a subsecond time scale. Short electrical stimulation trains delivered to the substantia nigra (60 pulses, 60 Hz) were used to evoke dopamine and adenosine release in the striatum. The adenosine A(1) receptor agonist N(6)-cyclopentyladenosine (CPA, 1 mg/kg, i.p.) decreased both adenosine and dopamine efflux, although the effect for adenosine occurred more quickly than for dopamine. The A(1) antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 6 mg/kg, i.p.) increased stimulated adenosine release. The effects of CPA were partially attenuated by the dopamine D(1) receptor antagonist SCH-23390. Thus, A(1) and D(1) receptors have a synergistic interaction that modulates both stimulated adenosine and dopamine. The decrease in adenosine is not a downstream effect of lowered dopamine release, as decreasing dopamine synthesis and release with α-methyl-p-tyrosine or increasing release with haloperidol had no effect on adenosine release. This study shows that A(1) receptors have some characteristics of an autoreceptor, including self-regulation of adenosine release.
Subject(s)
Adenosine/metabolism , Corpus Striatum/metabolism , Receptor, Adenosine A1/physiology , Adenosine/analogs & derivatives , Adenosine/pharmacology , Adenosine A1 Receptor Agonists/pharmacology , Adenosine A1 Receptor Antagonists/pharmacology , Analysis of Variance , Animals , Benzazepines/pharmacology , Dopamine/metabolism , Dopamine Antagonists/pharmacology , Drug Interactions , Electric Stimulation/methods , Electrochemistry/methods , Electrodes, Implanted , Male , Models, Biological , Neural Pathways/physiology , Rats , Rats, Sprague-Dawley , Substantia Nigra/physiology , Time Factors , Ventral Tegmental Area/physiology , Xanthines/pharmacologyABSTRACT
BACKGROUND: Glutamate transporters [also named excitatory amino acid transporters (EAATs)] bind and take up extracellular glutamate, a major excitatory neurotransmitter, and can regulate glutamatergic neurotransmission in synapses. As anaesthesia is proposed to be induced by enhancing inhibitory neurotransmission, inhibiting excitatory neurotransmission, or both we hypothesize that inhibition of EAAT activity can increase the anaesthetic requirement. METHODS: The minimum alveolar concentration (MAC, the anaesthetic concentration required to suppress movement in response to noxious stimulation in 50% of subjects) for isoflurane was determined in adult male Sprague-Dawley rats after intrathecal administration of EAAT inhibitors. RESULTS: Application of DL-threo-beta-benzyloxyaspartate, a selective EAAT inhibitor, dose- and time-dependently increased the MAC for isoflurane. The MAC was 109 (1)% and 116 (4)% of the baseline, respectively, for 0.2 and 0.4 micromol of DL-threo-beta-benzyloxyaspartate 15 min after the injection of the drug (n=5, P<0.05 compared with the baseline MAC). Intrathecal injection of dihydrokainate, a selective inhibitor of EAAT type 2, also increased the MAC for isoflurane. CONCLUSIONS: These results suggest that EAAT in the spinal cord can regulate the requirement of isoflurane to induce immobility. EAAT2 may be involved in this effect.
