Pro-cognitive Effects Research Articles

Low-dose chronic prenatal alcohol exposure abolishes the pro-cognitive effects of angiotensin IV

Prenatal ethanol exposure (PAE) in humans results in a spectrum of disorders including deficits in learning and memory. Animal models to date have typically used high ethanol doses but have not identified the biochemical changes underlying the cognitive deficit. This study used treatment of mouse breeding harems with 5% ethanol via drinking water throughout pregnancy and lactation and explored the behavioural consequences in the progeny at 3–6 months of age using the open field test, novel object recognition test and elevated plus maze to measure anxiety and memory consolidation. The effects of angiotensin IV on behaviour of the progeny were also determined. The results indicated that PAE increased anxiety-like behaviour as determined in the open field test in male but not female progeny. In control animals, angiotensin IV enhanced memory consolidation in males, but this effect was abolished by PAE. The abolition of the pro-cognitive effect of angiotensin IV was not a consequence of increased anxiety, and there was some evidence of a long-lasting anxiolytic effect of angiotensin IV in the male PAE progeny. These results suggest that PAE may act via alteration of the actions of the brain renin-angiotensin system to impair memory consolidation, but these effects may be partially sex-dependent.

Minimal effects of prolonged smoking abstinence or resumption on cognitive performance challenge the “self-medication” hypothesis in schizophrenia

One prominent, long-standing view is that individuals with schizophrenia smoke cigarettes more than the general population to “self-medicate” cognitive deficits and other symptoms. This study tested the self-medication hypothesis by examining the effects of smoking abstinence and resumption on cognition in patients with schizophrenia. Nicotine-dependent smokers with schizophrenia (n=26) were trained on a cognitive battery and then hospitalized to achieve and maintain confirmed abstinence from smoking for ~1 week. Cognition was tested while smoking as usual (baseline), one day after smoking cessation (early abstinence), ~1 week later (extended abstinence), and within ~3 weeks of resuming smoking (resumption). The test battery included measures of processing speed, attention, conflict resolution, verbal memory, working memory, verbal fluency, and executive function to evaluate multiple cognitive domains affected by schizophrenia. Positive and negative symptoms of schizophrenia, depressive symptoms, and dyskinesia were also measured at baseline and after prolonged abstinence. There were no significant changes in global cognitive test performance with smoking cessation, abstinence, or resumption. There were small decreases in a measure of processing speed and delayed verbal recall with abstinence, but these findings failed to survive adjustments for multiple comparisons. Surprisingly, in this within subject “On-Off-Off-On” design, there were no significant effects of early or prolonged abstinence from smoking on cognitive and behavioral measures in smokers with schizophrenia. The results of this study challenge the widely held “self-medication” hypothesis of smoking and schizophrenia, question the extent of pro-cognitive effects of smoking and nicotine in schizophrenia, and support encouraging smoking cessation in schizophrenia.

Comparative assessment of cognitive function and mood dynamics in patients with depression and eating disorders in the process of treatment

Eating disorders of bulimic type are among the most common comorbidities with depression. The objective is to evaluate cognitive function and mood dynamics in patients with depression and eating disorders in pharmacotherapy. In total, 52 outpatients, who met criteria for “major depressive episode” (ICD-10), participated. The level of depression was estimated with Hamilton Depression rating scale (HAM-D) and cognitive function–Montreal Cognitive Assessment (MoCa). Sample was divided into two groups. Patients of group 1 also met criteria for eating disorder of bulimic type and patients of group 2 did not have any eating disorder. Treatment included standard doses of SSRI. Assessments were performed after 2, 4 and 8 weeks (D14, D30, D60). The level of HAM-D was significantly greater (P < 0.05) in eating disorders group (16.75 ± 2.83 in group 1; 13.04 ± 1.93 in group 2 at screening) and significance was preserved till D60 (9.39 ± 2.54 in group 1; 6.32 ± 1.27 in group 2 at D60). Clinically significant antidepressive effect was revealed faster in group 2 (at D7) compared to group 1 (at D14). Overall score of MoCA was significantly lower (P < 0.05) in eating disorders group (20.33 ± 0.54 in group 1; 23.43 ± 2.32 in group 2 at screening) at all stages of treatment (23.39 ± 0.78 in group 1; 26.96 ± 3.27 in group 2 at D60) and it reached normal range (25 and more) only in group 2 at D60. Significant change from screening was revealed at D30 at group 2 and at D60 at group 1.ConclusionEating disorder have an impact on SSRI treatment efficacy including antidepressive and procognitive effects. It is necessary to reveal eating disorders as a co-morbidity in patients with depression.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Combined Norepinephrine and Dopamine Reuptake Inhibition for Long‐Term Memory Enhancement

