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Biomedical subjects

K G Lloyd

Publications and source records attributed to K G Lloyd.

At least 73 records · Page 4Linked to original sources
PubMed1982

Action of progabide in the photosensitive baboon, Papio papio.

Progabide is a GABA agonist which is nontoxic and crosses the blood-brain barrier. Progabide was tested in naturally and allylglycine-induced photosensitive baboons (Papio papio). Intravenous injection of various doses (30 to 100 mg/kg) of progabide induced a protective effect against intermittent light stimulation (25 Hz) in both test situations. This protection lasted 10 to 120 min. This duration was dose-dependent and was generally shorter in allylglycine-treated than in naturally photosensitive baboons. At all doses, progabide reinforced rhythmic activities in the frontorolandic and occipital regions. At doses greater than 50 mg/kg, progabide produced a mild sedation with somnolence and myorelaxation, all effects which could be reversed by sensory stimulation. These data confirm the anticonvulsant properties of progabide in another animal model.

Allylglycine↗
PubMed1982

gamma-Aminobutyric acid (GABA) receptor stimulation. II. Specificity of progabide (SL 76002) and SL 75102 for the GABA receptor.

Progabide and its immediate metabolite SL 75102 displace [3H]gamma-aminobutyric acid (GABA), [3H]muscimol and [3H]isoguvacine from their binding sites to membranes prepared from rat brain or human cerebellum and increase (SL 75102) [3H]flunitrazepam binding to rat cerebral cortex membranes. In contrast, these compounds have very weak or no effects on alpha or beta noradrenergic, histamine, muscarinic cholinergic or glycine receptors or on the [3H]imipramine or [3H]kainate binding sites. Neither progabide nor SL 75102 inhibit GABA synthesis, metabolism or uptake. Also, the uptake of norepinephrine, serotonin and dopamine into synaptosomes of cerebral regions is not affected by progabide. [3H]GABA release from substantia nigra slices is decreased by SL 75102 and progabide, in agreement with the hypothesis of a GABAergic autoreceptor controlling GABA release from its nerve terminals. These data suggest a specific agonist action of progabide and SL 75102 on GABA receptors.

Animals↗
PubMed1982

gamma-Aminobutyric acid (GABA) receptor stimulation. I. Neuropharmacological profiles of progabide (SL 76002) and SL 75102, with emphasis on their anticonvulsant spectra.

Progabide (4-([(4-chlorophenyl) (5-fluoro-2-hydroxyphenyl)-methylene]amino) butanamide) is a gamma-aminobutyric acid (GABA) receptor agonist which readily enters the brain. In the body, progabide is metabolized to three active metabolites: SL 75102, gabamide and GABA. Progabide and SL 75102 readily enter the brain and GABA and gabamide are also formed within this organ. Both progabide and SL 75102 exhibit a broad spectrum of anticonvulsant activities against seizures which involve GABA-mediated events (bicuculline, picrotoxinin and pentylenetetrazol) or which are apparently independent of GABAergic mechanisms (penicillin, strychnine, electroshock and audiogenic seizures). These data support the hypothesis that direct GABA receptor stimulation is an effective means of controlling convulsions of various origins. Progabide and SL 75102 have relatively minor secondary effects in comparison to commonly used antiepileptics. Myorelaxation occurs, but only at doses higher than the ED50 values in convulsant tests. Furthermore, these compounds are not sedative. Finally, these GABA agonists have a complex action in the extrapyramidal system. Anticonvulsant doses are antagonistic to dopamine receptor-mediated behaviors, whereas much lower doses seem to facilitate the effects of dopaminergic transmission.

Animals↗
PubMed1981

Biochemical evidence of dysfunction of brain neurotransmitters in the Lesch-Nyhan syndrome.

Different brain regions were removed post mortem from three patients with the Lesch-Nyhan syndrome and were examined for alterations in hypoxanthine-guanine phosphoribosyl transferase (HGPRT), adenine phosphoribosyl transferase, and biochemical indexes of norepinephrine, dopamine, serotonin, gamma-aminobutyric acid (GABA), and acetylcholine neuron function, as compared with age-matched controls. The level of HGPRT activity in the material from patients with the Lesch-Nyhan syndrome was less than 1 per cent of control levels, whereas adenyl phosphoribosyl transferase was not significantly altered. All biochemical aspects of the function of dopamine-neuron terminals in the striatum (except dihydroxyphenylacetic acid levels) were decreased to 10 to 30 per cent of the control values. Serotonin and 5-hydroxyindoleacetic acid levels were increased, striatal choline acetyltransferase levels were low, and striatal glutamic acid decarboxylase and guanylate cyclase activities were unaltered. The disruption of the balance between the functions of GABA, dopamine, and acetylcholine neurons in the extrapyramidal system probably accounts for some of the symptoms observed in the Lesch-Nyhan syndrome (e.g., choreoathetosis).

