Search PubMed⌕ Search

Biomedical subjects

K G Lloyd

Publications and source records attributed to K G Lloyd.

At least 37 records · Page 2Linked to original sources
PubMed1988

CSF gradients for amino acid neurotransmitters.

Amino acid concentrations were measured in CSF samples obtained by lumbar puncture in 51 patients, cervical puncture in 16 patients, spinal drains in nine patients, ventricular taps in five patients and from below a spinal block in six patients. There was evidence of a rostrocaudal gradient for GABA and taurine and a reverse gradient for alanine and asparagine. Lumbar CSF glycine concentrations rose with increasing age whilst GABA concentrations fell. Women had significantly lower concentrations of asparagine and glutamine and elevated taurine compared to men. The influence of biological factors and gradients must be taken into account before the interpretation of changes in CSF amino acid concentrations.

Adult↗
PubMed1988

Differentiation of activities within the GABAA-chloride ionophore complex by means of 35-S-TBPS binding.

From the above results, it is evident that both alpidem and zolpidem modulate the GABAA receptor linked chloride ionophore in an allosteric manner via omega 1 anxiolytic/hypnotic recognition sites. As both are highly specific for the omega 1 site, with little affinity for the omega 2 site, it appears that omega 1 site activation is sufficient to fully engage the various linkages within the GABAA receptor supramolecular complex, resulting in modulation of the chloride ionophore. This action is related to an enhanced affinity of the recognition site for TBPS. Under the present conditions (high sodium chloride, frozen well-washed membranes), several (but not all, e.g. zolpidem) anxiolytics and hypnotics decreased TBPS binding at very high (100-500 microM) concentrations. This effect is unlikely related to the pharmacological activity of these compounds, as it is insensitive to flumazenil and occurs only at concentrations which would be supra-toxic. In contrast, the enhancement of TBPS binding by these anxiolytics and hypnotics occurs within the range of, and correlates with, their therapeutic plasma levels and their affinity for omega 1/omega 2 receptors. The present findings suggest that a different degree of linkage for different compounds occurs between the GABAA receptor and the omega 1/omega 2 receptor mediated enhancement of TBPS binding, as the action of alpidem is completely reversed by bicuculline, whereas for zopidem and flunitrazepam a component of the TBPS enhancement is bicuculline insensitive. A Ro 5-4864 sensitive site (probably not the omega 3 site) occurs with the GABAA receptor supramolecular complex, which apparently participates in the enhancement of TBPS binding.(ABSTRACT TRUNCATED AT 250 WORDS)

Allosteric Regulation↗
PubMed1988

Ifenprodil and SL 82.0715 as cerebral anti-ischemic agents. II. Evidence for N-methyl-D-aspartate receptor antagonist properties.

The effects of the anti-ischemic agents ifenprodil and its derivative SL 82.0715 ((+/-)-alpha-(4-chlorophenyl)-4-[(4-fluorophenyl) methyl]-1-piperidineethanol] have been analyzed in a number of models indicative of N-methyl-D-aspartate (NMDA) antagonistic potential in vitro and in vivo. Ifenprodil and SL 82.0715 potently and noncompetitively antagonize the stimulatory effects of NMDA on cyclic GMP production in immature rat cerebellar slices (IC50 values, 0.4 and 10 microM, respectively), as well as the NMDA-evoked [3H]acetylcholine release in adult rat striatal slices (IC50 values, 1.6 and 6.6 microM, respectively). Ifenprodil is 10 times more potent than (+/-)3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) but less active than the reference noncompetitive NMDA channel blockers [MK 801, ((+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5,10-imine ], phencyclidine and 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP)] in these models. Ifenprodil and SL 82.0715 partially displace (maximal displacement 40-50% at 10 microM) the NMDA receptor ligand [3H]CPP from its binding site to rat brain membranes (IC50 values, 0.1 and 0.3 microM, respectively) in a noncompetitive manner; in the micromolar range the two agents also partially displace the NMDA channel ligand [3H]TCP from its binding site to rat brain membranes, and noncompetitively antagonize the L-glutamate-induced increase in [3H]TCP binding. Ifenprodil (0.01-1 microM) partially antagonizes the depolarizing effects of NMDA on the immature rat hemisected spinal cord in vitro. In mouse cultured spinal cord neurons, ifenprodil dose-dependently antagonizes the depolarizing effects of micropressure applied NMDA. Inhibition of the effects of NMDA in this model by ifenprodil and SL 82.0715 is noncompetitive. In vivo and after systemic i.p. administration, ifenprodil and SL 82.0715 antagonize the stimulatory effects of intrastriatally dialyzed NMDA on striatal dopamine release in rats (ID50 values, 0.9 and 0.3 mg/kg, respectively), and block the harmaline-evoked increase in cerebellar cyclic GMP production in mice (ID50 values, 3 and 4 mg/kg, respectively). These results indicate that ifenprodil is a noncompetitive NMDA antagonist which has a mechanism of action distinct from either the reference competitive NMDA receptor antagonists (CPP and 2-amino-5-phosphonovalerate) or the noncompetitive NMDA channel blockers (phencyclidine, TCP and MK 801). The potent NMDA antagonistic effects of the ifenprodil class of compounds are likely to be related to the demonstrated anti-ischemic potential of these compounds.

