Role of the ventromedial nucleus of the thalamus in motor behaviour—I. Effects of focal injections of drugs

An assortment of drugs was injected into one or both ventromedial nuclei of the thalamus, to see how these influenced stereotypy, locomotion and posture in spontaneously behaving and actively rotating rats. Unilateral intrathalamic muscimol promoted weak ipsiversive circling, while bilateral treatment gave catalepsy. Similar injections of 4-amino-hex-5-enoic acid, which inhibits γ-aminobutyrate metabolism, raised γ-aminobutyrate levels in the ventromedial nuclei more than three-fold yet had none of these behavioural effects. The indirectly acting γ-aminobutyrate agonists flurazepam and cis-1,3-aminocyclohexane car☐ylic acid had little effect on posture and locomotion and, like muscimol and 4-amino-hex-5-enoic acid, elicited only very weak stereotypies. Procaine behaved like the γ-aminobutyrate antagonist bicuculline, provoking vigorous locomotor hyperactivity and teeth chattering if given uni- or bilaterally. Pretreatment of one ventromedial nucleus with muscimol or 4-amino-hex-5-enoic acid, and to a lesser extent flurazepam or cis-1,3-aminocyclohexane car☐ylic acid, gave rise to pronounced ipsilateral asymmetries when combined with a large systemic dose of apomorphine. Contraversive rotations were initiated by unilateral stereotaxic injection of muscimol into the substantia nigra pars reticulata, or with apomorphine from the supersensitive striatum in unilaterally 6-hydroxydopamine lesioned rats. Drug treatments in the ipsilateral ventromedial nucleus showed a similar rank order of potency at inhibiting these circling behaviours, seemingly by reducing apomorphine-induced posture and muscimol-induced hypermotility. The suppression of circling by muscimol in these tests was highlighted by introducing the compound into the ventromedial nucleus at the height of circling activity. Both types of circling stimulus lost the capacity to increase locomotion, but still caused head turning and stereotypy in rats made cataleptic with bilateral ventromedial muscimol. Treating one ventromedial thalamus with muscimol greatly intensified any pre-existing posture directed towards that side, and vice versa.

These data suggest that the ventromedial nucleus is not involved with the expression of stereotyped behaviours, but can profoundly influence posture and locomotion, especially in the presence of some other motor stimulus. The recovery of circus movements in rats with impaired ventromedial nucleus function implies this nucleus is not essential for the execution of circling in these models.     

Effects of L-DOPA on GABA metabolism in chick brain and retina

The effects of an oral subacute treatment with l-DOPA on GAD, GABA and GABA-T in chick n. basalis (homologous to the mammalian striatum), brain hemispheres, brain-stem and retina were studied. A significant increase in n. basalis GAD activity associated with an increase in GABA content and decrease of GABA-T activity was shown to occur. Similar effects were observed in the brain-stem except for GABA-T which was stimulated. In contrast, in brain hemispheres, l-DOPA produced a decrease in GAD and GABA-T activity. No changes, however, were observed in GAD activity at the retinal level, whereas GABA-T activity was significantly decreased and GABA content increased. In conclusion, the present experiments show that in some areas of the brain the administration of l-DOPA is able to affect GABA turnover.     

Multiple effects of repeated administration of γ-acetylenic gaba on rat brain metabolism

When 4-amino-hex-5-ynoic acid, the acetylenic analogue of GABA, is given chronically to rats (50 mg/kg) over a period of 8 days, several biochemical modifications are found in the brain. The following enzymatic activities are severely affected: GABA-T, GAD, Ala-T and to a lesser extent GOT and CSA-T. The drug does not appear to interfere with pyridoxal phosphate synthesis. Increases in cerebral GABA, glutamate, alanine, phenylalanine, ornithine and taurine levels were observed. There were no changes in the levels of GAD and GABA-T apoenzymes despite a chronic increase in the brain GABA level. These biochemical alterations are accompanied by behavioural changes including ‘grand mal’ like seizures and a modification of feeding activity. Considering the multiple biochemical effects of the drug, these behavioral changes are probably not related to a specific alteration in GABA metabolism.     

The effect of the convulsant allylglycine (2-amino-4-pentenoic acid) on the activity of glutamic acid decarboxylase and the concentration of GABA in different regions of guinea pig brain

Intraperitoneal administration of allylglycine to guinea pigs resulted in convulsions approximately 3 hr later. The concentration of GABA and the activity of GAD were significantly reduced in three brain areas, namely the cochlear nucleus, inferior colliculus and cerebral cortex, with the smallest changes being observed in the cortex. There were large in vitro regional variations in the extent of the allylglycine inhibition in brain areas from guinea pig, cat and rat, with those areas rich in GAD activity being least affected. Endogenous GAD activities in the brain regions were found to be inversely correlated with the percentage allylglycine inhibition (P < 0.005). Other inhibitors of GAD activity i.e. NaCl, Zn²⁺ and thiosemicarbazide showed no such regional variation of inhibition. The results suggest that the regional differences in allylglycine inhibition reflect anomalies of the metabolism of the drug per se, and probably do not indicate regional differences in GABA turnover and metabolism.     

