Naheed Mirza

Nicotine enhances sustained attention in the rat under specific task conditions

Abstractu2002Although 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 (0.05–0.4xa0mg/kg, SC) reversed the deficits induced by a signal length of 0.25xa0s (weak signal) or an inter-trial-interval of either 20xa0s (low event rate) or 1xa0s (high event rate) was assessed. Nicotine (0.15xa0mg/kg) improved accuracy and decreased omission errors under low event rate conditions only. However, nicotine (0.05/0.15xa0mg/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.

Nicotine in an animal model of attention.

Studies in smokers have suggested that at least part of the improved psychomotor performance produced by nicotine is the result of an effect on attention. Many animal experiments have assessed the effects of nicotine and its antagonists on diverse types of learning and memory but relatively few have looked at it in tasks designed to assess attention. In a five-choice serial reaction time task (5-CSRTT), rats with restricted access to food were presented with an array of five holes; illumination of a randomly selected hole signalled that a nose-poke into it would be reinforced by food presentation. Initially, signal length and the inter-trial interval (ITI) were varied and the procedure was demonstrated to satisfy some criteria for a vigilance task. The effects of nicotine on deficits in performance induced by varying signal length and ITI were assessed. Under appropriate conditions, small doses of nicotine increased the percentage of correct responses (accuracy), decreased omission errors and reaction time, and increased anticipatory responses. Subsequently, the effects of varying the ITI were examined more extensively in a slightly modified task. Here, nicotine produced small but robust, highly significant dose-related increases in accuracy, as well as decreases in omission errors and reaction times. Nicotine also increased accuracy when light stimuli were presented in an unpredictable manner. The nicotine antagonist mecamylamine produced a modest deficit in reaction time only. It is concluded that appropriate doses of nicotine can produce robust improvements in performance of normal rats in an attentional task. The effect cannot be attributed easily to changes in sensory or motor capability, learning or memory and may provide the measures needed to investigate the neuropharmacological and neuroanatomical bases of the elusive attentional effect of nicotine.

The role of nicotinic and muscarinic acetylcholine receptors in attention

Abstractu2002Rationale: 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.

Pharmacological comparison of anticonvulsant drugs in animal models of persistent pain and anxiety.

Signs and symptoms of persistent pain are associated with neuronal hyperexcitability within nociceptive pathways. This manifests behaviourally as a decrease in the nociceptive threshold to sensory stimulation, and is closely correlated with altered affective pain processing and increased expression of anxiety-like symptoms. Anticonvulsant drugs can have marked analgesic actions in animals and humans, and some have also been reported to possess anxiolytic-like properties in animals. In the current study, we have compared the antinociceptive actions of diazepam (allosteric GABA(A) receptor modulator), gabapentin (binds to alpha(2)delta Ca(2+) channel subunit), lamotrigine, riluzole and phenytoin (Na(+) channel blockers), levetiracetam (unknown mechanism), sodium valproate (potentiates GABA-mediated inhibition), ethosuximide (T-type Ca(2+) channel blocker) and retigabine (K(v)7 channel opener) in the rat formalin test, with their anxiolytic actions in the rat conditioned emotional response (CER) model of anxiety. Lamotrigine, gabapentin, riluzole, retigabine and ethosuximide attenuated second phase nociceptive responses in the formalin test. Lamotrigine, gabapentin and riluzole also displayed an anxiolytic-like profile in the CER model. Notably, the minimum doses of these drugs required to attenuate anxiety behaviour were similar to, or considerably lower than those needed to reverse pain-like behaviours. Diazepam was anxiolytic but only attenuated pain-like behaviours at sedative doses. The other drugs tested were inactive in both models. Our data suggests: (i) an antiepileptic mechanism of action per se is not necessarily sufficient for a compound to display antinociceptive and/or anxiolytic actions; and (ii) the combined antinociceptive and anxiolytic-like profiles of lamotrigine, gabapentin and riluzole suggests that these compounds likely modulate both sensory and affective dimensions of pain.

