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G K Lloyd

Publications and source records attributed to G K Lloyd.

33 records · Page 2Linked to original sources
PubMed1997

Effects of lobeline and dimethylphenylpiperazinium iodide (DMPP) on N-methyl-D-aspartate (NMDA)-evoked acetylcholine release in vitro: evidence for a lack of involvement of classical neuronal nicotinic acetylcholine receptors.

Biochemical, behavioral and electrophysiological evidence suggests interactions between pathways containing neuronal nicotinic acetylcholine receptors (NAChRs) and excitatory amino acid receptors. Recently, protective effects of nicotine against N-methyl-D-aspartate (NMDA)-induced toxicity in primary cortical cultures were reported. To address possible interactions between NAChR and NMDA receptor containing pathways, several NAChR agonists were evaluated for their effects on NMDA-evoked [3H]acetylcholine ([3H]ACh) release from slices of rat striatum. Nicotine, cytisine and epibatidine had no effect on NMDA-evoked release or basal release of [3H]ACh over a wide range of concentrations. Lobeline and dimethylphenylpiperazinium iodide (DMPP), however, decreased basal [3H]ACh release and attenuated NMDA-evoked [3H]ACh release with EC50 values of 35 and 155 microM, respectively. The NAChR antagonists, dihydro-beta-erythroidine (DH beta E) and d-tubocurarine had no effect on NMDA-evoked [3H]ACh release, whereas mecamylamine attenuated the NMDA-evoked [3H]ACh evoked release with an EC50 value of 144 microM. Methyllycaconitine (MLA), a highly selective and potent antagonist of the alpha-bungarotoxin-sensitive alpha 7 NAChR subtype, also had no effect on NMDA-evoked [3H]ACh release at concentrations upto 10 microM. The inhibitory effects of DMPP and lobeline on NMDA-evoked [3H[ACh release were relatively insensitive to mecamylamine, d-tubocurarine, MLA and DH beta E. In addition, DMPP or lobeline-induced attenuation of basal [3H]ACh release was insensitive to blockade by sulpiride, a dopamine (D2) receptor antagonist. In contrast to their effects on NMDA-evoked striatal [3H]ACh release, both DMPP and lobeline increased basal release of striatal [3H]DA and hippocampal [3H]norepinephrine ([3H]NE) and did not attenuate NMDA-evoked release of these two transmitters. Instead, DMPP and lobeline appeared to have an additive effect on both NMDA-evoked hippocampal [3H]NE release and striatal [3H]DA release. These pharmacological results suggest that the inhibitory effects on lobeline and DMPP on striatal [3H]ACh release are independent of their interactions with classical NAChRs or the NMDA receptor complex itself.

Acetylcholine↗
PubMed1997

Pharmacological characterization of SIB-1765F: a novel cholinergic ion channel agonist.

Nicotine, the prototypical agonist for neuronal nicotinic acetylcholine receptors (NAChR), nonselectively activates NAChR limiting its use in elucidating the function of NAChR subtypes. SIB-1765F is a subtype selective NAChR agonist that displaces [3H]-nicotine binding with an IC50 of 4.6 nM and [3H]-cytisine binding with an IC50 of 12.2 nM which is 2000- to 6000-fold lower than its displacement of [3H]-QNB or [125I]-alpha-bungarotoxin. SIB-1765F did not inhibit human or rat cholinesterases or the uptake of [3H]-DA in synaptosomal preparations. SIB-1765F mimicked (-)-nicotine in stimulating [3H]-DA release from rat striatal and olfactory tubercle slices, with EC50 values of 99.6 and 39.6 microM, respectively. Such stimulation was sensitive to mecamylamine and DH beta E. SIB-1765F also released endogenous DA in the striatum and the nucleus accumbens as measured by in vivo microdialysis. SIB-1765F was less efficacious than (-)-nicotine at stimulating [3H]-NE release from rat hippocampal slices; in contrast, SIB-1765F increased [3H]-NE release from rat thalamic and cortical slices with efficacies approaching those of (-)-nicotine. Similar to (-)-nicotine and (+/-)-epibatidine, subcutaneous administration of SIB-1765F increased the turnover rate of dopamine ex vivo both in the striatum and olfactory tubercles in a mecamylamine-sensitive manner. Because the release of striatal DA and hippocampal NE appears to be regulated by distinct NAChR, differential effects of SIB-1765F on striatal DA and hippocampal NE release supports the NAChR subtype selectivity of SIB-1765F compared to (-)-nicotine. This is further demonstrated by observations showing that SIB-1765F has a higher affinity for h alpha 4 beta 2 NAChR relative to h alpha 4 beta 4 NAChRs in displacing [3H]-epibatidine binding and increasing cytosolic CA+2 concentration in cell lines stably expressing h alpha 4 beta 2 or h alpha 4 beta 4.