The psychostimulants amphetamine and methylphenidate are highly effective cognitive enhancers, particularly for their ability to enhance long‐term memory (LTM). While psychostimulants have been argued to exert their procognitive effects exclusively through norepinephrine transporter (NET) inhibition and their reinforcing effects exclusively through dopamine transporter (DAT) inhibition, there is increasing evidence that DAT also plays a critical role in learning and memory, including LTM enhancement. In the present study, we examined the effects of a drug combination of a potent NET inhibitor with a weak DAT inhibitor, using Pavlovian fear conditioning. While NET or DAT inhibition alone failed to enhance LTM across a wide range of doses (Carmack et al., 2014), we found that combined NET/DAT inhibition produced robust enhancements in immediate and long‐term fear memory acquisition. These findings support the theory that both NET and DAT inhibition are required for psychostimulant‐induced LTM enhancement. Additionally, we propose that a pharmaceutical combination of moderate NET inhibition and weak DAT inhibition could lead to the development of a non‐stimulating, non‐addictive, and non‐controlled, yet highly effective cognitive enhancer.Support or Funding InformationNIH grant DA020041 (SGA)

65. Effects of NMDA Receptor Antagonism in Patients With Schizophrenia: Improvement in Markers of Cortical Oscillatory Dynamics

Abstract Background: NMDA receptor-associated oscillations in the gamma frequency band (30–80 Hz) are thought to underlie a variety of cognitive processes known to be disrupted in patients with schizophrenia (SZ). NMDA receptor functioning can be assessed in subjects by measuring evoked power and phase synchronization of gamma frequency oscillations in response to auditory steady state stimulation (ASSR). Therefore, both evoked power and phase synchronization of gamma frequency have promising applications as translational biomarkers for procognitive therapeutics. In previous work, we reported the low-to-moderate affinity NMDA-receptor antagonist, memantine, enhanced prepulse inhibition of startle and mismatch negativity in SZ patients. Here, we report the effects of a single dose of memantine on evoked power and phase synchronization of ASSR obtained in our previous study. Methods: SZ patients (n = 18; M:F=11:7; mean age = 37.7 years; range:21–48) and healthy comparison subjects (n = 14; M:F = 10:4; age = 26.6 years; range:19–36) completed 2 test days separated by 1 week. On each test day, subjects received either memantine 20 mg (p.o.) or placebo in a double-blind, randomized, counterbalanced, within-subject, crossover design. The ASSR paradigm was used to measure evoked gamma power and phase locking in response to 40 Hz click trains. Results: Patients with SZ had reduced evoked gamma power and phase locking, consistent with previous reports (main effect of group - Power: F = 5.89, df = 1.30, P < .025; Phase locking: F = 12.47, df 1.30, P < .0015). Memantine-enhanced evoked power and phase locking in both SZ and healthy comparison subjects (drug effect - Power: F = 6.40, df 1.30, P < .02; Phase locking: F = 8.49, df 1.30, P <.007). Memantine effects on both gamma power and phase locking were also significant when groups were matched for age (Ps < .005 and .0008, respectively). Memantine-associated enhancement of gamma power and phase locking in SZ patients correlated negatively with age (Ps < .0015 and .005, respectively). Significant relationships were also identified in patients between memantine effects on gamma power and phase locking (r = .74, P < .0005), gamma power and mismatch negativity (r = .54, P < .025), and phase locking and prepulse inhibition of startle (r = −.59, P < .027). Conclusion: A single dose of memantine normalized biomarkers of cortical oscillatory dynamics associated with NMDA receptor dysfunction in SZ patients. Our ongoing studies will clarify whether these acute changes are associated with beneficial clinical and functional outcomes and whether they predict enduring pro-cognitive effects. These data suggest gamma band ASSR parameters can be used as translational endpoints in early-phase clinical trials and in procognitive drug discovery.

