Biomedical subjects

A V Terry

Publications and source records attributed to A V Terry.

45 records · Page 3Linked to original sources

PubMed1993

Further biological activities of the novel choline analogs selenonium choline and acetylselenonium choline.

The pharmacological actions of the novel choline analog, selenonium choline [(CH3)2Se+CH2CH2OH] and its acetyl ester acetylselenonium choline (ASeCh) were studied in vivo and in vitro. ASeCh produced a dose-related decrease in mean arterial pressure in the rat similar to acetylcholine (ACh) but was 1% to 2% as potent. ASeCh demonstrated agonist activity on the rat isolated ileum and was approximately 2% as active as ACh. Selenonium chlorine (SeCh) was taken up and acetylated in brain tissue slices in a time- and concentration-dependent manner. The use of KCl as a loading stimulus did not increase the uptake of SeCh but increased tissue levels of ASeCh 1.5-fold over the control concentrations. The uptake of SeCh was described by a single low-affinity uptake component (Km = 167 microM) that was not blocked by hemicholinium-3. In contrast, hemicholinium significantly blocked the acetylation of SeCh. Compared with basal release, depolarization with KCl caused a significant release of ASeCh into the incubation medium. A neural specificity was suggested for the in vitro uptake of SeCh. Acetylation of SeCh in vivo in the rat after intraventricular administration was similar to the extent of acetylation of [2H4]-choline. ASeCh bound to both M1 and M2 cholinergic receptors with 2% to 3% of the affinity observed for ACh. These data suggest that SeCh may satisfy criteria for a false neurotransmitter precursor.

Acetylation↗

PubMed1992

Effects of concomitant cholinergic and adrenergic stimulation on learning and memory performance by primates.

Physostigmine and other centrally-acting acetylcholinesterase inhibitors are currently being examined for their potential in the treatment of Alzheimer's Disease. The ability to employ this class of agents is limited by the potential for debilitating and dangerous side effects. Clonidine and related drugs have recently been demonstrated to enhance memory performance in monkeys. Clonidine also inhibits the function of cholinergic neurons in specific brain regions and reduces certain side effects of physostigmine. Seven adult macaque monkeys performing a delayed matching-to-sample (DMTS) task received regimens of increasing doses of clonidine and physostigmine on separate occasions to determine the 'best dose' of each agent in terms of enhanced memory performance. The best doses were combined as a single administration and performance compared to that using the two drugs alone. The combination regimen of clonidine and physostigmine was more effective than either drug alone in enhancing memory performance. Part of the benefit may have been due to the ability to employ significantly higher doses of physostigmine in the combination regimen. A single injection of the combination resulted in enhanced performance both on the day of administration as well as on the following day. These results are consistent with the ability of clonidine to limit the expression or intensity of certain physostigmine-induced autonomic side effects, while allowing the cognitive beneficial effects of the cholinesterase inhibitor.

Animals↗

PubMed1992

Selected biological activities of novel selenonium choline analogs.

1. The novel choline analogs selenonium choline (SeCh) and acetylselenonium choline (ASeCh) have been examined for selected biological activities. 2. ASeCh was found to be an alternative substrate for acetylcholine esterase with Km and Vmax values similar to acetylcholine. 3. ASeCh and SeCh inhibited acetylthiocholine hydrolysis by acetylcholinesterase with IC50 values similar to acetylcholine and choline. 4. SeCh exerted a protective action against physostigmine and DFP induced toxicity. 5. SeCh (85 mg/kg) was found to be 3 times more toxic in mice than choline.

Acetylcholine↗

PubMed1989

Prevention of physostigmine-, DFP-, and diazinon-induced acute toxicity by monoethylcholine and N-aminodeanol.

1. Choline, and the choline analogues monoethylcholine (MEC) and N-aminodeanol (NAD) were examined for prophylactic activity in acute acetylcholinesterase inhibitor toxicity in mice. The rank order of potency of the compounds was MEC greater than NAD greater than choline. 2. Simultaneous administration of MEC (60 mg kg-1) or NAD (200 mg kg-1) with physostigmine reduced lethality to 17 and 13% respectively. MEC (60 mg kg-1) completely protected against disopropylfluorophosphate (DFP) and diazinon toxicity, and NAD reduced lethality to 17% for both agents. Choline (200 mg kg-1) exhibited only negligible antidotal activity against the inhibitors. 3. In vitro concentrations of choline, MEC, and NAD, similar to the estimated concentration obtained in vivo in the acute toxicity study, produced mixed inhibition of mouse brain acetylcholinesterase. The inhibition was dose-related and was additive to the inhibition produced by the cholinesterase inhibitors. 4. All three analogues reduced ligand binding at the nicotinic, M1, and M2 receptors. The rank order of potencies for the analogues at each receptor was nicotinic: (choline greater than MEC greater than NAD), M1: (MEC greater than choline greater than NAD), and M2: (MEC greater than choline greater than NAD). 5. It is proposed that the analogues prevent acetylcholinesterase inhibitor toxicity peripherally by interacting with acetylcholinesterase, and/or by competing with acetylcholine for binding to cholinoceptors.

