H3 receptor antagonists reverse delay-dependent deficits in novel object discrimination by enhancing retrieval

Rationale

Accumulated evidence suggests a role for histamine in cognition and the use of H₃ receptor antagonists in the treatment of learning and memory disorders.

Objectives

The aim of the current study was to investigate the cognition enhancing properties of ciproxifan, an H₃ receptor antagonist, after natural forgetting in normal adult rats.

Materials and methods

The novel object discrimination task, a recognition memory test based on spontaneous exploratory behaviour, was used. Briefly, rats exposed to two identical objects during an acquisition trial can discriminate between a novel object and a familiar one during a subsequent choice trial after a short delay but not after a 24-h inter-trial interval.

Results

The scopolamine (0.5 mg/kg, i.p.)-induced impairment after a short delay was abolished by ciproxifan (p?p?p?1 antagonist, or zolantidine (10 mg/kg), an H₂ antagonist, prevented the retrieval enhancement effect of ciproxifan (p?p?Conclusions Histamine H₃ receptor antagonists restore the performance of rats impaired by scopolamine and enhance recognition memory after acute administration before the retrieval phase via a mechanism dependent on H₁ and H₂ receptor activation.     

Histamine and H3 receptor-dependent mechanisms regulate ethanol stimulation and conditioned place preference in mice

Rationale

Neuronal histamine has a prominent role in sleep–wake control and body homeostasis, but a number of studies suggest that histamine has also a role in higher brain functions including drug reward.

Objective

The present experiments characterized the involvement of histamine and its H3 receptor in ethanol-related behaviors in mice.

Materials and methods

Male histidine decarboxylase knockout (HDC KO) and control mice were used to study the role of histamine in ethanol-induced stimulation of locomotor activity, impairment of motor coordination, and conditioned place preference (CPP). Male C57BL/6Sca mice were used to study the effects of H3 receptor antagonist in the effects of ethanol on locomotor activity.

Results

The HDC KO mice displayed a weaker stimulatory response to acute ethanol than the wild-type (WT) mice. No differences between genotypes were found after ethanol administration on accelerating rotarod. The HDC KO mice showed stronger ethanol-induced CPP than the WT mice. Binding of the GABA_A receptor ligand [³H]Ro15-4513 was not markedly changed in HDC KO mouse brain and thus could not explain altered responses in KO mice. Ethanol increased the activity of C57BL/6Sca mice, and H3 receptor antagonist ciproxifan inhibited this stimulation. In CPP paradigm ciproxifan, an H3 receptor inverse agonist potentiated ethanol reward.

Conclusions

Histaminergic neurotransmission seems to be necessary for the stimulatory effect of ethanol to occur, whereas lack of histamine leads to changes that enhance the conditioned reward by ethanol. Our findings also suggest a role for histamine H3 receptor in modulation of the ethanol stimulation and reward.     

Effects of nicotine withdrawal on cognition in a clinical trial setting

Rationale

Smoking withdrawal has been widely established to produce a range of impairments to the quality of several major domains of cognitive function including attention, working memory and episodic memory.

Objectives

This study was conducted to determine the degree to which smoking withdrawal will produce impairments in cognitive function in phase I clinical trials.

Methods

Healthy male volunteers who were housed in a clinical trial facility for 16 days underwent periods of ad libitum smoking and smoking withdrawal.

Results

Smoking withdrawal disrupted aspects of attention and episodic verbal recall and recognition.

Conclusions

This study confirms previous work showing cognitive declines in smoking withdrawal and illustrates that such effects occur in ongoing safety and tolerability studies of new medicines and thus require careful consideration for the assessment of cognitive function in such trials as well as the accurate attribution of adverse events to the safety profiles of the medicines.     

Chronic cannabidiol treatment improves social and object recognition in double transgenic APPswe/PS1∆E9 mice

Rationale

Patients suffering from Alzheimer’s disease (AD) exhibit a decline in cognitive abilities including an inability to recognise familiar faces. Hallmark pathological changes in AD include the aggregation of amyloid-β (Aβ), tau protein hyperphosphorylation as well as pronounced neurodegeneration, neuroinflammation, neurotoxicity and oxidative damage.

Objectives

The non-psychoactive phytocannabinoid cannabidiol (CBD) exerts neuroprotective, anti-oxidant and anti-inflammatory effects and promotes neurogenesis. CBD also reverses Aβ-induced spatial memory deficits in rodents.

