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M W Decker

Publications and source records attributed to M W Decker.

At least 55 records · Page 3Linked to original sources
PubMed1995

Influence of separate and combined septal and amygdala lesions on memory, acoustic startle, anxiety, and locomotor activity in rats.

The septohippocampal system and the amygdala have been implicated in cognitive and emotional processes. A series of experiments was conducted to examine the effects of separate and combined lesions of these areas on a variety of behaviors, including: startle responses to acoustic stimuli; sensory gating, using prepulse inhibition of acoustic startle; anxiety, using the elevated plus-maze; locomotor activity in an open field; and memory, using both a spatial discrimination version of the Morris water maze and the inhibitory (passive) avoidance test. Both septal and fimbria-fornix lesions markedly impaired the acquisition of spatial information in the water maze, had anxiolytic-like effects in the elevated plus-maze, increased reactivity to footshock, and had marginal effects on prepulse inhibition and baseline startle. Septal and fimbria-fornix lesions also increased locomotor activity in the later stages of a session of open field exploration, but only septal lesions produced "freezing" during the early portion of this session and during inhibitory avoidance training. Amygdala lesions markedly impaired prepulse inhibition of acoustic startle. Amygdala lesions also attenuated the effects of septal lesions on freezing in the open field and on footshock reactivity, but did not affect the anxiolytic-like effects or hyperactivity associated with septal lesions. Amygdala lesions by themselves had no significant effect on water maze performance, but significantly potentiated the effects of septal lesions. These results suggest that there are dissociations between the effects of septal and fimbria-fornix lesions and that the interactions between the amygdala and septum in cognitive and emotional processes are task dependent.

Acoustic Stimulation↗
PubMed1995

ABT-418: discriminative stimulus properties and effect on ventral tegmental cell activity.

Previous studies have established that ABT-418 [(S)-3-methyl-5-(1 methyl-2-pyrrolidinyl)isoxazole hydrochloride] is a novel neuronal nicotinic acetylcholine receptor (nAChR) ligand with cognitive enhancing and anxiolytic-like activity 3- to 10-fold more potent than (-)-nicotine in rodents. A series of experiments was conducted to determine the discriminative stimulus properties of ABT-418 in comparison with (-)-nicotine, and to determine the relative potencies of these compounds on ventral tegmental area (VTA) neurons. While rats were able to discriminate (-)-nicotine 1.9 mumol/kg in 39 days, they were not able to discriminate 1.9 or 6.2 mumol/kg ABT-418 from a saline solution during 50 days of training. In rats trained to discriminate 1.9 mumol/kg (-)-nicotine, a reduced generalization was induced by ABT-418 at 1.9 and 6.2 mumol/kg, an effect completely blocked by the cholinergic channel blocker mecamylamine (15 mumol/kg, IP). However, in extensively trained rats, intraperitoneal or subcutaneous injections of ABT-418 induced 78-82% generalization at the 6.2 mumol/kg dose. The predominant metabolites of (-)-nicotine and ABT-418 (continine and A-87770, respectively) were devoid of any effect in nicotine-trained rats. The reduced potency of ABT-418 in nicotine-trained rats is consistent with the electrophysiological findings showing that ABT-418 is 3-fold less potent than (-)-nicotine in activating dopamine-containing neurons in the VTA area.

Animals↗
PubMed1995

Improvement in performance of a delayed matching-to-sample task by monkeys following ABT-418: a novel cholinergic channel activator for memory enhancement.

