Motivational Disturbances Research Articles

Neuronal Coding of Implicit Emotion Categories in the Subcallosal Cortex in Patients with Depression

The subcallosal cingulate and adjacent ventromedial prefrontal cortex (collectively referred to here as the subcallosal cortex or SCC) have been identified as key brain areas in emotional processing. The SCC's role in affective valuation as well as severe mood and motivational disturbances, such as major depression, has been largely inferred from measures of neuronal population activity using functional neuroimaging. On the basis of imaging studies, it is unclear whether the SCC predominantly processes 1) negatively valenced affective content, 2) affective arousal, or 3) category-specific affective information. To clarify these putative functional roles of the SCC, we measured single neuron activity in the SCC of 15 human subjects undergoing deep brain stimulation for depression while they viewed emotionally evocative images grouped into categories that varied in emotional valence (pleasantness) and arousal. We found that the majority of responsive neurons were modulated by specific emotion categories, rather than by valence or arousal alone. Moreover, although these emotion-category-specific neurons responded to both positive and negative emotion categories, a significant majority were selective for negatively valenced emotional content. These findings reveal that single SCC neuron activity reflects the automatic valuational processing and implicit emotion categorization of visual stimuli. Furthermore, because of the predominance of neuronal signals in SCC conveying negative affective valuations and the increased activity in this region among depressed people, the effectiveness of depression therapies that alter SCC neuronal activity may relate to the down-regulation of a previously negative emotional processing bias.

Motivational disturbances and effects of L-dopa administration in neurofibromatosis-1 model mice.

Children with neurofibromatosis type 1 (NF1) frequently have cognitive and behavioral deficits. Some of these deficits have been successfully modeled in Nf1 genetically-engineered mice that develop optic gliomas (Nf1 OPG mice). In the current study, we show that abnormal motivational influences affect the behavior of Nf1 OPG mice, particularly with regard to their response to novel environmental stimuli. For example, Nf1 OPG mice made fewer spontaneous alternations in a Y-maze and fewer arm entries relative to WT controls. However, analysis of normalized alternation data demonstrated that these differences were not due to a spatial working memory deficit. Other reported behavioral results (e.g., open-field test, below) suggest that differential responses to novelty and/or other motivational influences may be more important determinants of these kinds of behavior than simple differences in locomotor activity/spontaneous movements. Importantly, normal long-term depression was observed in hippocampal slices from Nf1 OPG mice. Results from elevated plus maze testing showed that differences in exploratory activity between Nf1 OPG and WT control mice may be dependent on the environmental context (e.g., threatening or non-threatening) under which exploration is being measured. Nf1 OPG mice also exhibited decreased exploratory hole poking in a novel holeboard and showed abnormal olfactory preferences, although L-dopa (50 mg/kg) administration resolved the abnormal olfactory preference behaviors. Nf1 OPG mice displayed an attenuated response to a novel open field in terms of decreased ambulatory activity and rearing but only during the first 10 min of the session. Importantly, Nf1 OPG mice demonstrated investigative rearing deficits with regard to a novel hanging object suspended on one side of the field which were not rescued by L-dopa administration. Collectively, our results provide new data important for evaluating therapeutic treatments aimed at ameliorating NF1-associated cognitive/behavioral deficits.