The novel antipsychotic drug brexpiprazole, alone and in combination with escitalopram, facilitates prefrontal glutamatergic transmission via a dopamine D1 receptor-dependent mechanism

Brexpiprazole (Rexulti®), a novel D2/3 receptor (R) partial agonist, was recently approved as monotherapy for schizophrenia, demonstrating effectiveness against both positive and negative symptoms, and also approved as add-on treatment to antidepressant drugs, inducing a potent antidepressant effect with a faster onset compared to an antidepressant given alone. Moreover, brexpiprazole has demonstrated pro-cognitive effects in preclinical studies. To explore whether the observed effects may be mediated via modulation of prefrontal glutamatergic transmission, we investigated the effect of brexpiprazole, alone and in combination with the SSRI escitalopram, on prefrontal glutamatergic transmission using in vitro electrophysiological intracellular recordings of deep layer pyramidal cells of the rat medial prefrontal cortex (mPFC). Nanomolar concentrations of brexpiprazole potentiated NMDAR-induced currents and electrically evoked EPSPs via activation of dopamine D1Rs, in similarity with the effect of the atypical antipsychotic drug clozapine. The effect of an ineffective concentration of brexpiprazole was significantly potentiated by the addition of escitalopram. When combined with escitalopram, brexpiprazole also potentiated AMPAR-mediated transmission, in similarity with the clinically rapid acting antidepressant drug ketamine. The effect on the AMPAR-mediated currents was also D1R dependent. In conclusion, our data propose that brexpiprazole exerts a clozapine-like potentiation of NMDAR-mediated currents in the mPFC, which can explain its efficacy on negative symptoms of schizophrenia and the pro-cognitive effects observed preclinically. Moreover, add-on brexpiprazole to escitalopram also potentiated AMPAR-mediated transmission, which may provide a neurobiological explanation to the faster antidepressant effect of add-on brexpiprazole in major depression.

Effects of the 5-HT6 receptor antagonist idalopirdine on extracellular levels of monoamines, glutamate and acetylcholine in the rat medial prefrontal cortex

Idalopirdine (Lu AE58054) is a high affinity and selective antagonist for the human serotonin 5-HT6 receptor (Ki 0.83nM) in phase III development for mild-to-moderate Alzheimer's disease as an adjunct therapy to acetylcholinesterase inhibitors (AChEIs). We have studied the effects of idalopirdine on extracellular levels of monoamines, glutamate and acetylcholine in the medial prefrontal cortex (mPFC) of freely-moving rats using microdialysis. Idalopirdine (10mg/kg p.o.) increased extracellular levels of dopamine, noradrenaline and glutamate in the mPFC and showed a trend to increase serotonin levels. No effect was observed on acetylcholine levels. The AChEI donepezil (1.3mg/kg s.c.) significantly increased the levels of acetylcholine. Pretreatment with idalopirdine 2h prior to donepezil administration potentiated the effect of donepezil on extracellular acetylcholine levels. The idalopirdine potentiation of donepezil-induced increase in acetylcholine levels was also observed during local infusion of idalopirdine (6µg/ml) into the mPFC by reverse dialysis. The data from the current study may provide a mechanistic model for the pro-cognitive effects observed with administration of idalopirdine in donepezil-treated patients with Alzheimer's disease observed in the phase 2 studies (Wilkinson et al. 2014).

Effects of nicotine on response inhibition and interference control.

