Monoamine Transmitters Research Articles

Enzymes related to monoamine transmitter metabolism in brain microvessels.

The activities of tyrosine hydroxylase, aromatic L-aminoacid decarboxylase, monoamine oxidase, and catechol-O-methyltransferase were measured in microvessel (capillaries and venules), parenchymal arterioles, and pial vessels from rat brains, and the decarboxylase activity was compared in brain microvessels from rabbit, cat, dog, pig, cow, baboon, and man. Cranial sympathectomy was performed to estimate the neuronal contribution to the enzyme activities. All vascular regions had substantial activities of the various enzymes studied. The activity of aromatic L-aminoacid decarboxylase in cerebral microvessels was high in rat, dog, pig, cow, and man; intermediate in rabbit and cat; and low in baboon. In addition to this enzyme, cerebral microvessels also contained tyrosine hydroxylase and monoamine oxidase. Aromatic aminoacid decarboxylase and monoamine oxidase serve an enzymatic barrier function at the microvascular level, whereas the main function of tyrosine hydroxylase is probably to synthesize monoamines within nerve terminals that remain in close association with microvessels under the conditions used for preparation of the microvascular fraction. In larger intracerebral and pial vessels monoamine oxidase was present both in the wall itself and in perivascular sympathetic nerves; the remaining two enzymes had a primarily neuronal localization. The latter types of vessels also contained catechol-O-methyltransferase in their walls.

Inverse relationship between whole brain monoamine levels and audiogenic seizure susceptibility in mice: Failure to replicate

Whole brain levels of 5-HT and NE in audiogenic seizure susceptible DBA mice were compared with those of the nonsusceptible C57BL/6 strain at different ages and in two separate laboratories that used different assay procedures. Contrary to previous reports, there were no significant differences between the susceptible and nonsusceptible animals in whole brain levels of either amine at the age of peak seizure susceptibility. Differential stress associated with capturing the susceptible mice had no effect on brain levels of NE. The data question the suggestion that deficits in brain monoamine transmission capable of being indexed by lower whole brain levels of NE and/or 5-HT play a role in genetically determined susceptibility to audiogenic seizures.

Mechanism of action of valproate

The anticonvulsant action of valproate differs according to the test system studied (acute animal model, chronic drug therapy) partly because of differences in pharmacokinetic and metabolic phenomena. In man, circulating valproate is largely (95%) plasma protein bound, and is eliminated slowly (t 1 2 ) = 6–16 hr ). In rodents and dogs, protein binding is less, and elimination faster ( t 1 2 1–2 hr ). Omega and beta oxidation occurs in man; intermediate metabolites (including succinyl-CoA) may be biochemically and pharmacologically active. Valproate produces a marked cerebral accumulation of acid metabolites of monoamine transmitters (HVA and 5HIAA). Enhancement of GABA-mediated inhibition remains an interesting hypothesis. Evidence is available for selective synaptic accumulation of GABA (and decrease of aspartate), but there is not yet evidence for enhanced physiological release of GABA (or decreased release of dicarboxylic amino acids). Kinetic studies on GABA-transaminase inhibition suggest that valproate, 20–50 mM, is needed to block brain GABA metabolism at this step. The effects of inhibition of succinic semialdehyde dehydrogenase or reductase by valproate on GABA-mediated synaptic inhibition need to be established.

Histofluorescence study on monoamine entry into the brain before and after opening of the blood-brain barrier by various mechanisms.

The relationship between exogenous, circulating monoamines to the wall of cerebral microvessels, and the entrance of these amines into the cerebral parenchyma was studied by the formaldehyde histofluorescence technique in rats. No monoamine fluorescence could be detected in the wall tissue of the microvessels (pericytes and andothelial cells) unless either MAO or COMT were inhibited; these are integral to the blood-brain barrier mechanisms to monoamines. After transient opening of the morphologic blood-brain barrier by either a hypertonic of hypertensive insult, the amine fluorescence in the walls of the microvessels was intensified compared to that which was noted after monoamine oxidase inhibition by itself. Following opening of the structural blood-brain barrier, the circulating amines also passed through into the neuropil where they were concentrated within neurons, as demonstrated by prior depletion of endogenous monoamine transmitters by reserpine. Thus, both enzymatic and morphologic mechanisms in the blood-brain barrier ar involved in impeding the passage of monoamines into the cerebral parenchyma.

Intracellular actions of monoamine transmitters.

Intracellular injections of noradrenaline or dopamine in spinal motoneurones of cats have a clear depolarizing action associated with particularly marked depression of spike potentials and their after-hyperpolarization, but with little slowing-down of the falling phase of the action potential. These effects are associated with an increase in input resistance, and they are reversible and reproducible in the same neurone. Intracellular injections of 5-hydroxytryptamine have some depolarizing action and increased input resistance, but they produced no comparable depression of the action potential and tended to enhance the after-potentials and increase excitability. It is concluded that changes in intracellular levels of monoamines, whether physiological or drug induced, may be of significance for central neuronal function.

Neuropharmacology and aging.

