GABA-mimetic Drugs Research Articles

GABA-mimetic drugs enhance apomorphine-induced contralateral turning in rats with unilateral nigrostriatal dopamine denervation: implications for the therapy of Parkinson's disease.

The underlying mechanisms responsible for advanced Parkinson's disease's becoming refractory to dopamimetic therapies are unclear. Postmortem brain studies indicate that patients with Parkinson's disease have decreased basal ganglia gamma-aminobutyric acid (GABA) function in addition to profound striatal dopamine (DA) deficiencies. In experimental animals, GABA-utilizing striatal and nigral projection neurons appear to mediate motor behaviors arising from the stimulation of striatal DA receptors by agonists. We have examined the ability of directly and indirectly acting GABA-mimetic drugs to alter turning behavior elicited by administering apomorphine, a DA agonist, to rats with unilateral lesions of dopaminergic nigrostriatal neurons. Low doses of directly acting postsynaptic GABA agonists (progabide, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin--3-01) or a neuronal GABA transport inhibitor (SKF 100330-A) potentiate apomorphine-induced turning. Higher doses of these agents or acute inhibition of GABA catabolism inhibits turning. Our results suggest that low doses of certain GABA mimetics will improve the responses of patients with Parkinson's disease to concurrent DA receptor agonist therapy.

The effects of the gaba-mimetic drugs, progabide and baclofen, on the biochemistry and function of 5-hydroxytryptamine and noradrenaline

Administration to mice of a single dose of (±)-baclofen (5 mg kg ) or progabide (100 mg kg ) significantly inhibited the head-twitch response mediated by 5-hydroxytryptamine (5-HT 2) receptors 30 min (but not 3 hr) later, when the response was produced by injection of carbidopa (25 mg kg ) plus 5-hydroxytryptophan (5-HTP; 100 mg kg ). No change was seen in the head-twitch response when induced at this time by 5-methoxy- N, N-dimethyltryptamine (5-MeODMT; 5 mg kg ). Inhibition of the head-twitch response after injection of 5-HTP was produced by pretreatment with (−)-baclofen, but not (+)-baclofen; injection of(+)-baclofen with the (−)-baclofen did not alter the attenuation of the behaviour produced by the active isomer. Twenty-four hours after the last injection of progabide, given repeatedly (100 mg kg injected 5 times over 10 days) specific binding of [ 3H]ketanserin in the frontal cortex was enhanced and the head-twitch response to both 5-HTP and 5-MeODMT was markedly increased. The sedation response mediated by α 2-adrenoceptors, which followed the injection of clonidine (0.25 mg kg ) was attenuated. Repeated administration of baclofen (10 mg kg per day in drinking water) also increased the number of 5-HT 2 receptors in the frontal cortex (16%) and enhanced the head-twitch behaviour after injection 5-HTP or 5-MeODMT. Clonidine-induced sedation, number of β-adrenoceptors in the cortex and apomorphine-induced locomotor activity were all unchanged. These data suggest that the up-regulation of the number of 5-HT 2 receptors and behaviour mediated by 5-HT 2 receptors after repeated administration of progabide results from the drug inhibiting the release of 5-HT by an action at GABA B receptors (as suggested by the identical effect of baclofen). The change in the sedation induced by clonidine, produced by progabide, may therefore result from an action at GABA A sites. The data are discussed in relation to the changes in the biochemistry and function of monoamines induced by repeated electroconvulsive shock.

The role of striatal cholinergic mechanisms for the development of limb rigidity: An electromyographic study in rats

The muscarinic cholinergic agonist bethanechol (0.25–1.0 μg) injected bilaterally into various parts of the rat neostriatum induced a tonic electromyogram (EMG) activity in the gastrocnemius muscle which is considered to be a measure of limb rigidity. This tonic EMG activity was found to be dose-dependent and muscarine-specific since it could be blocked by coadministration of the muscarinic antagonist N-methylscopolamine (1.0 μg). Tonic EMG activity of comparable amount was observed after injections of bethanechol (1.0 μg) into all regions of the neostriatum but not into the globus pallidus, thalamus, zona incerta or cortex. The tonic EMG activity induced by intrastriatal injection of bethanechol (1.0 μg) was abolished by a subsequent injection of the GABAmimetic drug muscimol (25 ng) into the posterior part of the substantia nigra pars reticulata suggesting that bethanechol-induced limb rigidity is mediated via impairment of GABAergic transmission within the substantia nigra pars reticulata.