Nicotine is a cholinergic agonist with known pro-cognitive effects in the domains of alerting and orienting attention. However, its effects on attentional top-down functions such as response inhibition and interference control are less well characterised. Here, we investigated the effects of 7mg transdermal nicotine on performance on a battery of response inhibition and interference control tasks. A sample of N=44 healthy adult non-smokers performed antisaccade, stop signal, Stroop, go/no-go, flanker, shape matching and Simon tasks, as well as the attentional network test (ANT) and a continuous performance task (CPT). Nicotine was administered in a within-subjects, double-blind, placebo-controlled design, with order of drug administration counterbalanced. Relative to placebo, nicotine led to significantly shorter reaction times on a prosaccade task and on CPT hits but did not significantly improve inhibitory or interference control performance on any task. Instead, nicotine had a negative influence in increasing the interference effect on the Simon task. Nicotine did not alter inter-individual associations between reaction times on congruent trials and error rates on incongruent trials on any task. Finally, there were effects involving order of drug administration, suggesting practice effects but also beneficial nicotine effects when the compound was administered first. Overall, our findings support previous studies showing positive effects of nicotine on basic attentional functions but do not provide direct evidence for an improvement of top-down cognitive control through acute administration of nicotine at this dose in healthy non-smokers.

Repeated Nicotine Strengthens Gamma Oscillations in the Prefrontal Cortex and Improves Visual Attention

Nicotine has strong addictive as well as procognitive properties. While a large body of research on nicotine continues to inform us about mechanisms related to its reinforcing effects, less is known about clinically relevant mechanisms that subserve its cognitive-enhancing properties. Understanding the latter is critical for developing optimal strategies for treating cognitive deficits. The primary brain region implicated in cognitive functions improved by nicotine is the prefrontal cortex (PFC). Here we assessed the impact of nicotine on unit activity and local field potential oscillations in the PFC of behaving rats. An acute dose of nicotine produced a predominantly inhibitory influence on population activity, a small increase in gamma oscillations, and a decrease in theta and beta oscillations. After a daily dosing regimen, a shift to excitatory–inhibitory balance in single-unit activity and stronger gamma oscillations began to emerge. This pattern of plasticity was specific to the gamma band as lower frequency oscillations were suppressed consistently across daily nicotine treatments. Gamma oscillations are associated with enhanced attentional capacity. Consistent with this mechanism, the repeat dosing regimen in a separate cohort of subjects led to improved performance in an attention task. These data suggest that procognitive effects of nicotine may involve development of enhanced gamma oscillatory activity and a shift to excitatory–inhibitory balance in PFC neural activity. In the context of the clinical use of nicotine and related agonists for treating cognitive deficits, these data suggest that daily dosing may be critical to allow for development of robust gamma oscillations.

Indispensable role of the voltage-gated calcium channels in the procognitive effects of angiotensin IV.

Voltage-gated calcium channels (VGCCs) play a major role in brain functioning, including that of cognition-related structures such as cerebral cortex and hippocampus. Cellular mechanisms underlying learning and memory enhancing effect of the neuropeptide angiotensin IV (Ang IV) have been linked to VGCCs but only in respect of its long-term potentiation (LTP)-inducing effect. To assess behaviorally effects of L- and T-type VGCCs blocking drugs in low, behaviorally inactive, doses on Ang IV facilitation of recall of aversively (foot-shock) and appetitively (curiosity for novelty) motivated behaviors. About 240 male Wistar rats were used. All animals received oral (p.o.) dose of nimodipine (12mg/kg) or mibefradil (1mg/kg) dissolved in saline or saline alone followed by an intracerebroventricular (i.c.v.) injection of 1nmol of Ang IV dissolved in 2μl of normal saline or saline alone 15min later. Groups of about 10 rats, separate for each experiment, were tested for recall of aversively (inhibitory avoidance, IA) and appetitively (object recognition, OR) reinforced behaviors. To verify lack of unspecific motor and emotional effects of our treatments separate groups of rats were tested in open field (OF) and elevated 'plus' maze (EPM), respectively. Both, nimodipine and mibefradil prevented recall facilitating effects of subsequently injected Ang IV. The peptide as well as both VGCCs blocking drugs had no (OF), or only negligible (EPM) effects on motor performance and emotionality of rats. The data support a notion about key role of the functional VGCCs in neuronal procognitive effects of Ang IV.

