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  • 1
    Electronic Resource
    Electronic Resource
    Preclinical Pharmacology of ABT-418: A Prototypical Cholinergic Channel Activator for the Potential Treatment of Alzheimer's Disease (1995)
    Oxford, UK : Blackwell Publishing Ltd
    CNS drug reviews 1 (1995), S. 0 
    Details
    ISSN: 1527-3458
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1527-3458.1995.tb00274.x
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  • 2
    Electronic Resource
    Electronic Resource
    Calcium-Dependent Release of Tyrosine in Brain Elicited by Stimulation of Neuropeptide Receptors (1987)
    Oxford, UK : Blackwell Publishing Ltd
    Journal of neurochemistry 48 (1987), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: We sought to establish whether the endogenous opiate-receptor agonist Met-enkephalin (m-ENK) selectively modulates the release of endogenous tyrosine (Tyr) from brain slices prepared from the corpus striatum (CS). Amino acids (AAs) released from slices of CS and, for comparison, cerebral cortex (Cx) were measured by HPLC. Incubation of slices with m-ENK (1-10 μM) increased the basal release of Tyr (up to 293% of control) from CS, but not Cx, whereas other nonneurotransmitter AAs, phenylal-anine (Phe) and valine (Val), were unchanged. The release of the putative neurotransmitter AAs glutamate (Glu), tau-rine (Tau), and glycine (Gly) were similarly increased by 50–150% with m-ENK in slices of CS, but not Cx. The enhanced release of AAs by m-ENK was prevented by removal of extracellular Ca2+ or by preincubation with the opiate receptor antagonist naloxone. Neuronal depolarization by potassium (5–55 mM) in the presence of Ca2+ did not affect the release of Tyr, whereas release of neurotransmitter AAs such as γ-aminobutyric acid (GABA) were markedly increased. The increase in basal Tyr release by m-ENK was not the result of a decreased uptake of Tyr. Relative to slices, the basal release of Tyr, Phe, and Val from a synaptosomal (P2) preparation of CS was small (8–51%) compared to that of GABA, Gly, Glu, and Tau (49–123%). Nonetheless, m-ENK (10 μM) markedly increased the release of Tyr (to 833%), but not Glu, Gly, and Tau from the P2 fraction. Other neuropeptides including cholecystokinin octapeptide (CCK-8), thyrotropin-releasing hormone (TRH), and vaso-active intestinal peptide (VIP) facilitated the release of Tyr from brain slices in a regionally specific pattern. We conclude that: (1) Tyr is released from nerve terminal-enriched preparations of CS, but not Cx, by m-ENK via an opiate receptor-mediated, Ca2+-dependent process with regional selectivity; (2) neuronal depolarization alone, however, does not affect the release of Tyr; (3) CCK-8, TRH, and VIP also increase Tyr release with regional specificity, suggesting that receptors for other neuropeptides may also modulate Tyr release. The specific neuronal source and functional role of Tyr released from elements of CS via activation of opiate receptors remain to be elucidated.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1111/j.1471-4159.1987.tb05705.x
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  • 3
    Electronic Resource
    Electronic Resource
    Evidence for Nicotinic Receptors Potentially Modulating Nociceptive Transmission at the Level of the Primary Sensory Neuron: Studies with F11 Cells (1997)
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 69 (1997), S. 0 
    Details
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Abstract: F11 cells are a dorsal root ganglion (DRG) cell line used to model the function of authentic type C, peptidergic, nociceptive neurons. The cellular events underlying the antinociceptive effects of (±)-epibatidine, a nicotinic acetylcholine receptor (nAChR) ligand that is 200-fold more potent than morphine, is unknown. The present study investigated the ability of cholinergic channel activators (ChCAs) to effect nAChR-gated ion flux and modulate the release of substance P (SP), a neuropeptide identified to play a critical role in nociception. The prototypical agonists (−)-nicotine and (−)-cytisine, the ganglionic stimulant 1,1-dimethyl-4-phenylpiperazinium, the novel ChCA ABT-418 [(S)-3-methyl-5-(-1-methyl-2-pyrrolidinyl)isoxazole], and (±)-epibatidine evoked a concentration-dependent stimulation of rubidium (86Rb+) efflux with EC50 values of 14.2 ± 1.6, 63.4 ± 24, 3.8 ± 2.0, 29.8 ± 2.6, and 0.019 ± 0.001 µM as well as maximal intrinsic activities of 100, 97, 69, 75, and 102%, respectively. The noncompetitive nAChR antagonist mecamylamine potently antagonized (−)-nicotine-evoked ion flux, whereas the competitive antagonist dihydro-β-erythroidine was a weak antagonist, giving support to an α3β4 nAChR subtype. In addition, concentrations of (±)-epibatidine, similar to those necessary to induce maximal 86Rb+ efflux, evoked spontaneous release of SP from these cells, which was blocked by mecamylamine. Furthermore, prolonged exposure to (±)-epibatidine desensitized the functional response of the nAChR in this cell line (IC50 = 12 ± 9 nM). These findings in F11 cells provide a model to investigate the role nAChRs play in modulating DRG cell function, and may lead to insights into the role these receptors have in modulating nociceptive transmission.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1046/j.1471-4159.1997.69030930.x