Topological analysis of the brainstem of the reedfish, Erpetoichthys calabaricus

The neuronal distribution of 7-aminobutyric acid (GABA) transaminase (GABA-T), the enzyne which metabolizes GABA, has been mapped in rat brain. The method involves staining for newly synthesized GABA-T by the previously established nitro blue tetrazolium technique in animals killed 8–48 hours after administration of gabaculine, an irreversible inhibitor of GABA-T. Neuronal staining is obscured by staining of other elements if initial suppression is inadequate or survival times postgabaculine are too long. With appropriate conditions, GABA-T-positive neuronal somata can be widely detected. The stained cells include neuronal groups previously reported to be GAB Aergic on the basis of glutamate decarboxylase (GAD)-col-chicine immunocytochemistry and other methods, i.e.: Purkinje, basket, Golgi, and stellate neurons of the cerebellum; basket and stellate neurons of the hippocampus; granule and periglomerular cells of the olfactory bulb; magnocellular neurons of the hypothalamus; and neurons of the striatum, pallidum, entopeduncular nucleus, cortex, medial septal area, diagonal band, substantia innominata, reticular nucleus of the thalamus, substantia nigra, and dorsal raphe. Other cells that stain intensely for GABA-T and may be GABAergic include neurons in the midlateral septal area, accumbens, the central medial and basal. nucler of the amyugdala, zona in certa, the brainstem reticular formation, central gray, interstitial nucleus of Cajal, and various thalamic nuclei including the periventricular, intralami-nar, rhomboid, and subparafascicular. Known non-GABA neuronal groups are negative for GABA-T staining under these conditions, reinforcing the hypothesis that GABA neurons are far more GABA-T intensive than other neurons.     

Distribution of sodium valproate and gaba metabolism in cns of the rat

The distribution of VPA has been investigated in several brain areas of the rat, and GABA increases were measured. A biphasic exponential decay was observed for VPA; the slowest decrease was noted in the olfactory bulbs and in the hypothalamus where GAD and GABA-T activities were the highest. The data may be correlated with the prolonged effect of VPA in these areas.     

小鼠肝匀浆对脑GABA降解的抑制作用

用偶联酶学荧光分光光度法测定脑GABA-T活性,在小鼠肝昏迷模型中证实了Ferenci等报道的肝昏迷兔血清能抑制脑GABA降解的实验结果,并首次报道了正常及肝昏迷小鼠LHS对脑GABA降解也有抑制作用。说明正常肝细胞中存在有对脑GABA降解有抑制作用的物质。它是肝脏特有的或主要存在于肝脏。对GABA降解抑制物参与肝昏迷发病机制的可能性进行了讨论。     

Epilepsy in the Renaissance: A survey of remedies from 16th and 17th century German herbals

Ethnopharmacological relevance

Before modern anticonvulsive drugs were developed people in central Europe used herbal remedies to treat epilepsy. Hundreds of different plants for this indication can be found in German herbals of the 16th and 17th centuries. Here we compile these plants and discuss their use from a pharmacological perspective.

Materials and methods

Nine of the most important European herbals of the 16th and 17th century including Bock (1577), Fuchs (1543), Mattioli (1590), 103 and 104, Brunfels (1532), Zwinger (1696), and Tabernaemontanus (1591, 1678) were searched for terms related to epilepsy, and plants and recipes described for its treatment were documented. We then searched scientific literature for pharmacological evidence of their effectiveness. Additionally the overlapping of these remedies with those in De Materia Medica by the Greek physician Dioscorides was studied.

Results

Two hundred twenty one plants were identified in the herbals to be used in the context of epilepsy. In vitro and/or in vivo pharmacological data somehow related to the indication epilepsy was found for less than 5% of these plants. Less than 7% of epilepsy remedies are in common with De Materia Medica.

Conclusions

Numerous plants were used to treat epilepsy in the 16th and 17th centuries. However, few of these plants have been investigated with respect to pharmacological activity on epilepsy related targets.     

Effect of contraceptive steroids on gamma-aminobutyric acid metabolism and pyridoxal kinase activity in rat brain

Adult female albino rats were administered oral contraceptive steroids daily for 3 months and γ-aminobutyric acid (GABA) content as well as the GABA metabolizing enzyme(s) activity were assayed. GABA content of the brain was found to be elevated in both estrogenic and progestogenic hormone-treated animals. However, no significant change was observed either in glutamic acid decarboxylase (EC 4.1.1.15) activity or in γ-aminobutyric acid transminase (EC 2.6.1.19) activity of brain tissue in hormone-treated animals. Interestingly, parallel to the increase of GABA content, a concomitant elevation of pyridoxal kinase (PL-kinase) (EC 2.7.1.35) activity was observed. It seems that the increase in the GABA concentration by the contraceptive steroids might have been mediated through an elevated pyridoxal kinase activity of the brain. The possible mechanism and interrelationship between the metabolic activities is discussed.     

Irreversible inhibitors of GABA transaminase induce antinociceptive effects and potentiate morphine

The irreversible inhibitors of GABA-transaminase, γ-acetylenic GABA and γ-vinyl GABA, were examined for antinociceptive actions in rodents. An antinociceptive effect unaccompanied by ataxia was demonstrated in mice on the 52°C hot-plate and in rats in a tail-stimulation procedure and was maximal at 4–6 hr after drug administration, which correlates temporally with reported maximal increases of brain GABA. The antinociceptive effect was antagonized by a subconvulsive dose of bicuculine (0.5 mg/kg, i.p.) in rats, but could not be prevented by naloxone (1 mg/kg, i.p.) in mice. Only the (+)-stereoisomer γ-vinyl GABA, active as a GABA-transaminase inhibitor, was antinociceptive. The effects appear to be causally related to elevated cerebral GABA levels. The profile of these agents in the tail stimulation test in rats suggests a specific antinociceptive effect since vocalization and vocalization after-discharge were similarly affected. The analgesic actions of morphine in mice on the 56°C hot-plate were enhanced 5 hr after the administration of γ-acetylenic GABA or γ-vinyl GABA. The compounds did not alter the naloxone-precipitated morphine withdrawal syndrome in the rat.It is concluded that γ-acetylenic GABA and γ-vinyl GABA can produce distinct antinociceptive effects in rats and mice related to increased brain GABA levels, but which are not opioid-like in nature.