The Role of Phosphodiesterase-2 in Psychiatric and Neurodegenerative Disorders.

Cyclic nucleotide PDEs are a super-family of enzymes responsible for regulating intracellular levels of the second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Through their catalysis, PDEs are able to exert tight regulation over these important intracellular signaling cascades. Previously, PDEs have been implicated in learning and memory, as well as in mood disorders, such as anxiety and depression. PDE2 is of special interest due to its high level of expression in the forebrain, specifically in the isocortex, entorhinal cortex, striatum, hippocampus, amygdala, and medial habenula. Many of these brain regions are considered participants of the limbic system, which is known as the emotional regulatory center of the brain, and is important for modulating emotion and long-term memory. Therefore, PDE2s coincidental expression in these areas suggests an important role for PDE2 in these behaviors, and researchers are continuing to uncover the complex connections. It was shownthat PDE2 inhibitors have pro-cognitive effects in tests of memory, including the object recognition test. PDE2 inhibitors are also protective against cognitive deficits in various models of cognitive impairment. Additionally, PDE2 inhibitors are protective against many different forms of stress-induced anxiety-like and depression-like behaviors. Currently, there is a great need for novel therapeutics for the treatment of mood and cognitive disorders, especially anxiety and depression, and other neurodegenerative diseases, such as Alzheimer's disease, and PDE2 is emerging as a viable target for future drug development for many of these diseases.

Specific Agonists and Antagonists of Serotonergic Receptors in theTreatment of Cognitive Symptoms in Alzheimer's Disease

In Alzheimer’s disease, decreasing activity of acetylcholine and GABA in the hippocampus and prefrontal cortex are combined with cognitive deficits and with the formation of beta-amyloid. Neurotransmitter alterations in these brain regions are described, while a neurotransmitter imbalance with hypoactivity of muscarinic cholinergic, serotonergic and GABAergic neurons and hyperactivity of noradrenergic and glutamatergic neurons can be found. Serotonin including some specific receptors play an essential role in cognitive symptoms in Alzheimer’s disease. Neural networks in the hippocampus and prefrontal cortex are described. Animal experiments and clinical trials about the pro-cognitive effect of 5-HT4 and 5HT7 agonists and of 5-HT3 and 5-HT6 antagonists are mentioned. The question should be investigated, whether a hybrid of a GABAA agonist and an NMDA antagonist is of a therapeutic value in mild Alzheimer’s disease.

Nicotine and symptoms of schizophrenia: the 2017 picture

The tendency of people who suffer with schizophrenia to consume large amounts of cigarettes and to extract more nicotine from these cigarettes is well-known. A sizeable body of work investigating this has concluded that smoking in people with schizophrenia improves the dysfunctional sensory gating intrinsic to this disease. This has been recognised at least since the late 1980s. Consequently, the pro-cognitive effect of nicotine is now well-recognised and has led to the investigation of nicotinic receptor modulators as potential treatments for schizophrenia. Particular interest has focused on the treatment of negative symptoms in this illness. While there is a solid theoretical basis for this line of drug development, in practice, later-stage drug trials of compounds such as TC-5619 (bradanicline) in Phase 2 and EVP-6124 (encenicline) in Phase 3 have been disappointing. Numerous intolerable side-effects have been important in limiting the clinical use of such compounds. It is conceivable that the reason for intolerable side-effects might be a consequence of the wide distribution of nicotinic cholinergic receptors: α7 nicotinic receptors are found in several cerebral areas, in the spleen and in lymphocytes at lymph nodes.Later-stage drug development trials which reveal insurmountable administration problems are perhaps indicative of the great practical distance between theoretical recognition of a potential therapeutic agent and its eventual translational appearance in the armory against an illness. Given that this is the case it may still be worthwhile to look at the simple administration of exogenous nicotine via e-cigarettes or chewing-gum as an adjunctive agent in the treatment of schizophrenia in the interim. More prosaically, the banning of smoking in many hospital premises in the UK has led to a difficulty in the practical management of acutely ill people with schizophrenia in the in-patient setting. In a group of people who are profoundly psychiatrically unwell, and often physically compromised to some degree because of their cigarette consumption, alternative management techniques for the latter must be explored. Use of exogenous nicotine replacement in a less harmful delivery manner than cigarettes in a group of people who have a clear physiological reason for smoking -i.e. to increase their deficient endogenous cerebral nicotine levels – is worthwhile to investigate. Very recent work in exactly this direction has been undertaken. Nursing management of such patients may be greatly improved as a result, as may their on-going engagement with the therapeutic team. Here is an illustration of how theoretical considerations eventually come to have a pragmatic consequence in the day-to-day management of people with severe and enduring mental illnesses like schizophrenia.

