Polypharmacy Management of Antipsychotics in Patients with Schizophrenia.

Schizophrenia is a chronic psychiatric disease that is characterized by psychotic symptoms, including positive, negative, affective, and aggressive symptoms, as well as cognitive dysfunction, and is primarily treated using drug therapy, the continuation of which is essential to prevent recurrence/recrudescence. Various second-generation antipsychotics with pharmacological properties or adverse events that differ from those of conventional antipsychotics have recently been introduced, and pharmaceutical management is required for drug efficacy assessments and adverse event monitoring/management of these drugs. Antipsychotic monotherapy (APM) is the gold standard treatment for schizophrenia and is recommended in various guidelines. However, a subgroup of patients with schizophrenia do not or only partially respond to APM. Therefore, antipsychotic polypharmacy (APP), in which ≥2 antipsychotics are combined, has been routinely utilized to compensate for insufficient responses to APM in clinical practice. APP has recently been proposed as an evidence-based treatment option, but does not consider clinicians' experience. However, the risk of APP-related adverse events is high. The application of APP needs to be carefully reviewed, whilst taking into consideration patient backgrounds. Furthermore, the risk of APP-related adverse events is higher in elderly patients than in the general population; therefore, caution is needed. This review discusses the merits of APP, matters that need to be considered, and a switch from APP to APM, and also focuses on the application of APP in clinical practice.

Students' perception of a hybrid interprofessional education course in a clinical diabetes setting: a qualitative study.

OBJECTIVES: To explore what the student participants learned and how they felt about the use of three educational settings, namely, face-to-face workshop setting, asynchronous and synchronous online learning environments and interactions with outpatients in a real-world clinical setting in a hybrid interprofessional education course. METHODS: This qualitative study used semi-structured in-depth interviews with healthcare undergraduate student participants in a course comprising workshops in three educational settings. A total of 15 healthcare undergraduate students, which included four medical, three pharmacy, five nursing and three nutrition students, completed this IPE course. All students agreed to participate in the study. We conducted four focus groups selected using convenient sampling. Focus group transcripts were analysed using the 'Steps for Coding and Theorization' qualitative data analysis method. We investigated the students' perception through the experience of three educational settings in the hybrid interprofessional education course. RESULTS: The students recognised that this course had three types of educational spaces, namely, real, semi-real and unreal. Then, the positive changes in the awareness of students are trained in recognition of the patient perspective, the recognition of the roles discharged by the other professions and the recognition of the functions of their own profession after experiencing the educational spaces designated for this course. CONCLUSIONS: The repeated experience of participants to real, semi-real and unreal educational spaces promoted changes over time in the students' awareness of interprofessional competencies with respect to patient-centred care and ameliorated their readiness to undertake interprofessional tasks.

Trend survey on adverse event profiles of antipsychotic long-acting injections and oral agents using the Japanese adverse drug event report database.

This study aims to assess the differences in adverse event profiles of long-acting injectable antipsychotics (LAIs) and oral antipsychotics (OAPs) using real-world data in the Japanese Adverse Drug Event Report database. Reporting odds ratios were determined using disproportionality analysis to estimate the risk of adverse events for LAIs and OAPs. Differences in adverse event profiles between formulations were determined after propensity score matching. Time-to-onset of adverse events was compared between LAIs and OAPs using the Weibull shape parameter. Signals were detected for approximately 50% of the adverse events (12 of 22) with LAIs and for the majority of adverse events (19 of 22) with OAPs. LAIs was associated with significantly lower reporting rate than OAPs for extrapyramidal symptom, neuroleptic malignant syndrome, and dystonia. For QT prolongation, convulsions, and hyperglycemia associated with LAIs, the 95% Confidence Interval of ß included 1 in time-to-onset analysis. Real-world data suggest that LAIs tend to reduce the occurrence of extrapyramidal symptom and neuroleptic malignant syndrome, but a number of other adverse events have potential risks as well as OAPs. In addition, onset of adverse events with LAIs have been shown to be slightly delayed, requiring more careful long-term monitoring.

Effectiveness in Switching from Antipsychotic Polypharmacy to Monotherapy in Patients with Schizophrenia: A Case Series.