Development of tolerance to the anticonvulsant effect of GABAmimetic drugs in genetically epilepsy-prone gerbils

Three drugs which increase GABA-mediated inhibitory neurotransmission in the brain, namely the GABA degradation inhibitors aminooxyacetic acid (AOAA) and γ-acetylenic GABA (GAG), and the GABA receptor agonist THIP (gaboxadol), were administered to epilepsy-prone gerbils via subcutaneously implanted osmotic minipumps for 2 weeks. The antiepileptic drugs valproic acid (VPA) and diazepam were also included in the experiments. After one day of constant rate application, all GABAmimetics markedly suppressed seizure activity induced in the gerbils by air blast stimulation, but anticonvulsant efficacy of the drugs was lost after 8 and 14 days of treatment. With VPA, only moderate anticonvulsant effects were found because only sub-therapeutic drug levels (about 40 μg/ml plasma) were reached via minipump administration. The experiments with diazepam could only be evaluated in part because of instability of the drug in aqeous solution. Determination of brain GABA metabolism in the gerbils indicated that reduction of GABA synthesis may be responsible, at least in part, for development of tolerance to the antoconvulsant effects of AOAA and GAG.

Effects of GABA-Mimetic Drugs on Turnover of Histamine in the Mouse Brain

AbstractThe effect of GABA-mimetics on histaminergic activity in the mouse brain was investigated. Systemic administration of muscimol (2 and 5 mg/kg). THIP (5–15 mg/kg) and aminooxyacetic acid (AOAA) (25 mg/kg) but not baclofen (2.5–15 mg/kg) inhibited the pargylme (65 mg/kg)-mduced accumulation of tele-methylhistamine (t-MH). There was no regional difference in the inhibitory effect of muscimol on the t-MH accumulation by pargyline treatment. Muscimol and AOAA also inhibited decrease in the histamine (HA) level induced by α-fluoromethylhistidme (50 mg/kg). a specific inhibitor of histidine decarboxylase. These results suggest that these GABA-mimetics reduce the HA turnover in the mouse bram.

Rigidity and catalepsy after injections of muscimol into the ventromedial thalamic nucleus: an electromyographic study in the rat.

The cataleptic state induced by injection of the GABAmimetic drug muscimol into the rat's ventromedial thalamic nucleus (VM) was examined using an electromyographic (EMG) approach. Muscimol in doses up to 50 ng/0.5 microliter injected into the VM induced a tonic EMG activity in the gastrocnemius muscle which is considered to be a measure of limb rigidity. This tonic EMG activity was found to be dose-dependent, GABA specific and locus specific. By recording EMG signals from chronically implanted electrodes in awake, unrestrained rats it was shown that muscular reactions serving to maintain the animal's static equilibrium were intact in the state of VM induced catalepsy. However, animals were unable to initiate movements or locomotion even when they were forced by strong external stimuli. It was found that the animals' immobility was due to an inability to induce a phasic activation of their muscles whereas tonic activation still occurred. It is concluded that the rat's VM is part of a neuronal chain conducting information relevant for the expression of limb rigidity, the VM is involved in the central mechanisms responsible for the phasic activation of a set of muscles.

Antagonism of N-methyl-D,L-aspartic acid-induced convulsions by antiepileptic drugs and other agents