Materials and methods

Thus we determined the therapeutic-like effects of chronic CBD treatment (20 mg/kg, daily intraperitoneal injections for 3 weeks) on the APP_swe/PS1?E9 (APPxPS1) transgenic mouse model for AD in a number of cognitive tests, including the social preference test, the novel object recognition task and the fear conditioning paradigm. We also analysed the impact of CBD on anxiety behaviours in the elevated plus maze.

Results

Vehicle-treated APPxPS1 mice demonstrated impairments in social recognition and novel object recognition compared to wild type-like mice. Chronic CBD treatment reversed these cognitive deficits in APPxPS1 mice without affecting anxiety-related behaviours.

Conclusions

This is the first study to investigate the effect of chronic CBD treatment on cognition in an AD transgenic mouse model. Our findings suggest that CBD may have therapeutic potential for specific cognitive impairments associated with AD.     

Effects of dimethylaminoethanol pyroglutamate (DMAE p-Glu) against memory deficits induced by scopolamine: evidence from preclinical and clinical studies

Rationale

Dimethylaminoethanol pyroglutamate (DMAE p-Glu) is a compound resulting from the reaction between dimethylaminoethanol (an indirect precursor of acetylcholine) and pyroglutamic acid (a cyclic derivative of glutamic acid having procholinergic properties and promnesic effects in both animals and man).

Objectives

The present study undertook preclinical and clinical evaluations to test a potential therapeutic utility for DMAE p-Glu in cognitive impairments related to central cholinergic deficit.

Materials and methods

In preclinical study, DMAE p-Glu was studied in rats by intracerebral microdialysis in conscious freely moving animals, on performance of rats in the Morris water maze test of spatial memory, and on the deficit in passive avoidance behavior induced by scopolamine. The clinical study examined the effect of DMAE p-Glu on cognitive deficits induced by an intravenous injection of scopolamine in healthy young male subjects.

Results

In rat experiments, DMAE p-Glu increased the extracellular levels of choline and acetylcholine in the medial prefrontal cortex, as assessed by intracerebral microdialysis, improved performance in a test of spatial memory, and reduced scopolamine-induced memory deficit in passive avoidance behavior. Clinical study results show that scopolamine induced a memory deficit and that DMAE p-Glu produced a significant positive effect on scores in the Buschke test, as well as a slight but significant difference on choice reaction time.

Conclusion

These results indicate that DMAE p-Glu reduces the deleterious effect of scopolamine on long-term memory in healthy volunteers and suggest that DMAE p-Glu might be effective in reducing memory deficits in patients with cognitive impairment.     

Extrasynaptic GABAA receptor activation reverses recognition memory deficits in an animal model of schizophrenia

Rationale

Schizophrenia is a complex psychiatric disorder comprised of three main classes of symptoms: positive, negative and cognitive symptoms. Currently, no approved treatment exists for the cognitive symptoms. There is thus a great need for research aiming at identifying novel targets for treatment of this indication. Several neurotransmitter systems are affected in schizophrenia patients, including the ??-amino butyric acid (GABAergic) system, demonstrated by reduced parvalbumin-containing interneurons, glutamate decarboxylase (GAD) and the GABA transporter GAT-1. Furthermore, gene expression of several GABA_A receptor sub-units, such as ??1, ??4 and ?? is reduced in the dorsolateral prefrontal cortex of schizophrenia patients.

Objectives

The psychotomimetic NMDA receptor antagonist phencyclidine (PCP) is frequently employed to model schizophrenia in animal disease models. Sub-chronic PCP treatment of female hooded Lister rats has repeatedly been shown to induce impairments in object recognition memory, and this model was therefore chosen for the examination of the potential of positive modulation of extrasynaptic GABA_A receptors in alleviating the PCP-induced deficit.

Results

Rats treated sub-chronically with PCP showed significant impairments in recognition memory. This deficit was reversed by positive modulation of extrasynaptic GABA_A receptors.

Conclusion

The present study shows that extrasynaptic GABA_A receptors may present a novel target for the development of therapeutics aimed at improving cognitive deficits in schizophrenia.     

5-HT6 receptor blockade differentially affects scopolamine-induced deficits of working memory, recognition memory and aversive learning in mice

Rationale

Blockade of 5-HT6 receptors (5-HT6R) is known to improve cognitive performances in the rodent. This improvement has been hypothesized to be the result, at least in part, of a modulation of the cholinergic neurotransmission.

