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Recent evidence indicates that supplementation with a specific combination of nutrients may affect cell membrane synthesis and composition. To investigate whether such nutrients may also modify the physical properties of membranes, and affect membrane-bound processes involved in signal transduction pathways, we studied the effects of nutrient supplementation on G protein-coupled receptor activation in vitro. In particular, we investigated muscarinic receptors, which are important for the progression of memory deterioration and pathology of Alzheimer's disease. Nerve growth factor differentiated pheochromocytoma cells that were supplemented with specific combinations of nutrients showed enhanced responses to muscarinic receptor agonists in a membrane potential assay. The largest effects were obtained with a combination of nutrients known as Fortasyn™ Connect, comprising docosahexaenoic acid, eicosapentaenoic acid, uridine monophosphate as a uridine source, choline, vitamin B6, vitamin B12, folic acid, phospholipids, vitamin C, vitamin E, and selenium. In subsequent experiments, it was shown that the effects of supplementation could not be attributed to single nutrients. In addition, it was shown that the agonist-induced response and the supplement-induced enhancement of the response were blocked with the muscarinic receptor antagonists atropine, telenzepine, and AF-DX 384. In order to determine whether the effects of Fortasyn™ Connect supplementation were receptor subtype specific, we investigated binding properties and activation of human muscarinic M1, M2 and M4 receptors in stably transfected Chinese hamster ovary cells after supplementation. Multi-nutrient supplementation did not change M1 receptor density in plasma membranes. However, M1 receptor-mediated G protein activation was significantly enhanced. In contrast, supplementation of M2- or M4-expressing cells did not affect receptor signaling. Taken together, these results indicate that a specific combination of nutrients acts synergistically in enhancing muscarinic M1 receptor responses, probably by facilitating receptor-mediated G protein activation.

Choline is an important component of the human diet and is required for the endogenous synthesis of choline-containing phospholipids, acetylcholine and betaine. Choline can also be synthesisedde novoby the sequential methylation of phosphatidylethanolamine to phosphatidylcholine. Vitamins B6, B12and folate can enhance methylation capacity and therefore could influence choline availability not only by increasing endogenous choline synthesis but also by reducing choline utilisation. In the present experiment, we determined whether combined supplementation of these B vitamins affects plasma choline concentration in a rat model of mild B vitamin deficiency which shows moderate increases in plasma homocysteine. To this end, we measured plasma choline and homocysteine concentrations in rats that had consumed a B vitamin-poor diet for 4 weeks after which they were either continued on the B vitamin-poor diet or switched to a B vitamin-enriched diet for another 4 weeks. Both diets contained recommended amounts of choline. Rats receiving the B vitamin-enriched diet showed higher plasma choline and lower plasma homocysteine concentrations as compared to rats that were continued on the B vitamin-poor diet. These data underline the interdependence between dietary B vitamins and plasma choline concentration, possibly via the combined effects of the three B vitamins on methylation capacity.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in the elderly. Substantial evidence suggests a role for nutrition in the management of AD and especially suggests that interventions with combinations of nutrients are more effective than single-nutrient interventions. The specific multi-nutrient combination Fortasyn™Connect (FC), shown to improve memory in AD, provides phosphatide precursors and cofactors and is designed to stimulate the formation of phospholipids, neuronal membranes, and synapses. The composition comprises nucleotides, omega-3 polyunsaturated fatty acids (n3 PUFA), choline, B-vitamins, phospholipids, and antioxidants. The current study explored the protective properties of FC in a membrane toxicity model of AD, the amyloid-β 1-42 (Aβ42) infused rat, which shows reduced exploratory behavior in an Open Field and impaired cholinergic functioning. To this end, rats were fed an FC enriched diet or a control diet and five weeks later infused with vehicle or Aβ42 into the lateral ventricle. Ten weeks post-infusion Aβ42-rats fed the FC diet showed increased membrane n3 PUFA and phosphatidylcholine content while they did not show the reductions in exploratory behavior or in choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT) immunoreactivity that were seen in Aβ42-rats fed the control diet. We conclude that FC protects the cholinergic system against Aβ42-induced toxicity and speculate that the effects of FC on membrane formation and composition might be supportive for this protective effect. Based on these data a long-term intervention study was started in the prodromal stages of AD (NTR1705, LipiDiDiet, EU FP7).