Post-Stroke Apathy: An Exploratory Longitudinal Study

Introduction: Post-stroke apathy is a disturbance of motivation evidenced by low initiative, difficulties in starting, sustaining or finishing any goal-directed activity, low self-activation or self-initiated behavior and emotional indifference. Apathy is a common behavioral disturbance in stroke survivors. We aimed to analyze the relationship between post-stroke apathy at 1 year after stroke and (1) apathy in acute phase; (2) demographic, pre-stroke predisposing conditions (previous mild cognitive impairment, alcohol abuse, mood/anxiety disorder) and clinical features (stroke type and location, neurological symptoms); (3) post-stroke depression and post-stroke cognitive impairment, and (4) post-stroke functional outcome, quality of life and the perception of health. Methods: Consecutive stroke (infarct/intracerebral hemorrhage) patients without aphasia or consciousness disturbances were included in the acute phase of stroke and assessed at 1 year after stroke. We assessed apathy with the clinically rated version of the Apathy Evaluation Scale. We also assessed post-stroke depression (Montgomery Asberg Depression Rating Scale) and post-stroke cognitive impairment (attention, mental flexibility, verbal, motor and graphomotor initiative, and non-verbal and verbal abstract reasoning, and Mini-Mental State Examination), functional outcome (Barthel Index), quality of life and perception of health (EuroQol). Data were analyzed using bivariate associations (χ² and t test) and stepwise multivariate analysis. Results: We included 76 stroke patients [32.9% women, mean age 62.9 years (SD = 10.9) and a mean of 6.9 (SD = 4.3) years of education]. Apathy was present in 17 patients in the acute phase and in 18 (23.7%) patients at 1 year after stroke. At 1 year after stroke, 41% of the acute apathetic patients remained apathetic. Sixty-one percent of new cases of post-stroke apathy were detected. Post-stroke apathy was associated only with previous cognitive impairment, apathy in acute stroke, post-stroke cognitive impairment, verbal abstract reasoning and with worse Barthel Index scale scores. In the multivariate logistic regression model, verbal abstract reasoning (odds ratio, OR = 7.03) and apathy in acute stroke (OR = 3.8) were identified as independent factors for post-stroke apathy at 1 year. Apathetic patients did not report worse quality of life or health. Conclusion: Apathy in acute stroke phase was a reliable indicator of post-stroke apathy. Apathy should be assessed in both phases. Verbal abstract reasoning impairment was also an independent factor for post-stroke apathy impairing patients' ability to reason about goal-directed activity. Even though apathetic patients had worse post-stroke functional outcome, they did not report losing quality of life or having worse health.

Fronto-striatal atrophy correlates of neuropsychiatric dysfunction in frontotemporal dementia (FTD) and Alzheimer's disease (AD).

Behavioural disturbances in frontotemporal dementia (FTD) are thought to reflect mainly atrophy of cortical regions. Recent studies suggest that subcortical brain regions, in particular the striatum, are also significantly affected and this pathology might play a role in the generation of behavioural symptoms.OBJECTIVETo investigate prefrontal cortical and striatal atrophy contributions to behavioural symptoms in FTD.METHODSOne hundred and eighty-two participants (87 FTD patients, 39 AD patients and 56 controls) were included. Behavioural profiles were established using the Cambridge Behavioural Inventory Revised (CBI-R) and Frontal System Behaviour Scale (FrSBe). Atrophy in prefrontal (VMPFC, DLPFC) and striatal (caudate, putamen) regions was established via a 5-point visual rating scale of the MRI scans. Behavioural scores were correlated with atrophy rating scores.RESULTSBehavioural and atrophy ratings demonstrated that patients were significantly impaired compared to controls, with bvFTD being most severely affected. Behavioural-anatomical correlations revealed that VMPFC atrophy was closely related to abnormal behaviour and motivation disturbances. Stereotypical behaviours were associated with both VMPFC and striatal atrophy. By contrast, disturbance of eating was found to be related to striatal atrophy only.CONCLUSIONFrontal and striatal atrophy contributed to the behavioural disturbances seen in FTD, with some behaviours related to frontal, striatal or combined fronto-striatal pathology. Consideration of striatal contributions to the generation of behavioural disturbances should be taken into account when assessing patients with potential FTD.

