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Prefrontal glutamate release evoked through activation of α4β2* nicotinic acetylcholine receptors (nAChRs) situated on thalamic glutamatergic afferents mediates cue detection processes and thus contributes to attentional performance. However, little is known about the respective contributions of the high sensitivity and low sensitivity (LS) stoichiometries of the α4β2 nAChR, (α4)2(β2)3 and (α4)3(β2)2, to these processes. In the present study we employed glutamate-sensitive microelectrodes and the (α4)3(β2)2-selective positive allosteric modulator (PAM) NS9283 to investigate the importance of the LS α4β2 nAChR for glutamate release in the rat medial prefrontal cortex (mPFC). Firstly, the signaling evoked by physiologically relevant ACh concentrations through the (α4)3(β2)2 nAChR in HEK293 cells was potentiated by NS9283, consistent with the classification of NS9283 as a PAM. In urethane-anesthetized rats, intra-prefrontal pressure ejections of NS9283 evoked glutamatergic transients. Importantly, this glutamate release was attenuated by removal of cholinergic projections to the recording area. This finding indicates that the effects of NS9283 depend on endogenous ACh, again consistent with effects of a PAM. We then conducted microdialysis to demonstrate the presence of extracellular ACh in urethane-anesthetized control rats. While detectable, those levels were significantly lower than in awake rats. Finally, the amplitudes of glutamatergic transients evoked by local pressure ejections of a low concentration of nicotine were significantly augmented following systemic administration of NS9283 (3.0mg/kg). In conclusion, our results indicate that a LS α4β2 nAChR PAM such as NS9283 may enhance the cholinergic modulation of glutamatergic neurotransmission in the cortex, thereby perhaps alleviating the attentional impairments common to a range of brain disorders., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Several metabolic neuroimaging studies have indicated that bipolar patients with mania exhibit alterations in metabolic activity, suggesting that perturbations in corticolimbic function contribute to the functional deficits associated with the disease. Because pharmacological stimulation of K(v)7 channel function has shown anti-manic like efficacy in the D-amphetamine and chlordiazepoxide (AMPH+CDP) induced hyperactivity mouse model of mania, we addressed whether this effect of K(v)7 channels could be associated with changes in cerebral [¹⁴C]2-deoxyglucose (2-DG) uptake, a surrogate marker of brain metabolic activity. Acute administration of the Kv7 channel modulators, retigabine (pan K(v)7.2-K(v)7.5 channel opener) and ICA-27243 (K(v)7.2/K(v)7.3 channel-preferring opener) reduced 2-DG uptake in several mouse forebrain structures with a brain regional signature similar to the mood stabilizers, lithium and valproate. Combined administration of AMPH+CDP enhanced 2-DG uptake in the striatum, cortex and thalamus, and both retigabine and ICA-27243 fully prevented this stimulatory effect of AMPH+CDP. In addition, both K(v)7 channel openers dose-dependently increased phospho-serine-9 levels of GSK3β in the prefrontal cortex and hippocampus, a common molecular mechanism shared by anti-manic drugs. In combination, these data emphasize the potential of K(v)7 channel openers in the treatment of bipolar disorder, and suggest that heteromeric K(v)7.2/K(v)7.3 channels may present a novel anti-manic therapeutic target., (© 2012 Neurosearch A/S. Journal of Neurochemistry © 2012 International Society for Neurochemistry.)

The acquisition of a water maze based task requiring egocentric spatial orientation in the absence of distal cues was studied in four groups of rats: animals in which the fimbria-fornix had been transected, rats that received bilateral ablations of the anteromedial prefrontal cortex, animals in which both of these structures had been lesioned, and a sham-operated control group. Isolated lesions of both the anteromedial prefrontal cortex and the hippocampus were associated with a significantly impaired task acquisition. Both of these individually lesioned groups did, however, eventually demonstrate full functional recovery by reaching the task proficiency of the sham-operated control group. In contrast, the group in which both of these structures had been lesioned failed to demonstrate full functional recovery and was severely and long-lastingly impaired when compared to all other groups. Behavioural challenges in the form of a no-platform session and two reversals of platform position demonstrated that while the sham-operated control group and the group subjected to fimbria-fornix transections in isolation utilized rather pure egocentric orientation strategies, the two prefrontally lesioned groups (and especially the combined lesion group) employed a different set of solution strategies which at least partly relied on a "circling" method. Even in the behaviour of the prefrontally lesioned groups, however, indications of a certain level of cognitive representations of the platform positions were seen. It is concluded that both the prefrontal cortex and the hippocampus contribute to the mediation of egocentric spatial orientation. Furthermore, the hippocampus is a significant and potentially irreplaceable part of the neural substrate of functional recovery of the presently studied task after prefrontal lesions--while the prefrontal cortex may play a similar role with respect to hippocampal lesions.

J. Neurochem. (2012) 121, 373-382. Abstract Several metabolic neuroimaging studies have indicated that bipolar patients with mania exhibit alterations in metabolic activity, suggesting that perturbations in corticolimbic function contribute to the functional deficits associated with the disease. Because pharmacological stimulation of Kv7 channel function has shown anti-manic like efficacy in the D-amphetamine and chlordiazepoxide (AMPH+CDP) induced hyperactivity mouse model of mania, we addressed whether this effect of Kv7 channels could be associated with changes in cerebral [14C]2-deoxyglucose (2-DG) uptake, a surrogate marker of brain metabolic activity. Acute administration of the Kv7 channel modulators, retigabine (pan Kv7.2-Kv7.5 channel opener) and ICA-27243 (Kv7.2/Kv7.3 channel-preferring opener) reduced 2-DG uptake in several mouse forebrain structures with a brain regional signature similar to the mood stabilizers, lithium and valproate. Combined administration of AMPH+CDP enhanced 2-DG uptake in the striatum, cortex and thalamus, and both retigabine and ICA-27243 fully prevented this stimulatory effect of AMPH+CDP. In addition, both Kv7 channel openers dose-dependently increased phospho-serine-9 levels of GSK3β in the prefrontal cortex and hippocampus, a common molecular mechanism shared by anti-manic drugs. In combination, these data emphasize the potential of Kv7 channel openers in the treatment of bipolar disorder, and suggest that heteromeric Kv7.2/Kv7.3 channels may present a novel anti-manic therapeutic target. [ABSTRACT FROM AUTHOR]

Various evidence indicate that schizophrenia is a neurodevelopmental disorder. Epidemiological observations point to oxygen deficiencies during delivery as one of the early risk factors for developing schizophrenia. The aim of the present study was to examine the effect of postnatal anoxia in rats. Anoxia was experimentally induced by placing 9-day-old rat pups for 6 min in a chamber saturated with 100% nitrogen (N2). Exposure to anoxia on postnatal day (PND) 9 resulted in significantly reduced subcortical dopamine metabolism and turnover, as measured by striatal 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) concentrations. Furthermore, in the anoxic group only, striatal HVA concentrations were negatively correlated to prefrontal cortical N-acetylaspartate (NAA) levels. Similar findings of distorted prefrontal–subcortical interactions have recently been reported in schizophrenic patients. There was no effect of postnatal anoxia on either baseline or d-amphetamine-induced deficit in the prepulse inhibition (PPI) paradigm in adulthood. Accordingly, although oxygen deficiency early in life has been discussed as vulnerability factor in developing schizophrenia, exposure to postnatal anoxia in the rat does not show clear-cut phenomenological similarities with the disorder. [Copyright &y& Elsevier]