This review has attempted to convey the idea that the current concepts of psychotropic drug actions are based largely around the monoamine transmitter systems. Several of the hypotheses which implicate abnormalities of these systems as factors involved in the aging brain are discussed. It is suggested that the current lack of specific geriatric psychotropic agents is in part a reflection of our ignorance of the neurochemical basis of the aging process.

THE ROLE OF SEROTONIN AND DOPAMINE IN HYPOTHALAMIC‐PITUITARY FUNCTION

Neuroendocrinology has developed as a major discipline out of the important early concepts of Harris (1948) and the subsequent findings in the early 1960’s demonstrating that the brain and, in particular, the hypothalamus, exerted an inhibitory influence on prolactin secretion (Pasteels, 1963; Talwalker et al., 1963; Danon e t al., 1963) and a stimulating influence on growth hormone (GH) secretion from the pituitary gland (Roth et al., 1963; Abrams et al., 1964). That these hypothalamic influences were mediated by the brain monoamine transmitters was suggested from the findings of many groups (e.g. Kanematsu e t al., 1963; Ratner et al., 1965; Muller et al., 1967; Blackard & Heidingsfelder, 1968; Van Maanen & Smelik, 1968) who used drugs such as reserpine and a-adrenergic blocking agents which interfere with the activity of the brain monoamines. The individual roles of specific monoamines in hypothalamic pituitary function have been investigated in diverse ways. The use of intraventricular injection of the amines dopamine, noradrenaline and serotonin in the rat has, despite its limitations (Hokfelt & Fuxe, 1972), laid much groundwork in this area (Schneider & McCann, 1970; Kamberi et al., 1970, 1971; Marks et al., 1970; Collu et al., 1972). The development of fluorescence histochemistry (Corrodi & Jonsson, 1967; Fuxe et al., 1970) has enabled the localization of hypothalamic monoamine cell bodies to be established, as well as aspects of the function of amine neuronal groups such as the tuberoinfundibular dopaminergic (TIDA) neurons in the control of prolactin-and gonadotrophin secretion (Hokfelt & Fuxe, 1972). Another approach t o the problem of establishing in vivo the specific roles for the monoamines has been to use either precursors which produce specific monoamines, or drugs which selectively interfere with the activity of monoamines (Donoso el al., 1971;Kleinberg et al., 1971; Friesen et al., 1972; Smythe & Lazarus, 1973a, b; Smythe et al., 1973; Bivens, 1973; Plonk, 1974; Smythe & Lazarus, 1974; Smythe, 1975a, b, 1976; Muller et al., 1976; Liuzzi et al., 1976; Chambers B Chihara et al., 1976). These many procedures have established that either dopamine or serotonin is involved in some aspect of secretory control mechanisms of each of the anterior pituitary hormones.

Influence of p-chloroamphetamine on female sexual reflexes and brain monoamine levels

The effect of p-chloroamphetamine(PCA) on female sexual reflexes was biphasic. Administration of PCA to receptive females initially terminated ongoing sexual behavior and this effect was correlated with the release of monoamines, particularly serotonin (5-HT). Sexual reflexes were abolished within 15 min of PCA injection. Other reflexes, including reciprocal forepaw treading, lateral head weaving, hindlimb abduction and Straub tail, were elicited by PCA. The long term infuence of PCA was the opposite. A facilitation of female sexual behavior occurred accompanied by a relatively specific depletion of 5-HT (10 mg/kg, 66% depletion; 20 mg/kg, 80% depletion) with both dopamine and norepinephrine depleted by less than 15%. This long term facilitation of female sexual reflexes was not blocked by dexamethazone suggesting that PCA was acting directly on the neural substrate for mating and did not produce it facilitation via adrenal progesterone. This biphasic infuence of PCA on mating reflexes, paralleling its effect on monoamine transmission, suggests serotonergic involvement in the integration of mating behavior.

The use of autoradiographic techniques for the identification and mapping of transmitter-specific neurones in the brain

We now know of at least six different transmitter substances used in synaptic transmission in the mammalian CNS, In most cases, however, only fragmentary information is available on the distribution of the various categories of transmitter-specific neurone in the CNS. Thus, for example, while gamma-aminobutyric acid (GABA) is thought to be an important inhibitory transmitter substance in many regions of the CNS (for reviews see Curtis and Johnston, 1970; Hebb, 1970; Krnjevic, 1970; Iversen, 1972), it is by no means clear precisely which inhibitory neurones use GABA as transmitter, nor indeed whether any inhibitory neurones using transmitters other than GABA exist in various regions of the brain. Only in the case of the monoamine transmitters, noradrenaline (NA), dopamine (DA) and 5-hydroxytryptamine (5-HT) is there any detailed information on the distribution of neuronal pathways involving specific transmitters. This information has become available during the past ten years, following the development of histochemical techniques which allow direct visualization of formaldehyde condensation derivatives of the monoamines in the fluorescence microscope (Carlsson, Falck and Hillarp, 1962; Dahlstrom and Fuxe, 1965; Fuxe, 1965).