Apathy Secondary to Stroke: A Systematic Review and Meta-Analysis

Background: Apathy is a disturbance of motivation, frequent in survivors of stroke. Several studies have evaluated the rate of apathy secondary to stroke and risk factors. Different conclusions and contradictory findings have been published. We aimed to perform a systematic review and meta-analysis of all studies evaluating apathy secondary to stroke to better estimate its rate and risk factors, and explore associations with poorer outcomes. Methods: We searched PubMed, Cochrane Library, PsychINFO and PsycBITE databases and screened references of included studies and review articles for additional citations. Search results and data extraction was performed independently. We systematically reviewed available publications reporting investigations on ischemic and intracerebral hemorrhagic stroke and apathy. Quality assessment of the studies was performed independently. Subgroup analyses were performed according to stroke phase (acute and post-acute), stroke past history (first-ever and any-stroke) and patient age (younger and older patients). Pooled odds ratios (OR) and standardized mean difference, and 95% confidence intervals (CI), were derived by random-effects meta-analysis. Heterogeneity was assessed with I² test. Results: From the initial 1,399 publications, we included 19 studies (2,221 patients). The pooled rate of apathy was 36.3% (95% CI 30.3–42.8; I² = 46.8), which was similar for acute [39.5% (95% CI 28.9–51.1)] and post-acute phase [34.3% (95% CI 27.8–41.4)], and about three times higher than the rate of depression [12.1% (95% CI 8.2–17.3)]. Apathetic patients were on average 2.74 years older (95% CI 1.25–4.23; I² = 0%). No gender differences were found. Depression (OR 2.29; 95% CI 1.41–3.72; I² = 44%) and cognitive impairment (OR 2.90; 95% CI 1.09–7.72; I² = 14%) were more frequent and severe in apathetic patients. Apathy rate was similar for ischemic and hemorrhagic stroke type and for left- and right-sided hemispheric lesions. Clinical global outcome was similar between apathetic and nonapathetic patients. Conclusion: Apathy secondary to stroke is a more frequent neuropsychiatric disturbance than depression. Apathetic patients are more frequently and severely depressed and cognitively impaired. A negative impact of apathy secondary to stroke on clinical global outcome cannot be ascribed. Future research should properly address its predictor factors and evaluate the impact of apathy treatment options in stroke patients.

Q16 Exercises for self-perception as an alternative type of physiotherapeutic practice increase motivation for other therapeutic interventions in HD

BackgroundAs the disease progresses, people with Huntington's disease (HD) have a decreased awareness of their body and develop their own movement patterns. Therefore, specialised physiotherapy input is essential at each...

Elevated Levels of Soluble Total and Hyperphosphorylated Tau Result in Early Behavioral Deficits and Distinct Changes in Brain Pathology in a New Tau Transgenic Mouse Model

Tauopathies, characterized by hyperphosphorylation and aggregation of tau protein, include frontotemporal dementias and Alzheimer's disease. To explore disease mechanisms and investigate potential treatments, we generated a transgenic (tg) mouse line overexpressing human tau441 with V337M and R406W mutations. Biochemical characterization of these TMHT (Thy-1 mutated human tau) mice showed a significant increase in human transgene expression relative to endogenous murine tau by Western blot and multi-array immunosorbent assay. Only soluble total tau and phosphorylated tau (ptau at residue Thr¹⁸¹, Ser¹⁹⁹, Thr²³¹ and Thr²³⁵), but not insoluble total tau and ptau were increased. Application of the Phospho-Tau SRM assay revealed that phosphorylation at Ser³⁹⁶ and Ser⁴⁰⁴ in soluble tau in the presence of the R406W mutation was at baseline levels in the cortex of TMHT mice compared to non-tg littermates. Histological analyses showed a progressive increase in human tau protein in the amygdala over age, while hippocampal tau levels remained constant from 2 months onwards. Behavioral testing of TMHT mice in the Morris water maze revealed a distinct progressive spatial learning impairment starting already at 5 months of age. Furthermore, we showed that the TMHT mice have early olfactory deficits. These impairments are unbiased by any motor disturbance or lack of motivation. Our results prove that combination of the V337M and R406W mutations of tau accelerates human tau phosphorylation and induces tau pathology as well as cognitive deficits, making this model a suitable tool for basic research on tau as well as in vivo drug testing.