ABT-418, a newly characterized centrally acting cholinergic channel activator (ChCA), was evaluated for its ability to improve performance in a delayed matching-to-sample (DMTS) task by mature macaques well trained in the task. Previous studies in rodents have indicated that ABT-418 shares the memory/cognitive enhancing actions of nicotine, but without many of nicotine's dose-limiting side effects. As DMTS provides a measure both of general cognitive function (the matching concept) and of recent memory, it was hypothesized that some doses of ABT-418 would enhance the monkeys' ability to correctly perform the DMTS task. Intramuscular administration of ABT-418 significantly enhanced DMTS performance at low (2-32.4 nmol/kg) doses. In fact, the drug was slightly more potent that nicotine in this regard, and all eight animals tested in this study exhibited enhanced performance at one or more doses. ABT-418 produced the greatest improvement in DMTS performance at the longest delay interval. In animals repeatedly tested with their individualized "Best Dose", DMTS performance increased on average by 10.1 +/- 3.5 percentage points correct, which was equivalent to an increase of 16.2% over baseline performance. ABT-418 did not significantly affect response times, i.e., latencies to make a choice between stimuli, or latencies to initiate new trials. Whereas nicotine enhanced DMTS performance both on the day of administration and on the following day (in the absence of drug), ABT-418-induced enhanced performance was detected only on the day of administration. Finally, single daily administration of the individualized best dose in three monkeys over a period of 8 days generally maintained enhancement of DMTS performance. Thus, the data were not consistent with the development of significant tolerance to the drug's mnemonic actions. In contrast to nicotine, no overt toxicity or side effects to acute or repeated administration of the drug were noted. Thus, ABT-418 represents a prototype of a new class of nicotinic agonists designed for the potential treatment of human dementias having a low profile of toxicity.

Animals↗
PubMed1995

Diversity of neuronal nicotinic acetylcholine receptors: lessons from behavior and implications for CNS therapeutics.

Although the molecular biology of neuronal nicotinic acetylcholine receptors (nAChRs) provides evidence for multiple receptor subtypes, few selective pharmacological tools exist to identify these subtypes in vivo. However, the diversity of behavioral effects of available nAChR agonists and antagonists reviewed in this paper suggests that neuronal nAChR subtypes may play distinct roles in a variety of behavioral outcomes. Further characterization of the behavioral effects of the activation of discrete nAChR subtypes may eventually provide information useful in designing selective nAChR ligands targeting a variety of CNS disorders.

Analgesia↗
PubMed1995

Is epibatidine really analgesic? Dissociation of the activity, temperature, and analgesic effects of (+/-)-epibatidine.

The experiments in the present study were designed to determine if the activity, temperature, and analgesic effects of (+/-)-epibatidine treatment could be dissociated. Initially (i.e., 15 min) (+/-)-epibatidine treatment (0.1 mumol/kg = 28 micrograms/kg, IP) impaired rotorod performance, decreased activity, decreased temperature, and increased jump latency (e.g., analgesic effect). For the remaining time points measured (i.e., 30, 60, and 120 min), activity and temperature remained significantly reduced. In contrast, by 120 min (+/-)-epibatidine's effects on rotorod performance and analgesia (jump latency) were not observed. When administered after (+/-)-epibatidine (0.05 mumol/kg, IP), mecamylamine treatment (5 mumol/kg = 1 mg/kg, IP) produced a potentiation of analgesia. This potentiation effect was not observed on activity and temperature measures. The effect of (+/-)-epibatidine treatment (0.1 mumol/kg, IP) was also determined in mice with central nicotinic receptor blockade induced by treatment with chlorisondamine (23 mumol/kg = 10 mg/kg, IP). An (+/-)-epibatidine-induced reduction in activity was not attenuated in chlorisondamine-treated mice and only a minimal effect was observed on (+/-)-epibatidine-induced hypothermia in chlorisondamine-treated mice. In contrast, in chlorisondamine-treated mice (+/-)-epibatidine's analgesic effect was attenuated. Taken together, these data suggest that various centrally mediated effects of (+/-)-epibatidine can be dissociated.

Analgesics, Non-Narcotic↗
PubMed1995

Potential treatment of Alzheimer disease using cholinergic channel activators (ChCAs) with cognitive enhancement, anxiolytic-like, and cytoprotective properties.