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  • 4
    Electronic Resource
    Electronic Resource
    Novel Isoxazoles which Interact with Brain Cholinergic Channel Receptors Have Intrinsic Cognitive Enhancing and Anxiolytic Activities (1994)
    s.l. : American Chemical Society
    Journal of medicinal chemistry 37 (1994), S. 1055-1059 
    Details
    ISSN: 1520-4804
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1021/jm00034a002
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  • 5
    Electronic Resource
    Electronic Resource
    ABT-418: discriminative stimulus properties and effect on ventral tegmental cell activity (1995)
    Springer
    Psychopharmacology 119 (1995), S. 368-375 
    Details
    ISSN: 1432-2072
    Keywords: ABT-418 ; Nicotine ; Nicotinic acetylcholine receptors ; Drug discrimination ; Mecamylamine ; Ventral tegmental area
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract 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 µmol/kg in 39 days, they were not able to discriminate 1.9 or 6.2 µmol/kg ABT-418 from a saline solution during 50 days of training. In rats trained to discriminate 1.9 µmol/kg (−)-nicotine, a reduced generalization was induced by ABT-418 at 1.9 and 6.2 µmol/kg, an effect completely blocked by the cholinergic channel blocker mecamylamine (15 µmol/kg, IP). However, in extensively trained rats, intraperitoneal or subcutaneous injections of ABT-418 induced 78–82% generalization at the 6.2 µmol/kg dose. The predominant metabolites of (−)-nicotine and ABT-418 (cotinine 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02245851
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  • 6
    Electronic Resource
    Electronic Resource
    Central nicotinic receptor agonists ABT-418, ABT-089, and (–)-nicotine reduce distractibility in adult monkeys (1998)
    Springer
    Psychopharmacology 136 (1998), S. 50-58 
    Details
    ISSN: 1432-2072
    Keywords: Key words Cognition ; Distractibility ; ( ; )-Nicotine ; ABT-418 ; ABT-089 ; Monkey ; Delay matching
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Increased distractibility is associated with both Alzheimer’s disease and attention deficit disorder. The present study examined the effects of (–)-nicotine and the novel central nicotinic receptor (nAChR) agonists ABT-418 [(S)-3-methyl-2-pyrrolidinyl)isoxazole] and ABT-089 [2-methyl-3-(2-(S)-pyrrolindinylmethoxy)- pyridine dihydrochloride] on the delayed recall accuracy of adult monkeys exposed to distracting stimuli. Unpredictable exposure to a random visual array produced marked decrements in recall accuracy on trials with the shortest delay intervals, reducing the accuracy on these trials by 23.4%. Intramuscular (IM) administration of (–)-nicotine, in doses of 5.4–43.3 nmol/kg, attenuated the effect of the distractor, but did not completely prevent it. Both ABT-418 (2.0–16.2 nmol/kg, IM) and ABT-089 (16.4–32.8 nmol/kg, IM) prevented distractibility, producing increases of 7.5–25.0% in accuracy on trials disrupted by distractor exposure. Further, both compounds also improved accuracy on trials during which distractors were not presented, an effect which was not observed after (–)-nicotine administration. Nicotinic-mediated side effects were not observed following administration of any compound. Thus, nAChR stimulation reduces distractibility in adult monkeys and may, therefore, represent a target for the pharmacologic treatment of disorders associated with susceptibility to distraction. ABT-418 and ABT-089 appear to be particularly useful in this regard, a likely result of their selective agonist activity at nAChRs expressed in the brain.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130050538
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  • 7
    Electronic Resource
    Electronic Resource
    Improvement in accuracy of delayed recall in aged and non-aged, mature monkeys after intramuscular or transdermal administration of the CNS nicotinic receptor agonist ABT-418 (1997)