In Japan, drug therapy for schizophrenia is characterized by high-dose antipsychotic polypharmacy, which is an uncommon approach internationally. In this study, we reduced the number of antipsychotic agents in 5 patients using the Safety Correction of High-dose Antipsychotic Polypharmacy (SCAP) method and conducted a survey regarding treatment satisfaction. The switch from polypharmacy to monotherapy was achieved in all patients. There was no deterioration in psychiatric symptoms, and adverse reactions were reduced. Three of the subjects were satisfied with the decrease in the number of antipsychotic agents and dose-reduction. These results suggest that the SCAP method is a safe and useful method that can be applied in a clinical setting.

Assessment of the Latent Adverse Events of Antipsychotic Treatment Using a Subjective Questionnaire in Japanese Patients with Schizophrenia.

OBJECTIVE: The adverse effects of antipsychotic agents can have a marked influence on medication adherence. In this study, we.investigated the adverse events of antipsychotics that are less likely to be reported by patients and the reasons why such symptoms remain latent. METHODS: Data were collected by interviewing patients using a subjective questionnaire, and the associations between unreported symptoms and background factors were investigated. RESULTS: A total of 306 patients with schizophrenia or schizoaffective disorder were examined. Their major symptoms were daytime sleepiness (50.0%), weight gain (42.2%), and sexual dysfunction (38.9%). Sexual dysfunction was nominal significantly more common among the patients that had been treated with antipsychotic agent polypharmacy (odds ratio [OR], 2.14; 95% confidence interval [CI], 1.07 to 4.30), and was nominal significantly more common among outpatients (OR, 1.78; 95% CI, 1.02 to 3.13). Only approximately 30% of the patients had reported their symptoms to their physicians. CONCLUSION: Patients receiving antipsychotic treatment tolerate some symptoms and do not feel able to report them to their physicians. The most common reason for this is an insufficient patient-physician relationship. Sexual dysfunction is especially hard to identify because it is a delicate problem, and our findings demonstrate that subjective questionnaires are helpful for detecting such symptoms.

Effects of communication skill training (CST) based on SPIKES for insurance-covered pharmacy pharmacists to interact with simulated cancer patients.

BACKGROUND: With the development of pharmacotherapy and radiotherapy, cancer treatment is being shifted from surgical to outpatient services, consequently increasing insurance-covered pharmacies' frequency of dealing with cancer patients. As the psychology of these patients is complex, it is necessary for pharmacists to educate them in consideration of their cognitive/medical and psychosocial aspects. This study analyzed cancer patient management by pharmacists working in such pharmacies and their communication skills before and after communication skill training based on SPIKES, a six-step protocol for delivering bad news, to confirm the usefulness of such training. METHODS: The study involved 20 pharmacists working in insurance-covered pharmacies within Aichi Prefecture. Before and after communication skill training, role-play sessions were held using standardized patients, whose levels of satisfaction were subsequently measured. Patient management by the pharmacists was analyzed using the Roter Interaction Analysis System as a method to analyze dialogues. RESULTS: The rate of each category, representing the pharmacists' conversation styles when dealing with the patients, changed after communication skill training as follows: [Giving information]: decreased from 37.0 to 27.6%; [Empathy statements]: increased from 12.0 to 17.2%; and [Data gathering]: increased from 18.0 to 23.3%. The increase was particularly marked in: [Acceptance], accepting patients' emotions and events in line with [Empathy statements]; [Promoting dialogues] as a sub-category of [Building a relationship]; and [Checks for understanding] as a sub-category of [Data gathering]. Furthermore, the results of pharmacist assessment by the patients, including their levels of overall satisfaction, showed significant correlations with [Empathy statements] and [Building a relationship]. CONCLUSIONS: Communication skill training may be effective to improve pharmacists' conversation styles to listen to patients more attentively, accept their emotions, and provide education in accordance with their needs, rather than unilaterally providing information. TRIAL REGISTRATION: The study was approved by the Ethical Review Board of Meijo University as a research activity involving humans (approval number: H26-1).

[Qualitative Research to Investigate the Needs of Pharmacists and Drug Therapy of Cancer Patients].

We performed a survey of cancer patients' needs for drug treatment and support from pharmacists during treatment and evaluated the support that cancer patients can expect from community pharmacists in the future. The patients consisted of 16 members of the Cancer Patient Association in Aichi prefecture who underwent chemotherapy. The results of a semistructured group interview were qualitatively analyzed using the grounded theory method. Patients undergoing chemotherapy had high hopes for its effectiveness but were worried about side effects and medical costs. To overcome these problems, they hoped for a decrease in the economic burden, compassionate-use system, and development of novel drugs. The patients had anxiety because the side effects of chemotherapy often caused physical and psychological damage. Despite patients' confusion, pharmacists sometimes did not give adequate explanations to them. The patients expected more from pharmacists regarding medication support and hoped for a system allowing continuous side effect monitoring and consultation without hesitation. For patients undergoing cancer chemotherapy who are confused regarding side effects, pharmacists should understand the patient explanatory model and become more involved with patients as partners in treatment.