Objective

We assessed the effects of 5-HT6R blockade on selected types of memory relevant to functional deficits of ageing and neurodegenerative diseases, in mice that present a scopolamine-induced cholinergic disruption of memory.

Method

Following the selection of an adequate dose of scopolamine to induce cognitive deficits, we have studied the effects of the selective 5-HT6R antagonist SB-271046, alone or in combination with scopolamine, on working memory (spontaneous alternation task in the T-maze), recognition memory (place recognition) and aversive learning (passive avoidance).

Results

SB-271046 alone failed to affect working memory, recognition memory and aversive learning performances. In contrast, SB-271046 was able to reverse the scopolamine-induced deficits in working memory (only at 30?mg?kg^?1) and those of acquisition and retrieval of aversive learning (dose-dependent effect); scopolamine-induced deficits in episodic-like memory (acquisition and retrieval) were partially counteracted by 5-HT6R blockade.

Conclusion

The modulation between 5-HT6R and the cholinergic system appears to be predominant for working memory and aversive learning, but not for other types of memory (i.e. episodic-like memory). Interactions between 5-HT6R and alternative neurotransmission systems (i.e. glutamatergic system) should be further studied. The respective involvement of these interactions in the memory disorders related to ageing and neurodegenerative diseases is of pivotal importance regarding the possible use of 5-HT6R antagonists in the treatment of memory disorders in humans.     

Decreases in recollective experience following acute alcohol: a dose–response study

Rationale

Acute alcohol intoxication induces a selective impairment of recognition memory associated with conscious recollection whilst recognition based on familiarity is left intact.

Objectives

We aimed to further elucidate the acute effects of alcohol on recognition memory by assessing three different doses of alcohol and examining the way in which this affected the recollection and familiarity components of recognition memory in comparison to a placebo group.

Methods

A double-blind independent design was used, and participants received either alcohol (0.4, 0.6 or 0.8 g/kg) or a placebo drink. Participants encoded word pairs with depth of processing manipulated under generate and read conditions. Recognition memory was assessed and recollective awareness was examined through use of the remember–know procedure.

Results

Alcohol produced a dose-dependent reduction in recognition memory associated with recollection, evidenced by decreases in the number of correctly recognised items with ‘remember’ responses compared to placebo. Recognition based on a familiarity, evidenced by ‘know’ responses, showed no differences between groups or pattern of reduction compared to the placebo group. However, a negative correlation was found between recognition based on familiarity and levels of intoxication.

Conclusions

Alcohol-induced impairments in recognition memory occur in a dose-dependent manner, specifically driven by reductions in recognition associated with conscious awareness.     

Cariprazine, a dopamine D3-receptor-preferring partial agonist, blocks phencyclidine-induced impairments of working memory, attention set-shifting, and recognition memory in the mouse

Rationale

A major challenge in the pharmacological treatment of psychotic disorders is the effective management of the associated cognitive dysfunctions. Novel concepts emphasize a potential benefit of partial agonists acting upon dopamine D₂-like receptors in ameliorating these cognitive deficits, and pre-clinical studies suggest that D₃-receptor-preferring compounds can exert pro-cognitive effects.

Objective

The objective of the study was to use acute phencyclidine (PCP) treatment to model the cognitive deficits of schizophrenia in mice, and to test the efficacy of the novel, dopamine D₃-receptor-preferring drug cariprazine in ameliorating the severity of PCP-triggered cognitive deficits.

Methods

One group of wild-type or D₃-receptor knockout mice was acutely treated with either saline or phencyclidine (PCP, 1 mg/kg). A separate group of mice was treated with cariprazine prior to PCP administration. Both groups were then tested in three cognitive tasks: social interaction/recognition and recognition memory, spatial working memory, and attention-set-shifting.

Results

PCP effectively disrupted social recognition and social recognition memory, spatial working memory, and extradimensional attention set-shifting. Cariprazine pretreatment significantly attenuated the emergence of these cognitive deficits in PCP-treated wild-type mice, but not in PCP-treated D₃-receptor knockout mice.

Conclusions

In an animal model of PCP-induced cognitive impairment, cariprazine pretreatment significantly diminished PCP-triggered cognitive deficits, and studies on knockout mice show that dopamine D₃ receptors contribute to this effect.     