Kleefstra syndrome in three adult patients: Further delineation of the behavioral and neurological phenotype shows aspects of a neurodegenerative course

Kleefstra syndrome (KS), previously known as the 9q subtelomeric deletion syndrome (9qSTDS) is caused by haploinsufficiency of the EHMT1 gene. Both a single mutation and 9q34 microdeletions encompassing the entire gene can be responsible for this syndrome which is characterized by intellectual disability, hypotonia, and typical dysmorphisms, and may be associated with congenital heart and/or renal defects and epilepsy. Its behavioral phenotype has recently been described and comprises particular sleep disturbances and apathy. In this report, the evolution of the behavioral profile of KS is outlined by the description of three female patients aged 19, 33, and 43 years, respectively. In two patients, the syndrome was caused by an intragenic mutation and in the third by a 9q34 microdeletion encompassing the EHMT1 gene. MRI scanning of the brain in the two eldest patients demonstrated multifocal subcortical signal abnormalities. In general, the severity of the behavioral and motor deficiencies increased over time and became apparent after adolescence. It is concluded that the "regressive" phenotype of KS seems to be associated with the EHMT1 gene in particular. In addition, the utility of uncritical use of a classificatory diagnostic approach is discussed in the context of the motor and motivational disturbances that are prominent in this syndrome.

P.1.g.012 The pro-cognitive profile of the phosphodiesterase 2A inhibitor BCR909 highlights its utility as a novel treatment for diseases with cognitive decline

Cholinergic and GABAergic neurons in the medial septal/vertical limb of the diagonal band of Broca (MS/vDB) area project to the hippocampus and constitute the septohippocampal pathway, which has been implicated in learning and memory. There is also evidence for extrinsic and intrinsic glutamatergic neurons in the MS/vDB, which by regulating septohippocampal neurons can influence hippocampal functions. The potential role of glutamatergic N-methyl-d-aspartate (NMDA) receptors within the MS/vDB for spatial and emotional learning was studied using the water maze and step-through passive avoidance (PA) tasks, which are both hippocampal-dependent. Blockade of septal NMDA receptors by infusion of the competitive NMDA receptor antagonist d-(−)-2-amino-5-phosphonopentanoic acid (d-AP5) (0.3–5 μg/rat), infused 15 min prior to training, impaired spatial learning and memory at the 5 μg dose of d-AP5, while doses of 0.3 and 1 μg per rat had no effect. The impairment in spatial learning appears not to be caused by sensorimotor or motivational disturbances, or anxiogenic-like behavior. Thus, d-AP5-treated rats were not impaired in swim performance or visuospatial abilities and spent more time in the open arms of the elevated plus-maze. In the PA task, intraseptal d-AP5 infused 15 min before training impaired retention as examined 24 h after training. This impairment was observed already at the 0.3 μg dose, suggesting that NMDA receptors within the MS/vDB may be more important for emotional than spatial memory. In summary, the present data indicate that changes in septal glutamate transmission and NMDA receptor activity can influence activity-dependent synaptic plasticity in the hippocampus and thereby learning and memory.

Emerging Evidence of Connectomic Abnormalities in Schizophrenia

Schizophrenia is an etiologically and clinically heterogeneous psychiatric disorder, characterized by psychotic symptoms, motivational disturbances, and cognitive disorganization. Pioneers of neuropathology such as Meynert and Wernicke proposed in the late 19th century that schizophrenia is

‘Every obese male with type 2 diabetes should be screened for hypogonadism’

