Elsevier

Brain Research

Volume 833, Issue 2, 3 July 1999, Pages 272-277
Brain Research

Research report
Actions of 8-Bromo-cyclic-GMP on neurones in the rat thalamus in vivo and in vitro

https://doi.org/10.1016/S0006-8993(99)01556-5Get rights and content

Abstract

The diffusible intercellular messenger nitric oxide may have a modulatory role in the thalamus and this action may be mediated via activation of soluble guanylate cyclase. In order to investigate this possibility, we applied the cyclic-GMP analogue 8-Bromo-cyclic-GMP (8-Br-cGMP) onto neurones in the ventrobasal and lateral geniculate nuclei of the thalamus in anaesthetised rats, and compared its effects with those of a nitric oxide donor. 8-Br-cGMP enhanced the responses of neurones to iontophoretically applied NMDA and AMPA. Furthermore, somatosensory and visual responses of ventrobasal and lateral geniculate neurones were enhanced to 274±76% and 217±69% of control values, respectively. These effects were similar to those seen with nitric oxide donors in this study and previous work from this laboratory. When applied to thalamic neurones in an in vitro slice preparation, 8-Br-cGMP caused a membrane depolarisation associated with a decrease in input resistance. These findings indicate that activation of guanylate cyclase can cause a membrane depolarisation of thalamic neurones in vitro, and that this effect is sufficient to enhance action responses to ionotropic glutamate receptor stimulation via either exogenous agonists or sensory stimulation.

Introduction

The intercellular messenger molecule nitric oxide (NO) has been suggested to have a role in synaptic modulation in the sensory nuclei of the thalamus [7]. There are several lines of evidence in support of this suggestion: anatomical studies have revealed the presence of nitric oxide synthase (NOS) and NADPH-diaphorase in neurones ascending from the brainstem to the thalamus 2, 18, 21, 22, and nitric oxide can be released in the thalamus in vivo upon stimulation of these fibres 12, 23. Furthermore, the biosynthetic precursor of NO, l-arginine, is found in thalamic astrocytes 1, 11, and is known to be released in the thalamus upon sensory stimulation [7]. Iontophoretic application of nitric oxide donors or l-arginine to neurones in the rat ventrobasal thalamus (VB) results in a potentiation of responses to both somatosensory and excitatory amino acid stimuli 7, 16. These results are consistent with data obtained in vitro, where application of a nitric oxide donor, SIN-1, to cat and guinea pig thalamo-cortical neurones resulted in a membrane depolarisation associated with a decrease in membrane resistance [13]. This effect was mimicked and occluded by 8-Bromo-cyclic-GMP (8-Br-cGMP), a membrane-permeant analogue of the second messenger cyclic-GMP [9], suggesting that nitric oxide may exert its effects by stimulation of soluble guanylate cyclase to increase production of cyclic-GMP in the thalamus [13]. This idea is supported by the finding that there are high levels of cyclic GMP binding sites and type II cyclic-GMP- dependent protein kinase in the thalamus 3, 8. In the feline dorsal lateral geniculate nucleus (LGN) in vivo, iontophoretic application of inhibitors of nitric oxide synthesis causes a reduction in visual responses, whereas nitric oxide donors have a potentiating effect 5, 6. Similar modulatory effects are seen on NMDA responses but not responses to other excitatory amino acids in the same experiments. However, these workers could not mimic the effects of nitric oxide donors with 8-Br-cGMP [5]. There thus, appears to be some discrepancy concerning the mechanism of NO modulation of thalamic transmission.

We thus, considered it important to verify firstly, whether the effects which we have previously described with l-arginine and nitric oxide donors in VB could be mimicked by 8-Br-cGMP. Secondly, could similar effects be observed in the dLGN, as might be expected if the nitric oxide modulatory system has a similar role throughout the sensory thalamus? We have therefore, carried out a series of in vivo experiments with 8-Br-cGMP in the VB and dLGN of the rat in order to address these questions. Furthermore, we have carried out some in vitro experiments in order to provide more information concerning the mode of action of 8-Br-cGMP in the rat thalamus and to compare this with previous data obtained in the cat and guinea pig dLGN [13]. Some of these experiments have been described in abstract form [15].

Section snippets

Methods

Extracellular single-neurone recordings were made from thalamic neurones in adult rats anaesthetised with urethane (1.2 g/kg, IP) using multi-barrel glass iontophoretic pipettes, as detailed previously 14, 16. The central recording barrel of the micro-pipette was filled with 4 M NaCl; one of the outer barrels was filled with 1 M NaCl for automatic balancing of iontophoretic currents while each of the remaining outer barrels was filled with one of the following: N-methyl-d-aspartate (NMDA, 0.1

Actions of 8-Br-cGMP on LGN and VB neurones in vivo

Recordings were made from eight VB neurones and ten dLGN neurones responsive to both NMDA and AMPA and to either somatosensory (air-jet) or visual stimuli, respectively. In all of these neurones, iontophoretic application of 8-Br-cGMP (30–80 nA) resulted in a potentiation of both NMDA and AMPA responses to a similar extent (Table 1). At the same time, responses to sensory stimuli were also potentiated (Table 1). Examples of these actions are shown in Fig. 1.

It was apparent that the effects of

Discussion

Our previous work on neurones in the VB in vivo showed that l-arginine and nitric oxide donors could potentiate sensory responses, as well as NMDA and AMPA responses 7, 16. The data which we present here with SIN-1 on LGN neurones are entirely consistent with those findings, and indeed our results with SIN-1 in LGN are qualitatively similar to those which we obtained with SIN-1 in VB [16].

It is noteworthy that iontophoretic application of 8-Br-cGMP had virtually identical effects on VB and LGN

Acknowledgements

This work was supported by the Human Frontiers Science Programme.

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