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

J Neurosci. 2001 Feb 1;21(3):1076-85. doi: 10.1523/JNEUROSCI.21-03-01076.2001.


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 A(1) receptors (Rainnie et al., 1994). However, adenosine effects on synaptic inputs to LDT neurons has not been previously reported. We found that both evoked glutamatergic EPSCs and GABAergic IPSCs were reduced by adenosine (50 micrometer). A presynaptic site of action for adenosine A(1) 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 A(1) agonist N6-cyclohexyladenosine (100 nm) but not by the A(2) agonist N6-[2-(3,5-dimethoxyphenyl)-2-(methylphenyl)-ethyl]-adenosine (10 nm). The A(1) receptor antagonist 8-cyclopentyltheophylline (CPT; 200 nm) potentiated the evoked EPSCs, suggesting the presence of a tonic activation of presynaptic A(1) receptors by endogenous adenosine. The adenosine kinase inhibitor, 5-iodotubercidin (10 micrometer), 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 A(1) receptors on excitatory terminals and postsynaptic A(1) receptors. Furthermore, an alteration of adenosine kinase activity modifies the degree of this inhibitory tone.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine / metabolism*
  • Adenosine / pharmacology
  • Adenosine Kinase / antagonists & inhibitors
  • Animals
  • Arousal / physiology
  • Electric Stimulation
  • Enzyme Inhibitors / pharmacology
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology
  • Female
  • Glutamic Acid / metabolism*
  • Glutamic Acid / pharmacology
  • In Vitro Techniques
  • Neural Inhibition / drug effects
  • Neural Inhibition / physiology
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism
  • Patch-Clamp Techniques
  • Potassium Channels / metabolism
  • Purinergic P1 Receptor Agonists
  • Rats
  • Rats, Long-Evans
  • Sleep / physiology
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology*
  • Tegmentum Mesencephali / cytology
  • Tegmentum Mesencephali / metabolism*
  • gamma-Aminobutyric Acid / metabolism


  • Enzyme Inhibitors
  • Potassium Channels
  • Purinergic P1 Receptor Agonists
  • Glutamic Acid
  • gamma-Aminobutyric Acid
  • Adenosine Kinase
  • Adenosine