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Biomedical subjects

K G Lloyd

Publications and source records attributed to K G Lloyd.

At least 55 records · Page 3Linked to original sources
PubMed1985

Non-benzodiazepine anxiolytics: potential activity of phenylpiperazines without 3H-diazepam displacing action.

Four phenylpiperazine derivatives exhibited an activity similar to benzodiazepines and meprobamate in the 4-plate test. One of these (compound IV) demonstrated anxiolytic like activity in a step-down avoidance technique, in electroshock induced aggression and in the staircase test. In contrast to benzodiazepines, compound IV was not anticonvulsant, myorelaxant or sedative. Confirmation of the anxiolytic activity of compound IV in animal models was obtained in 3 separate clinical trials in anxious patients. The mechanism of action of these phenylpiperazines appears to be different from the benzodiazepines as they do not displace 3H-diazepam binding nor do they interact with other elements of the GABA receptor macromolecular complex. Instead, compound IV interacts with both dopaminergic and serotoninergic neuron systems. Thus, from this data it would appear that an activity at the benzodiazepine recognition site is not obligatory for anxiolytic activity in man or in animals models.

Aggression↗
PubMed1985

[Implications of GABAergic synapses in neuropsychiatry].

The use of a multidisciplinary approach--laboratory and clinical pharmacology and experimental and human neurochemistry--has demonstrated that GABA neurons and receptors play a variety of functional roles in the mammalian brain. The present synopsis has been limited to some of the newer aspects of GABA neuron function. Thus there is strong evidence that GABA neurons are involved in the control of cerebral excitability (cf. tables I, II) and in the genesis of at least some seizures states, including certain types of human epilepsy (table III). Furthermore GABA receptor activation can be used to control seizures of diverse etiology and at least one GABA agonist, progabide, is effective in human epilepsy. There is a foundation for the belief that GABA neurons function in the control of affect and emotion. The most convincing evidence is from laboratory and clinical pharmacology studies in depression and models for the development of new antidepressant drugs. GABA agonists act as antidepressants not only in animal models such as learned helplessness, olfactory bulbectomy and the sleep-cycle but also demonstrate an antidepressant action in man. Additionally, the recent studies showing that chronic treatment by antidepressants, induce an increase in 3H-GABA "B" binding strongly support a GABAergic contribution in the mechanism of antidepressant drugs (cf. table IV). There is also some evidence for the hypothesis that GABA neurons and receptors participate in the biology of anxiety, or at least the mechanism of action of anxiolytics. This is based mainly on the known molecular pharmacology of the benzodiazepine receptor and the evidence in animal models for anxiety (table V). However in clinical trials the GABA agonist progabide is only a weak anxiolytic. A major function of GABA neurons and receptors is the regulation of the nigro-striatal dopamine pathway (table VI) and the expression of dopamine receptor mediated events (table VII). This modulation probably occurs via at least 3 mechanisms: a tonic inhibition of dopamine neuron activity regulating dopamine synthesis, turnover and release; a long term modulation controlling striatal dopamine receptor numbers, modification of the expression of dopaminergic transmission distal to the dopaminergic synapse.

4-Aminobutyrate Transaminase↗
PubMed1985

Upregulation of gamma-aminobutyric acid (GABA) B binding sites in rat frontal cortex: a common action of repeated administration of different classes of antidepressants and electroshock.

The action of different classes of clinically effective antidepressants and electroshock on gamma-aminobutyric acid (GABA) B recognition sites in the frontal cortex was compared to that of other psychotropic agents. After either prolonged (6-18 days) s.c. infusion via osmotic minipumps or repeated i.p. injections of different antidepressants, or a series of electroshocks, treatment was halted and 72 hr later the animals were sacrificed, the brain was dissected and frozen. All major antidepressants (desipramine, amitryptyline or maprotiline), several newer compounds with reported antidepressant activity (viloxazine, zimelidine, fluoxetine, citalopram, progabide, fengabine, sodium valproate, mianserin, trazodone or nomifensine) as well as pargyline and repeated electroshocks, up-regulated GABA B binding in the rat frontal cortex but not hippocampus. This appeared to be a maximum binding effect, but in some instance the kinetics were more complex. Reserpine, diphenylhydantoin and phenobarbital down-regulated GABA B binding in the frontal cortex, whereas this was unaltered by haloperidol, chlorpromazine or diazepam administration. Desipramine up-regulated GABA B binding in a dose- and time-dependent manner (minimum effective dose, 1.25 mg/kg/day s.c. for 18 days; onset of action, 6 days at 5 mg/kg/day s.c.). Together with the rather sparse data in the literature on GABA in depression and antidepressant drug action, these findings support a common GABAergic mechanism of action of antidepressant drugs and electroshock, mediated via GABA B synapses.