TAK-063, a phosphodiesterase 10A inhibitor, modulates neuronal activity in various brain regions in phMRI and EEG studies with and without ketamine challenge

TAK-063 is a selective phosphodiesterase 10A (PDE10A) inhibitor that produces potent antipsychotic-like and pro-cognitive effects at 0.3mg/kg (26% PDE10A occupancy in rats) or higher in rodents through the balanced activation of the direct and indirect pathways of striatal medium spiny neurons (MSNs). In this study, we evaluated the specific binding of TAK-063 using in vitro autoradiography (ARG) and the modulation of brain activity using pharmacological magnetic resonance imaging (phMRI) and electroencephalography (EEG). [3H]TAK-063 significantly accumulated in the caudate—putamen (CPu), ventral pallidum (VP), substantia nigra (SN), hippocampus (Hipp), and amygdala (Amy), but not in the frontal cortex (Fcx), brainstem (Bs), or cerebellum (Cb) in an ARG study using rat brain sections. [3H]TAK-063 accumulation in the CPu was more than eighteen-fold higher than that in the Hipp and Amy. TAK-063 at 0.3mg/kg increased the blood oxygenation level-dependent (BOLD) signal in the striatum and Amy, and decreased it in the Fcx in a phMRI study with anesthetized rats. TAK-063 at 0.3mg/kg significantly reduced the ketamine-induced increase in EEG gamma power both in awake and anesthetized rats. TAK-063 at 0.2mg/kg (35% PDE10A occupancy in monkeys) also reduced the ketamine-induced increase in EEG gamma power in awake monkeys. In line with the EEG data, TAK-063 at 0.3mg/kg reversed the ketamine-induced BOLD signal changes in the cortex, Bs, and Cb in a phMRI study with anesthetized rats. These data suggest that TAK-063 at about 30% PDE10A occupancy modulates activities of multiple brain regions through activation of neuronal circuits in rats and monkeys.

P.1.l.003 - A systematic review of melatonin for insomnia in older people

This is a secondary data analysis from our erythropoietin (EPO) trials. We examine (I) whether EPO improves speed of complex cognitive processing across bipolar and unipolar disorder, (II) if objective and subjective baseline cognitive impairment increases patients׳ chances of treatment-efficacy and (III) if cognitive improvement correlates with better subjective cognitive function, quality of life and socio-occupational capacity. Patients with unipolar or bipolar disorder were randomized to eight weekly EPO (N=40) or saline (N=39) infusions. Cognition, mood, quality of life and socio-occupational capacity were assessed at baseline (week 1), after treatment completion (week 9) and at follow-up (week 14). We used repeated measures analysis of covariance to investigate the effect of EPO on speed of complex cognitive processing. With logistic regression, we examined whether baseline cognitive impairment predicted treatment-efficacy. Pearson correlations were used to assess associations between objective and subjective cognition, quality of life and socio-occupational capacity. EPO improved speed of complex cognitive processing across affective disorders at weeks 9 and 14 (p≤0.05). In EPO-treated patients, baseline cognitive impairment increased the odds of treatment-efficacy on cognition at weeks 9 and 14 by a factor 9.7 (95% CI:1.2-81.1) and 9.9 (95% CI:1.1-88.4), respectively (p≤0.04). Subjective cognitive complaints did not affect chances of treatment-efficacy (p≥0.45). EPO-associated cognitive improvement correlated with reduced cognitive complaints but not with quality of life or socio-occupational function. As the analyses were performed post-hoc, findings are only hypothesis-generating. In conclusion, pro-cognitive effects of EPO occurred across affective disorders. Neuropsychological screening for cognitive dysfunction may be warranted in future cognition trials.