Effects of Prescription Drug Reduction on Quality of Life in Community-Dwelling Patients with Dementia.

PURPOSE: Due to the use of multiple drugs and prevalence of diminished cognitive function, community-dwelling elderly individuals are more likely to have drug-related issues. We examined changes in quality of life (QOL) and activities of daily living (ADL) 3 months and 6 months after reducing drug use of dementia patients who had newly begun community-dwelling care. METHODS: Prescription drug use was reduced in the intervention group, whereas the non-intervention group continued their regimen or began using additional drugs. QOL and ADL were assessed with the Japanese version of the EQ-5D and the Barthel Index, respectively. RESULTS: Subjects were 32 individuals aged ≥65 years who had begun community-dwelling between March and July 2014 and had received approval for long-term care insurance. On average, the intervention group (n = 19) stopped using 2.6 prescription drugs. After 6 months, the differences in the QOL and ADL scores in the intervention group were -0.03 ± 0.29 and 6.32 ± 18.6, respectively, while the differences in the QOL and ADL scores in the non-intervention group (n = 13) were -0.13 ± 0.29 and -2.69 ± 23.7, respectively. In the intervention group, ADL scores were significantly increased by 14.0 ± 11.1 6 months after reduced benzodiazepine use. CONCLUSIONS: QOL was maintained with reduced drug use, while ADL score was slightly increased. In addition, the reduction of benzodiazepine use significantly increased ADL. In order to reduce polypharmacy among community-dwelling elderly patients, it is necessary to create an opportunity for pharmacists to re-examine their prescriptions.

Additional BCAA-enriched nutrient mixture improves the nutritional condition in cirrhotic patients with hypoalbuminemia despite treatment with regular BCAA granules: A pilot study.

BACKGROUND/AIMS: To elucidate the effect of adding branched-chain amino acid (BCAA)-enriched nutrient mixtures in cirrhotic patients with hypoalbuminemia despite the use of BCAA granules. MATERIALS AND METHODS: A BCAA-enriched nutrient mixture containing 5.6 g of BCAA and 210 kcal was additionally administered in 40 cirrhotic patients with hypoalbuminemia despite their treatment with BCAA granules containing 12 g of BCAA. Laboratory data were assessed at 6 months before beginning additional therapy, at baseline, and at 6 months after baseline. RESULTS: Serum albumin levels significantly decreased from 6 months before baseline (3.14±0.47 g/dL) to baseline (2.83±0.46 g/dL), despite the treatment with BCAA granules (p<0.001), and tended to increase from baseline to 6 months after baseline (2.95±0.42 g/dL) (p=0.084). In the subset of 23 patients without hepatocellular carcinoma treatments, upper gastrointestinal tract bleeding, or albumin infusion, serum albumin levels significantly increased from baseline (2.93±0.38 g/dL) to 6 months after baseline (3.15±0.34 g/dL) (p=0.014). CONCLUSION: Additional therapy with BCAA-enriched nutrient mixtures increased serum albumin levels of the cirrhotic patients with hypoalbuminemia despite the treatment with BCAA granules and without hepatocellular carcinoma treatment, upper gastrointestinal tract bleeding, or albumin infusion.

Nicotine ameliorates impairment of working memory in methamphetamine-treated rats.

Nicotine is hypothesized to have therapeutic effects on attentional and cognitive abnormalities in psychosis. In this study, we investigated the effect of nicotine on impaired spatial working memory in repeated methamphetamine (METH)-treated rats. Rats were administered METH (4 mg/kg, s.c.) once a day for 7 days, and their working memory was assessed with a delayed spatial win-shift task in a radial arm maze. The task consisted of two phases, a training phase and a test phase, separated by a delay. Control animals showed impaired performance in the test phase when the delay time was increased to 120 min or longer, while METH-treated rats showed impaired performance with a shorter delay time of 90 min. Memory impairment in METH-treated rats persisted for at least 14 days after drug withdrawal. METH-induced impairment of working memory was reversed by nicotine (0.3mg/kg, p.o., for 7 days), but the effect was diminished 7 days after the withdrawal. In control rats, nicotine decreased the number of working memory errors in the test with delay time of 120 min when administered before the training phase. Neither post-training nor pre-test administration of nicotine had any effect on working memory. These findings suggest that nicotine may have some protective effect against the impairment of working memory.

