Elsevier

Neuroscience

Volume 94, Issue 3, October 1999, Pages 775-783
Neuroscience

Neurotensin depolarizes cholinergic and a subset of non-cholinergic septal/diagonal band neurons by stimulating neurotensin-1 receptors

https://doi.org/10.1016/S0306-4522(99)00364-4Get rights and content

Abstract

Identified cholinergic and a subtype of non-cholinergic, fast-firing neurons were recorded intracellularly in vitro from slices of guinea-pig brain. Recorded neurons were within the boundaries of the medial septum and vertical limb of the diagonal band of the forebrain. The effects of superfused neurotensin and neurotensin receptor antagonists were measured under single-electrode current clamp. Neurotensin consistently caused a dose-dependent, slow depolarization of cholinergic neurons that was accompanied by an increase in membrane resistance and a block of the long-duration (1–10 s) post-spike afterhyperpolarization when present. Neurotensin also blocked a shorter duration, slow afterhyperpolarization, but only in a minority of cholinergic neurons. When present, inhibition of the slow afterhyperpolarization changed the spike pattern from single spikes to short bursts. Inhibition of post-spike afterhyperpolarizations by neurotensin reversed more slowly than did other effects of neurotensin. Tetrodotoxin did not prevent the depolarizing effect of neurotensin. The non-selective neurotensin receptor antagonist, SR142948A, blocked the depolarizing effect of neurotensin but the low-affinity receptor antagonist, levocabastine, did not. A subgroup of non-cholinergic, fast-firing neurons (23%) was also depolarized by neurotensin, an effect antagonized by SR142948A but not levocabastine. Neurotensin did not effect post-spike voltage transients or change the firing pattern of non-cholinergic neurons.

These data suggest that neurotensin causes a slow depolarization and increased excitability of cholinergic and some non-cholinergic neurons in an area of the brain that projects to the hippocampus. Neurotensin type 1 receptors appear to mediate these effects. Neurotensin may modulate hippocampal-dependent learning and memory processes through its effects on septohippocampal neurons.

Section snippets

In vitro slice preparation

Preparation of brain slices for electrophysiological recordings was done as described previously.17., 33. In brief, male and female albino guinea-pigs (Harlan Sprague–Dawley) weighing 200–400 g were decapitated, and the brain was quickly removed and placed in ice-cold oxygenated physiological solution. The forebrain was trimmed with a razor blade and fixed to a vibrating tissue slicer chuck with cyanoacrylate glue. Coronal slices of the forebrain (400–500 μm) were cut 0.5–2 mm anterior to the

Effects of neurotensin on membrane potential and membrane resistance

A sample of 47 MS/vDB neurons was recorded in slices of guinea-pig forebrain. Twenty-five neurons were classified as cholinergic neurons based upon previously established electrophysiological characteristics.17., 18., 19. Twenty-two neurons were classified as non-cholinergic, fast afterhyperpolarization (fast AHP) type neurons. A third type of MS/vDB neuron, a burst-firing type neuron, was found too infrequently to be included in this study. Table 1 summarizes some of the active and passive

Increase in cholinergic neuron excitability: likely mechanisms

Data presented here suggest that NT induces a slow depolarization of cholinergic MS/vDB neurons. Depolarization was accompanied by a small increase in membrane resistance in most neurons, and a decrease in the Ca2+-dependent K+ current that is responsible for the long component of the post-spike AHP (long AHP). The long AHP is most probably the apamin-insensitive AHP that has been seen after single spikes or spike trains in these and other neurons.33., 44., 47. The long AHP in MS/vDB neurons

Conclusions

NT was found to have multiple effects on cholinergic and non-cholinergic MS/vDB neurons that together resulted in a slow depolarization, reduced post-spike AHPs and enhanced excitability. Cholinergic neurons with a sufficiently large low-voltage-activated calcium current could be induced to fire in bursts. The actions of NT appear to be mediated by NT-1 receptors. Selective stimulation of basal forebrain NT-1 receptors may hold promise for increasing cortical cholinergic tone in diseases such

Acknowledgments

This work was supported by an MBRS research grant from NIH (GM0803; J. G. Townsel, administrative P.I.) and by an HBCU research grant supplement from NIH (DA05255; C. Napier, P.I.).

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