The 5-HT6 receptor antagonist idalopirdine potentiates the effects of donepezil on gamma oscillations in the frontal cortex of anesthetized and awake rats without affecting sleep-wake architecture

The 5-HT6 receptor is a promising target for cognitive disorders, in particular for Alzheimer's disease (AD). The high affinity and selective 5-HT6 receptor antagonist idalopirdine (Lu AE58054) is currently in development for mild-moderate AD as adjunct therapy to acetylcholinesterase inhibitors (AChEIs). We studied the effects of idalopirdine alone and in combination with the AChEI donepezil on cortical function using two in vivo electrophysiological methods. Neuronal network oscillations in the frontal cortex were measured during electrical stimulation of the brainstem nucleus pontis oralis (nPO) in the anesthetized rat and by an electroencephalogram (EEG) in the awake, freely moving rat. In conjunction with the EEG study, we investigated the effects of idalopirdine and donepezil on sleep-wake architecture using telemetric polysomnography. Idalopirdine (2 mg/kg i.v.) increased gamma power in the medial prefrontal cortex (mPFC) during nPO stimulation. Donepezil (0.3 and 1 mg/kg i.v.) also increased cortical gamma power and pretreatment with idalopirdine (2 mg/kg i.v.) potentiated and prolonged the effects of donepezil. Similarly, donepezil (1 and 3 mg/kg s.c.) dose-dependently increased frontal cortical gamma power in the freely moving rat and pretreatment with idalopirdine (10 mg/kg p.o.) augmented the effect of donepezil 1 mg/kg. Analysis of the sleep-wake architecture showed that donepezil (1 and 3 mg/kg s.c.) dose-dependently delayed sleep onset and decreased the time spent in both REM and non REM sleep stages. In contrast, idalopirdine (10 mg/kg p.o.) did not affect sleep-wake architecture nor the effects of donepezil. In summary, we show that idalopirdine potentiates the effects of donepezil on frontal cortical gamma oscillations, a pharmacodynamic biomarker associated with cognition, without modifying the effects of donepezil on sleep. The increased cortical excitability may contribute to the procognitive effects of idalopirdine in donepezil-treated AD patients.

Positive allosteric modulators of the α7 nicotinic acetylcholine receptor potentiate glutamate release in the prefrontal cortex of freely-moving rats

Positive allosteric modulators (PAMs) of α7 nicotinic acetylcholine receptors (α7nAChRs) exhibit pro-cognitive effects in animal models of schizophrenia and are targets for the discovery of cognition-enhancing drugs. However, little is known about their in vivo mechanism of action because such studies have been performed in vitro. Here we test the hypothesis that PAMs’ potentiation of glutamate release in prefrontal cortex depends upon the level of endogenous cholinergic activity. NMDA stimulation of the nucleus accumbens shell (0.05–0.30 μg in 0.5 μL) increased extracellular choline (0.87 ± 0.15 – 1.73 ± 0.31 μM) and glutamate (0.15 μg, 3.79 ± 0.87 μM) in medial prefrontal cortex, and the glutamate release was prevented by local infusions of MLA (6.75 μg, 0.19 ± 0.06 μM). The lower dose (1 mg/kg) of AVL3288 (type I) potentiated the glutamate release to a greater degree after the high dose of NMDA (0.30 μg; 84.7% increase vs AVL vehicle) versus the low dose of NMDA (0.05 μg; 24.2% increase), whereas glutamate release was inhibited when the high dose of NMDA was combined with the high dose of AVL3288 (64.2% decrease). In contrast, PNU120596 (type II) only potentiated glutamate release when the high dose (9 mg/kg) was combined with the low dose of NMDA (0.05 μg; 211% increase from PNU vehicle). Collectively, the results suggest a potential in vivo mechanism for the pro-cognitive effects of PAMs and provide the proof-of-concept for the continued focus on allosteric modulation of cortical α7nAChRs for cognition-enhancing drug development.