Acetylcholine↗
PubMed1981

GABA receptors distribution in rat substantia nigra.

The perikarya of the dopaminergic and non-dopaminergic neurons contained in the substantia nigra were selectively destroyed by a proper, local injection of 6-hydroxydopamine or kainic acid, respectively. Both lesions resulted in a marked decrease of the nigral GABA-binding sites. The effect of 6-hydroxydopamine was restricted to the high affinity receptors, while kainic acid specifically decreased the low affinity ones.

Animals↗
PubMed1981

Involvement of the amygdala in the effect of antidepressants on the passive avoidance deficit in bulbectomised rats.

In the present study the role of the amygdala is demonstrated in the effect of antidepressant drugs on passive avoidance learning in bulbectomised rats. Imipramine, amitriptyline, or fluoxetine injected bilaterally (2 X 10 microgram) into the medial part of the amygdala improves passive avoidance learning by bulbectomised rats. Systemic pretreatment with metergoline attenuates the effect of local imipramine or fluoxetine injection. Microinjection of serotonin but not noradrenaline into the amygdala improves passive avoidance learning by bulbectomised rats. The relevance of the amygdala in the behavioral effects of antidepressants in animals is discussed.

Amitriptyline↗
PubMed1981

Involvement of caudate nucleus, amygdala or reticular formation in neuroleptic and narcotic catalepsy.

Local injection of haloperidol into the caudate nucleus produced catalepsy in contrast to the weak effects of morphine injected at the same site. Injection of either haloperidol or morphine into the amygdala did not have any cataleptogenic effect. Both haloperidol and morphine produced catalepsy when injected into the reticular formation. Naloxone injected into the reticular formation completely reversed the catalepsy following intraperitoneal morphine but not haloperidol. Pretreatment with alpha-methyl-p-tyrosine potentiated the effect of haloperidol injected into either the reticular formation or caudate nucleus. Phentolamine but not lignocaine or metergoline, injected into the reticular formation also caused a cataleptic response. The results confirm the caudate nucleus as a site for haloperidol catalepsy and in addition, suggest the reticular formation as a primary site for morphine catalepsy and a secondary site for haloperidol catalepsy; additionally a noradrenergic modulation of catalepsy may occur within this brainstem region.

Amygdala↗
PubMed1981

Neuropharmacological actions of GABA agonists: predictability for their clinical usefulness.

From the data presented and the clinical studies reviewed, it would appear that the tests presently used to forecast the clinical effects of GABA agonists are rather accurate in their predictability. Thus, these tests are positive for antiepileptic, antispastic and antidyskinetic potential; they are negative for schizophrenia and are at best equivocal for Huntington's disease. This is parallelled in a surprisingly close matter by the antidyskinetic, anticonvulsant and antispastic effects of at least one GABA agonist (progabide) in preliminary clinical testing. It is concluded the non-toxic GABA agonists will be useful in a variety of neurological disorders without precipatating incapacitating side effects.

Antipsychotic Agents↗
PubMed1980

The neuropathology of GABA neurons in extrapyramidal disorders.

Dysfunction of neurons in the extrapyramidal system (EPS) which use GABA as their neurotransmitter can be noted in both degenerative diseases of the EPS and in iatrogenic (i.e. drug-induced)disorders of EPS function. In Huntington's chorea there is a loss of both GABA neurons and GABA receptors in the striatum; those remaining GABA receptors likely have an altered kinetic profile, with a higher affinity for GABA than the receptors found in the non-Huntington's brain. In Parkinson's disease the lower levels of L-glutamic acid decarboxylase observed in the EPS is likely not associated with neuronal cell loss but is likely secondary to the dopamine neuron loss. These alterations in GABA neuron function and the long-term changes associated with chronic L-DOPA therapy may be related to Parkinsonian tremor. The drug-induced dyskinesias (L-DOPA, neuroleptic) appear to be associated with a relative hypo-function of EPS GABA neurons, especially in relation to DA neuron function, whereas in the case of drug-induced Parkinsonism the opposite may be the case. The function and dysfunction of GABA neurons in the EPS cannot be seen as a separate entity, but must be considered in relation to alterations in other EPS neurons, especially dopamine and acetylcholine.

Basal Ganglia Diseases↗
PubMed1980

The potential of GABA-mimetics in the therapy of extrapyramidal disorders.

GABA mimetics inhibit extrapyramidal DA and ACh neurons and affect an unknown system beyond both DA and ACh receptors, which is involved in extrapyramidal motor outputs. Based on these data, the rationale is discussed for the clinical use of GABA mimetics in Huntington's chorea, parkinsonian tremor, L-DOPA or neuroleptic-induced dyskinesias.

Antipsychotic Agents↗