Animals↗
PubMed1984

Chronic antidepressants and GABA "B" receptors: a GABA hypothesis of antidepressant drug action.

Amitryptyline (10 mg/kg), desipramine (5 mg/kg), citalopram (10 mg/kg) and viloxazine (10 mg/kg) were administered to rats either acutely (decapitation 1 hr after i.p. injection) or subacutely (by subcutaneous minipump implantation for 18 days followed by decapitation 24 hr after removal). After acute administration there was not any consistent alteration in GABA levels, GAD activity, 3H GABA "A" or 3H-GABA "B" receptor binding or 3H-nipecotic acid binding to the recognition site for GABA uptake in the frontal cortex or hippocampus. Upon subacute antidepressant drug infusion, GABA levels, GAD activity and 3H-GABA-"A" binding showed only scattered differences in drug treated animals as compared to saline treated rats. However, 3H-GABA "B" binding in the frontal cortex was consistently elevated after all drug treatments (in % of control: amitryptyline = 155%; desipramine = 151%; citalopram = 173%; viloxazine = 189%). Scatchard analysis showed that this was due to a Bmax increase without an effect in Kd. These findings were reproduced by subacute administration of pargyline, a MAO inhibitor. These data suggest that GABA "B" receptors may be involved in the mechanism of action of antidepressant drugs and provide a link between GABAergic and monoaminergic hypotheses of depression.

Amitriptyline↗
PubMed1984

Akinesia after locally applied morphine near the nucleus raphe pontis of the rat.

Morphine (10 micrograms/microliter) was injected into different sites within the pontine brainstem in different groups of rats with indwelling guide cannulae. The rats were tested for the persistence of abnormal postures as a measure for the degree of akinesia. Local morphine was most effective in inducing akinesia at a site identical or close to the nucleus raphe pontis. Midline injections were effective in contrast to bilateral injections. Fenfluramine, a serotonin releaser, strongly potentiated morphine akinesia.

Animals↗
PubMed1984

The comparative effects of benzodiazepines, progabide and PK 9084 on acquisition of passive avoidance in mice.

Acquisition of passive avoidance following aversive conditioning to a dark compartment was measured in mice under the influence of one of seven benzodiazepines, the GABA-mimetic drug progabide or PK 9084, a nonbenzodiazepine ligand on benzodiazepine receptors. The drugs were administered prior to the training trial and retention was measured in the absence of the drug 24 h later. Oral administration (dose in mg/kg in parentheses) of flunitrazepam (0.1), lorazepam (1.0), nitrazepam (3.0), diazepam (10), flurazepam (10) and chlordiazepoxide (30), all prevented retention whereas progabide (100-800) and PPK 9084 (10-100) were ineffective. In comparison to effects on motor capacity none of the benzodiazepines was outstanding in its acquisition interfering effects.

Animals↗
PubMed1984

Ethyl alcohol on escape from electrical periaqueductal gray stimulation in rats.

In a procedure to measure the escape latency and threshold for aversive electrical stimulation of the Peri-Aqueductal Gray (PAG) the effect of ethyl alcohol was tested in order to validate aversive PAG stimulation further as a model for testing potential anxiolytics. Doses of 0.2-1.6 g/kg were given orally in an ascending sequence and were found to increase escape latency and threshold. A second dose of 0.8 g/kg had no effect, suggesting development of tolerance. Spontaneous activity in the test environment was not changed by alcohol. These results indicate specific effects of alcohol on aversive stimulation and reinforce the suggestion to use this phenomenon as a model for human anxiety.

