Adenosine-mediated presynaptic modulation of glutamatergic transmission in the laterodorsal tegmentum

The laterodorsal tegmentum (LDT) neurons supply most of the cholinergic tone to the brainstem and diencephalon necessary for physiological arousal. It is known that application of adenosine in the LDT nucleus increases sleep in vivo (Portas et al., 1997) and directly inhibits LDT neurons in vitro by activating postsynaptic adenosine A₁ receptors (Rainnie et al., 1994). However, adenosine effects on synaptic inputs to LDT neurons has not been previously reported. We found that both evoked glutarnatergic EPSCs and GABAergic IPSCs were reduced by adenosine (50 μM). A presynaptic site of action for adenosine A₁ receptors on glutamatergic afferents was suggested by the following: (1) adenosine did not affect exogenous glutamate-mediated current, (2) adenosine reduced glutamatergic miniature EPSC (mEPSC) frequency, without affecting the amplitude, and (3) inhibition of the evoked EPSC was mimicked by the A₁ agonist N6-cyclohexyladenosine (100 nM) but not by the A₂ agonist N6-[2-(3,5-dimethoxyphenyl)-2-(methylphenyl)-ethyl]-adenosine (10 nM). The A₁ receptor antagonist 8-cyclopentyltheophylline (CPT; 200 nM) potentiated the evoked EPSCs, suggesting the presence of a tonic activation of presynaptic A₁ receptors by endogenous adenosine. The adenosine kinase inhibitor, 5-iodotubercidin (10 μM), mimicked adenosine presynaptic and postsynaptic effects. These effects were antagonized by CPT or adenosine deaminase (0.8 IU/ml), suggesting mediation by increased extracellular endogenous adenosine. Together, these data suggest that the activity of LDT neurons is under inhibitory tone by endogenous adenosine through the activation of both presynaptic A₁ receptors on excitatory terminals and postsynaptic A₁ receptors. Furthermore, an alteration of adenosine kinase activity modifies the degree of this inhibitory tone.