Compounds that activate neuronal nicotinic acetylcholine receptors (nAChRs) may have potential benefit in the treatment of dementia, especially Alzheimer disease (AD). This article summarizes the preclinical pharmacology of ABT-418 [(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl) isoxazole], a novel analog of (-)-nicotine that is being clinically evaluated for the treatment of AD. ABT-418 is a cholinergic channel activator (ChCA) with cognitive enhancement and anxiolytic-like activity possessing a substantially reduced side-effect profile compared to (-)-nicotine [Arneric SP, Sullivan JP, Briggs CA, et al. (S)-3-Methyl-5-(1-Methyl-2-Pyrrolidinyl)Isoxazole (ABT-418): A novel cholinergic ligand with cognition enhancing and anxiolytic activity. I. In vitro activity. J Pharmacol Exp Ther 1994 ;270:310-318; Decker MW, Brioni JD, Sullivan JP, et al. (S)-3-Methyl-5-( 1-Methyl-2-Pyrrolidinyl)Isoxazole (ABT-418): A novel cholinergic ligand with cognition-enhancing and anxiolytic activities: II. In vivo characterization. J Pharmacol Exp Ther 1994a;270:319-328; Decker MW, Curzon P, B rioni JD, Arne ric SP. Effects of ABT-418, a novel cholinergic channel ligand, on place learning in septal-lesioned rats. Eur J Pharmacol 1994;261:217-222; Garvey DS, Wasicak JT, Decker MW, et al. Novel isoxazoles which interact with brain cholinergic channel receptors have intrinsic cognitive enhancing and anxiolytic activities. J Med Chem 1994;37:1055-1059]. ABT-418 may be the first agonist of nAChRs to be developed and evaluated specifically for the treatment of AD. Some brief speculation will be given on the potential benefits that this or other ChCAs may have in treating neurodegenerative disorders as compared with (-)-nicotine, and how this differs from other potential treatment approaches.

Alzheimer Disease↗
PubMed1995

Cholinergic channel activators: novel opportunities for the treatment of CNS disorders.

Negative connotations associated with the use of (-)-nicotine has limited medicinal chemistry research in the area of nAChRs [5]. However, recent evidence suggests that a diversity of nAChR subunits exist, that each subtype may be involved in mediating specific neurochemical/behaviors, and that these subtypes have a defined pharmacology that may be selectively targeted [1]. (+/-)-Epibatidine, GTS-21 and ABT-418 differentially interact with nAChR subtypes to elicit a diversity of behavioral effects including analgesia, neuroprotection and cognitive enhancement. These agents therefore represent important new pharmacological probes to dissect the nAChR subtype(s) mediating specific pharmacological responses to nAChR activation.

Animals↗
PubMed1995

Animal models of cognitive function.

Various of animal models of cognitive function have been developed both to discover neural processes underlying cognition and to develop and test novel therapeutic interventions. Lesion models used in basic research have specified brain circuits involved in discrete cognitive behaviors, and simple system models have identified electrophysiological and biochemical events that might mediate processes such as learning and memory. Models used for drug screening for potential cognition enhancers have been less successful. Drug-screening models have identified several compounds as being of potential use as treatments for cognitive dysfunction prominent in conditions such as Alzheimer's disease. Unfortunately, most of these compounds have not been successful in clinical studies. This paper reviews representative model systems used for basic research and provides a more extensive treatment of models used to screen drugs, with an emphasis on models that attempt to mimic the cholinergic hypofunction characteristic of Alzheimer's disease. Included also are evaluations of the utility of models for drug screening and a discussion of possible reasons for discrepancies between preclinical and clinical evaluations of potential cognition enhancers.

Animals↗
PubMed1994

Effects of ABT-418, a novel cholinergic channel ligand, on place learning in septal-lesioned rats.

Septal lesions disrupt septohippocampal neurotransmission and impair spatial memory. (-)-Nicotine reduces the memory deficits but has substantial side effect liabilities. Previous studies have demonstrated that ABT-418 is a novel, selective ligand for neuronal nicotinic acetylcholine receptors. In the current study, ABT-418 (0.19 and 1.9 mumol/kg, i.p.) administered before training significantly attenuated lesion-induced deficits in a spatial discrimination version of the Morris water maze. As lesion-induced learning deficits might parallel the cognitive deficits characteristic of Alzheimer's disease, these results suggest that ABT-418 may be useful in the treatment of this condition.

Animals↗
PubMed1994

Clozapine attenuates the discriminative stimulus properties of (-)-nicotine.