Animals↗
PubMed1997

Effects of a novel cholinergic ion channel agonist SIB-1765F on locomotor activity in rats.

SIB-1765F ([+/-]-5-ethynyl-3-(1-methyl-2-pyrrolidinyl)pyridine fumarate) is a novel nicotinic acetylcholine receptor (NAChR) agonist displaying a different in vitro pharmacological profile than nicotine and epibatidine, suggestive of NAChR subtype selectivity. Our study describes the effects of SIB-1765F on locomotor activity in rats, which were compared to those observed for nicotine and epibatidine. The three NAChR agonists decreased or increased locomotor activity in rats naive or habituated to the test apparatus, respectively. The transient reduction in locomotor activity induced by SIB-1765F was quantitatively similar to those induced by nicotine and epibatidine but, unlike the effects of nicotine and epibatidine, was not blocked by the NAChR antagonists mecamylamine and dihydro-beta-erythroidine, suggesting different mechanisms of action. Furthermore, SIB-1765F produced a larger and longer-lasting increase in locomotor activity when administered to rats familiar with the test apparatus. Mecamylamine and dihydro-beta-erythroidine but not hexamethonium blocked the increase in locomotor activity induced by SIB-1765F, suggesting that SIB-1765F elicits this effect predominantly through the activation of central NAChR. The SIB-1765F-induced increase in locomotor activity was also attenuated by selective D1 and D2 dopamine receptor antagonists, implying that this increase in locomotor activity is mediated through the activation of dopamine receptors subsequent to the release of dopamine. Based on these results, SIB-1765F appears to have a different locomotor activity profile than nicotine and epibatidine.

Animals↗
PubMed1997

Interactions between a novel cholinergic ion channel agonist, SIB-1765F and L-DOPA in the reserpine model of Parkinson's disease in rats.

SIB-1765F, a novel nicotinic acetylcholine receptor agonist, was tested for its efficacy in attenuating reserpine-induced hypolocomotion in rats. SIB-1765F was administered alone or in combination with L-DOPA and its effects were compared to those of nicotine, d-amphetamine and amantadine in the same conditions. Consistent with previous reports, reserpine-induced hypolocomotion was reversed by L-DOPA (plus benserazide), d-amphetamine and amantadine in a dose-dependent manner and the effect of L-DOPA in reserpine-treated rats was potentiated by amantadine. SIB-1765F also increased the locomotor activity of reserpine-treated rats and potentiated the effect of L-DOPA on reserpine-induced hypolocomotion. The onset of potentiation of L-DOPA by SIB-1765F was rapid (< 5 min) compared to the onset of potentiation by amantadine (> 105 min). Interestingly, nicotine did not attenuate reserpine-induced hypolocomotion nor did it affect the action of L-DOPA on reserpine-treated rats. Biochemical analysis of levels of dopamine and its metabolites, dihydroxyphenylacetic and homovanillic acid, indicated that, in contrast to amphetamine, SIB-1765F did not inhibit dopamine reuptake. The effect of SIB-1765F in reserpine-treated rats was attenuated by alpha-methyl-p-tyrosine, implying that SIB-1765F acts by releasing dopamine from both reserpine-insensitive and reserpine-sensitive pools. Our findings demonstrate that nicotinic acetylcholine receptor agonists may offer a new therapeutic approach to the symptomatic treatment of the motor deficits in patients with Parkinson's disease.

Amantadine↗
PubMed1996

Evaluation of anti-nociceptive effects of neuronal nicotinic acetylcholine receptor (NAChR) ligands in the rat tail-flick assay.