Animals↗
PubMed1987

Effects of the GABA receptor agonist, progabide, upon local cerebral glucose utilization.

The effects of a specific GABA receptor agonist, progabide, have been examined on local cerebral glucose utilization through the use of the autoradiographic [14C]2-deoxyglucose technique in conscious rats. The intraperitoneal administration of progabide (80-320 mg.kg-1) resulted in a heterogeneous pattern of significantly reduced glucose utilization throughout the 50 discrete regions of the brain that were studied. Insignificant decreases in local cerebral glucose use were noted following the low dose of progabide (80 mg.kg-1). Following progabide (160 mg.kg-1), reductions of approximately 20% in glucose utilization were observed in most of the extrapyramidal system (substantia nigra, pars compacta and reticulata; globus pallidus; caudate nucleus), some thalamic nuclei (lateral geniculate body, anterior and ventrolateral thalamic nuclei), a number of areas related to the limbic system (cingulate cortex; amygdala; hypothalamus; lateral habenula; nucleus accumbens; dorsal hippocampus as well as the CA3 field) and the raphé nuclei. In contrast, layer IV of the neocortex, the cerebellum and cerebellar nuclei, displayed only minimal (10-15%) reductions in glucose utilization. At the highest dose (320 mg.kg-1) examined, progabide effected widespread though heterogeneously distributed decreases in glucose use. The overall pattern of decreased glucose use seen with progabide was different from that noted with previously studied GABA-mimetic drugs, such as muscimol, except for those changes observed in the extrapyramidal and sensory-motor areas for which similar dose-response relationships occurred. A significant correlation was observed between progabide-induced decreases in glucose utilization and in serotonin synthesis in a number of brain areas. The pattern of progabide-induced changes in integrated functional activity is compatible with its neurochemical spectrum and could indicate the loci at which its anticonvulsant, antidepressant and extrapyramidal activities are initiated.

Animals↗
PubMed1987

Anti-apomorphine effects of phenothiazine drug metabolites.

The potencies in producing muscle relaxation, and in antagonizing apomorphine-induced climbing and hypothermia in mice, were examined for chlorpromazine, levomepromazine and their main metabolites, and for fluphenazine and 7-hydroxy fluphenazine. 3-Hydroxy chlorpromazine was more potent than chlorpromazine in antagonizing apomorphine-induced climbing, while levomepromazine and 3-hydroxy levomepromazine were equipotent in this test. The 3-hydroxy metabolites of chlorpromazine and levomepromazine were more potent than the parent compounds in antagonizing hypothermia, and had significantly weaker muscle relaxant effects than the parent compounds. The 7-hydroxy and N-monodesmethyl metabolites were generally less potent that the parent compounds in antagonizing apomorphine-induced effects. N-Monodesmethyl levomepromazine had a pronounced muscle relaxant effect, like levomepromazine itself. The sulphoxide metabolites of chlorpromazine and levomepromazine were inactive in all tests. Their potencies in these tests indicate that among the metabolites 7-hydroxy chlorpromazine, N-monodesmethyl chlorpromazine and 3-hydroxy levomepromazine, which have all been identified in plasma from patients, may contribute to the antipsychotic effects of the drugs, and furthermore that N-monodesmethyl levomepromazine may contribute to the sedative effects of levomepromazine.

Animals↗
PubMed1987

GABA and affective disorders.