Animals↗
PubMed1983

The potential use of GABA agonists in psychiatric disorders: evidence from studies with progabide in animal models and clinical trials.

Progabide, a new antiepileptic GABA agonist of moderate affinity for GABA receptors, has been studied in a number of psychiatric disorders and the results compared with the action of this drug in animal models. In an animal model for anxiety (the aversive response to periaqueductal grey stimulation in the rat) progabide had a similar action to that of diazepam. However in clinical trials to date the effect of the GABA agonist was inferior to that of benzodiazepines. As progabide diminishes both the nigrostriatal dopamine neuron activity and the effects of striatal dopamine receptor activation, a trial in schizophrenic patients was undertaken. Progabide was devoid of any evident antipsychotic action. However a certain improvement in responsiveness to the environment and in social interactions was noticed in hebephrenic and schizoaffective syndromes. This lack of antipsychotic effect of progabide may be a reflection of the weak activity of GABA agonists on limbic dopamine neurons. In these various clinical trials a definite improvement of affect and mood was noted in those patients receiving progabide. In clinical trials in depressed patients progabide produces a significant reduction in depressive symptoms, an action similar to that of imipramine both for the global clinical rating and the HRSD. This antidepressant activity is reflected by the action of progabide in behavioural models of depression such as olfactory bulbectomy, learned helplessness and the sleep-wake cycle.

Adjustment Disorders↗
PubMed1983

Enhanced effect of haloperidol and apomorphine after hypophysectomy: pharmacokinetic considerations.

The behavioural effects of both apomorphine (stereotypies) and haloperidol (catalepsy and reversal of stereotypies) were significantly enhanced in hypophysectomized rats compared with sham-operated rats. Both the efficacy and duration of action were increased Hypophysectomized animals had significantly greater brain haloperidol concentrations than did sham-operated animals. The data suggest that changes in brain drug concentrations following hypophysectomy at least partially explain the behavioural alterations seen in this test situation.

Animals↗
PubMed1983

Neurochemical and neuropharmacological indications for the involvement of GABA and glycine receptors in neuropsychiatric disorders.

From binding studies using 3H-GABA and 3H-strychnine in dissected human brain material, inhibitory amino acid neurotransmitter receptors have a widespread distribution in the human CNS. Generally GABA receptors are predominant in the forebrain and upper brainstem whereas glycine receptors are more localized in the lower brainstem and spinal cord. Some areas (eg. the substantia nigra) have appreciable quantities of both receptors. Although glycine receptors are altered in some pathological conditions (eg. in Parkinson's disease, in the substantia nigra) the neuropharmacology of the glycine system is still poorly understood. On the other hand the GABA system has been intensively studied. Dysfunction of GABA receptors occurs in various neurological states, as epilepsy, Parkinson's disease and Huntington's chorea. Furthermore GABA agonists are active in animal models for dyskinesia, epilepsy and depression, amongst others. Clinical studies with progabide confirm these findings in animal models, and suggest that low-medium affinity GABA agonists are more appropriate clinical agents than are high or very high affinity GABA agonists. From these and many other findings there appears to be a very large potential for creating new pharmacological agents for different neuropsychiatric disorders based on agonist activity at inhibitory amino-acid receptors. From the example of progabide these compounds can be made not only specific for the receptor involved, but also to have a lower incidence of neurotoxic effects than presently available drugs.

Central Nervous System↗
PubMed1983

Pharmacological and therapeutic actions of GABA receptor agonists.

GABA receptor agonists, e.g. progabide, modify the activity of several brain neuronal systems which are implicated in the pathogenesis of some neuropsychiatric disorders. Thus, alterations in noradrenergic and serotoninergic transmissions induced by progabide may be a mechanism involved in the antidepressant action of this drug in the clinic. The antagonism of the neuroleptic-induced increase in dopamine receptor sensitivity and the decrease in dopamine synthesis and release may be responsible for the effectiveness of the GABA receptor agonists in the treatment of neuroleptic- and L-DOPA-induced dyskinesia. This action of GABA receptor agonists also suggests their therapeutic potential in mania. Finally, decrease in cellular excitability induced by GABA receptor agonists, e.g. progabide, accounts for their efficacy in epilepsy.