Candesartan prevents impairment of recall caused by repeated stress in rats

Rationale

Deleterious effects of psychological stress on memory are increasingly important. Overexpression of the AT₁ angiotensin receptors in brain has been found to participate in several negative effects of chronic stress including hypertension and a cognitive impairment.

Objective

In this study, we searched for the protective effects the AT₁ angiotensin receptor blockade with candesartan against the adverse effects of repeated stress on recall of aversively and appetitively motivated behaviours in rats.

Methods

Two groups of male Wistar rats were repeatedly stressed by keeping them daily (2 h/21 days) in tight plastic tubes. The subjects of the group 1 received candesartan (0.1 mg/kg, orally) each day before the stressing procedure. The rats of the group 2 received vehicle. Another two groups of rats (3 and 4) receiving candesartan and vehicle, respectively, were appropriately handled but not stressed. Next day, after ending the repeated stress procedure, all rats were tested in two cognitive paradigms: inhibitory avoidance (IA) and object recognition (OR).

Results

Stressed animals displayed decreased recall of the IA behaviour (p?<?0.01) and decreased OR (p?<?0.05). These effects were not seen in the animals stressed and concomitantly treated with candesartan. The auxiliary tests designed to control for the possible unspecific contribution of motor (open field) and emotional (elevated “plus” maze) effects of the experimental procedures to results of the cognitive tests showed no such contribution.

Conclusion

These data strongly suggest that the AT₁ angiotensin receptor blockade effectively counteracts deleterious effects of stress on recall of aversively and appetitively motivated memories in rats.     

Sex differences in escalation of methamphetamine self-administration: cognitive and motivational consequences in rats

Rationale

Male rats escalate methamphetamine (meth) intake during long-access meth self-administration, show enhanced reinstatement of meth-seeking, and exhibit meth-induced memory impairments. However, the impact of long-access daily meth self-administration on reinstatement and cognitive dysfunction has not been assessed in females, even though clinical studies on meth addiction have shown differences between men and women.

Objectives

This study determined whether male and freely cycling female rats: (1) escalate meth intake in a 6-h daily-access period relative to 1-h access; (2) show different sensitivity to meth primed reinstatement after short- and long-access conditions; and (3) show deficits in novel object and object in place recognition memory.

Methods

Male and female Long–Evans rats self-administered meth in limited (1-h/day) or extended (6-h/day) daily access sessions. After 21?days, meth access was discontinued, and rats entered an abstinence period. On the seventh and 14th days of abstinence, rats were assessed for recognition memory using tests for: (a) novel object recognition memory and (b) object-in-place memory. Rats were tested for reinstatement of meth-seeking following extinction of responding.

Results

Female rats self-administered more meth and escalated intake faster than males during extended, but not limited, daily access. Both males and females in the extended, but not limited, access groups showed memory deficits on both tasks. Female rats showed greater reinstatement to meth-seeking with lower doses of meth priming injections than males.

Conclusions

Relative to males, females were equally susceptible to meth-induced memory deficits but exhibited higher meth intake and greater relapse to meth-seeking.     

Impulsivity, attention, memory, and decision-making among adolescent marijuana users

Rationale

Marijuana is a popular drug of abuse among adolescents, and they may be uniquely vulnerable to resulting cognitive and behavioral impairments. Previous studies have found impairments among adolescent marijuana users. However, the majority of this research has examined measures individually rather than multiple domains in a single cohesive analysis. This study used a logistic regression model that combines performance on a range of tasks to identify which measures were most altered among adolescent marijuana users.

Objectives

The purpose of this research was to determine unique associations between adolescent marijuana use and performances on multiple cognitive and behavioral domains (attention, memory, decision-making, and impulsivity) in 14- to 17-year-olds while simultaneously controlling for performances across the measures to determine which measures most strongly distinguish marijuana users from nonusers.

Methods

Marijuana-using adolescents (n?=?45) and controls (n?=?48) were tested. Logistic regression analyses were conducted to test for: (1) differences between marijuana users and nonusers on each measure, (2) associations between marijuana use and each measure after controlling for the other measures, and (3) the degree to which (1) and (2) together elucidated differences among marijuana users and nonusers.

Results

Of all the cognitive and behavioral domains tested, impaired short-term recall memory and consequence sensitivity impulsivity were associated with marijuana use after controlling for performances across all measures.

Conclusions

This study extends previous findings by identifying cognitive and behavioral impairments most strongly associated with adolescent marijuana users. These specific deficits are potential targets of intervention for this at-risk population.     