Comparison of the Novel Subtype-Selective GABAA Receptor-Positive Allosteric Modulator NS11394 [3′-[5-(1-Hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile] with Diazepam, Zolpidem, Bretazenil, and Gaboxadol in Rat Models of Inflammatory and Neuropathic Pain

Spinal administration of GABAA receptor modulators, such as the benzodiazepine drug diazepam, partially alleviates neuropathic hypersensitivity that manifests as spontaneous pain, allodynia, and hyperalgesia. However, benzodiazepines are hindered by sedative impairments and other side effect issues occurring mainly as a consequence of binding to GABAA receptors containing the α1 subunit. Here, we report on the novel subtype-selective GABAA receptor-positive modulator NS11394 [3′-[5-(1-hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile], which possesses a functional efficacy selectivity profile of α5 > α3 > α2 > α1 at GABAA α subunit-containing receptors. Oral administration of NS11394 (1–30 mg/kg) to rats attenuated spontaneous nociceptive behaviors in response to hindpaw injection of formalin and capsaicin, effects that were blocked by the benzodiazepine site antagonist flumazenil. Ongoing inflammatory nociception, observed as hindpaw weight-bearing deficits after Freunds adjuvant injection, was also completely reversed by NS11394. Likewise, hindpaw mechanical allodynia was fully reversed by NS11394 in two rat models of peripheral neuropathic pain. Importantly, NS11394-mediated antinociception occurred at doses 20 to 40-fold lower than those inducing minor sedative or ataxic impairments. In contrast, putative antinociception associated with administration of either diazepam, zolpidem, or gaboxadol only occurred at doses producing intolerable side effects, whereas bretazenil was completely inactive despite minor influences on motoric function. In electrophysiological studies, NS11394 selectively attenuated spinal nociceptive reflexes and C-fiber-mediated wind-up in vitro pointing to involvement of a spinal site of action. The robust therapeutic window seen with NS11394 in animals suggests that compounds with this in vitro selectivity profile could have potential benefit in clinical treatment of pain in humans.

NS11394 [3′-[5-(1-Hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile], a Unique Subtype-Selective GABAA Receptor Positive Allosteric Modulator: In Vitro Actions, Pharmacokinetic Properties and in Vivo Anxiolytic Efficacy

The novel positive allosteric modulator NS11394 [3′-[5-(1-hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile] possesses a functional selectivity profile at GABAA receptors of α5 > α3 > α2 > α1 based on oocyte electrophysiology with human GABAA receptors. Compared with other subtype-selective ligands, NS11394 is unique in having superior efficacy at GABAA-α3 receptors while maintaining low efficacy at GABAA-α1 receptors. NS11394 has an excellent pharmacokinetic profile, which correlates with pharmacodynamic endpoints (CNS receptor occupancy), yielding a high level of confidence in deriving in vivo conclusions anchored to an in vitro selectivity profile and allowing for translation to higher species. Specifically, we show that NS11394 is potent and highly effective in rodent anxiety models. The anxiolytic efficacy of NS11394 is most probably mediated through its high efficacy at GABAA-α3 receptors, although a contributory role of GABAA-α2 receptors cannot be excluded. Compared with benzodiazepines, NS11394 has a significantly reduced side effect profile in rat (sedation, ataxia, and ethanol interaction) and mouse (sedation), even at full CNS receptor occupancy. We attribute this benign side effect profile to very low efficacy of NS11394 at GABAA-α1 receptors and an overall partial agonist profile across receptor subtypes. However, NS11394 impairs memory in both rats and mice, which is possibly attributable to its efficacy at GABAA-α5 receptors, albeit activity at this receptor might be relevant to its antinociceptive effects (J Pharmacol Exp Ther 327:doi;10.1124/jpet.108.144, 2008). In conclusion, NS11394 has a unique subtype-selective GABAA receptor profile and represents an excellent pharmacological tool to further our understanding on the relative contributions of GABAA receptor subtypes in various therapeutic areas.

Developing analgesics by enhancing spinal inhibition after injury: GABAA receptor subtypes as novel targets

The use of genetically-engineered mice has identified alpha2- and alpha3-subunit containing GABA(A) receptors as principal contributors to the spinal disinhibition that occurs after inflammation and neuropathic injury. Pharmacological comparison of subtype selective allosteric modulators such as NS11394 and L838417 with either non-selective or full GABA(A) receptor modulators indicates that in addition to involvement of specific subunits per se, the level of efficacy at individual alpha subunits appears to be a critical determinant of analgesic activity. Combined, these complementary approaches identify the restoration of spinal inhibition after inflammatory, and especially neuropathic injury (the primary focus of this article), as a possible unifying mechanism for providing analgesia in patients with chronic pain.

