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Edward D Levin - One of the best experts on this subject based on the ideXlab platform.

  • Decreasing Nicotinic receptor activity and the spatial learning impairment caused by the NMDA glutamate antagonist dizocilpine in rats.
    European Journal of Pharmacology, 2014
    Co-Authors: Dennis A. Burke, Pooneh Heshmati, Ehsan Kholdebarin, Edward D Levin
    Abstract:

    Abstract Nicotinic systems have been shown by a variety of studies to be involved in cognitive function. Nicotinic receptors have an inherent property to become desensitized after activation. The relative role of Nicotinic receptor activation vs. net receptor inactivation by desensitization in the cognitive effects of Nicotinic drugs remains to be fully understood. In these studies, we tested the effects of the α7 Nicotinic receptor antagonist methyllycaconitine (MLA), the α4β2 Nicotinic receptor antagonist dihydro-β-erythroidine (DHβE), the nonspecific Nicotinic channel blocker mecamylamine and the α4β2 Nicotinic receptor desensitizing agent sazetidine-A on learning in a repeated acquisition test. Adult female Sprague–Dawley rats were trained on a repeated acquisition learning procedure in an 8-arm radial maze. MLA (1–4 mg/kg), DHβE (1–4 mg/kg), mecamylamine (0.125–0.5 mg/kg) or sazetidine-A (1 and 3 mg/kg) were administered in four different studies either alone or together with the NMDA glutamate antagonist dizocilpine (0.05 and 0.10 mg/kg). MLA significantly counteracted the learning impairment caused by dizocilpine. The overall choice accuracy impairment caused by dizocilpine was significantly attenuated by co-administration of DHβE. Low doses of the non-specific Nicotinic antagonist mecamylamine also reduced dizocilpine-induced repeated acquisition impairment. Sazetidine-A reversed the accuracy impairment caused by dizocilpine. These studies provide evidence that a net decrease in Nicotinic receptor activity can improve learning by attenuating learning impairment induced by NMDA glutamate blockade. This adds to evidence in cognitive tests that Nicotinic Antagonists can improve cognitive function. Further research characterizing the efficacy and mechanisms underlying Nicotinic antagonist and desensitization induced cognitive improvement is warranted.

  • Sazetidine-A, a selective α4β2 Nicotinic acetylcholine receptor ligand: effects on dizocilpine and scopolamine-induced attentional impairments in female Sprague–Dawley rats
    Psychopharmacology, 2011
    Co-Authors: Amir H. Rezvani, Marty Cauley, Yingxian Xiao, Milton L. Brown, Mikell A. Paige, Brian E. Mcdowell, Kenneth J. Kellar, Hannah Sexton, Edward D Levin
    Abstract:

    Background Neuronal Nicotinic receptor systems have been shown to play key roles in cognition. Nicotine and Nicotinic analogs improve attention and Nicotinic Antagonists impair it. This study was conducted to investigate the role of α4β2 Nicotinic receptors in sustained attention using a novel selective α4β2 Nicotinic receptor ligand, sazetidine-A. Methods Female rats were trained to perform the signal detection task to a stable baseline of accuracy. The rats were injected with saline, sazetidine-A (0.01, 0.03, and 0.1 mg/kg), dizocilpine (0.05 mg/kg), or their combination; or, in another experiment, the rats were injected with the same doses of sazetidine-A, scopolamine (0.02 mg/kg), or their combination. Results Percent hit and percent correct rejection showed that dizocilpine caused significant ( p  

  • Sazetidine-A, a selective α4β2 Nicotinic acetylcholine receptor ligand: effects on dizocilpine and scopolamine-induced attentional impairments in female Sprague-Dawley rats.
    Psychopharmacology, 2011
    Co-Authors: Amir H. Rezvani, Marty Cauley, Hannah G. Sexton, Yingxian Xiao, Milton L. Brown, Mikell A. Paige, Brian E. Mcdowell, Kenneth J. Kellar, Edward D Levin
    Abstract:

    Background Neuronal Nicotinic receptor systems have been shown to play key roles in cognition. Nicotine and Nicotinic analogs improve attention and Nicotinic Antagonists impair it. This study was conducted to investigate the role of α4β2 Nicotinic receptors in sustained attention using a novel selective α4β2 Nicotinic receptor ligand, sazetidine-A.