Bipolar Disorder↗
PubMed1983

Indications for the use of gamma-aminobutyric acid (GABA)-agonists in convulsant disorders.

From studies using pharmacological models of convulsive disorders and also from the neurochemical analysis of epileptogenic tissue removed during neurosurgical resection (cortectomy), there is strong evidence that at least a subgroup of epileptic disorders may be linked (among other things) to a deficit in GABAergic neurotransmissions. This deficit may be found at the level of GABA synthesis or at the GABA-recognition site; whether these GABA neurons are lost or are dysfunctional is not yet answered. This suggests that GABA-agonists will be of potential use in epilepsy. GABA-agonists (progabide, SL 75102, muscimol, THIP) for the classical GABA-recognition sites as well as other compounds active at sites in the GABA-receptor macromolecular complex (eg, diazepam and phenobarbital) exhibit a wide range of anticonvulsant effects in different animal models and species. However, for some of these compounds (eg, muscimol) secondary central effects occur at the same dose level as the anticonvulsant actions, and for others (eg, THIP) such secondary effects may limit the use to certain types of seizures. This problem may be related to the high affinity of such compounds for the GABA recognition site as compounds with a more moderate affinity (eg, progabide, SL 75102) have a wider margin between anticonvulsant and secondary central effects in rodents. Clinical results using progabide suggests that the GABA hypothesis of convulsive disorders has indeed a rational foundation as a significant percent of refractory or unresponsive epileptic patients with different types of seizures (eg, complex partial or primary generalized) have a significant clinical improvement with this GABA-agonist.

Animals↗
PubMed1982

Enhancing GABAergic transmission reverses the aversive state in rats induced by electrical stimulation of the periaqueductal grey region.

In a proposed rat model for anxiety (electrical stimulation of the periaqueductal grey region), progabide (a GABA agonist) and diazepam both increased the latency to escape to a safe compartment and also the current needed to induce the escape response (escape threshold). Furthermore, the effects of progabide and diazepam were greater than additive in their actions on the escape response as when given together in normally subliminal doses, the combination exerted a marked anti-aversive effect. These actions of the drugs alone or in combination could not be explained by non-specific motor effects. Blockade of GABA receptors by bicuculline greatly reduced or abolished the action of progabide and diazepam (single administration). Sodium valproate, which indirectly augments GABAergic transmission, also increased the escape latency and escape threshold whereas, in contrast, diphenylhydantoin accentuated the aversive effects of stimulation of the periaqueductal grey. Haloperidol increased the escape latency and threshold but not other signs of distress following central stimulation (vocalization, jumping) which were effectively blocked by progabide and diazepam. The action of haloperidol was completely explicable by an interference with motor mechanisms. These results are interpreted as an indication that GABA agonists have an anti-aversive action in this proposed rat model for anxiety and, furthermore, that GABA receptors at least partially mediate the actions of benzodiazepines in this model.

Animals↗
PubMed1982

Cortical modulation of striatal function.