Rats were trained to discriminate 1.9 mumol/kg (-)-nicotine (0.3 mg/kg) from saline in a standard two-bar operant conditioning paradigm with food reinforcement. The effect of neuronal nicotinic acetylcholine receptor (nAChR) agonists and antagonists were verified, and the participation of dopaminergic receptors subtypes in the expression of the (-)-nicotine cue was investigated with cis-flupentixol (D1-D2 antagonist), haloperidol (D2 antagonist) and clozapine (D4 antagonist). The stereoselectivity of the behavioral response was indicated by the 10-fold less sensitivity to (+)-nicotine in (-)-nicotine-trained rats. (+/-)-Anabasine and (-)-cytisine exhibited partial agonist profiles at the 1.9 mumol/kg dose while (-)-lobeline was devoid of any effect in doses up to 19 mumol/kg. (-)-Lobeline did not show antagonist properties in this paradigm. The nicotinic channel blockers mecamylamine, chlorisondamine and hexamethonium were inactive on their own but mecamylamine and chlorisondamine were able to block the effect of (-)-nicotine. Clozapine attenuated the (-)-nicotine cue while cis-flupentixol and haloperidol were ineffective. Similar doses of cis-flupentixol significantly blocked the locomotor stimulant effect of (-)-nicotine in rats indicating that blockade of dopaminergic receptors was achieved at the doses used in the drug discrimination studies. These data suggest that the discriminative stimulus properties of (-)-nicotine are mediated through neuronal nAChRs and involves the activation of dopaminergic receptors of the D4 subtype.

Alkaloids↗
PubMed1994

Effect of nicotine, lobeline, and mecamylamine on sensory gating in the rat.

In normal subjects, if an acoustic startle stimulus is immediately preceded by a small brief change in background noise intensity, the magnitude of the subsequent startle response is decreased. This prepulse inhibition (PPI) of an acoustic startle response has been shown to be associated with sensorimotor gating. PPI is disrupted in schizophrenic patients and has been linked to attentional disorders characteristic of this disease. We tested the effects of (-)-nicotine, (0.19, 0.62, and 1.9 mumol/kg IP) (equivalent to 0.03, 0.1, and 0.3 mg/kg base) and the nicotinic cholinergic receptor (nAChR) channel blocker, mecamylamine (5.0 and 50 mumol/kg IP) (equivalent to 1.0 and 10.0 mg/kg) on PPI of the acoustic startle response in the rat. Nicotine increased the PPI at the lowest prepulse signal levels but not at the stronger levels. Mecamylamine was without effect at 5.0 mumol/kg, but the 50 mumol/kg dose decreased the inhibition at both weak and strong prepulse (PP) levels. Mecamylamine (5.0 mumol/kg) pretreatment did not block the (-)-nicotine-induced increase in PPI. Lobeline (0.19, 0.62, 1.9, and 6.2 mumol/kg IP) (equivalent to 0.071, 0.23, 0.71, and 2.3 mg/kg) was without effect. These results are consistent with a mecamylamine-insensitive effect of nicotine to improve gating in normal rats. The nAChR subtype involved in producing nicotine's increase of PPI needs further investigation.

Acoustic Stimulation↗
PubMed1994

Characterization of high voltage spindles and spatial memory in young, mature and aged rats.

EEG was recorded from rats of three age groups, and high voltage spindles (HVS) were measured during waking immobility. Total mean spindling times in 4- (young), 10- (mature) and 22- (aged) month-old rats were 0.3 +/- 0.1, 20.4 +/- 7.4 and 33.4 +/- 14.9 s, respectively. Spatial memory was assessed in these rats using a discrimination version of the Morris water maze. Performance (as measured by number of choice errors) was compared with the extent of HVS activity by characterizing rats as "spindling" if the total average duration of HVS discharges exceeded 5 s, and "non-spindling" if these discharges averaged less than 5 s. Spindling and nonspindling rats had similar performance during training; however, on a 14-day retention trial, spindling rats had a significantly higher mean error score of 2.8 +/- 0.5 compared with 1.2 +/- 0.3 for nonspindling rats (p = 0.011). These results show that spindling activity increases in mature and aged rats, and that HVS discharges may be an electrophysiological change that parallels the progression of brain dysfunction associated with memory impairment.

Action Potentials↗
PubMed1994

(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole (ABT 418): a novel cholinergic ligand with cognition-enhancing and anxiolytic activities: II. In vivo characterization.

