GABAergic Processes Research Articles

Dopamine in manic depressive illness: A pharmacological synthesis

If the clinical symptoms of mania are a consequence of increased activity in central dopaminergic (DA) pathways in predisposed individuals, then drugs increasing DA neurotransmission should precipitate or exacerbate mania in such people, whereas drugs which reduce DA neurotransmission should ameliorate manic symptoms. Of the drugs which enhance DA neurotransmission, those which increase synthesis of DA (levodopa), those which promote DA release (amphetamine), and those which act directly as agonists or DA receptors (bromocriptine) have all been shown to precipitate mania. Conversely, drugs which reduce DA neurotransmission by inhibiting synthesis (α-methylparatyrosine) or by blocking DA receptors (pimozide) are effective in reducing manic symptoms. DA systems are not working in isolation; evidence is presented showing an influence on manic illness of central cholinergic and GABA-ergic processes. It is suggested that there is an interacting set of neurotransmitter pathways linking the limbic system and the ventral tegmental (A10) are involving DA, acetylcholine and GABA upon which drugs can act to influence the course of a manic illness.

Modulatory and inhibitory processes in the visual cortex

The functional role of three putative neurotransmitter systems in the visual cortex is compared; the GABAergic inhibitory interneurons, the interneurones containing somatostatin and the cholinergic input originating from the nucleus basalis of Meynert (nbM). Evidence is presented to support the role of GABAergic processes in the generation of the functional structure of the visual cortex and the view that the cholinergic input exerts a neuromodulatory influence enhancing stimulus selective responses. Although the neuropeptide somatostatin produces facilitatory and inhibitory effects on visual cortical cells there is no clear functional pattern to its action. The possible significance of this data and the interaction of SSt with GABA is discussed in the light of evidence that they may coexist in some cells.

Histochemische und biochemische Untersuchungen am Hippocampus und Neocortex der Wistarratte: I. Carboxylsäureesterasen, Transmitterenzyme und Transmitter im Normaltier

Some enzymatic parameters of neuronal transmission as well as the occurrence and the properties or carboxylic ester hydrolases in the hippocampal region of the wistar rat are investigated by histochemical and comparable biochemical methods. The acetylcholinesterase-, the monoamine oxidase- and the GABA-transaminase reaction are found at fibre structures, the course of which is seen more or less clearly. The histochemical picture of these enzymes is very different in each hippocampal layer and mainly limited by the corresponding number of reacting fibres. The origin and attribution of the fibres to the afferent and efferent systems are discussed. The occurrence of the acetylcholinesterase, the monoamine oxidase and the GABA-transferase as well as of the biogenic amines and the GABA are hints for the existence of cholinergic as well as aminergic and GABA-ergic processes of transmission in the hippocampal region. In the hippocampal region, the cingular and the optic cortex carboxylic ester hydrolases acetylcholinesterase, unspecific cholinesterase and the A-, B- and C-esterase could be demonstrated. The acetylcholinesterase of the hippocampal region is for the most part firmly membrane-bound and exists at least in two multiple, formalin-sensitive forms which are histochemically located in fibre structures. The unspecific cholinesterase, localized in the hippocampal region within vessel and capillary walls, exists in an electrophoretic mobile, formalin-sensitive form. Nearly half of the enzymes is soluble. A preferred binding to definite cell organelles was not demonstrable. In the hippocampal region the 3 multiple forms of the A-esterase are formalin-instable lyoenzymes. Good solubility and high formalin-sensitivity are the reason, why A-esterases are not demonstrable with usually histochemical methods. In the hippo ampal region the B-esterase is tightly bound to n electrophoretic mobile formalin-sensitive form in the microsomal fraction. In the cytoplasm of the neurones the desmoenzyme appears more or less granular. The 3 multiple forms of the C-esterase are formalin-sensitive to a different degree. Good solubility and low formalin-sensitivity, compared to the A-esterases are responsible for the fact, that the C-esterases can be shown histochemically only after en-bloc-fixation. The reaction products are granular. The similar behaviour of C-esterase and acid phosphatase, stated by many tests, suggests the C-esterases of the B- and C-type results in the same reactivity of pyramidal and granular cells of the hippocampal region. Some small, very strongly reacting cells belong to other cell types (probably basket cells or polymorphic cells).