The effect of bilateral section of the corticostriatal projections or of selective bilateral ablation of the frontal cortex on behavioral and biochemical parameters related to striatal function were investigated in the rat. Either lesion almost completely prevented the cataleptogenic action of haloperidol: this effect was observed as soon as 3 days and lasted for at least 3 months after surgery, paralleling a reduction in striatal glutamate uptake. Also, such lesions enhanced the apomorphine-induced stereotyped behavior (as measured 21 days after surgery). In the striatum, dopamine, dihydroxyphenylacetic acid, acetylcholine and substance P levels as well as choline acetyltransferase and glutamic acid decarboxylase activities were unaffected 10 or 21 days after either type of lesion. In the substantia nigra, substance P levels were unchanged 10 days following suction of the frontal cortex, but glutamic acid decarboxylase was reduced at 21 days postsurgery. Cortical lesions only partially prevented the reduction in striatal acetylcholine concentrations and did not affect the increase in striatal dihydroxyphenylacetic acid caused by haloperidol. Finally, lesions of the corticostriatal pathways failed to affect the apomorphine-induced increase in striatal acetylcholine levels, reduction of the potassium (20 mM) evoked [3H]acetylcholine release in striatal slices preloaded with [3H]choline and decrease of striatal dihydroxyphenylacetic acid concentrations. These findings indicate that the frontal cortex influences extrapyramidal function by a mechanism which--in behavioral terms--is antagonistic to dopamine-mediated events. As indicated by the biochemical data, this mechanism does not involve changes in striatal dopaminergic and cholinergic neuron activity. This mechanism may utilize: (1) corticostriatal glutamatergic neurons as suggested by the reduction in striatal glutamate uptake following lesions; and (2) GABAergic pathways as suggested by the reduction of nigral glutamic acid decarboxylase activity as well as by the finding that GABA receptor agonists reinstate haloperidol-induced catalepsy.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1982

Decreased amino acids in various brain areas of patients with Lesch-Nyhan syndrome.

In an effort to further understand the pathogenesis of Lesch-Nyhan syndrome, an X-linked recessive disease of purine metabolism associated with a deficiency of hypoxanthine-guanine phosphoribosyltransferase, we have analyzed the amino acids in autopsy brain material obtained from five patients and six controls. The amino acids glycine and glutamine serve as substrates for the synthesis of purines in man. Amino acids were measured in the occipital cortex, limbic cortical area, cerebellar cortex, hippocampus and putamen. In general the amino acids were usually lower in concentration in brain material from affected individuals. Most dramatically decreased were threonine, serine, valine, isoleucine, lysine and arginine. Only glutamine and urea were higher than controls. Glutamate, gamma-aminobutyrate and cystathionine were essentially unaffected. The data reported here do not support a role for increased glycine in the pathogenesis of this disease as implied by findings previously reported in cultured cell lines (Skaper and Seegmiller 1976, 1977). The current findings suggest that individuals with Lesch-Nyhan syndrome have a generally lower concentration of free amino acids in brain. This decrease may be involved in the etiology of the disease or the decrease may be a result of the generally malnourished state of these individuals. These results imply that affected patients have a limited supply of amino acid precursors available for the synthesis of either proteins or neurotransmitters that the brain requires for normal function. Thus, the low amino acid pools could be an important factor in the brain dysfunction observed in patients with Lesch-Nyhan syndrome.

Adolescent↗
PubMed1982

Glycine receptors in the human substantia nigra as defined by [3H]strychnine binding.

Specific [3H]strychnine binding was used to identify the glycine receptor macromolecular complex in human spinal cord, substantia nigra, inferior olivary nucleus, and cerebral cortex. In material from control patients a high-affinity KD (3--8 nM) was observed in the spinal cord and the substantia nigra, both the pars compacta and the pars reticulata. This is very similar to the values observed in the rat and bovine spinal cord (8 and 3 nM, respectively) and rat substantia nigra (12 nM). In the human brain the distribution of [3H]strychnine binding (at 10 nM) was: spinal cord = substantia nigra, pars compacta greater than substantia nigra, pars reticulata = inferior olivary nucleus greater than cerebral cortex. The binding capacity (Bmax) of the rat brain (substantia nigra or spinal cord) was approximately 10-fold that of the human brain. [3H]Strychnine binding was significantly decreased in the substantia nigra from Parkinson's disease patients, both in the pars compacta (67% of control) and the pars reticulata (50% of control), but not in the inferior olivary nucleus. The results were reproduced in preliminary experiment in rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle. In the substantia nigra from patients who died with Huntington's disease, [3H]strychnine binding tended to be high (150% of control, NS) in both the pars compacta and the reticulata. [3H]Strychnine binding was unaltered in the substantia nigra of patients with senile dementia. Together with previous neurophysiological and neuropharmacological findings, those results support the hypothesis of glycine receptors occurring on dopamine cell bodies and/or dendrites in the substantia nigra.

Adult↗