Adenosine inhibition of mesopontine cholinergic neurons: implications for EEG arousal - PubMed (original) (raw)

Adenosine inhibition of mesopontine cholinergic neurons: implications for EEG arousal

D G Rainnie et al. Science. 1994.

Erratum in

Abstract

Increased discharge activity of mesopontine cholinergic neurons participates in the production of electroencephalographic (EEG) arousal; such arousal diminishes as a function of the duration of prior wakefulness or of brain hyperthermia. Whole-cell and extracellular recordings in a brainstem slice show that mesopontine cholinergic neurons are under the tonic inhibitory control of endogenous adenosine, a neuromodulator released during brain metabolism. This inhibitory tone is mediated postsynaptically by an inwardly rectifying potassium conductance and by an inhibition of the hyperpolarization-activated current. These data provide a coupling mechanism linking neuronal control of EEG arousal with the effects of prior wakefulness, brain hyperthermia, and the use of the adenosine receptor blockers caffeine and theophylline.

PubMed Disclaimer

Figures

Fig. 1

Fig. 1

Endogenous AD exerts a tonic inhibition in the LDT and DBB, in vitro. (A) Spike frequency histogram of extracellularly recorded action potential firing in a neuron of the LDT. Superfusion with AD (100 μM) causes a marked reduction of firing frequency and CPT (10 μM) causes a prolonged increase in firing frequency. (B) In the DBB, application of CPT (10 μM) similarly increases firing rates, and subsequent exogenous AD decreased firing rates. (C) Application of 8-_p_-ST (50 μM) mimics the effect of CPT in an LDT neuron. (D) Whole-cell voltage-clamp recording of the response of a histochemically identified LDT cholinergic neuron to OPT application. _E_m, membrane potential. Digital subtraction of steady-state voltage-current relations obtained before and during OPT (10 μM) reveals a CPT-induced current with voltage and kinetic characteristics of _I_h. (Inset) Enhanced inward relaxation during CPT application. The relatively hyperpolarized reversal potential for _I_h may reflect a small additional presynaptic input evoked by CPT.

Fig. 2

Fig. 2

Exogenous AD application reduces an inwardly relaxing _I_h current in LDT neurons. (A) Current traces of an LDT neuron before and during AD application. Voltage step commands (−10 to −50 mV; 500 ms) from a holding potential of −60 mV reveal a slow inwardly relaxing current of increasing amplitude (upper traces). The presence of AD (20 μM) reduces the expression of the inward relaxation (lower traces). (B) A plot of the voltage-current relation determined for the inward relaxation before and during AD application. (Inset) The inward relaxation current (_I_relax) was calculated by subtraction of the instantaneous current (_I_i) from the steady-state current (_I_ss) for each of the current traces in (A).

Fig. 3

Fig. 3

Exogenous AD application evokes a membrane hyperpolarization mediated by activation of an inwardly rectifying K+ conductance in neurons of the LDT. (A) In a whole-cell current-clamp recording, AD evokes a membrane hyperpolarization and an associated decrease in membrane input resistance. (B) Current trace from another neuron voltage clamped at _V_h = −60 mV. Application of AD evokes an outward current and an associated increase in membrane conductance. Downward deflections in (A) and (B) reflect the voltage and current response to 100-pA, 20-mV hyperpolarizing step commands 200 ms in duration that were used to determine the resistance and conductance. (C) A plot of AD current as a function of membrane potential reveals AD activation of an inwardly rectifying K+ conductance. AD current was calculated by digital subtraction of the current evoked by “ramping” the neuron from −100 to −40 mV [see (B)] in control from that obtained during AD application. (D) AD chord conductance G as a function of membrane potential is well fit by a Boltzmann equation (dashed line) with a half-activation potential _V_1/2 of −85 mV and a slope factor of k = 9 [same neuron as in (C)].

Similar articles

Cited by

References

    1. The behavioral effects of caffeine and theophylline seem to derive from their activity as adenosine antagonists [inhibition constant Kl < 60 μM for the A1 and A2 receptors; Sattin A, Rall TW. Mol. Pharmacol. 1970;6:13.; Ponjs F, Bruns F, Daly JW. J. Neurochem. 1980;34:1319. Snyder SH. Annu. Rev. Neurosci. 1985;8:103. rather than their activity as either phosphodiesterase inhibitors [constant for 50% inhibition IC.50 > 350 μM; Choi OH, Shamin MT, Padgett WL, Daly JW. Life Sci. 1988;43:387. or mediators of intracellular calcium release [median effective concentration EC50 = 6 mM; McPherson PS, et al. Neuron. 1991;7:17. Kuba K. J. Physiol. 1980;298:547. Neering IR, McBurney RN. Nature. 1984;309:158. Freil DD, Tsien RW. J. Physiol. 1992;450:217.
    1. Borbély AA. Hum. Neurobiol. 1982;1:195. - PubMed
    2. Feinberg I, et al. Electroencephalogr. Clin. Neurophysiol. 1985;61:134. - PubMed
    1. Horne J. Experientia. 1992;48:941. - PubMed
    1. McGinty D, Szymusiak R. Trends Neurosci. 1990;13:480. - PubMed
    1. Yanik G, Glaum S, Radulovacki M. Brain Res. 1987;403:177. - PubMed
    2. Virus RB, et al. Neuropsychopharmacology. 1990;3:243. - PubMed

MeSH terms

Substances

LinkOut - more resources