The caffeine-binding adenosine A2A receptor induces age-like HPA-axis dysfunction by targeting glucocorticoid receptor function.

Caffeine is associated with procognitive effects in humans by counteracting overactivation of the adenosine A2A receptor (A2AR), which is upregulated in the human forebrain of aged and Alzheimer’s disease (AD) patients. We have previously shown that an anti-A2AR therapy reverts age-like memory deficits, by reestablishment of the hypothalamic-pituitary-adrenal (HPA) axis feedback and corticosterone circadian levels. These observations suggest that A2AR over-activation and glucocorticoid dysfunction are key events in age-related hippocampal deficits; but their direct connection has never been explored. We now show that inducing A2AR overexpression in an aging-like profile is sufficient to trigger HPA-axis dysfunction, namely loss of plasmatic corticosterone circadian oscillation, and promotes reduction of GR hippocampal levels. The synaptic plasticity and memory deficits triggered by GR in the hippocampus are amplified by A2AR over-activation and were rescued by anti-A2AR therapy; finally, we demonstrate that A2AR act on GR nuclear translocation and GR-dependent transcriptional regulation. We provide the first demonstration that A2AR is a major regulator of GR function and that this functional interconnection may be a trigger to age-related memory deficits. This supports the idea that the procognitive effects of A2AR antagonists, namely caffeine, on Alzheimer’s and age-related cognitive impairments may rely on its ability to modulate GR actions.

Pro-Cognitive Effects of Non-Peptide Analogues of Soluble Amyloid Peptide Precursor Fragment sAPP.

We studied pro-cognitive effect of two heterocyclic low-molecular-weight compounds that serve as non-peptide analogues of soluble fragment of amyloid peptide precursor (sAPP). Intracerebroventricular and systemic administration of peptide mimetics P2 and P5 improved weak memory on the model of passive avoidance in chicks and in the object location task in mice. Both compounds were effective if administered close to the moment of training or 4 h after it. The time windows and dose range for the pro-cognitive effects of the mimetics were similar to those observed in previous studies with sAPP peptide fragments.

Improvement of attention with amphetamine in low- and high-performing rats.

Attentional deficits occur in a range of neuropsychiatric disorders, such as schizophrenia and attention deficit hyperactivity disorder. Psychostimulants are one of the main treatments for attentional deficits, yet there are limited reports of procognitive effects of amphetamine in preclinical studies. Therefore, task development may be needed to improve predictive validity when measuring attention in rodents. This study aimed to use a modified signal detection task (SDT) to determine if and at what doses amphetamine could improve attention in rats. Sprague-Dawley rats were trained on the SDT prior to amphetamine challenge (0.1, 0.25, 0.75 and 1.25mg/kg). This dose range was predicted to enhance and disrupt cognition with the effect differing between individuals depending on baseline performance. Acute low dose amphetamine (0.1 and 0.25mg/kg) improved accuracy, while the highest dose (1.25mg/kg) significantly disrupted performance. The effects differed for low- and high-performing groups across these doses. The effect of amphetamine on accuracy was found to significantly correlate with baseline performance in rats. This study demonstrates that improvement in attentional performance with systemic amphetamine is dependent on baseline accuracy in rats. Indicative of the inverted U-shaped relationship between dopamine and cognition, there was a baseline-dependent shift in performance with increasing doses of amphetamine. The SDT may be a useful tool for investigating individual differences in attention and response to psychostimulants in rodents.