Therapeutic potential of nicotine for methamphetamine-induced impairment of sensorimotor gating: involvement of pallidotegmental neurons.

INTRODUCTION: We have previously found that a disruption to prepulse inhibiton (PPI) induced by methamphetamine (METH) is associated with impaired functioning of pallidotegmental neurons, which play a crucial role in PPI of the startle reflex, through the activation of gamma-aminobutyric acid type B receptors in pedunculopontine tegmental neurons in mice. OBJECTIVES: Here, we examined the effect of nicotine on METH-induced impairment of PPI of the startle reflex focusing on dysfunctional pallidotegmental neurons and the neural system. RESULTS: Nicotine (0.15-0.5 mg/kg) ameliorated the deficit in PPI induced by acute METH, and the ameliorating effect of nicotine was antagonized by nicotinic receptor antagonists such as methyllycaconitine and dihydro-beta-erythroidine. The acute METH-induced disruption of PPI was accompanied by suppression of c-Fos expression in the lateral globus pallidus (LGP) as well as its induction in the caudal pontine reticular nucleus (PnC) in mice subjected to the PPI test. Nicotine-induced amelioration of PPI deficits in METH-treated mice was accompanied by a reversal of the changes in c-Fos expression in both the LGP and PnC to the basal level. CONCLUSIONS: Nicotine is effective in ameliorating the impairment of PPI caused by METH, which may be associated with normalization of the pallidotegmental neurons.

Involvement of pallidotegmental neurons in methamphetamine- and MK-801-induced impairment of prepulse inhibition of the acoustic startle reflex in mice: reversal by GABAB receptor agonist baclofen.

We have previously demonstrated that pallidotegmental GABAergic neurons play a crucial role in prepulse inhibition (PPI) of the startle reflex in mice through the activation of GABA(B) receptors in pedunculopontine tegmental neurons. In this study, we investigated whether PPI disruption induced by methamphetamine (METH) or MK-801 is associated with the dysfunction of pallidotegmental neurons. Furthermore, we examined the effects of baclofen, a GABA(B) receptor agonist, on METH- and MK-801-induced PPI impairment. Acute treatment with METH (3 mg/kg, subcutaneouly (s.c.)) and MK-801 (>0.3 mg/kg, s.c.) significantly disrupted PPI, accompanied by the suppression of c-Fos expression in lateral globus pallidus induced by PPI. Furthermore, acute treatment with METH and MK-801 stimulated c-Fos expression in the caudal pontine reticular nucleus (PnC) in mice subjected to the PPT test, although PPI alone had no effect on c-Fos expression. Repeated treatment with 1 mg/kg METH for 7 days, which did not affect PPI acutely, showed similar effects on PPI and c-Fos expression to acute treatment with METH (3 mg/kg). Baclofen dose-dependently ameliorated PPI impairment induced by acute treatment with METH (3 mg/kg) and MK-801 (1 mg/kg), and decreased METH- and MK-801-stimulated c-Fos expression in PnC to the basal level. These results suggest that dysfunction of pallidotegmental neurons is involved in PPI disruption caused by METH and MK-801 in mice. GABA(B) receptor may constitute a putative target in treating neuropsychiatric disorders with sensorimotor gating deficits, such as schizophrenia and METH psychosis.

Dopamine D1 receptors regulate protein synthesis-dependent long-term recognition memory via extracellular signal-regulated kinase 1/2 in the prefrontal cortex.

Several lines of evidence suggest that extracellular signal-regulated kinase1/2 (ERK1/2) and dopaminergic system is involved in learning and memory. However, it remains to be determined if the dopaminergic system and ERK1/2 pathway contribute to cognitive function in the prefrontal cortex (PFC). The amount of phosphorylated ERK1/2 was increased in the PFC immediately after exposure to novel objects in the training session of the novel object recognition test. An inhibitor of ERK kinase impaired long-term recognition memory 24 h after the training although short-term memory tested 1 h after the training was not affected by the treatment. The dopamine D1 receptor agonist increased ERK1/2 phosphorylation in the PFC in vivo as well as in cortical neurons in vitro. Microinjection of the dopamine D1 receptor antagonist into the PFC impaired long-term recognition memory whereas the D2 receptor antagonist had no effect. Immunohistochemistry revealed that exposure to novel objects resulted in an increase in c-Fos expression in the PFC. Microinjection of the protein synthesis inhibitor anisomycin into the PFC impaired the long-term recognition memory. These results suggest that the activation of ERK1/2 following the stimulation of dopamine D1 receptors is necessary for the protein synthesis-dependent long-term retention of recognition memory in the PFC.