    Springer
    Psychopharmacology 130 (1997), S. 276-284 
    Details
    ISSN: 1432-2072
    Keywords: Key words Cognition ; Nicotine ; Delayed recall ; Monkeys ; Aging ; Transdermal ; Memory
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  ABT-418 was evaluated for its ability to enhance accuracy on a delayed matching-to-sample (DMTS) task by aged monkeys following intramuscular administration, and in non-aged mature monkeys following transdermal application. Aged monkeys were impaired in their performance of the DMTS task such that the longest delay intervals performed at above-chance levels extended only to 20 s. In contrast, for non-aged, mature animals, delay intervals extended to 140 s. In aged monkeys, the response to ABT-418 was highly individualized with animals responding to one or more doses in the range of 2–259 nmol/kg. A systematic dose-dependent enhancement of DMTS accuracy was not observed. When the individualized ”best dose” was administered on a separate occasion, overall DMTS accuracy was increased by 12.6%. By 24 h after administration, accuracy was at control levels. In young monkeys, a significant dose-dependent enhancement of DMTS performance (an overall increase of 11.25% above baseline accuracy) was observed 5 h after application of a transdermal patch designed to maintain steady-state plasma levels of ABT-418 of 40–60 ng/ml over a 24-h period. Again there was some individual responsiveness to one of the three doses. When data included only the individualized best doses of ABT-418 for each animal, a similar enhancement of accuracy was observed for both the 5-h and 24-h test intervals. In neither the aged nor the young cohorts was enhancement of performance associated with altered response latencies or with any overt side effects of ABT-418. Thus, these data are consistent with the ability of ABT-418 to improve DMTS performance in both young and aged monkeys. In aged monkeys, this response was observed only after administration of individualized optimal doses for different monkeys. In young monkeys, a more systematic enhancement of DMTS accuracy was observed. Further, transdermal delivery of ABT-418 in non-aged monkeys demonstrated prolonged performance enhancement compared with IM injection to at least 24 h after patch administration.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130050240
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  • 8
    Electronic Resource
    Electronic Resource
    Spontaneous release of endogenous aspartate and glutamate from rat striatal slices is increased following destruction of local neurons by ibotenic acid (1988)
    Springer
    Neurochemical research 13 (1988), S. 423-428 
    Details
    ISSN: 1573-6903
    Keywords: Aspartate ; glutamate ; GABA ; ibotenic acid ; striatum ; endogenous amino acids
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We sought to determine in rat striatum whether the release of neurotransmitter amino acids aspartate (Asp), glutamate (Glu) and gamma-aminobutyric acid (GABA) were affected by local neurons. To do so, unilateral microinjections of ibotenic acid, an excitotoxin that destroys local neurons without affecting fibers of passage, were made into the striatum. Release of endogenous amino acids from lesioned and intact striatal slices were measured by HPLC one week later. The effectiveness and specificity of the lesion were confirmed by measuring the enzyme activity associated with extrinsic dopamine neurons (tyrosine hydroxylase; 111±14%), intrinsic GABA neurons (glutamic acid decarboxylase; 19±7%) and intrinsic acetylcholine neurons (choline acetyltransferase; 37±10%). Destruction of local striatal neurons markedly attenuated the release of GABA (41±12% of control) elicited by depolarization with K+ (35 mM), but did not significantly reduce the K+-evoked release of Asp (80±17%) and Glu (92±8%). However, spontaneous release of Asp and Glu was significantly greater than that observed in unlesioned tissue (159±18% and 209±27%, respectively), while the spontaneous release of GABA was not significantly reduced (75±43%). Although release of the neurotransmitter amino acids Asp, Glu and GABA were affected by the lesion, the release of the non-neurotransmitter amino acid tyrosine was unaffected. These data are consistent with the hypotheses that: 1) the predominant source of releasable stores of endogenous Asp and Glu in the striatum arises from extinsic neurons, and 2) that the spontaneous release of Asp and Glu from axon terminals in the striatum may be regulated, at least in part, by local inhibitory neurons.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01268876
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