Xanthoceraside attenuates tau hyperphosphorylation and cognitive deficits in intracerebroventricular-streptozotocin injected rats

Rationale

Xanthoceraside, a novel triterpenoid saponin extracted from the fruit husks of Xanthoceras sorbifolia Bunge, reverses cognitive deficits in intracerebroventricular injection of Aβ25–35 or Aβ1–42 mice. However, whether xanthoceraside has a positive effect on hyperphosphorylated tau protein remains unclear.

Objectives

We investigated the effects of xanthoceraside on behavioural impairments induced by intracerebroventricular injection of streptozotocin (STZ) in rats and its potential mechanisms.

Materials and methods

The rats were administered with xanthoceraside (0.06, 0.12 or 0.24 mg/kg) or vehicle once daily after STZ intracerebroventricular injections. The Y-maze test and novel object recognition test were performed 21 and 22 days after the second STZ injection, respectively. The levels of hyperphosphorylated tau, phosphatidylinositol-3-kinase (PI3K)/serine/threonine protein kinase B (Akt), glycogen synthase kinase-3β (GSK-3β), protein phosphatase 1 (PP-1) and protein phosphatase 2A (PP-2A) were also tested by Western blot.

Results

Xanthoceraside treatment significantly attenuated learning and memory impairments and reduced the level of STZ-induced hyperphosphorylated tau protein. Xanthoceraside also enhanced PP-2A and PP-1 expressions, increased PI3K (p85) and Akt (Ser473) phosphorylation and decreased GSK-3β (tyr216) phosphorylation.

Conclusions

Xanthoceraside has protective effect against learning and memory impairments and inhibits tau hyperphosphorylation in the hippocampus, possibly through the inhibition of the PI3K/Akt-dependent GSK-3β signalling pathway and an enhancement of phosphatases activity.     

Recreational cocaine polydrug use impairs cognitive flexibility but not working memory

Rationale

Chronic use of cocaine is associated with dysfunctions in frontal brain regions and dopamine D2 receptors, with poorer mental flexibility and a reduced ability to inhibit manual and attentional responses. Little is known, however, about cognitive impairments in the upcoming type of recreational cocaine polydrug user (1–4 g monthly consumption).

Objective

We studied whether recreational cocaine polydrug users, who do not meet the criteria for abuse or dependence, showed impairments in working memory (WM) and cognitive flexibility.

Methods

Controls and recreational cocaine polydrug users (who abstained from cocaine and other substances more than 1 week) were matched by sex, age, alcohol consumption, and IQ (Raven’s Standard Progressive Matrices). Groups were tested by using two cognitive tasks measuring cognitive flexibility and three tasks investigating the maintenance and monitoring of information in WM.

Results

Recreational cocaine polydrug users performed significantly worse than controls on tasks tapping cognitive flexibility, but show comparable performance in the active maintenance and monitoring of information in WM.

Conclusions

The findings suggest that recreational use of cocaine selectively impairs cognitive flexibility but not the maintenance of information in WM. The inability to adjust behavior rapidly and flexibly may have repercussions for daily life activities.     

Caloric restriction increases the sensitivity to the hyperphagic effect of nociceptin/orphanin FQ limiting its ability to reduce binge eating in female rats

Rationale

Several studies have documented impairments in memory processes as a result of ketamine administration; however, few studies have compared the profile of cognitive effects of ketamine to other drugs.

Objectives

The aim of this study was to compare the cognitive effects of ketamine with those of triazolam in healthy volunteers.

Methods

Doses of ketamine (0.2, 0.4 mg/kg intramuscular (i.m.)), triazolam (0.2, 0.4 mg/70 kg p.o.), and double-dummy placebos were administered to 20 volunteers under repeated measures, counterbalanced, double-blind conditions. Peak physiological, psychomotor, subjective, and cognitive effects were examined.

Results

Ketamine impaired balance when balance was assessed early in the task order, whereas triazolam impaired psychomotor coordination and divided attention irrespective of task order. Triazolam also tended to produce greater effects on working memory and episodic memory tasks than ketamine at doses that produced lower subjective effects and higher estimates of performance.

Conclusions

Ketamine produces less cognitive impairment than triazolam at doses that produced greater subjective effects. Thus ketamine does not produce the underestimation of cognitive impairment typically seen with triazolam.     

