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In vitro studies on central and peripheral monoamine neurons at the ultrastructural level

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Summary

Using ice-cold 3% potassium permanganate as a fixative (Richardson, 1966), isolated tissues from the central and peripheral nervous system were investigated in the electron microscope, with the object of identifying monoamine-containing neurons at the ultrastructural level. Thin brain slices and peripheral tissues from untreated rats and from rats treated with drugs interfering with monoamine metabolism (e.g. reserpine, H 44/68 or tetrabenazine) were incubated in physiological buffer solutions without and with monoamines in different concentrations. In certain cases, drugs interfering with monoamine metabolism (e.g. amphetamine, desipramine, cocaine or phenoxybenzamine) in different concentrations were added to the incubation medium.

The brain regions and peripheral tissues investigated were chosen on the basis of fluorescence-microscopical studies on the distribution of monoamine neurons (Fuxe, 1965c; Malmfors, 1965c; Norberg, 1965). In the brain, the caudate nucleus — which contains a dense plexus of dopamine (DA) nerve terminals — the periventricular region of the hypothalamus — which contains a dense plexus of noradrenaline (NA) nerve terminals — and the suprachiasmatic nucleus of the hypothalamus — which contains a dense plexus of 5-hydroxytryptamine (5-HT) nerve terminals — were investigated. The cerebral cortex and the nucleus ruber, which contain only a few or no monoamine nerve terminals were used as controls. The rat iris contains a dense plexus of NA nerve terminals.

In addition, brain regions and peripheral tissues containing monoamine nerve cell bodies were studied. However, since the incubation procedure seemed to cause marked morphological changes in the cell bodies, it was not, so far, possible to localize the monoamine storage sites in them.

Evidence was obtained that so-called small granular vesicles (diameter about 500 Å) are characteristic of central and peripheral monoamine neurons, and that these vesicles represent the main storage sites of the monoamines. The evidence is summarized as follows:

  1. 1.

    Incubation of slices from untreated rats without monoamines in the medium consistently revealed small granular vesicles only in regions known to contain NA nerve terminals.

  2. 2.

    Addition of monoamines to the incubation medium caused the appearance of small granular vesicles in boutons also in regions known to contain DA and 5-HT nerve terminals. However, even very high concentrations of monoamines in the medium did not cause the appearance of small granular vesicles in regions devoid of monoamine nerve terminals, e.g. in the nucleus ruber.

  3. 3.

    In slices from rats pretreated with drugs which deplete monoamine stores (e.g. reserpine and tetrabenazine), no small granular vesicles could be seen in any region studied.

  4. 4.

    Small granular vesicles reappeared after incubation of slices from rats pretreated with monoamine-depleting drugs in media containing monoamines in sufficiently high concentrations.

  5. 5.

    This reappearance could be prevented by adding to the incubation medium drugs, which are considered to block the uptake of amines through the nerve cell membrane (e.g. cocaine).

  6. 6.

    Quantitative analysis disclosed a good correlation in different brain regions between boutons containing small granular vesicles and monoamine-containing varicosities as revealed in the fluorescence microscope. About 16% of all boutons in the caudate nucleus, about 4% in the periventricular region, and about 5% in the suprachiasmatic nucleus contained small granular vesicles.

Furthermore, evidence was obtained that large granular vesicles present in the same boutons as the small granular vesicles may also contain monoamines. It has, however, to be pointed out that large granular and agranular vesicles in general in all probability also occur in non-monoaminergic neurons and that, thus, large granular vesicles cannot be considered specific for monoamine neurons (cf. Fuxe et al., 1965, 1966).

Typical axo-dendritic synapses of type I (Gray, 1961) were demonstrated in association with probable NA and 5-HT boutons. Probable DA and 5-HT boutons were also seen lying in contact with cell bodies, suggesting the existence of axo-somatic synapses.

The presence of small granular vesicles in boutons associated with synapses of type I gives further evidence for the view that monoamines are, in fact, transmitter substances in the central nervous system, since only small granular vesicles lie close to the synaptic cleft. Thus, small granular vesicles may be considered as equivalents of the synaptic vesicles (De Robertis and Bennett, 1954; Palade and Palay, 1954) thought to store and release preformed packets of transmitter substance, e.g. acetylcholine (Katz, 1962). Large granular vesicles, on the other hand, were almost always localized to parts of the boutons relatively far away from the synaptic cleft. This finding argues against the view that large granular vesicles are directly involved in the release of transmitter substance at the synaptic cleft.

Finally, the influence of the incubation medium on the fine structure of incubated tissues was studied, showing a marked swelling of the extracellular space and certain tissue components. These changes were, however, present only in the superficial parts of the tissue slices.

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  1. Department of Histology, Karolinska Institutet, Stockholm, Sweden

    Tomas Hökfelt

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The investigation was supported by grants from the Karolinska Institutet (Reservationsanslaget), by a grant from the Swedish Medical Research Council (12X-715-04A) and by grants from “Stiftelsen Therese och Johan Anderssons Minne” and “Svenska Livförsäkringsbolags nämnd för medicinsk forskning”.

For generous supplies of drugs I am indebted to the following companies: Swedish Ciba, Sweden (Serpasil®); The Swedish Pfizer, Stockholm, Sweden (Niamid®); Hoechst Anilin AB, Göteborg, Sweden (Corbasil®); Hässle, Göteborg, Sweden, through Dr. H. Corrodi (α-methyl-DA and H 44/68); Merck, Sharp & Dohme Research Lab., Rahway, N.J., U.S.A., through Firma Lindblom and Co., Stockholm, Sweden (Aramin®); Geigy, Basel, Switzerland (Pertofran®); Hoffmann-La Roche, Basel, Switzerland (tetrabenazine).

The skillful technical assistance of Mrs. Waldtraut Hiort and Mrs. Hjördis Köszeghy is gratefully acknowledged.

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Hökfelt, T. In vitro studies on central and peripheral monoamine neurons at the ultrastructural level. Z. Zellforsch. 91, 1–74 (1968). https://doi.org/10.1007/BF00336984

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