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.

Neuronal K v 7 channels are recognized as potential drug targets for treating hyperexcitability disorders such as pain, epilepsy, and mania. Hyperactivity of the amygdala has been described in clinical and preclinical studies of anxiety, and therefore, neuronal K v 7 channels may be a relevant target for this indication. In patch-clamp electrophysiology on cell lines expressing K v 7 channel subtypes, Maxipost (BMS-204352) exerted positive modulation of all neuronal K v 7 channels, whereas its Renantiomer was a negative modulator. By contrast, at the K v 7.1 and the large conductance Ca 2ϩ -activated potassium channels, the two enantiomers showed the same effect, namely, negative and positive modulation at the two channels, respectively. At GABA A receptors (␣ 1 ␤ 2 ␥ 2s and ␣ 2 ␤ 2 ␥ 2s ) expressed in Xenopus oocytes, BMS-204352 was a negative modulator, and the R-enantiomer was a positive modulator. The observation that the S-and R-forms exhibited opposing effects on neuronal K v 7 channel subtypes allowed us to assess the potential role of K v 7 channels in anxiety. In vivo, BMS-204352 (3-30 mg/kg) was anxiolytic in the mouse zero maze and marble burying models of anxiety, with the effect in the burying model antagonized by the R-enantiomer (3 mg/kg). Likewise, the positive K v 7 channel modulator retigabine was anxiolytic in both models, and its effect in the burying model was blocked by the K v 7 channel inhibitor 10,10-bis-pyridin-4-ylmethyl-10H-anthracen-9-one (XE-991) (1 mg/kg). Doses at which BMS-204352 and retigabine induce anxiolysis could be dissociated from effects on sedation or memory impairment. In conclusion, these in vitro and in vivo studies provide compelling evidence that neuronal K v 7 channels are a target for developing novel anxiolytics.

Spinal administration of GABA A 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 GABA A receptors containing the ␣ 1 subunit. Here, we report on the novel subtype-selective GABA A receptor-positive modulator NS11394 [3Ј-[5-(1-hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile], which possesses a functional efficacy selectivity profile of ␣ 5 Ͼ ␣ 3 Ͼ ␣ 2 Ͼ ␣ 1 at GABA A ␣ subunit-containing receptors.

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The novel positive allosteric modulator NS11394 [3Ј-[5-(1-hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile] possesses a functional selectivity profile at GABA A receptors of ␣ 5 Ͼ ␣ 3 Ͼ ␣ 2 Ͼ ␣ 1 based on oocyte electrophysiology with human GABA A receptors. Compared with other subtype-selective ligands, NS11394 is unique in having superior efficacy at GABA A -␣ 3 receptors while maintaining low efficacy at GABA A -␣ 1 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 GABA A -␣ 3 receptors, although a contributory role of GABA A -␣ 2 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 GABA A -␣ 1 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 GABA A -␣ 5 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 GABA A receptor profile and represents an excellent pharmacological tool to further our understanding on the relative contributions of GABA A receptor subtypes in various therapeutic areas.Preclinical studies using genetically modified mice suggest that GABA A -␣ 1 (Rudolph et al., 1999;McKernan et al., 2000), ␣ 2 (Low et al., 2000), and ␣ 5 (Collinson et al., 2002;Crestani et al., 2002)-containing receptors mediate the sedative/ motor-impairing, anxiolytic, and memory impairing effects of benzodiazepines, respectively. Pharmacologically, various nonbenzodiazepine compounds have been described that show either selective affinity (e.g., zolpidem and indiplon) or selective efficacy (e.g., L-838,417, SL651498, TP003, TPA023) for subtypes of GABA A receptors (Sanger et al., 1987;McKernan et al., 2000;Griebel et al., 2001;Dias et al., 2005;Atack et al., 2006). Such selectivity profiles have been argued to be the basis for selective behavioral profiles of these compounds in rodents and in some cases man. For example, zolpidem is selective for GABA A -␣ 1 -containing receptors, has a preferential sedative-hypnotic profile in animals, and is marketed as a sleep aid zolpidem tartrate (Ambien). Although additional compounds with various selectivity profiles have emerged, limited clinical data in patient populations exist to date (but see Basile...