Continuous kynurenine administration during the prenatal period,but not during adolescence,causes learning and memory deficits in adult rats

Rationale

Cognitive dysfunctions, including deficits in hippocampus-mediated learning and memory, are core features of the psychopathology of schizophrenia (SZ). Increased levels of kynurenic acid (KYNA), an astrocyte-derived tryptophan metabolite and antagonist of α7 nicotinic acetylcholine and N-methyl-d-aspartate receptors, have been implicated in these cognitive impairments.

Objectives

Following recent suggestive evidence, the present study was designed to narrow the critical time period for KYNA elevation to induce subsequent cognitive deficits.

Methods

KYNA levels were experimentally increased in rats (1) prenatally (embryonic day (ED) 15 to ED 22) or (2) during adolescence (postnatal day (PD) 42 to PD 49). The KYNA precursor kynurenine was added daily to wet mash fed to (1) dams (100 mg/day; control: ECon; kynurenine-treated: EKyn) or (2) adolescent rats (300 mg/kg/day; control: AdCon; kynurenine-treated: AdKyn). Upon termination of the treatment, all animals were fed normal chow until biochemical analysis and behavioral testing in adulthood.

Results

On the last day of continuous kynurenine treatment, forebrain KYNA levels were significantly elevated (EKyn +472 %; AdKyn +470 %). KYNA levels remained increased in the hippocampus of adult EKyn animals (+54 %), but were unchanged in adult AdKyn rats. Prenatal, but not adolescent, kynurenine treatment caused significant impairments in two hippocampus-mediated behavioral tasks, passive avoidance and Morris water maze.

Conclusions

Collectively, these studies provide evidence that a continuous increase in brain KYNA levels during the late prenatal period, but not during adolescence, induces hippocampus-related cognitive dysfunctions later in life. Such increases may play a significant role in illnesses with known hippocampal pathophysiology, including SZ.     

Aripiprazole ameliorates phencyclidine-induced impairment of recognition memory through dopamine D1 and serotonin 5-HT1A receptors

Rationale

Cognitive deficits, including memory impairment, are regarded as a core feature of schizophrenia. Aripiprazole, an atypical antipsychotic drug, has been shown to improve disruption of prepulse inhibition and social interaction in an animal model of schizophrenia induced by phencyclidine (PCP); however, the effects of aripiprazole on recognition memory remain to be investigated.

Objectives

In this study, we examined the effect of aripiprazole on cognitive impairment in mice treated with PCP repeatedly.

Materials and methods

Mice were repeatedly administered PCP at a dose of 10mg/kg for 14days, and their cognitive function was assessed using a novel-object recognition task. We investigated the therapeutic effects of aripiprazole (0.01–1.0mg/kg) and haloperidol (0.3 and 1.0mg/kg) on cognitive impairment in mice treated with PCP repeatedly.

Results

Single (1.0mg/kg) and repeated (0.03 and 0.1mg/kg, for 7days) treatment with aripiprazole ameliorated PCP-induced impairment of recognition memory, although single treatment significantly decreased the total exploration time during the training session. In contrast, both single and repeated treatment with haloperidol (0.3 and 1.0mg/kg) failed to attenuate PCP-induced cognitive impairment. The ameliorating effect of aripiprazole on recognition memory in PCP-treated mice was blocked by co-treatment with a dopamine D₁ receptor antagonist, SCH23390, and a serotonin 5-HT_1A receptor antagonist, WAY100635; however, co-treatment with a D₂ receptor antagonist raclopride had no effect on the ameliorating effect of aripiprazole.

Conclusions

These results suggest that the ameliorative effect of aripiprazole on PCP-induced memory impairment is associated with dopamine D₁ and serotonin 5-HT_1A receptors.     

The CRF1 receptor antagonist SSR125543 prevents stress-induced cognitive deficit associated with hippocampal dysfunction: Comparison with paroxetine and d-cycloserine

Rationale

The selective CRF₁ (corticotropin releasing factor type 1) receptor antagonist SSR125543 has been previously shown to attenuate the long-term cognitive deficit produced by traumatic stress exposure. Memory disturbances described in post-traumatic stress disorder (PTSD) patients are believed to be associated with changes in neuronal activity, in particular at the level of the hippocampus.