Antipsychotic drugs and catecholamine synapses

Publisher Summary This chapter discusses several antipsychotic drugs and catecholamine synapses. Reserpine, like certain other Rauwolfia alkaloids and some other agents, for example, the benzoquinolizines, causes depletion of monoamine stores, thereby very much reducing the amounts of monoamine transmitters available for release by the nerve impulses. If the antipsychotic agents act either as catecholamine depleters or as catecholamine receptor antagonists, it should be possible to induce similar actions by treatment with inhibitors of catecholamine synthesis. By means of α-methyltyrosine, it is possible to inhibit tyrosine hydroxylase virtually completely in experimental animals. This will result in some decrease in exploratory motor activity and disruption of conditioned behavior. However, it is difficult to attain a very severe catecholamine depletion by means of this agent because toxic doses causing crystalluria and renal damage have to be given.

Strychnine, morphine and monoamine depression

Strychnine has been applied by microiontophoresis to cells in the cerebral cortex of rats. On pyramidal tract cells no blockade of the suspected neurotransmitters noradrenaline, acetylcholine or 5-hydroxytryptamine was seen, but on nonpyramidal tract cells 25% of depressant responses to 5-hydroxytryptamine were reversibly antagonised by strychnine. Morphine has been tested similarly and has been shown not to interact with 5-hydroxytryptamine of noradrenaline. Strychnine has long been known as a convulsant alkaloid. Early neurophysiologists discovered that strychnine would cause high amplitude ‘spike’ discharges from the central nervous system (1), this being taken as the neural counterpart of strychnine seizures. Interest was therefore aroused by the report of Phillis & York (2) that in the cerebral cortex strychnine, applied by microiontophoresis, could antagonise depressant responses to suspected monoamine transmitters. Doubt is cast on this finding by the results of several groups of workers (3, 4, 5, 6, 7), who have failed to demonstrate any reduction by strychnine of either neural or noradrenaline-induced inhibition. The present study was therefore undertaken to reinvestigate the effects of strychnine on depressant responses to acetylcholine, noradrenaline and 5-hydroxytryptamine when these agents were applied by microiontophoresis to spontaneously active cells in the rat cerebral cortex. The study also investigates the possibility of an interaction between morphine and monoamine depressions. Each of the three putative transmitters tested here has been implicated in morphine's analgesic and possibly addictive properties (8, 9, 10, 11) and morphine antagonism of 5-hydroxytryptamine in the periphery is well known (12).

Glial cell function: uptake of transmitter substances.

Rabbit-brain fractions enriched in neuronal cell bodies and in glial cells accumulated norepinephrine, serotonin, dopamine, and gamma-aminobutyric acid, substances believed to serve as neurotransmitters in the central nervous system. Both neurons and glia were able to concentrate the monoamine transmitters about 4-fold from a medium containing 0.1-1 muM concentrations. However, the glial-cell fraction concentrated aminobutyrate over a 100-fold from the medium, in contrast to the neuronal fraction, which concentrated this amino acid only 4-fold. The uptake of aminobutyrate by glial cells was 30-50% of that of synaptosome preparations. Its uptake in all fractions was temperature sensitive, sensitive to metabolic inhibitors, and exhibited K(m) values of 0.72 muM for the neuronal fraction, 0.42 muM for the synaptosomal fraction, and 0.27 muM for the glial-cell fraction. These results are interpreted as evidence that the glial cell is involved in limiting the extracellular build-up of substances that might trigger synaptic transmission by removing any transmitters that may diffuse out of the synaptic cleft during the transmission of impulses. The possible function of the enormous ability of glia and synaptosomes to accumulate aminobutyrate is discussed in light of the actions and distribution of this substance in the central nervous system.

Reciprocal effects on alpha- and gamma-motoneurones of drugs influencing monoaminergic and cholinergic transmission.

AbstractThe reflex responses of α‐ and γ‐motoneurones to dorsal root stimulation were recorded in fine ventral roots or ventral root filaments of coccygeal or L6 segments in the lightly anaesthetized (Viadril®) intact rat. After administration of drugs inhibiting monoamine (MA) transmission (reset‐ pine, haloperidol, phenoxybenzamine) or facilitating acetylcholine (ACh) transmission (physostigmine) α‐motoneurone reflex responses increased and γ‐motoneurone responses decreased. After administration of drugs facilitating MA transmission (L‐DOPA) or inhibiting ACh transmission (atropine) α‐motoneurone activation decreased and γ‐motoneurone activation increased. The drugs had always reciprocal effects on α‐ and γ‐discharges, i.e. inhibition of the one type accompanied facilitation of the other. A hypothetical model is presented for the interpretation. The reciprocal changes of α‐ and γ‐motoneurone reflex activation are induced from antagonistic MA and ACh neurone systems (possibly projecting to the neostriatum). A drug induced shift of the MA‐ACh equilibrium in favour of the ACh neurones (by ACh facilitation or MA inhibition) turns muscle control towards a dominance of the a‐route. A shift of equilibrium in favour of MA neurones (by MA facilitation of ACh inhibition) turns motor control to a dominance of the γ‐route.