Hypogonadism is a clinical syndrome complex which consists of symptoms with or without signs and biochemical evidence of testosterone deficiency. The symptoms of testosterone deficiency are non-specific which can make the diagnosis difficult. Symptoms which are most commonly associated with testosterone deficiency are reduced or loss of libido, absent morning erections and erectile dysfunction.1 Other common symptoms include tiredness, fatigue, impaired physical endurance, loss of vitality, lack of motivation and mood disturbance. Erectile dysfunction Erectile dysfunction (ED) is a common complication in diabetic men with some reports finding up to 70% have the condition. The pathogenesis of ED in diabetic men is multi-factorial and can be due to a combination of these which include vasculopathy, neuropathy, psychological issues and testosterone deficiency. The presence of hypertension, smoking and higher waist circumference are associated with ED in diabetic men.2 Lower testosterone positively correlates with worsening IIEF (International Index of Erectile Function) in diabetic men. 2 Not all diabetic men with ED have testosterone deficiency but evidence shows that it is present in a significant number. NICE guidelines recommendation is to ‘review the issue of erectile dysfunction annually’.3 The European Association of Urology (EAU) guidelines on ED state that measurement of testosterone is a minimum requirement in the diagnostic evaluation. 4 Penile Doppler ultrasound has shown that basal systolic velocity and dynamic peak velocity after administration of a phosphodiesterase type 5 (PDE-5) inhibitor are significantly reduced in hypogonadal diabetic men when compared to eugonadal men with diabetes.5 Failure to respond to sildenafil is associated with low testosterone in diabetes. 6 Animal work has found that castration leads to reduction in vascular smooth muscle content in the corpus cavernosum, reduced elastic fibres and increased collagen in the tunica albuginea, fat deposition between the tunica and corpus cavernosum and reduced nerve sheath thickness in the cavernosal nerve.7 Prevalence of hypogonadism

Compulsive use of dopaminergic drug therapy in Parkinson's disease: Reward and anti-reward

A few Parkinson patients develop a disabling pattern of compulsive dopaminergic drug use ("dopamine dysregulation syndrome"-DDS). DDS patients commonly identify aversive dysphoric "OFF" mood-states as a primary motivation to compulsively use their drugs. We compared motoric, affective, non-motor symptoms and incentive arousal after overnight medication withdrawal and after levodopa in DDS and control PD patients. Twenty DDS patients were matched to 20 control PD patients for age, gender, and disease duration and underwent a standard levodopa challenge. Somatic symptomatology, positive and negative affective states, drug effects, reward responsivity, motor disability, and dyskinesias were tested in the "OFF"-state after overnight withdrawal of medications, and then after a challenge with a standard dose of levodopa, after a full "ON"-state was achieved. In the "OFF"-state, DDS patients reported lower positive affect, and more motor and non-motor disability. In the "ON"-state, DDS patients had higher expressions of drug "wanting," reward responsivity, and dyskinesias. Positive and negative affect, non-motor symptomatology, and motor disability were comparable. These findings suggest that affective, motivational, and motoric disturbances in PD are associated with the transition to compulsive drug use in individuals who inappropriately overuse their dopaminergic medication.

Dedicated personality disorder services: A qualitative analysis of service structure and treatment process

Background: In response to concerns about the quality of services for people with personality disorder, 11 new community-based services were set up in England.Aims: To identify factors that contribute to high quality care for people with personality disorder from the perspective of different stakeholders.Methods: Qualitative interviews with service users, carers, providers and commissioners of services at each of the 11 sites.Results: Despite marked differences in the structure of the services, key themes emerged concerning their general approach to service delivery. These include the need to combine psychological treatments with social interventions and opportunities for peer support, and the importance of clear boundaries which are shared by service users. Services need to actively involve users both in managing their crises, and in planning future service developments. Differences in the accounts of stakeholders emerged around the assessment process, provision of out-of-hours care, and the range and type of clients dedicated services should try to work with.Conclusions: These data highlight factors which stakeholders believe constitute high quality care for people with PD. Services should pay particular attention to supporting clients during assessment process and developing more effective ways to engage people with high levels of personality disturbance and low levels of motivation to change.