The effects of common antiepileptics, GABAmimetic drugs, excitatory amino acid antagonists as well as of clonidine, corynanthine, chlorpromazine and atropine were studied against clonic convulsion induced in mice by N-methyl-D,L-aspartic acid (NMDLA) after subcutaneous (340 mg/kg; ED 97) administration. Among the antiepileptics studied, valproate (ED 50: 340 mg/kg after subcutaneous injection of NMDLA) and diazepam (ED 50: 0.78 mg/kg after intravenous and 14 mg/kg after subcutaneous injection of NMDLA) antagonized NMDLA-induced convulsions, whereas phenobarbital (up to 80 mgkg), diphenylhydantoin (up to 50 mg/kg) and ethosuximide (500 mg/kg) were totally ineffective. Moreover, 2-amino-5-phosphonopentanoic acid and 2-amino-7-phosphonoheptanoic acid (but not glutamic acid diethyl ester), aminooxyyacetic acid, cetyl GABA and clonidine protected strongly against the convulsant whereas progabide was only weakly active. THIP showed a higher activity against intravenous than against subcutaneous NMDLA. Baclofen and atropine even increased mortality and the remaining agents exerted no significant protective action. The data suggest that NMDLA-induced convulsions can be blocked effectively by direct antagonism of NMDLA-produced excitation, enhancement of GABA-mediated inhibition, and activation of central α 2-adrenoceptors. The possible efficacy of valproate in cases of epilepsy with a distinct rise in plasma excitatory amino acid levels should be carefully considered.

Effect of intrastriatal administration of cholinergic and GABAergic agonists on apomorphine-induced circling.

The objectives of this study were (1) to clarify the effects of muscarinic and GABAergic agonists administered directly into the striatum on the circling behavior produced by dopamine (DA) receptor stimulation and (2) to determine whether the effects produced by these drugs are independent or are mediated through an interaction with GABAergic or cholinergic neuronal systems. Circling behavior was produced by the administration of apomorphine (AP) to rats previously injected into their right substantia nigra with 6-hydroxydopamine (6-OHDA). The circling induced by AP (0.5 mg/kg SC) reached a peak rate 5-10 min after injection. The intrastriatal administration of pilocarpine, a muscarinic receptor agonist, 10 min after AP administration produced a dose-dependent inhibition of the AP-induced circling. Similarly, several GABAmimetic drugs (muscimol, GABA, chlordiazepoxide, sodium valproate) also inhibited AP-induced circling in a dose-dependent manner. The intrastriatal administration of scopolamine, which blocks muscarinic cholinergic receptors, reversed the inhibitory effect of pilocarpine but not that of muscimol. However, picrotoxin, the GABAergic antagonist, reversed the inhibitory effect of both pilocarpine and muscimol. These results suggest that the stimulation of either muscarinic or GABAergic receptors in the striatum inhibits the effects of DA receptor stimulation. The inhibitory effect produced by pilocarpine may involve the activation of GABAergic receptors, presumably through stimulation of GABAergic neurons and subsequent release of GABA.

Enhancement of spike and wave discharges by GABAmimetic drugs in rats with spontaneous petit-mallike epilepsy

Certain Wistar rats from our laboratory colony present genetically determined seizures similar to human petit-mal absences. Muscimol, THIP and l-baclofen, agonists of GABA receptors, and gamma-vinyl GABA (GVG), an inhibitor of GABA degradation, enhanced the duration of spontaneous petitmal-like seizures in a dose-dependent fashion. These findings raise questions as to the role of GABAergic neurotransmission in the occurrence of this type of spontaneous spike and wave discharges.

Effects of a GABA-mimetic drug (sodium valproate) on visually evoked potentials in chronic schizophrenics.

Data were obtained from 14 chronically schizophrenic women (age 40-59) living in the same ward of a psychiatric hospital (Marburg, FRG), and having been treated with clozapine (450-600 mg/day) during the last 2 years. The uncontrolled study was initiated by the addition of sodium valproate (900 mg/day) for 3 months. The observation commenced after the discontinuation of the valproate medication with the evaluation of the symptoms (Brief Psychiatric Rating Scale, BPRS) and the visually evoked potentials (VEP). The VEP were recorded after 3, 12 and 30 days and the rating was repeated after 4 weeks. No significant changes in symptomatology were obtained with the BPRS in patients under combination therapy in comparison with the scores 30 days after discontinuation of the valproate medication. On the other hand, after single flash stimulation, the amplitudes of the components N110, P260, and N300 of the VEP were significantly (p less than 0.05) increased during the same time interval. These findings are interpreted as an expression of an inhibiting action of the GABA system on the reactivity of the visual system in chronic schizophrenics induced by the comedication of sodium valproate.