Recently sufficient evidence has accumulated to propose that a central GABAergic dysfunction may be primarily related to the pathology of affective disorders and that antidepressant mechanisms (pharmacological or electroconvulsive therapy, ECT) have an intrinsic GABAergic component. In depressed patients GABA levels are reported to be low in the CSF and plasma, and GABA synthesis is decreased in some brain areas, including the frontal cortex. GABAmimetics such as progabide and fengabine exert a therapeutic effect in depression. In behavioural laboratory models GABAmimetics exhibit antidepressant-like actions in the olfactory bulbectomized rat and in rats submitted to an inescapable shock (learned helplessness). Furthermore, antidepressant GABAmimetics decrease paradoxical sleep. In the olfactory bulbectomized rat, GABAB receptors are downregulated in the frontal cortex and in the learned helplessness model, GABA release is diminished in the hippocampus. These decreases are reversed by antidepressants in parallel with their behavioural activities. An intrinsic activity of widely varied antidepressants and ECT is the upregulation of GABAB receptors in the frontal cortex. This, together with the downregulation of beta-adrenergic receptors induced by these compounds, and the GABAB modulation of the beta-adrenergic second messenger system, strongly suggest that both GABAergic and beta-adrenergic responses are inherent to an antidepressant effect.

Animals↗
PubMed1987

GABA receptor agonists and extrapyramidal motor function: therapeutic implications for Parkinson's disease.

GABA receptor agonists display a dual action on DA-mediated events. One includes a decrease in DA release, reduction in DA receptor density, and decreased response of postsynaptic cells to dopaminergic stimulation; it results in antidopaminergic effects. The other consists of a reduction of striatal cholinergic activity resulting in a facilitation of dopaminergic effects. These two effects could be dissociated depending on the dose of GABA receptor agonists. This dual action probably explains the results of clinical trials showing either amelioration of parkinsonian symptoms with aggravation of L-DOPA-induced dyskinesia or improvement of dyskinesia without or with aggravation of parkinsonian symptoms.

Acetylcholine↗
PubMed1987

Fengabine, a novel antidepressant GABAergic agent. I. Activity in models for antidepressant drugs and psychopharmacological profile.

Fengabine (SL 79.229) is a novel benzylidene derivative with clinically proven antidepressant action. Fengabine is active in behavioral models for antidepressant drug action, reversing the passive avoidance deficit in olfactory bulbectomized rats, antagonizing the escape deficit in the learned helplessness model and decreasing paradoxical sleep in the rat. In contrast to tricyclic antidepressants, fengabine antagonizes 5-hydroxytryptophan-induced head twitches and only weakly reverses reserpine-induced ptosis. Fengabine inhibits neither monoamine uptake nor monoamine oxidase. A GABAergic mechanism of fengabine is indicated as bicuculline reverses its action in the olfactory bulbectomy and learned helplessness models. The wide-spectrum anticonvulsant action of fengabine is consistent with a GABA-mimetic action and is in contrast to the proconvulsant effect of most classical antidepressants.

Animals↗
PubMed1987

Fengabine, a novel antidepressant GABAergic agent. II. Effect on cerebral noradrenergic, serotonergic and GABAergic transmission in the rat.

The effects of fengabine (a novel benzylidene derivative possessing clinically demonstrated antidepressant action) on neurochemical parameters related to norepinephrine, serotonin and gamma-aminobutyric acid (GABA) neurons have been investigated in the rat and mouse brain. When given acutely, fengabine (50-1000 mg/kg i.p.) does not alter norepinephrine uptake but accelerates the turnover rate of norepinephrine in the rat brain as demonstrated by the enhancement of: the alpha-methyl-p-tyrosine-induced disappearance of norepinephrine in the hypothalamus; 3,4-dihydroxyphenylacetic acid levels in noradrenergic cell body areas; the pargyline-induced accumulation of normetanephrine in the hypothalamus; and 3,4-dihydroxyphenylethyleneglycol levels in the hypothalamus, septum and spinal cord. No tolerance to the effect of fengabine on the latter biochemical parameter was observed after repeated treatment for 2 weeks at doses of 100 or 200 mg/kg i.p., b.i.d. Fengabine (100 or 200 mg/kg i.p., b.i.d.), given for 14 days, causes a desensitization of isoprenaline-stimulated adenylate cyclase in septal and cortical slices of the rat but fails to modify cortical beta, alpha-1 or alpha-2 adrenoceptor binding sites. Fengabine (up to 400 mg/kg i.p.) has no effect on rat cerebral serotonin uptake, synthesis or metabolism. Moreover, when given subacutely (100 or 200 mg/kg i.p., b.i.d. for 2 weeks), it fails to alter rat cortical serotonine receptors or [3H]imipramine binding sites. Fengabine (up to 50-100 microM) is also inactive in vitro on [3H] GABA binding to GABAA or GABAB receptors in the rat brain or on GABA transaminase activity in the mouse brain.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Cerebrospinal fluid amino acid and monoamine metabolite levels of Papio papio: correlation with photosensitivity.