Gabaergic processes involved in the control of dopamine release from nigrostriatal dopaminergic neurons in the cat

Push-pull cannulae were used to study the release of 3H-dopamine ( 3H-DA) continuosly synthetized from L-3,5- 3H-tyrosine in the caudate nucleus and the substantia nigra of the “encéphale isolé” cat. GABA (10 −5M), muscimol (10 −6 M), γ-hydroxybutyrate (GHB, 10 −5 M), GABA-choline (GABA-CH, 10 −5 M) and amino-oxyacetic acid (AOAA, 10 −5 M) stimulated the release of 3H-DA in the caudate nucleus when introduced for 15 min in the superfusing medium. The initial stimulation of 3H-DA release was followed by an inhibition of transmitter release when GABA was introduced for a longer time (60 min) into the caudate nucleus. GABA (10 −5 M) had no effect on the release of 3H-DA in the substantia nigra. However, muscimol (10 −6 M), GHB (10 −5 M) and baclofen (10 −6 M) stimulated the dendritic release of 3H-DA when each was introduced for 15 min in the substantia nigra. The introduction for 15 min of GABA (10 −5 M), muscimol (10 −6 M), GHB (10 −5 M), GABA-Ch (10 −5 M) or baclofen (10 −6 M) into the substantia nigra simultaneously induced a stimulation of 3H-DA release in the ipsilateral caudate nucleus. A marked post stimulatory effect was seen with muscimol. When GABA (10 −5 M) was applied for 75 min into the substantia nigra, the initial stimulation of 3H-DA release (30 min) seen in the caudate nucleus was followed by a short-lasting inhibitory phase (15 min). This inhibition of 3H-DA release was followed by a second stimulation period. This multiphasic phenomenon was not seen with other compounds. The stimulation of 3H-DA release in the caudate nucleus induced by a 15 min nigral application of GABA (10 −5 M) was no longer seen when picrotoxin (10 −5 M) was added with GABA in the substantia nigra. On the basis of these results it is proposed that at least two types of GABAergic regulatory processes are involved in the control of the activity of the dopaminergic neurons in the substantia nigra. On the other hand, the interaction of GABA or GABA-related compounds with GABAergic receptors in the striatum may facilitate DA release from dopaminergic terminals through an intrastriatal interneuronal process. The secondary inhibition of 3H-DA release induced by GABA or GHB could be mediated by a non-GABAergic striato-nigral pathway.

Are benzodiazepines GABA antagonists?

ALTHOUGH benzodiazepines are widely used in routine medical practice their mechanism of action remains controversial1,2. Several authors have suggested that the action of benzodiazepines is to potentiate GABA-ergic processes in the central nervous system3–5. In addition, a number of studies have shown the effect of benzodiazepines to be antagonised by γ-amino-butyric acid (GABA) antagonists6,7. But, Steiner and Felix8 and Gahwiler9 have adopted the opposite view and reported that in the cerebellum and Deiters nucleus benzodiazepines antagonise the inhibitory action of GABA. On the other hand, Dray and Straughan6 have shown microiontophoretic applications of benzodiazepines to be inhibitory on the spontaneous and glutamate activity of neurones of the brain stem and were unable to confirm that benzodiazepines antagonise the action of GABA. Curtis et al.10 were also unable to confirm the results of Steiner and Felix8 on the neurones of the cerebellum and spinal cord. In the recent paper by Squires and Braestrup11 a direct interaction of benzodiazepines with GABA-receptors has been discarded. We have investigated the interaction between chlordiazepoxide (Librium) and GABA by observing the effects of simultaneous microiontophoretic application of both agents on the spontaneous and glutamate-evoked firing of single neurones of sensorimotor cortex of the rabbit and here we report that the actions of the two are synergistic.