Effects of THIP on chronic anxiety

The effects of THIP, a GABA agonist, were examined in patients with anxiety disorders. Eight patients were prescribed THIP (5-20 mg) to be taken three times a day for 2 weeks in a single-blind study, with placebo conditions preceding and following the active drug period. Anxiety ratings significantly decreased on several measures during active drug treatment and increased again with placebo administration. However, the anxiolytic effects of THIP appeared to be weak and occurred at, or close to dose levels which induced sedation and undesirable side effects. As with other GABA agonists and GABA-mimetic drugs, side effects included giddiness, depersonalization, poor concentration, and transitory delirious states, suggesting that excessive stimulation of the GABAergic system may disrupt normal brain functioning.

Prolactin-lowering and -releasing drugs. Mechanisms of action and therapeutic applications.

Drugs whose systemic and/or central administration induce suppression or stimulation of prolactin secretion are reviewed. The most commonly used prolactin-lowering drugs include: (a) direct-acting dopamine receptor agonists (e.g. dopamine, apomorphine and the ergot derivatives); (b) indirect-acting dopamine agonists (e.g. amphetamine, nomifensine, methylphenidate, amineptine); (c) drugs which impair serotoninergic neurotransmission (e.g. the neurotoxin 5,7-dihydroxytryptamine and the serotonin receptor antagonists methysergide and metergoline); (d) gamma-aminobutyric acid [GABA]-mimetic drugs (e.g. GABA, muscimol, ethanolamine-O-sulphate, sodium valproate); (e) histamine H2-receptor agonists; and (f) cholinergic (muscarinic and nicotinic) receptor agonists. Major prolactin-stimulating agents comprise: (a) dopamine receptor antagonists (e.g. classic and atypical antipsychotic drugs); (b) drugs differently capable of impairing central nervous system dopamine function (e.g. blockers of dopamine neurotransmission such as alpha-methyl-p-tyrosine and 3-iodo-L-tyrosine, false precursors such as alpha-methyldopa, and inhibitors of L-aromatic amino acid decarboxylase such as carbidopa and benserazide); (c) drugs enhancing serotoninergic neurotransmission (e.g. the serotoninergic precursors tryptophan and 5-hydroxytryptophan, direct-acting serotonin agonists such as quipazine and MK 212, and indirect-acting serotonin agonists such as fenfluramine); (d) blockers of serotonin reuptake (e.g. fluoxetine, fluvoxamine and clovoxamine); (e) H1-receptor agonists; and (f) H2-receptor antagonists (e.g. cimetidine). Some of the above classes of drugs (e.g. the indirect-acting dopamine agonists, dopamine receptor antagonists, GABA-mimetic drugs, dopamine receptor blocking drugs, and H2-antagonists) may be useful for selecting among hyperprolactinaemic patients those with a prolactin-secreting tumour in an early stage of the disease. Direct-acting dopamine receptor agonists, notably the ergot derivatives; are potent antigalactopoietic agents, can revert impaired gonadal function to normal in both female and male patients with hyperprolactinaemia, and may have antiproliferative effects on pituitary prolactin-secreting tumours. All prolactin-stimulating agents, but especially the dopamine receptor antagonists, are liable to induce alterations in gonadal function in subjects of either sex. In addition to their usage for diagnostic or therapeutic purposes, the above drugs appear to be invaluable tools for enabling a better understanding of the neurotransmitter control of prolactin secretion.

Sodium vaiproate and biperiden in neuroleptic‐induced akathisia, parkinsonism and hyperkinesia

ABSTRACT ‐ Fifteen psychiatric patients participated in a double‐blind cross‐over study of the effect of sodium valproate (a GABA mimetic drug), biperiden (an anticholinergic drug) and placebo in neuroleptic‐induced akathisia, parkinsonism and hyperkinetic movements. All patients had subjective and objective signs of akathisia, 11 had parkinsonism and 11 hyperkinesia, eight of which were tardive dyskinesia (TD) and three initial hyperkinesia. After a pretreatment washout period of 2 weeks, during which anticholinergic drugs, if any, were replaced by placebo, the patients were treated in three randomized periods of 4 weeks with sodium vaiproate, biperiden and placebo. Compared to placebo, sodium vaiproate (900–2400 mg/day, median 1700) had no significant effect on akathisia and parkinsonism, although akathisia was reduced in four patients (unchanged in 10 and increased in one) and parkinsonism was induced or aggravated in seven patients (unchanged in five and reduced in three). Sodium valproate, however, reduced hyperkinesia score (TD + initial hyperkinesia) from 1.6 to 1.2 (P < 0.05). Biperiden (6–18 mg/day, median 12) significantly reduced akathisia score from 1.4 to 0.6 (P < 0.01) and parkinsonism from 2.0 to 0.6 (P < 0.01), and increased TD score from 2.1 to 3.9 (P < 0.05). None of the drugs induced significant side effects. It is concluded that 1) sodium valproate has no significant effect on akathisia, but a slight beneficial effect in hyperkinetic movements, both TD and initial hyperkinesia, 2) sodium valproate may aggravate parkinsonism without necessarily aggravating akathisia, and 3) anticholinergic drugs like biperiden appear still to be the best treatment for akathisia.