  • ventral hippocampal α7 Nicotinic receptor blockade and chronic nicotine effects on memory performance in the radial arm maze
    Pharmacology Biochemistry and Behavior, 2001
    Co-Authors: Jane H Bettany, Edward D Levin
    Abstract:

    Abstract Chronic nicotine administration has been shown to significantly improve working memory. Nicotinic involvement in memory function critically involves the ventral hippocampus. Local ventral hippocampal infusions of the Nicotinic Antagonists mecamylamine, dihydro-β-erythroidine (DHβE) and methyllycaconitine (MLA) significantly impair working memory. The impairment caused by hippocampal infusion of the α4β2 antagonist DHβE is reversed by chronic systemic nicotine. This study determined the interaction of chronic systemic nicotine with acute ventral hippocampal infusions of the α7 antagonist MLA. Adult female Sprague–Dawley rats were trained on an 8-arm radial maze working memory task. Then they underwent ventral hippocampal cannulation and received sc implants of minipumps delivering nicotine (0 or 5 mg/kg/day for 28 days). Acute ventral hippocampal infusions of MLA (0, 4.88, 14.64 and 43.92 μg/side) were given during 3–4 weeks of chronic nicotine. MLA caused a significant dose-related memory impairment. In the rats not receiving nicotine, the 14.64 and 43.92 μg/side MLA doses caused significant memory impairment. Chronic systemic nicotine exposure did not block the MLA-induced memory impairment. Comparing the current results with MLA with previous results with DHβE, equimolar ventral hippocampal DHβE more effectively impaired memory than MLA, but the DHβE-induced impairment was more effectively reversed by chronic systemic nicotine administration.

  • Mutually potentiating effects of mecamylamine and Haloperidol in producing catalepsy in rats
    Drug Development Research, 1999
    Co-Authors: Edward D Levin, Patrick M. Lippiello
    Abstract:

    Haloperidol and other dopaminergic (DA) blockers have long been known to induce catalepsy. Recently, it has been reported that nicotine potentiates the cataleptic effect of haloperidol. However, this presents a quandary in terms of neural interactions between Nicotinic and DA systems. Nicotine promotes the release of DA in the striatum, which should attenuate haloperidol-induced catalepsy. To resolve this quandary, we assessed haloperidol interactions with nicotine and its antagonist mecamylamine in five studies. With low to moderate doses, we did not find that nicotine potentiated haloperidol-induced catalepsy. However, in two different studies we found that mecamylamine, a Nicotinic antagonist, significantly potentiated the haloperidol-induced catalepsy. This effect was seen with a dose of mecamylamine which, by itself, did not have any cataleptic effect. These results demonstrate that Nicotinic receptor blockade effectively potentiates catalepsy caused by DA blockade. This suggests that previously seen nicotine-induced potentiation of catalepsy may have been due to its desensitizing effect. Perhaps the use of Nicotinic Antagonists such as mecamylamine or nicotine + mecamylamine combinations would provide a useful adjunct to DA antagonist therapy in motor disorders such as Tourette's syndrome.

Amir H. Rezvani - One of the best experts on this subject based on the ideXlab platform.

C C Chang - One of the best experts on this subject based on the ideXlab platform.