Progress Toward a Resurgence and Remodeling of Psychotherapy for Schizophrenia: Editors’ Introduction to Special Issue of Clinical Case Studies

This special issue of Clinical Case Studies focuses on recent developments in the psychotherapy of schizophrenia. Approaches such as these are needed to address the multiple rate-limiting factors for psychotherapy outcome in this population, such as poor insight, comorbid disorders, low motivation, cognitive impairments, and self and interpersonal disturbances. In this introductory article, each of the case studies is briefly reviewed, with the goals of: (a) noting how each therapeutic approach fills a gap in current practice, and (b) placing the focus of treatment within a larger context of relevant research on schizophrenia. Concluding comments note the implications of these multiple therapeutic developments for future psychological treatment of schizophrenia.

Does deep brain stimulation induce apathy in Parkinson's disease?

Chronic deep brain stimulation (DBS) is an important therapeutic advancement for the treatment of motor symptoms in Parkinson's disease (PD). However, its effects on non-motor symptoms are not well understood. Several studies have reported motivational disturbances and apathy after DBS surgery. Recent studies are beginning to more carefully examine the relationship between DBS and apathy. This review summarizes and evaluates the current state of the literature on apathy after DBS surgery, discusses methodological limitations in the literature, and makes suggestions for future research.

Feed demand behavior in sea bass juveniles: Effects on individual specific growth rate variation and health (inter-individual and inter-group variation)

Feeding motivation is one major indicator of fish welfare and an investigation on the link between feed demand, growth and physiological variables in sea bass juveniles was developed. A computerized on-demand feeding system coupled with a PIT tag monitoring device was used to continuously record for 219 days the triggering activity of 150 individuals (initial average body weight 131.6 ± 1.80 g and coefficient of variation 16.8%). Each group was held in 400 l tanks at 22.2 ± 1.5 °C and light regime was 16:8 LD. In all the tanks, 89% of the fish actuated the trigger, but only two or three fish accounted for 45% of the total triggering activity. These few high-triggering individuals had a transient higher growth i.e. at the time an individual was the high-triggering fish in the tank, its Specific Growth Rate (SGR) increased and was higher than that of the other fish. However, high-triggering fish did not exhibit a higher initial and final body weight nor a higher average SGR than low- and zero-triggering fish. Fish of different triggering categories did not show differences in physiological variables (muscle composition, blood and tissues biochemistry). This study also revealed that when an imbalance between apparent daily feed tank consumption and feed demand was observed (i.e. wastage), it was mostly due to an increasing demand rather than a decreasing consumption; such wastage could often be linked to particular stressors (measuring day, population sampling or social interactions) and therefore, feeding motivation disturbances could be a relevant operational fish welfare indicator.

Protein malnutrition differentially alters the number of glutamic acid decarboxylase-67 interneurons in dentate gyrus and CA1–3 subfields of the dorsal hippocampus

In 30- and 90-day-old rats, using immunohistochemistry for glutamic acid decarboxylase 67 (GAD-67), we have tested whether malnutrition during different periods of hippocampal development produces deleterious effects on the population of GABA neurons in the dentate gyrus (DG) and cornu Ammonis (CA1–3) of the dorsal hippocampus. Animals were under one of four nutritional conditions: well-nourished controls (Con), prenatal protein malnourished (PreM), postnatal protein malnourished (PostM), and chronic protein malnourished (ChroM). We found that the number of GAD-67-positive (GAD-67+) interneurons was higher in the DG than in the CA1–3 areas of both Con and malnourished groups. Regarding the DG, the number of GAD-67+ interneurons was increased in PreM and PostM and decreased in ChroM at 30 days. At 90 days of age the number of GAD-67+ interneurons was increased in PostM and ChroM and remained unchanged in PreM. With respect to CA1–3, the number of labeled interneurons was decreased in PostM and ChroM at 30 days of age, but no change was found in PreM. At 90 days no changes in the number of these interneurons were found in any of the groups. These observations suggest that 1) the cell death program starting point is delayed in DG GAD-67+ interneurons, and 2) protein malnutrition differentially affects GAD-67+ interneuron development throughout the dorsal hippocampus. Thus, these changes in the number of GAD-67+ interneurons may partly explain the alterations in modulation of dentate granule cell excitability, as well as in the emotional, motivational, and memory disturbances commonly observed in malnourished rats.