Pharmacological studies on the prolonged depressant effects of baclofen on lumbar dorsal horn units in the cat

The pharmacological basis of the prolonged depressant effect of baclofen on small diameter afferent inputs to dorsal horn neurons was studied because of the possibility that this depression represents, at the cellular level, the mechanism of the analgesic effects of baclofen. When l-baclofen (0.1–3.0 mg/kg, i.v.) was given, the ensuing prolonged depression could not be mimicked or modified by the GABA-mimetic drug, muscimol (0.5–5.0 mg/kg, i.v.). Administration of the GABA antagonist, bicuculline (1–5 mg/kg, i.v.), partially reversed the depression induced by baclofen but even after large doses of bicuculline, subsequent administration of baclofen produced depression. The opiate antagonist naloxone (0.1–0.3 mg/kg, i.v.) and the glycine antagonist strychnine (0.1–0.2 mg/kg, i.v.) failed to block the prolonged depression induced by baclofen. These results suggest that baclofen is acting in the dorsal horn via a mechanism which excludes opiate receptors and glycine receptors and which only partially includes bicuculline-sensitive GABA receptors. The results are consistent with a possible action of baclofen on the recently proposed ‘novel GABA receptor’, or GABA B receptor, which is insensitive to bicuculline; if this indeed proves to be the case, then the present results suggest that at least in the spinal cord, these receptors are associated differentially with small diameter afferent fibres. However, regardless of the receptors involved, the most likely effect of baclofen is to reduce the amount of transmitter (or modulator) released from terminals of primary afferent fibres, and evidence is examined implicating glutamate and substance P. The transient, non-specific depressant effect (described in more detail in another publication) was prevented by bicuculline, and thus its effects are likely to be mediated by bicuculline-sensitive GABA receptors.

Comparative assay of anticonvulsant and toxic potencies of sixteen GABAmimetic drugs

The relative ability of 16 direct and indirect GABAmimetic drugs to elevate the threshold for electroconvulsions and pentetrazole seizures was studied in mice. The following drugs were tested: GABA and its pro drug cetyl GABA, the GABA agonists muscimol, THIP and progabide, the inhibitors of the high affinity GABA uptake (−)- and (+)-nipecotic acid ethyl ester, (±)-nipecotic acid methyl ester, (±)- cis-4-hydroxynipecotic acid methyl ester and guvacine methyl ester, and the inhibitors of GABA degradation aminooxyacetic acid, gabaculine, γ-acetylenic GABA, γ-vinyl GABA and ethanolamine-O-sulphate. Valproic acid was included as a reference standard. All drugs were administered intraperitoneally and their anticonvulsant potencies were compared at the previously established time of peak drug effect. All GABAmimetics gave rise to significant, dose-dependent threshold elevations. Most potent were muscimol, THIP and cetyl GABA, and least potent were γ-vinyl GABA and ethanolamine-O-sulphate. Determination of minimal neurotoxicity by means of the chimney test indicated that the anticonvulsant effect of most GABAmimetics was impaired by a narrow margin of safety. Only cetyl GABA, aminooxyacetic acid and progabide exhibited satisfactory margins of safety similar to those of valproic acid in any particular test. Based on the present data, cetyl GABA and progabide appear to be the most interesting compounds examined besides valproic acid and both GABAmimetics may be interesting as potential antiepileptic drugs.