(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole (ABT 418), an isoxazole analog of (-)-nicotine, is a potent agonist at the alpha-4/beta-2 subtype of neuronal nicotinic acetylcholine receptor (nAChR) that exists in mammalian brain (Arneric et al., 1994). Compared to (-)-nicotine, ABT 418 has reduced potency to interact with the subunit isoforms of nAChR found in sympathetic ganglia, and it does not compete for alpha-bungarotoxin binding sites in brain or at the neuromuscular junction. ABT 418 [minimum effective dose (MED), 0.062 mumol/kg i.p.) was 10-fold more potent in improving retention of avoidance learning in normal mice than (-)-nicotine, whereas the (R)-enantiomer of ABT 418, A-81754, was inactive. The memory-enhancing effect of ABT 418 was prevented by the nAChR channel blocker, mecamylamine. In the elevated plus-maze model of anxiety, ABT 418 (MED, 0.19 mumol/kg i.p.) increased open-arm exploration in mice, as previously shown for (-)-nicotine (MED, 0.62 mumol/kg i.p.). A-81754, did not have anxiolytic-like effects in this test. Unlike the classical anxiolytic, diazepam, ABT 418 did not impair rotorod performance in the dose range where beneficial effects occurred. In rats, ABT 418 (MED, 0.002 mumol/kg i.v.) was remarkably potent in enhancing basal forebrain-elicited increases in cortical cerebral blood flow, whereas resting cerebral blood flow was unaffected. Free running cortical electroencephalography in rats was unaffected by ABT 418 at a dose of 1.9 mumol/kg i.p., whereas the same dose of (-)-nicotine caused cortical activation (decreased power in the 1-13 Hz range and increased power in the 25-50 Hz range). Whereas ABT 418 was approximately 3- to 10-fold more potent than (-)-nicotine in memory enhancement and anxiolytic test paradigms, the compound had less emetic liability in dogs as compared to (-)-nicotine, and was less potent than (-)-nicotine in eliciting hypothermia, seizures, death and reduction of locomotor activity in mice. The measured pharmacokinetic or brain disposition properties of ABT 418 in rats did not account for the observed enhancement in efficacy with reduced toxicity as compared to (-)-nicotine. The potent cognitive-enhancing and anxiolytic properties obtained for ABT 418 in animal models without eliciting significant side effects suggest that this ligand is a selective activator of cholinergic channel-mediated behaviors. Thus, ABT 418 may represent a novel, safe and effective treatment of the cognitive and emotional dysfunctions associated with Alzheimer's disease.

Alzheimer Disease↗
PubMed1994

Anxiolytic-like effects of the novel cholinergic channel activator ABT-418.

The hydrochloride salt of (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl) isoxazole (ABT-418), a potent activator of select subtypes of neuronal nicotinic acetylcholine receptors enhanced retention in memory tests and induced anxiolytic-like effects in mice in the elevated plus maze. In the present studies in rats, ABT-418 induced a significant increase in the time spent by the rats in the open arms of the elevated plus maze (0.62 mumol/kg i.p.); the effect persisted up to 60 min after the injection and was blocked by mecamylamine (15 mumol/kg), a centrally acting nicotinic acetylcholine receptor channel blocker. ABT-418 was 6-fold and 1.6-fold more potent than diazepam and ondansetron, respectively. The anxiolytic-like effect of ABT-418 was observed after oral administration in rats (10-30 mumol/kg) and at slightly higher doses in 20-month-old rats (1.9 mumol/kg i.p.). Major metabolites of ABT-418 [(S)-1-methyl-5-(3-methyl-5-isoxazolyl)-2-pyrrolidinone, cis-ABT-418 N-oxide and trans-ABT-418 N-oxide] were inactive in the plus maze in mice up to 6.2 mumol/kg, did not affect body temperature and had minimal effects on locomotion. Like (-)-nicotine, ABT-418 was effective (4 and 13 mumol kg-1 day-1) to induce anxiolytic-like effects after a 14-day treatment through minipumps implanted subcutaneously. Acute administration of ABT-418 (0.62 mumol/kg i.p.) also attenuated the anxiogenic-like effect elicited by withdrawal from chronic (-)-nicotine treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1994

(+/-)-Epibatidine elicits a diversity of in vitro and in vivo effects mediated by nicotinic acetylcholine receptors.