Objectives

The present study aims at investigating whether the effects of SSR125543 (10 mg/kg/day for 2 weeks) on cognitive impairment induced by traumatic stress exposure are associated with changes in hippocampal excitability. Effects of SSR125543 were compared to those of the 5-HT reuptake inhibitor, paroxetine (10 mg/kg/day), and the partial N-methyl-d-aspartate (NMDA) receptor agonist, d-cycloserine (10 mg/kg/day), two compounds which have demonstrated clinical efficacy against PTSD.

Methods

Mice received two unavoidable electric foot-shocks. Then, 1 or 16 days after stress, they were tested for their memory performance using the object recognition test. Neuronal excitability was recorded during the third week post-stress in the CA1 area of the hippocampus. Drugs were administered from day 1 post-stress to the day preceding the electrophysiological study.

Results

Application of electric shocks produced cognitive impairment 16, but not 1 day after stress, an effect which was associated with a decrease in hippocampal neuronal excitability. Both stress-induced effects were prevented by repeated administration of SSR125543, paroxetine and d-cycloserine.

Conclusions

These findings confirm that the CRF₁ receptor antagonist SSR125543 is able to attenuate the behavioral effects of traumatic stress exposure and indicate that these effects are associated with a normalization of hippocampal neuronal excitability impaired by stress.     

Green tea extract enhances parieto-frontal connectivity during working memory processing

Rationale

It has been proposed that green tea extract may have a beneficial impact on cognitive functioning, suggesting promising clinical implications. However, the neural mechanisms underlying this putative cognitive enhancing effect of green tea extract still remain unknown.

Objectives

This study investigates whether the intake of green tea extract modulates effective brain connectivity during working memory processing and whether connectivity parameters are related to task performance.

Material and methods

Using a double-blind, counterbalanced, within-subject design, 12 healthy volunteers received a milk whey-based soft drink containing 27.5 g of green tea extract or a milk whey-based soft drink without green tea as control substance while undergoing functional magnetic resonance imaging. Working memory effect on effective connectivity between frontal and parietal brain regions was evaluated using dynamic causal modeling.

Results

Green tea extract increased the working memory induced modulation of connectivity from the right superior parietal lobule to the middle frontal gyrus. Notably, the magnitude of green tea induced increase in parieto-frontal connectivity positively correlated with improvement in task performance.

Conclusions

Our findings provide first evidence for the putative beneficial effect of green tea on cognitive functioning, in particular, on working memory processing at the neural system level by suggesting changes in short-term plasticity of parieto-frontal brain connections. Modeling effective connectivity among frontal and parietal brain regions during working memory processing might help to assess the efficacy of green tea for the treatment of cognitive impairments in psychiatric disorders such as dementia.     

Neonatal phencyclidine administration and post-weaning social isolation as a dual-hit model of ‘schizophrenia-like’ behaviour in the rat

Rationale

Schizophrenia is a debilitating disorder comprising positive, negative and cognitive deficits with a poorly defined neurobiological aetiology; therefore, animal models with greater translational reliability are essential to develop improved therapies.

Objectives

This study combines two developmental challenges in rats, neonatal phencyclidine (PCP) injection and subsequent rearing in social isolation from weaning, to attempt to produce more robust behavioural deficits with greater translational relevance to schizophrenia than either challenge alone.

Methods

Forty-two male Lister-hooded rat pups received the N-methyl-d-aspartate (NMDA) receptor antagonist, phencyclidine (PCP, 10 mg/kg, s.c.), or vehicle on post-natal day (PND) 7, 9 and 11 and were weaned on PND 23 into group housing (saline-treated n?=?11 or PCP-treated n?=?10) or isolation (saline n?=?10 or PCP n?=?11). Six weeks post-weaning, novelty- and PCP-induced (3.2 mg/kg) locomotor activity, novel object discrimination, prepulse inhibition of acoustic startle and contextual memory in a conditioned emotion response (CER) were recorded.

Results

Isolation rearing alone significantly elevated baseline locomotor activity and induced visual recognition memory impairment in novel object discrimination. Neonatal PCP treatment did not induce locomotor sensitisation to a subsequent acute PCP injection, but it impaired prepulse inhibition when combined with isolation rearing. CER freezing behaviour was significantly reduced by isolation rearing but an even greater effect occurred when combined with neonatal PCP treatment.

Conclusions

Neonatal PCP and isolation rearing both produce behavioural deficits in adult rats, but combined treatment caused a wider range of more severe cognitive impairments, providing a more comprehensive preclinical model to determine the neurobiological aetiology of schizophrenia than either treatment alone.