Successful treatment of ballism with diazepam

AbstractTwo patients with ballism were treated successfully with diazepam. It is suggested that diazepam acted as an indirect GABAmimetic drug to correct a functional GABA deficiency secondary to hyperactivity of the dopamine system in the subthalamic nucleus as a cause for ballism.

Etomidate stereospecifically stimulates forebrain, but not cerebellar, 3H-diazepam binding

3H-Diazepam binding to a total particulate fraction of rat forebrain is enhanced by (+)-etomidate and GABA, but not by (−)-etomidate. The enhancement of 3H-diazepam binding by (+)-etomidate was due to a two-fold increase in binding affinity, the maximal number of sites remained unchanged. The degree of stimulation with (+)-etomidate was higher than that obtained with GABA. THIP did not stimulate 3H-diazepam binding to forebrain, and did not reverse the enhanced binding seen with (+)-etomidate or GABA. In a synaptosomal membrane preparation of rat cerebellum, unlike (+)-etomidate, GABA and muscimol produced a marked stimulation of 3H-diazepam binding. (+)-Etomidate did not inhibit 3-muscimol binding to GABA receptors, nor did it activate or inhibit other in vitro receptor binding assays. The effects of (+)-etomidate on the benzodiazepine binding are different from those of gabamimetic drugs. It is proposed that like barbiturates, (+)-etomidate may affect benzodiazepine binding by interaction with the chloride ionophore which is coupled to the GABA-receptor.

The effects of GABA-ergic drugs on enkephalin-induced motor seizure phenomena in the rat.

1. The relationship between the effects of GABA-ergic drugs and D-ala2-met-enkephalinamide (DALA)-induced myoclonic contractions of inframandibular muscles has been studied in the rat. 2. GABA-ergic drugs altered enkephalin-induced myoclonic contractions in the following manner: (a) The GABA-mimetic drugs, muscimol, gabaculine and baclofen, decreased DALA-induced myoclonic contractions. (b) The GABA antagonist, bicuculline and the anticonvulsant substance, sodium valproate (dipropylacetic acid, DPA) potentiated DALA-induced myoclonic contractions. The potentiating effect of DPA is probably due to its opiate-like activity, since naloxone abolished this effect. 3. The modulatory effect of the GABA-mimetic drug on enkephalin-induced myoclonic contractions may give grounds for further study to test the possible use of other GABA-mimetic drugs and possibly opiate antagonists for the treatment of myoclonic syndromes.

Effects of some GABA-mimetic drugs on the antinociceptive activity of morphine and beta-endorphin in rats.

Intracerebroventricular administration of muscimol, a potent GABA-receptor agonist, counteracted the antinociceptive effect of morphine or beta-endorphin in rats as measured by the "tail flick" method. Muscimol's activity was reversed by bicuculline. Isoguvacine, another GABA agonist, as well as nipecotic acid and guvacine, two inhibitors of neuronal and glial uptake of GABA, also antagonized morphine's antinociceptive effect. A role of the central GABA-ergic system in mediating opiate antinociception is proposed.

Evidence that gaba mechanisms mediate the anxiolytic action of benzodiazepines: A study with valproic acid

Valproic acid and diazepam were tested for “anti-anxiety” activity in two animal tests known to predict the anxiolytic action of drugs. In one test, male hooded rats were trained to discriminate the “anxiomimetic” action of pentylenetetrazol from saline by responding on one of two levers for food reinforcement after pentylenetetrazol (1450 μmol/kg) injection and the other lever after saline injection. Once the pentylenetetrazol-saline discrimination was acquired, pretreatment with either diazepam (4.4–35.0 μmol/kg) or valproic acid (278–2220 μmol/kg) produced a dose-dependent antagonism of the “anxiomimetic” stimulus in this test. In the other test, male Wistar rats were trained to respond for milk reinforcement and to suppress those responses when the reinforcement was accompanied by the simultaneous delivery of foot shock. Treatment of these rats with diazepam (7–28 μmol/kg) or valproic acid (1110–2220 μmol/kg) antagonized the suppression of responding induced by the foot shock in a dose-dependent manner. In both tests, diazepam and valproic acid showed anxiolytic activity at doses which did not result in an overall suppression of responding. The demonstration of anxiolytic activity by the GABAmimetic drug, valproic acid, suggests that GABA mechanisms may mediate the anxiolytic action of benzodiazepines.