Animals↗

PubMedDate not supplied

Evaluation of two rodent delayed-response memory tasks: a method with retractable levers versus a method with closing doors.

The purpose of this study was to evaluate and compare two similar rodent memory tasks developed in our laboratory that employ stimulus discrimination and delayed response (light and tone stimuli and variable length delays) and to determine their sensitivity to the muscarinic-acetylcholine receptor (mAChR) antagonist, scopolamine hydrobromide (SCOP HBr), and its quaternary (methylbromide) analog (SCOP MBr). Male Wistar rats were trained in either an open chamber that employed retracting levers (RLM) during the delays, or a method that utilized closing doors (CDM) that separated the rats from the levers during delays to reduce positional (nonmnemonic) strategies. When the rats were well trained, dose-effect studies (microg/kg doses, s.c., 30 min before test sessions) of SCOP HBr or MBr were performed. Baseline performance was characterized by delay-dependent decreases in accuracy in both methods except when the tone was the stimulus in the RLM. SCOP HBr impaired performance in both tasks at the higher doses tested, although the effects were more consistent in the CDM task and accuracy associated with each stimulus was affected similarly. Surprisingly, SCOP MBr also impaired performance of each task, especially when the tone was the stimulus, while accuracy associated with the light was not affected in the CDM task. Overall, the results indicated that the CDM was a somewhat more reliable task, appearing to reduce positional strategies with less variability in response to the mAChR antagonists, although some stimulus-modality specific effects were noted. It also appears important to consider the peripheral effects of mAChR antagonists (and potential central effects of quaternary mAChR antagonists) when interpreting results from behavioral studies, especially those involving conditional discrimination and delayed response.

Acoustic Stimulation↗

PubMedDate not supplied

Nitric oxide synthase inhibition impairs spatial navigation learning and induces conditioned taste aversion.

The free radical gas nitric oxide (NO) is formed from the amino acid precursor L-arginine in brain regions which are associated with learning and the formation of memory. We have previously reported that administration of the nitric oxide synthase (NOS) inhibitor N omega-nitro-L-arginine methyl ester (L-Name) impairs delayed recall in non-human primates but that, at higher doses, impairment is associated with aversive gastrointestinal side effects. The purpose of the present study was to examine the effects of L-Name on learning in a rat spatial navigation task and to assess the ability of L-Name to induce a conditioned taste aversion (CTA) to a novel sucrose solution in a two-bottle choice paradigm. In the Morris water maze. L-Name (5, 20, and 50 mg/kg) markedly impaired cued spatial learning required to locate a hidden platform on three consecutive days of testing, but did not affect general activity levels. These data also demonstrated the ability of L-Name to induce a potent CTA, though only with the 20 and 50 mg/kg doses. Both the impairment of learning and CTA were blocked by administration of a mole equivalent dose of L-arginine, indicating that attenuated NO activity was associated with both behavioral effects. These data demonstrate that inhibition of NO activity by L-Name induces significant and selective impairment of cognitive performance at low pharmacologic doses (< 20 mg/kg). However, with higher doses of NOS inhibitors, impairment may be a secondary effect of drug-induced malaise, possibly related to peristaltic dysregulation of gastrointestinal musculature. Therefore, conclusions as to the mediation of learning and memory processes by CNS NO may be difficult to interpret without the use of selective, centrally-acting compounds.

Animals↗

PubMedDate not supplied

Effects of chronic, low-level organophosphate exposure on delayed recall, discrimination, and spatial learning in monkeys and rats.

Chronic exposure to low levels of organophosphate (OP) compounds impairs acetylcholine (ACh) degradation by acetylcholinesterase (AChE) and, in humans, may produce lasting neurotoxicity affecting cognitive function. The present studies examined the ability of such exposure to impair performance of well-learned cognitive tasks in two species, nonhuman primates and rats. During 25 days of exposure to a 0.01 mg/kg dose of the OP diisopropylfluorophosphate (DFP), mature adult monkeys were not impaired in their performance of a well-learned delayed matching-to-sample task (DMTS). However, erythrocyte AChE activity was reduced from predrug levels by 76.26 +/- 3.33% by 14 days after the initiation of DFP administration. Following titration of DFP to a 0.015 mg/kg dose for 15 days, DMTS performance remained at or above baseline levels. DMTS accuracy was moderately, but not significantly, reduced after titration to a dose of 0.02 mg/kg. However, decrements were associated with mild, overt symptoms of OP toxicity and performance returned to baseline levels after withdrawal from OP exposure. In rats, chronic exposure to a low-dose regimen of DFP (0.25 mg/kg/day for 14 days) impaired the ability to initially learn a spatial navigation task, but did not impair performance of previously learned stimulus discrimination and spatial navigation tasks. These data indicate that performance of memory tasks dependent upon reference concepts is not impaired by OP exposure regimens that impair acquisition of novel cognitive tasks prior to the onset of overt toxicity.