Nicotine-induced enhancements in the five-choice serial reaction time task in rats are strain-dependent.

Abstract.Rationale: Clinically, nicotine improves attention, but this has proven difficult to demonstrate preclinically. We tested nicotine in Sprague-Dawley (SD) and Lister hooded (LH) rats in the five-choice serial reaction time task. Since SD rats demonstrate lower asymptotic performance than LH rats, we surmised that nicotine would only improve performance in this strain. Methods: Rats were placed in operant chambers 10xa0min after nicotine treatment (0.001–0.2xa0mg/kg). Results: Nicotine dose-dependently increased correct responses only in SD rats (~20% at the highest dose). By contrast, nicotine dose-dependently increased omission errors and reduced trials completed in both strains of rat, and dose-dependently reduced tray responses in SD rats. Conclusion: The magnitude of improvement in accuracy seen with nicotine in SD rats is greater than previously demonstrated using lesion or parametric manipulation models in other strains of rat in this test of attention. Although this suggests that the SD strain may be a useful tool for future studies, other task parameters, such as stimulus duration, may have to be optimum to demonstrate the magnitude of improvement observed presently.

Lamotrigine has an anxiolytic-like profile in the rat conditioned emotional response test of anxiety : a potential role for sodium channels?

RationaleMany anticonvulsants are used in disorders other than epilepsy. For example, lamotrigine is reported to be effective in post-traumatic stress disorder and mania.ObjectiveWe assessed the effects of the anticonvulsants lamotrigine, valproate and carbamazepine in an animal model of anxiety. We assessed a wide range of pharmacological tools to delineate the mechanism of lamotrigine’s anxiolytic effect.MethodsWe assessed these compounds in the rat conditioned emotional response (CER) test of anxiety.ResultsLamotrigine (30–80xa0mg/kg) dose-dependently and reproducibly engendered an anxiolytic response in this test, with similar efficacy to benzodiazepines. Carbamazepine (20–40xa0mg/kg) and riluzole (10xa0mg/kg), which block Na+ channels by a similar mechanism as lamotrigine, were also anxiolytic. By contrast, valproate (100–600xa0mg/kg) was inactive and appears to differ in its interaction with Na+ channels. The SSRI paroxetine, the GABAA receptor positive modulator propofol, the NMDA antagonists memantine and (+)MK-801, and the Ca2+ channel antagonist nifedipine were all inactive in the CER test, suggesting these mechanisms may not mediate the anxiolytic effect of lamotrigine. More directly, we showed that the anxiolytic effect of lamotrigine could be blocked by co-administering rats with the Na+ channel activator veratrine (0.1xa0mg/kg). By contrast, neither the Ca2+ channel agonist BAYK8644 (0.5xa0mg/kg) nor the 5-HT1A or 5-HT1/2 antagonists WAY100635 (0.3xa0mg/kg) and metergoline (3xa0mg/kg), respectively, were able to block the effect.ConclusionLamotrigine’s anxiolytic effect in the CER test may be mediated via block of Na+ channels, and this may represent a target for the development of novel anxiolytics.

Kv7 Channels: Function, Pharmacology and Channel Modulators

K(v)7 channels are unique among K(+) channels, since four out of the five channel subtypes have well-documented roles in the development of human diseases. They have distinct physiological functions in the heart and in the nervous system, which can be ascribed to their voltage-gating properties. The K(v)7 channels also lend themselves to pharmacological modulation, and synthetic openers as well as blockers of the channels, regulating neuronal excitability, have existed even before the K(v)7 channels were identified by cloning. In the present review we give an account on the focused efforts to develop selective modulators, openers as well as blockers, of the K(v)7 channel subtypes, which have been undertaken during recent years, along with a discussion of the K(v)7 ion channel physiology and therapeutic indications for modulators of the neuronal K(v)7 channels.