In the present investigation, anti-nociceptive effects of neuronal nicotinic acetylcholine receptor (NAChR) ligands, (+)- and (-)-nicotine, cytisine, methylcarbamylcholine (MCC), dimethylphenylpiperazinium iodide (DMPP), and (+/-)-epibatidine were evaluated in the rat tail-flick assay both after subcutaneous (s.c.) and intracerebroventricular (i.c.v.) administration. The pharmacology of the tail-flick response to NAChR ligands after s.c. and i.c.v. routes was similar. Epibatidine was the most potent ligand examined with a longer duration of action than any other agonist. (-)-Nicotine was more active than (+)-nicotine indicating stereospecificity. ICV administration studies indicated an apparent partial agonist activity for (+)-nicotine in the tail-flick response. Tail-flick responses to NAChR agonists are independent of opioid and muscarinic pathways and appear to be mediated both by central and peripheral NAChR recognition sites. Central administration of MCC activates both NAChR and muscarinic anti-nociceptive mechanisms. Studies employing the alpha-adrenergic receptor alkylating agent, phenoxybenzamine or the noradrenergic neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), suggested that the NAChR-noradrenergic and NAChR-serotoninergic interactions play an important role in the tail-flick response. Studies employing a selective alpha-bungarotoxin-sensitive NAChR receptor antagonist, methyllycaconitine (MLA), suggested a minimal role for these receptors in the tail-flick response. The biochemical studies also indicated that a sub-population of NAChR receptors are located pre-synaptically on noradrenergic and/or serotoninergic pathways in the hippocampus.

Aconitine↗
PubMed1996

Epibatidine: a nicotinic acetylcholine receptor agonist releases monoaminergic neurotransmitters: in vitro and in vivo evidence in rats.

The effect of the neuronal acetylcholine-gated ion channel receptor agonist (+/-)-epibatidine was studied on neurotransmitter release in vitro and motor behavior in vivo. (+/-)-Epibatidine (3-300 nM) caused a concentration- and calcium-dependent release of [3H]-dopamine from striatal slices and [3H]-norepinephrine release from hippocampal and thalamic slices. (+/-)-Epibatidine-induced neurotransmitter release was inhibited in all three regions by mecamylamine (3 microM). In contrast, D-tubocurarine (10-100 microM) inhibited only (+/-)-epibatidine-induced [3H]-norepinephrine release from the hippocampus and the thalamus. Conversely, dihydro beta-erythroidine (3-100 microM) inhibited (+/-)-epibatidine-induced [3H]-dopamine release in the striatum without significantly altering [3H]-norepinephrine release from either the hippocampus or the thalamus. This is consistent with the observation that different nAChRs modulate dopamine release as compared with norepinephrine release. The effect of (+/-)-epibatidine on both [3H]-dopamine and [3H]-norepinephrine release was tetrodotoxin-sensitive, suggesting the involvement of sodium channels. (+/-)-Epibatidine (1-3 micrograms/kg s.c.) produced ipsilateral turning in the unilaterally [6(OH)-DA]-lesioned rat. This effect was mimicked by (-)-nicotine (0.35 mg/kg s.c.). Both (+/-)-epibatidine- and (-)-nicotine-induced turning were significantly inhibited by mecamylamine (3 mg/kg s.c.), indicating that the turning response was mediated by nAChRs. (+/-)-Epibatidine also increased locomotor activity in a dose-dependent manner. (+/-)-Epibatidine-induced hyperactivity was blocked by D1 and D2 receptor antagonists, SCH 23390 and eticlopride, respectively, suggesting that both dopamine receptor subtypes might be required for the locomotor effect of (+/-)-epibatidine. These results demonstrate that (+/-)-epibatidine displays nAChR agonist activity in the rat CNS and that certain effects are mediated via nAChR-stimulated catecholamine release and subsequent activation of corresponding receptors.

Animals↗
PubMed1995

Pharmacological characterization of neuronal acetylcholine gated ion channel receptor-mediated hippocampal norepinephrine and striatal dopamine release from rat brain slices.

Neuronal acetylcholine-gated ion channel receptor-mediated [3H]-norepinephrine ([3H]-NE) and [3H]-dopamine ([3H]-DA) release from rat hippocampal and striatal slices, respectively, were compared. The nicotinic receptor agonists (-)-nicotine, (-)-cytisine and 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) increased both [3H]-NE and [3H]-DA release in a concentration-dependent manner. The rank order of potency for the three agonists was DMPP > (-)-cytisine > (-)-nicotine for evoking [3H]-NE release and (-)-cytisine > DMPP = (-)-nicotine for releasing [3H]-DA. (-)-Cytisine acted as a partial agonist in stimulating DA release as it displayed lower efficacy and inhibited the agonistic effect of (-)-nicotine. (-)-Cytisine and (-)-nicotine were equally effective in stimulating NE release. The responses to a maximally effective concentration of (-)-nicotine, (-)-cytisine or DMPP on [3H]-NE release were blocked by 1 microM tetrodotoxin (TTX). In contrast, the effects of the various agonists on [3H]-DA release were not blocked by tetrodotoxin. The nicotinic receptor antagonists, d-tubocurarine (3-100 microM) and mecamylamine (1.0-10 microM) blocked the 3H-NE release induced by (-)-nicotine and DMPP in the rat hippocampal slice, whereas dihydro beta-erythroidine (3-300 microM) was without effect. In the striatum, mecamylamine (0.3-10 microM) and dihydro beta-erythroidine (3-100 microM) blocked the responses mediated by both agonists whereas d-tubocurarine (3-100 microM) was ineffective.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

GABAA receptor complex function in frontal cortex membranes from control and neurological patients.