Neural circuits containing pallidotegmental GABAergic neurons are involved in the prepulse inhibition of the startle reflex in mice.

BACKGROUND: Prepulse inhibition (PPI) of the startle response is a measure of the inhibitory function and time-linked information processing by which a weak sensory stimulus (the prepulse) inhibits the startle response caused by a sudden intense stimulus. We attempted to clarify the neuronal circuits underlying the control of PPI of the startle reflex in mice. METHODS: c-Fos immunohistochemistry was used to detect neurons activated by startle pulse and/or prepulse trials. Behavioural pharmacology and tracing studies were also conducted. RESULTS: The lateral globus pallidus (LGP) was activated by prepulses. Activation of the caudal pontine reticular nucleus (PnC) evoked by the startle pulses was inhibited under PPI conditions. Double-immunostaining revealed that c-Fos-positive cells in the LGP following prepulse trials were GABAergic neurons. Bilateral microinjections of lidocaine into the LGP resulted in an impairment of PPI. Fluoro-gold infusion into the PnC and the pedunculopontine tegmental nucleus (PPTg) retrogradely labeled neurons in the PPTg and LGP, respectively. Microinjections of phaclofen into the PPTg significantly impaired PPI. CONCLUSIONS: These results suggest that GABAergic neurons in the LGP which project to the PPTg play a crucial role through the activation of GABAB receptors in the regulation of PPI of the startle reflex in mice.

The rewards of nicotine: regulation by tissue plasminogen activator-plasmin system through protease activated receptor-1.

Nicotine, a primary component of tobacco, is one of the most abused drugs worldwide. Approximately four million people die each year because of diseases associated with tobacco smoking. Mesolimbic dopaminergic neurons mediate the rewarding effects of abused drugs, including nicotine. Here we show that the tissue plasminogen activator (tPA)-plasmin system regulates nicotine-induced reward and dopamine release by activating protease activated receptor-1 (PAR1). In vivo microdialysis revealed that microinjection of either tPA or plasmin into the nucleus accumbens (NAc) significantly potentiated whereas plasminogen activator inhibitor-1 reduced the nicotine-induced dopamine release in the NAc in a dose-dependent manner. Nicotine-induced dopamine release was markedly diminished in tPA-deficient (tPA-/-) mice, and the defect of dopamine release in tPA-/- mice was restored by microinjection of either exogenous tPA or plasmin into the NAc. Nicotine increased tPA protein levels and promoted the release of tPA into the extracellular space in the NAc. Immunohistochemistry revealed that PAR1 immunoreactivity was localized to the nerve terminals positive for tyrosine hydroxylase in the NAc. Furthermore, we demonstrated that plasmin activated PAR1 and that nicotine-induced place preference and dopamine release were diminished in PAR1-deficient (PAR1-/-) mice. Targeting the tPA-plasmin-PAR1 system would provide new therapeutic approaches to the treatment of nicotine dependence.

Enhanced antidepressant efficacy of sigma1 receptor agonists in rats after chronic intracerebroventricular infusion of beta-amyloid-(1-40) protein.

Treatment of depressive symptoms in patients suffering from neurodegenerative disorders remains a challenging issue, since few available antidepressants present an adequate efficacy during pathological aging. Previous reports suggested that selective sigma(1) receptor agonists might constitute putative candidates. We here examined the pharmacological efficacy of igmesine and (+)-SKF-10,047 and the sigma(1) receptor-related neuroactive steroid dehydroepiandrosterone sulfate, in rats infused intracerebroventricularly during 14 days with the beta-amyloid-(1-40) protein and then submitted to the conditioned fear stress test. Igmesine and (+)-SKF-10,047 significantly reduced the stress-induced motor suppression at 30 and 6 mg/kg, respectively, in beta-amyloid-(40-1)-treated control rats. Active doses were decreased, to 10 and 3 mg/kg, respectively, in beta-amyloid-(1-40)-treated animals. The dehydroepiandrosterone sulfate effect was also facilitated, both in dose (10 vs. 30 mg/kg) and intensity, in beta-amyloid-(1-40)-treated rats. Neurosteroid levels were measured in several brain structures after beta-amyloid infusion, in basal and stress conditions. Progesterone levels, both under basal and stress-induced conditions, were decreased in the hippocampus and cortex of beta-amyloid-(1-40)-treated rats. The levels in pregnenolone, dehydroepiandrosterone and their sulfate esters appeared less affected by the beta-amyloid infusion. The sigma(1) receptor agonist efficacy is known to be inversely correlated to brain progesterone levels, synthesized mainly by neurons that are mainly affected by the beta-amyloid toxicity. The present study suggests that sigma(1) receptor agonists, due to their enhanced efficacy in a nontransgenic animal model, may alleviate Alzheimer's disease-associated depressive symptoms.