  • Run‐down of neuromuscular transmission during repetitive nerve activity by Nicotinic Antagonists is not due to desensitization of the postsynaptic receptor
    British Journal of Pharmacology, 1991
    Co-Authors: Shihwun Hong, C C Chang
    Abstract:

    1 Whether the function of the postsynaptic acetylcholine receptor is use-dependently affected by repetitive nerve stimulation in the presence of competitive Antagonists was studied in the mouse phrenic nerve-hemidiaphragm preparation. 2 For electrophysiological experiments, the preparation was immobilized by synthetic μ-conotoxin, which preferentially blocks muscular Na-channels causing neither depolarization of the membrane potential, inhibition of quantal transmitter release, nor depression of Nicotinic receptor function. 3 High concentrations of cobratoxin depressed indirect twitches and endplate potentials (e.p.ps) without inducing waning of contractilities or run-down of trains of e.p.ps evoked at 10–100 Hz. However, waning and run-down were accelerated after washout of the toxin despite diminished postsynaptic receptor blockade. Once the run-down of e.p.ps was produced by washout or low concentrations of cobratoxin, further depression of e.p.p. amplitude with high concentrations of cobratoxin did not attenuate the e.p.p. rundown. 4 The degrees of waning of tetanus and trains of e.p.ps produced by a very high concentration of tubocurarine (20 μm) were also less than that caused at a 100 fold lower concentration, albeit the amplitudes of twitches and the first e.p.p. were depressed more rapidly and markedly. 5 Tubocurarine, like cobratoxin, depressed the amplitude of miniature endplate potentials (m.e.p.ps) more than e.p.ps. 6 In contrast to the steepened run-down of successive e.p.ps in the presence of low concentrations of either Nicotinic Antagonists, the amplitude of m.e.p.ps observed during repetitive stimulation was uniform and was not different from that before stimulation. 7 The results suggest that the e.p.p. run-down and tetanic fade induced by Nicotinic Antagonists are due to a slow kinetic blockade of presynaptic receptors and confirm that the e.p.p. run-down is not produced by a use-dependent failure of postsynaptic Nicotinic receptors. The roles of the presynaptic Nicotinic receptor in positive or negative feedback modulations of transmitter release are discussed.

  • run down of neuromuscular transmission during repetitive nerve activity by Nicotinic Antagonists is not due to desensitization of the postsynaptic receptor
    British Journal of Pharmacology, 1991
    Co-Authors: Shihwun Hong, C C Chang
    Abstract:

    1 Whether the function of the postsynaptic acetylcholine receptor is use-dependently affected by repetitive nerve stimulation in the presence of competitive Antagonists was studied in the mouse phrenic nerve-hemidiaphragm preparation. 2 For electrophysiological experiments, the preparation was immobilized by synthetic μ-conotoxin, which preferentially blocks muscular Na-channels causing neither depolarization of the membrane potential, inhibition of quantal transmitter release, nor depression of Nicotinic receptor function. 3 High concentrations of cobratoxin depressed indirect twitches and endplate potentials (e.p.ps) without inducing waning of contractilities or run-down of trains of e.p.ps evoked at 10–100 Hz. However, waning and run-down were accelerated after washout of the toxin despite diminished postsynaptic receptor blockade. Once the run-down of e.p.ps was produced by washout or low concentrations of cobratoxin, further depression of e.p.p. amplitude with high concentrations of cobratoxin did not attenuate the e.p.p. rundown. 4 The degrees of waning of tetanus and trains of e.p.ps produced by a very high concentration of tubocurarine (20 μm) were also less than that caused at a 100 fold lower concentration, albeit the amplitudes of twitches and the first e.p.p. were depressed more rapidly and markedly. 5 Tubocurarine, like cobratoxin, depressed the amplitude of miniature endplate potentials (m.e.p.ps) more than e.p.ps. 6 In contrast to the steepened run-down of successive e.p.ps in the presence of low concentrations of either Nicotinic Antagonists, the amplitude of m.e.p.ps observed during repetitive stimulation was uniform and was not different from that before stimulation. 7 The results suggest that the e.p.p. run-down and tetanic fade induced by Nicotinic Antagonists are due to a slow kinetic blockade of presynaptic receptors and confirm that the e.p.p. run-down is not produced by a use-dependent failure of postsynaptic Nicotinic receptors. The roles of the presynaptic Nicotinic receptor in positive or negative feedback modulations of transmitter release are discussed.

Yingxian Xiao - One of the best experts on this subject based on the ideXlab platform.

Kenneth J. Kellar - One of the best experts on this subject based on the ideXlab platform.