The functional integrity of the GABAA receptor-benzodiazepine (BZ) recognition site-Cl- ionophore complex was assessed by means of [35S]TBPS (t-butylbicyclophosphorothionate) binding to frontal cortex membranes prepared from frozen postmortem brain tissue taken from control (n = 4), Alzheimer (n = 7), Parkinson (n = 3) and Huntington's chorea (n = 2) patients. Specific [35S]TBPS binding was similar in control, Parkinson's disease and Huntington's chorea brains, but was significantly reduced (78% control, P less than 0.01) in frontal cortex membranes from Alzheimer's patients. The linkage between the BZ recognition sites and the GABAA receptor-linked Cl- ionophore was functionally intact in these membranes as BZ site agonists (zolpidem, alpidem, flunitrazepam and clonazepam) enhanced [35S]TBPS binding under the conditions used (well-washed membranes in the presence of 1.0 M NaCl). Zolpidem (BZ1 selective) exhibited a biphasic enhancement in control membranes whereas the other compounds induced a bell-shaped concentration-response curve. The enhancement of [35S]TBPS binding by alpidem, flunitrazepam and clonazepam was greater in frontal cortex membranes from Alzheimer's patients than in controls whereas it tended to be reduced in membranes from the brains of Huntington's chorea patients. These studies demonstrate the functional integrity of the GABAA receptor macromolecular complex and also the usefulness of [35S]TBPS binding in the study of human postmortem tissue.

Adult↗
PubMed1990

The activity of zolpidem and other hypnotics within the gamma-aminobutyric acid (GABAA) receptor supramolecular complex, as determined by 35S-t-butylbicyclophosphorothionate (35S-TBPS) binding to rat cerebral cortex membranes.

The present study compares the effects of different hypnotics acting at omega 1/omega 2 sites (zolpidem, zopiclone, flunitrazepam and triazolam) on 35S-t-butylbicyclophosphorothionate (35S-TBPS) binding to well-washed rat cerebral membranes, in the presence of 1M NaCl. Under these conditions, all compounds enhanced 35S-TBPS binding in the 0.05 to 10 microM range with EC50 values and maximal enhancement of: zolpidem, 84 nM and 36%; flunitrazepam, 8 nM and 41%; zopiclone, 171 nM and 51%; triazolam, 2 nM and 42%. Under these conditions, gamma-aminobutyric acid enhanced 35S-TBPS binding with an EC50 of 240 nM and a 38% maximal increase. The EC50 values for the stimulation of 35S-TBPS binding are well correlated, with (r = 0.97) the affinity of these compounds at omega 1/omega 2 sites, and are in the same concentration range. This enhanced binding was due to an altered apparent affinity for the 35S-TBPS recognition site without any change in the number of sites (Scatchard analysis). The effect of zolpidem and other hypnotics was antagonized by flumazenil. This was an apparently competitive antagonism in the case of zolpidem or flunitrazepam, whereas for zopiclone, increasing the concentration of the hypnotic did not overcome the antagonism. Bicuculline only partially antagonized the hypnotic-induced enhancement of 35S-TBPS binding. This antagonism was more effective for zopiclone (-57%) than for either zolpidem (-33%) or flunitrazepam (-30%). Zolpidem and the other hypnotics studied induced a fast component of dissociation which was not observed in the control membranes. These findings are consistent with the hypothesis that omega 1/omega 2 agonists increase the frequency of openings of the chloride ionophore, with both gamma-aminobutyric acid-A receptor-dependent and -independent mechanisms.

Animals↗
PubMed1986

The toxicity of gossypol to the male rat.

When (+/-) gossypol acetic acid was administered to male Sprague-Dawley rats for 26 weeks, the most significant toxicological finding was marked suppression of body weight gain in rats receiving 25 mg/kg per day. Minor biochemical changes were noted at this dosage level. Terminal studies showed 6 out of 20 rats receiving 25 mg/kg per day to have varying degrees of testicular pathology. Five mg/kg per day was shown to be a "no effect" level.

Animals↗