[Effects of sigma receptor ligands on psychiatric disorders].

It has recently been suggested that sigma receptors are involved in psychiatric disorders. Sigma 1 receptor antagonists are effective in animal models of positive symptoms, cognitive deficit and disruption of prepulse inhibition in schizophrenia. They also inhibit the development and expression of the conditioned place preference induced by cocaine. On the other hand, sigma 1 receptor agonists reduce the immobility time in the forced swimming and tail suspension tests. Furthermore, sigma 1 receptor agonists attenuate the conditioned fear stress (CFS) response (which is not attenuated by typical anxiolytics or antidepressants) in rodents. The attenuating effects are mediated through sigma 1 receptors, which are closely related to the mesolimbic dopaminergic systems. Sigma 1 receptor agonists also have anti-amnesic effects in various experimental models. Neurosteroids such as dehydroepiandrosterone sulfate and pregnenolone sulfate attenuate the CFS response and have anti-amnesic effects, the effects being mediated via sigma 1 receptors. These findings suggest that sigma receptors are novel potential targets for the treatment of psychiatric disorders such as schizophrenia, drug abuse, depression and dementia.

[Anti-dementia drugs for Alzheimer disease in present and future].

Alzheimer disease(AD) is characterized as neurodegenerative disease showing impairment of cognitive function, death of neuronal cells, numerous numbers of senile plaques and tangle of neurofilaments. There are two different hypotheses that neurotoxicity of aggregated amyloid beta protein(A beta) and hyperphosphorylation of tau protein are the causes of AD. The dysfunction of cholinergic neuronal system is observed in the early stage of AD. Therefore, the strategy to increase of acetylcholine (ACh) level in brain by using ACh esterase inhibitor is mainstream in the present. We have tacrine, donepezil, rivastigmine and galantamine. Tacrine, the first drug for AD, is replaced by other drugs, because of its hepatic toxicity. Galantamine binds allosteric sites of nicotine receptor and stimulates it in addition to its inhibitory effect on ACh esterase. Metamantine was approved in EU in 2002. It is non-competitive inhibitor of NMDA receptors, and dopamine releaser, which has neuroprotective effect. All of the above drugs improve cognitive function of patients, and they could delay hospitalization for 7 months or more. In the present anti-inflammatory drugs, anti-oxidative drugs and estrogen are under investigation. As anti-A beta therapy, inhibitors of beta -and gamma-secretase, A beta aggregation inhibitors, A beta degradation stimulators and A beta vaccination are possible strategies. The inhibitors of tau protein phosphorylation and activators of phosphates could be that of anti-tau protein phosphorylation. Additionally, it is expected to have the strategies such as neuroregeneration by neurotorophic factors and immunopyline ligands, and supply of neuronal cells by gene therapy and human ES cells.

Learning and memory in two different reward tasks in a radial arm maze in rats.

In an eight-arm radial maze, working and reference memory can be assessed simultaneously in the fixed position of reward task (FPRT) in which half of the arms are baited and their positions are fixed throughout the training trails. We characterized performance of rats in the variable position of reward task (VPRT), in which four out of eight arms were baited, but the positions were varied in every training trial. In the VPRT, the rats learned to choose all arms without any discrimination between baited and non-baited arms and the memory retention was time-dependent. The performance of rats in the FPRT was impaired by altering the spatial organization of the extramaze cues while it was not affected in the VPRT. The number of Fos-positive cells transiently increased in the cerebral cortex and hippocampus of both groups of animals during the training. Finally, bilateral lesions of the dorsal hippocampus resulted in an impairment of working memory in the FPRT and the performance of the rats in the VPRT. These results suggest that different strategies are used between the FPRT and VPRT but the hippocampus plays an important role in performance of rats trained for the VPRT as well as FPRT.