Several putative neurotransmitter amino acids and monoamine metabolites were measured in the cerebrospinal fluid of spontaneously photosensitive baboons (Papio papio) at different periods with varying degrees of photosensitivity in the same animals. At maximum photosensitivity the inhibitory amino acids gamma-aminobutyric acid and taurine were lower, and those of asparagine (metabolite of the excitatory amino acid aspartate) were higher, than when the animals were not photosensitive. Thus a decreased inhibition and perhaps increased excitation correlates with the level of photosensitivity.

Amino Acids↗
PubMed1986

Zolpidem, a novel nonbenzodiazepine hypnotic. I. Neuropharmacological and behavioral effects.

Zolpidem [N,N,6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide hemitartrate] is reported to be a rapid onset, short duration hypnotic that interacts at the benzodiazepine recognition site. The present report establishes the neuropsychopharmacological profile of zolpidem and compares it with those of benzodiazepine hypnotics. Although in mice the effects of zolpidem are qualitatively similar to those of midazolam, triazolam and flunitrazepam, sedation with zolpidem occurs at doses 10 and 20 times lower than those inducing anticonvulsant and myorelaxant effects, respectively. In contrast, the benzodiazepines studied induce sedation at doses causing myorelaxation and which are 2 to 6 times superior to those antagonizing pentetrazole-induced convulsions. In the rat, zolpidem induces sleep (as indicated behaviorally and electrocorticographically) and displays anticonflict activity in a punished drinking paradigm, as do the benzodiazepines. However, whereas benzodiazepine hypnotics induce EEG sleep patterns in curarized rats at doses similar or inferior to those active in the conflict test (in freely moving animals), the hypnotic effect of zolpidem is seen at doses 10 times lower than those producing an anticonflict effect. Moreover, a qualitative difference between the effects of zolpidem and benzodiazepines is observed in electrocorticographic recordings obtained in curarized rats: electrocorticographic hypersynchronization induced by zolpidem is dominated by the energy increase within the 2 to 4 Hz band whereas the benzodiazepines increase predominantly energy levels within the 12 to 14 Hz band. Studies of the sleep-wakefulness cycle in the rat and the cat revealed that hypnotic doses of zolpidem do not alter the pattern of physiological sleep, although elevated doses of the drug decrease paradoxical sleep and increase slow wave sleep. In rats trained to discriminate chlordiazepoxide, zolpidem fails to generalize with the chlordiazepoxide-associated lever indicating that the compound and benzodiazepines do not share the same discriminative stimulus properties. Nevertheless, the anticonvulsant, hypnotic, myorelaxant and anticonflict effects of zolpidem are antagonized by benzodiazepine receptor antagonist Ro 15-1788 and CGS 8216 indicating an involvement of the benzodiazepine recognition site in the action of this drug. The highly selective sedative effect of zolpidem (as compared to myorelaxant and anticonvulsant effects) suggests that it may possess a specificity for certain subtypes of benzodiazepine receptors.

Animals↗
PubMed1986

[Amino acids in human epileptogenic foci].

The functional status of GABA synapses together with tissue levels of other putative neurotransmitter amino acids was studied in epileptogenic foci (identified by stereo-EEG) removed neurosurgically from 14 epileptic patients unresponsive to anti-epileptic medication. L. glutamic acid decarboxylase was lower than normal in epileptogenic cortical tissue from 10 to 12 patients. 3H-GABA-"A" receptor binding was low in all epileptogenic tissue examined. GABA levels were unchanged, whereas glutamate was increased in 7 patients. These studies confirm previous observations that there is a decreased functional activity of GABA synapses in a high proportion of epileptogenic foci. Therefore these data indicate that there is indeed an imbalance between excitatory and inhibitory neurotransmitter systems.

Amino Acids↗
PubMed1986

Alterations of GABA-mediated synaptic transmission in human epilepsy.

Although animal models consistently indicate that gamma-amino-butyric acid (GABA) synaptic function (GABA levels, synthesis, uptake and/or receptors) is decreased in seizure states, there is little evidence to date in support of such a hypothesis for human epilepsy. This chapter presents the results of an in-depth study of the activity of the GABA-synthesizing enzyme L-glutamic acid decarboxylase (GAD) in brain tissue removed during neurosurgical resection for intractable epilepsy. The tissue studied is unique in that identified (by stereo EEG) foci were excised (rather than large blocks of tissue containing mixtures of foci and nonepileptic material) and compared with nonepileptic (stereo EEG and morphological definitions) tissue from the same patients. In patients in which there was no indication of a tumor, GAD activity in the foci was low in more than 50% of the patients examined. Furthermore, when the population distribution of GAD was compared in epileptic versus nonepileptic tissue fragments from all patients, the peak distribution of epileptic tissue fragments occurred at much lower GAD activities than for the nonepileptic fragments (0-20 versus 41-80 nmol CO2/mg protein X hr, respectively). A small subgroup of epileptic fragments occurred with a normal GAD distribution, indicating that the presence of an epileptic focus was not invariably associated with low GAD activity. When the low levels of GABA "A" binding sites in these epileptic tissue fragments are taken into consideration in combination with the low GAD levels, then it can be estimated that 60 to 70% of the present patient population had deficient GABAergic transmission in epileptic foci as compared to nonepileptic brain tissue from the same patients. It follows that the GABA hypothesis of human epilepsy is not an exclusive or unitary hypothesis, and some patients appear to have normally functioning GABA synapses (as assessed biochemically) in epileptogenic areas. Thus, other neurotransmitter and neurohumoral systems certainly play a role in the epileptic process.