Animals↗

PubMedDate not supplied

Effects of concomitant cholinergic and adrenergic stimulation on learning and memory performance by young and aged monkeys.

The beneficial effects of physostigmine and other centrally acting AChE inhibitors on learning and memory processes have been documented in several studies. Some of these compounds are currently being examined for their potential in the treatment of Alzheimer's disease. However, the ability to employ this class of agents alone is limited by the potential for debilitating and dangerous side effects. In addition, a growing body of evidence also suggests a role for a number of other transmitter systems in this disorder. Agents such as clonidine that address adrenergic deficits have recently been demonstrated to enhance memory performance in monkeys. Clonidine also inhibits the function of cholinergic neurons in specific brain regions and reduces certain side effects of physostigmine. This evidence provided the impetus to evaluate a combination of physostigmine and clonidine in a learning and memory paradigm in monkeys. Seven young adult and three aged macaque monkeys performing a delayed matching-to-sample task received regimens of increasing doses of clonidine and physostigmine on separate occasions to determine the optimal dose of each agent in terms of enhanced memory performance. The optimal dose of clonidine was combined with a series of physostigmine doses and performance was compared to that using the two drugs alone. The best combination regimen of clonidine and physostigmine was more effective than either drug alone in enhancing memory performance. Part of the benefit may have been due to the ability of the animals to tolerate significantly higher doses of physostigmine in the combination regimen.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗

PubMedDate not supplied

Plasma membrane ordering agent pluronic F-68 (PF-68) reduces neurotransmitter uptake and release and produces learning and memory deficits in rats.

A substantial body of evidence indicates that aged-related changes in the fluidity and lipid composition of the plasma membrane contribute to cellular dysfunction in humans and other mammalian species. In the CNS, reductions in neuronal plasma membrane order (PMO) (i.e., increased plasma membrane fluidity) have been attributed to age as well as the presence of the beta-amyloid peptide-25-35, known to play an important role in the neuropathology of Alzheimer's disease (AD). These PMO increases may influence neurotransmitter synthesis, receptor binding, and second messenger systems as well as signal transduction pathways. The effects of neuronal PMO on learning and memory processes have not been adequately investigated, however. Based on the hypothesis that an increase in PMO may alter a number of aspects of synaptic transmission, we investigated several neurochemical and behavioral effects of the membrane ordering agent, PF-68. In cell culture, PF-68 (nmoles/mg SDS extractable protein) reduced [3H]norepinephrine (NE) uptake into differentiated PC-12 cells as well as reduced nicotine stimulated [3H]NE release. The compound (800-2400 microg/kg, i.p., resulting in nmoles/mg SDS extractable protein in the brain) decreased step-through latencies and increased the frequencies of crossing into the unsafe side of the chamber in inhibitory avoidance training. In the Morris water maze, PF-68 increased the latencies and swim distances required to locate a hidden platform and reduced the time spent and distance swam in the previous target quadrant during transfer (probe) trials. PF-68 did not impair performance of a well-learned working memory task, the rat delayed stimulus discrimination task (DSDT), however. Studies with 14C-labeled PF-68 indicated that significant (pmoles/mg wet tissue) levels of the compound entered the brain from peripheral (i.p.) injection. No PF-68 related changes were observed in swim speeds or in visual acuity tests in water maze experiments, rotorod performance, or in tests of general locomotor activity. Furthermore, latencies to select a lever in the DSDT were not affected. These results suggest that PF-68 induced deficits in learning and memory without confounding peripheral motor, sensory, or motivational effects at the tested doses. Furthermore, none of the doses induced a conditioned taste aversion to a novel 0.1% saccharin solution indicating a lack of nausea or gastrointestinal malaise induced by the compound. The data indicate that increases in neuronal plasma membrane order may have significant effects on neurotransmitter function as well as learning and memory processes. Furthermore, compounds such as PF-68 may also offer novel tools for studying the role of neuronal PMO in mnemonic processes and changes in PMO resulting from age-related disorders such as AD.

Animals↗