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  • 1
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    CNS drug reviews 11 (2005), S. 0 
    ISSN: 1527-3458
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Retigabine [D23129; N-(2-amino-4-(4-fluorobenzylamino)-phenyl)carbamic acid ethyl ester] is an antiepileptic drug with a recently described novel mechanism of action that involves opening of neuronal KV7.2–7.5 (formerly KCNQ2-5) voltage-activated K+ channels. These channels (primarily KV7.2/7.3) enable generation of the M-current, a subthreshold K+ current that serves to stabilize the membrane potential and control neuronal excitability. In this regard, retigabine has been shown to have a broad-spectrum of activity in animal models of electrically-induced (amygdala-kindling, maximal electroshock) and chemically-induced (pentylenetetrazole, picrotoxin, NMDA) epileptic seizures. These encouraging results suggest that retigabine may also prove useful in the treatment of other diseases associated with neuronal hyperexcitability. Neuropathic pain conditions are characterized by pathological changes in sensory pathways, which favor action potential generation and enhanced pain transmission. Although sometimes difficult to treat with conventional analgesics, antiepileptics can relieve some symptoms of neuropathic pain. A number of recent studies have reported that retigabine can relieve pain-like behaviors (hyperalgesia and allodynia) in animal models of neuropathic pain. Neuronal activation within several key structures within the CNS can also be observed in various animal models of anxiety. Moreover, amygdala-kindled rats, which have a lowered threshold for neuronal activation, also display enhanced anxiety-like responses. Retigabine dose-dependently reduces unconditioned anxiety-like behaviors when assessed in the mouse marble burying test and zero maze. Early clinical studies have indicated that retigabine is rapidly absorbed and distributed, and is resistant to first pass metabolism. Tolerability is good in humans when titrated up to its therapeutic dose range (600-1200 mg/day). No tolerance, dependence or withdrawal potential has been reported, although adverse effects can include mild dizziness, headache, nausea and somnolence. Thus, retigabine may prove to be useful in the treatment of a diverse range of disease states in which neuronal hyperexcitability is a common underlying factor.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    Psychopharmacology 117 (1995), S. 430-437 
    ISSN: 1432-2072
    Keywords: Nicotine ; Lobeline ; Isoarecolone ; Nornicotine ; Anabasine ; Cytisine ; Mecamylamine Locomotor activity ; Rats
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effects of nicotine and related compounds on locomotor activity were compared in experimentally naive rats and in animals chronically exposed to nicotine and the photocell test chambers. In experimentally naive rats, all nicotinic compounds decreased locomotion in a dose-related manner and the rank order of potency was (−)-nicotine〉(+)-nornicotine〉(+)-nicotine 〉 cytisine 〉 lobeline 〉 anabasine. Mecamylamine attenuated the locomotor depressant effects of most of the agonists, except lobeline. In rats previously exposed to nicotine and the test apparatus for several weeks, (−)-nicotine increased locomotor activity in a dose-related manner, with a maximal increase to 400% of baseline at a dose of 0.4 mg/kg. One or more doses of (+)-nicotine, (+)-nornicotine and anabasine also increased locomotor activity in these animals, although the maximal effects seen were in all cases less than the maximal effect of (−)-nicotine. Cytisine and lobeline failed to increase locomotor activity at any dose tested. These conclusions were not altered by consideration of the time-courses for the effects of the different drugs. Thus, the results confirm that the locomotor stimulant and depressant effects of nicotine can be dissociated from each other, a finding that may be explained by differences in their actions at nicotinic receptors.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Springer
    Psychopharmacology 138 (1998), S. 266-274 
    ISSN: 1432-2072
    Keywords: Key words Nicotine ; Sustained attention ; Vigilance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Although nicotine has cognitive enhancing effects in both animals and humans, most studies in humans have only shown consistent improvements in sustained attention. Moreover, many studies with smokers have been criticised, since nicotine may simply be relieving withdrawal-induced deficits. The present study investigated the effect of nicotine on sustained attention in drug-naïve rats using a five-choice serial reaction time task. Initially, the task was demonstrated to satisfy some of the criteria for the construct validity of a vigilance task: reducing signal length and either increasing or decreasing the inter-trial interval significantly (P〈0.05) impaired performance. Whether nicotine (0.05–0.4 mg/kg, SC) reversed the deficits induced by a signal length of 0.25 s (weak signal) or an inter-trial-interval of either 20 s (low event rate) or 1 s (high event rate) was assessed. Nicotine (0.15 mg/kg) improved accuracy and decreased omission errors under low event rate conditions only. However, nicotine (0.05/0.15 mg/kg) improved reaction time and increased anticipatory responses under both weak signal and low event rate conditions. There was no effect of nicotine on performance under high event rate conditions. Under the low event rate condition, nicotine enhanced the ability of rats to maintain attention (i.e. accuracy) throughout a session. These findings suggest (i) that nicotine’s effect on attention depends upon task characteristics; (ii) these effects on attention may reflect self-reports by smokers that nicotine aids concentration, particularly in stressful situations, and (iii) nicotinic agonists may have therapeutic benefits in patient populations suffering from attentional deficits.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    Psychopharmacology 148 (2000), S. 243-250 
    ISSN: 1432-2072
    Keywords: Key words Attention ; Scopolamine ; Mecamylamine ; Oxotremorine ; Physostigmine ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: This study tried to determine the relative roles of muscarinic and nicotinic cholinergic receptors in attentional processing. Methods: The effects of cholinoceptor agonists and antagonists, and of an anticholinesterase, were studied on performance of rats in a five-choice serial reaction time task. Results: Scopolamine (0.1 mg/kg) and mecamylamine (5.0 mg/kg) produced deficits in accuracy and reaction time, respectively. This may suggest a differential role for the two types of cholinoceptors in information processing. Combinations of sub-threshold doses of scopolamine (0.01–0.03 mg/kg) and mecamylamine (0.5–1.6 mg/kg), which alone did not affect accuracy or reaction time, did not produce significant deficits in attention. However, the pattern of effects after combined treatment suggested that the differential deficits seen with these drugs alone remained. The anticholinesterase physostigmine (0.1 mg/kg) and the non- selective muscarinic agonist oxotremorine (0.03 mg/kg) induced severe behavioural disruption at doses that appeared to be relatively well tolerated in previous studies; this precluded the derivation of accuracy and response time data at these doses. At lower doses, neither physostigmine (0.05 mg/kg) nor oxotremorine (0.003 mg/kg) significantly affected any performance measure; this may reflect the ability of both drugs to indirectly or directly activate presynaptic muscarinic receptors that inhibit acetylcholine release, respectively. Conclusions: Both muscarinic and nicotinic cholinoceptors may be important in attention but they may serve different roles in information processing; this hypothesis could be tested using tasks that place different emphasis on different stages of information processing.
    Type of Medium: Electronic Resource
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