Animals↗
PubMed1985

The effect of different types of cortical lesions on drug-induced catalepsy in rats: a pharmacological analysis.

The effect of bilateral lesions of various cortical areas on neuroleptic- and non-neuroleptic-induced catalepsy was studied in the rat. Ablation of the frontal or parietal cortex led to a marked decrease in haloperidol catalepsy, whereas lesions of the occipital cortex, or of the olfactory bulbs did not affect catalepsy, when measured 3 weeks post lesion in all cases. The frontal cortex lesions also diminished the cataleptic state induced by cis-flupenthixol, (+)-butaclamol and chlorpromazine, but failed to affect that induced by reserpine, tetrabenazine or morphine. Four months after the frontal lesions, haloperidol catalepsy was at control values, and a rebound phenomenon was observed at 10 months post lesion. The homeostatic mechanisms seem to have stabilized at 18 months post lesion when haloperidol catalepsy had returned to control levels.

Animals↗
PubMed1985

Subchronic administration of GABAergic agonists elevates [3H]GABA binding and produces tolerance in striatal dopamine catabolism.

Directly and indirectly acting GABAergic agonists were assessed for their ability to alter striatal dopamine catabolism after subchronic administration (7-14 days) via subcutaneously implanted osmotic minipumps. THIP, kojic amine and baclofen failed to alter striatal DOPAC and HVA concentrations, but THIP and kojic amine were effective after a single acute dose. Striatal GABA levels proved difficult to elevate when inhibitors of GABA transaminase were released from minipumps, but a high dose of gamma-vinyl GABA increased GABA by 44% of control, although striatal dopamine and DOPAC levels were unaltered. [3H]GABA binding studies revealed that THIP and kojic amine, but not baclofen or gamma-acetylenic GABA, produced large increases in [3H]GABA 'A' binding (150 and 228% of control respectively) which were attributable to altered densities of binding sites without changes in affinity. Despite alterations in GABAergic function, nigrostriatal dopaminergic neurones seem to develop tolerance to the effects of GABAergic drugs.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1985

Induction and reversal of dopamine dyskinesia in rat, cat, and monkey.

Abnormal involuntary movements (AIMs, stereotyped or dyskinetic movements) were induced with different dopamine mimetics in rat, cat, and monkey. In the rat only stereotyped movements were observed, whereas in the cat dopamine agonists (apomorphine) preferentially induced dyskinesia but dopamine/noradrenaline uptake inhibitors (d-amphetamine, nomifensine) induced predominantly stereotypes; L-dopa induced an equal, low, number of both kinds of movements in the cat. In the monkey with bilateral lesions of the nigrostriatal dopamine pathways the AIMs could be divided into type 1 dyskinesia (behavioral), type 2 dyskinesia (oral and psychomotor), and chorea. GABA agonists (progabide, muscimol) had a biphasic action on apomorphine stereotypes in the rat, slightly (10%-20%) augmenting these movements at low doses and antagonizing (greater than 50%) them at higher doses. As these latter doses of progabide also antagonize apomorphine-induced circling in rats with a unilateral lesion of the substantia nigra, it is likely that this action is exerted at or beyond the dopamine target cell. In cats the dyskinetic movements induced by apomorphine were abolished by progabide. In contrast, L-dopa-induced stereotypies were resistant to the antidyskinetic action of progabide, and at low doses of L-dopa an increased incidence of stereotypies was noted. In the monkey, the type 1 dyskinesia following L-dopa and piribedil were also relatively resistant to progabide administration, whereas the type 2 dyskinesia and chorea were abolished by progabide. These studies are parallel to and support the clinical observations that dyskinetic movements following a direct action at the dopamine receptor (tardive dyskinesia) may be reversed by progabide whereas those associated with dopamine neuron activity, perhaps together with noradrenergic activation (L-dopa dyskinesia), are resistant to the antidyskinetic action of progabide.

Animals↗