(+/-)-Epibatidine, exo-2-(6-chloro-3-pyridyl)-7-azabicyclo-[2.2.1] heptane, is a novel, potent analgesic agent that acts through nicotinic acetylcholine receptor (nAChR) mechanisms. This study sought to establish whether (+/-)-epibatidine, like (-)-nicotine, also displays a wide diversity of behavioral responses that are known to be elicited by nAChR activation or whether it demonstrates subtype selectivity for its interactions with nAChRs.(+/-)-Epibatidine displaced [3H](-)-cytisine binding to the alpha 4 beta 2 nAChR subtype in rat brain membranes with high affinity (Ki, 43 pM). The compound was approximately 5000-fold less potent (Ki = 230nM) in the displacement of [125I] alpha-bungarotoxin binding from the alpha-bungarotoxin-sensitive nAChR subtype present in rat brain but was a potent inhibitor (Ki, 2.7 nM) of [125I] alpha-bungarotoxin binding to the nAChR subtype in Torpedo electroplax, which is similar to that present in the neuromuscular junction. Functionally, (+/-)-epibatidine enhanced 86Rb+ flux in IMR 32 cells with an EC50 value of 7 nM. It was some 3000-fold more potent than (-)-nicotine (EC50 value, 21,000 nM) and was approximately 150-fold more potent (EC50 value, 0.4 nM) than (-)-nicotine (EC50 value = 60 nM) in increasing [3H]dopamine release from rat striatal slices. Remarkably, (+/-)-epibatidine was 40% to 50% more efficacious than (-)-nicotine in both functional assays. Both functional effects were blocked by the nAChR channel blocker, mecamylamine (100 microM). (+/-)-Epibatidine was 300 to 1000 times more potent than (-)-nicotine in the reduction of body temperature and locomotor activity in mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaloids↗
PubMed1993

Nicotinic receptor agonists exhibit anxiolytic-like effects on the elevated plus-maze test.

The effects of nicotinic receptor agonists on the elevated plus-maze test of anxiety were investigated in CD1 mice after intraperitoneal injections. Nicotine and lobeline, but not cytisine, exhibited a significant increase in the time spent by the mice in the open arms, a measure of anxiolytic activity. Nicotine also increased the total number of arm entries, a measure of general activity, but this effect was secondary to its anxiolytic-like properties. Nicotinic receptor antagonists on their own did not modify the behavior of mice in the maze. The effect of nicotine was mediated by central nicotinic receptors as it was blocked by the centrally-acting nicotinic antagonists mecamylamine and chlorisondamine, but not by hexamethonium (a peripherally acting blocker). Cotinine, the major metabolite of nicotine, was evaluated at different times after systemic injections and had no effect in the plus-maze. The anxiolytic-like profile induced by nicotinic receptor stimulation was not associated with potentiation of alcohol effects, a liability associated with the benzodiazepine therapy. This study demonstrates the anxiolytic-like properties of nicotine and lobeline in mice, and suggests that central nicotinic receptors are involved in the expression of emotional behavior.

Alkaloids↗
PubMed1993

Linopirdine (DuP996) facilitates the retention of avoidance training and improves performance of septal-lesioned rats in the water maze.

The behavioral effects of 3,3-bis(4-pyridinylmethyl)-1-phenylindolin-2-one [linopirdine (DuP996)] were investigated on retention of the inhibitory avoidance test in normal mice and acquisition of spatial discrimination in the two-platform water maze task in septal-lesioned rats (a model of cholinergic dysfunction characteristic of Alzheimer's disease). Linopirdine significantly enhanced retention of the inhibitory avoidance response in mice (0.026 mumol/kg) and also reduced the number of errors made by septal-lesioned rats in the water maze to a level comparable to sham-operated animals. At this dose, no effects were observed on septal-lesion-induced hyperactivity in an open field or in unoperated rats tested in the elevated plus-maze anxiolytic test. This study extends previous findings of facilitatory effects of linopirdine on memory and demonstrates improved spatial learning in septal-lesioned rats. As the facilitatory effects on memory are not accompanied by a reduction in the hyperactive state present in septal-lesioned animals, a dissociation between cognitive and noncognitive effects of linopirdine can be differentiated in septal-lesioned rats.

Animals↗