Effect of Memantine on Cue-Induced Alcohol Craving in Recovering Alcohol-Dependent Patients

Ethanol blocks N-methyl-d-aspartic acid (NMDA) glutamate receptors. Increased NMDA receptor function may contribute to motivational disturbances that contribute to alcoholism. The authors assessed whether the NMDA receptor antagonist memantine reduces cue-induced alcohol craving and produces ethanol-like subjective effects. Thirty-eight alcohol-dependent inpatients participated in three daylong testing sessions in a randomized order under double-blind conditions. On each test day, subjects received 20 mg of memantine, 40 mg of memantine, or placebo, and subjective responses to treatment were assessed. The level of alcohol craving was assessed before and after exposure to an alcohol cue. Memantine did not stimulate alcohol craving before exposure to an alcohol cue, and it attenuated alcohol cue-induced craving in a dose-related fashion. It produced dose-related ethanol-like effects without adverse cognitive or behavioral effects. These data support further exploration of whether well-tolerated NMDA receptor antagonists might have a role in the treatment of alcoholism.

Effect of Memantine on Cue-Induced Alcohol Craving in Recovering Alcohol-Dependent Patients

Objective: Ethanol blocks N -methyl- d -aspartic acid (NMDA) glutamate receptors. Increased NMDA receptor function may contribute to motivational disturbances that contribute to alcoholism. The authors assessed whether the NMDA receptor antagonist memantine reduces cue-induced alcohol craving and produces ethanol-like subjective effects. Method: Thirty-eight alcohol-dependent inpatients participated in three daylong testing sessions in a randomized order under double-blind conditions. On each test day, subjects received 20 mg of memantine, 40 mg of memantine, or placebo, and subjective responses to treatment were assessed. The level of alcohol craving was assessed before and after exposure to an alcohol cue. Results: Memantine did not stimulate alcohol craving before exposure to an alcohol cue, and it attenuated alcohol cue-induced craving in a dose-related fashion. It produced dose-related ethanol-like effects without adverse cognitive or behavioral effects. Conclusions: These data support further exploration of whether well-tolerated NMDA receptor antagonists might have a role in the treatment of alcoholism.

N-methyl- d-aspartate receptors in the medial septal area have a role in spatial and emotional learning in the rat

Cholinergic and GABAergic neurons in the medial septal/vertical limb of the diagonal band of Broca (MS/vDB) area project to the hippocampus and constitute the septohippocampal pathway, which has been implicated in learning and memory. There is also evidence for extrinsic and intrinsic glutamatergic neurons in the MS/vDB, which by regulating septohippocampal neurons can influence hippocampal functions. The potential role of glutamatergic N-methyl- d-aspartate (NMDA) receptors within the MS/vDB for spatial and emotional learning was studied using the water maze and step-through passive avoidance (PA) tasks, which are both hippocampal-dependent. Blockade of septal NMDA receptors by infusion of the competitive NMDA receptor antagonist d-(−)-2-amino-5-phosphonopentanoic acid ( d-AP5) (0.3–5 μg/rat), infused 15 min prior to training, impaired spatial learning and memory at the 5 μg dose of d-AP5, while doses of 0.3 and 1 μg per rat had no effect. The impairment in spatial learning appears not to be caused by sensorimotor or motivational disturbances, or anxiogenic-like behavior. Thus, d-AP5-treated rats were not impaired in swim performance or visuospatial abilities and spent more time in the open arms of the elevated plus-maze. In the PA task, intraseptal d-AP5 infused 15 min before training impaired retention as examined 24 h after training. This impairment was observed already at the 0.3 μg dose, suggesting that NMDA receptors within the MS/vDB may be more important for emotional than spatial memory. In summary, the present data indicate that changes in septal glutamate transmission and NMDA receptor activity can influence activity-dependent synaptic plasticity in the hippocampus and thereby learning and memory.