The effect of supplementation with the omega 3 polyunsaturated fatty acid (n3 PUFA) docosahexaenoic acid (DHA) on membrane composition and amyloid-β₁₋₄₂ (Aβ₄₂) secretion was studied in human amyloid-β protein precursor-transfected Chinese Hamster Ovary (CHO) cells. Twenty-four hour incubation with a range of DHA concentrations resulted in a dose-dependent increase in membrane DHA and eicosapentaenoic acid content and a decrease in arachidonic acid content. In addition, DHA supplementation caused a dose-dependent reduction in the secreted Aβ₄₂ levels and resulted in a 4-8 fold decrease in extracellular prostaglandin E₂ (PGE₂) levels. Tocopherol, which was added to DHA to prevent oxidation, may have contributed to the effect of DHA, since it slightly decreased extracellular Aβ₄₂ and PGE₂ levels when given alone. The addition of selective COX2 inhibitors Celebrex and curcumin to the culture medium resulted in a significant and comparable inhibition of PGE₂ release, but did not inhibit Aβ₄₂ secretion, and even significantly increased Aβ₄₂ production in this cell system. Together, the present data show that, whereas both DHA and COX2 inhibitors may reduce PGE₂ production, only DHA in the presence of tocopherol significantly reduced Aβ₄₂ production and concurrently changed membrane lipid composition in CHO cells. It is concluded that in this in vitro setting DHA reduced Aβ₄₂ secretion through membrane-related, but not PGE₂-related mechanisms.

Alzheimer disease is characterized by accumulation of the β-amyloid peptide (Aβ) generated by β- and γ-secretase processing of the amyloid precursor protein (APP). The intake of the polyunsaturated fatty acid docosahexaenoic acid (DHA) has been associated with decreased amyloid deposition and a reduced risk in Alzheimer disease in several epidemiological trials; however, the exact underlying molecular mechanism remains to be elucidated. Here, we systematically investigate the effect of DHA on amyloidogenic and nonamyloidogenic APP processing and the potential cross-links to cholesterol metabolism in vivo and in vitro. DHA reduces amyloidogenic processing by decreasing β- and γ-secretase activity, whereas the expression and protein levels of BACE1 and presenilin1 remain unchanged. In addition, DHA increases protein stability of α-secretase resulting in increased nonamyloidogenic processing. Besides the known effect of DHA to decrease cholesterol de novo synthesis, we found cholesterol distribution in plasma membrane to be altered. In the presence of DHA, cholesterol shifts from raft to non-raft domains, and this is accompanied by a shift in γ-secretase activity and presenilin1 protein levels. Taken together, DHA directs amyloidogenic processing of APP toward nonamyloidogenic processing, effectively reducing Aβ release. DHA has a typical pleiotropic effect; DHA-mediated Aβ reduction is not the consequence of a single major mechanism but is the result of combined multiple effects.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in the elderly. Substantial evidence suggests a role for nutrition in the management of AD and especially suggests that interventions with combinations of nutrients are more effective than single-nutrient interventions. The specific multi-nutrient combination Fortasyn™Connect (FC), shown to improve memory in AD, provides phosphatide precursors and cofactors and is designed to stimulate the formation of phospholipids, neuronal membranes, and synapses. The composition comprises nucleotides, omega-3 polyunsaturated fatty acids (n3 PUFA), choline, B-vitamins, phospholipids, and antioxidants. The current study explored the protective properties of FC in a membrane toxicity model of AD, the amyloid-β 1-42 (Aβ42) infused rat, which shows reduced exploratory behavior in an Open Field and impaired cholinergic functioning. To this end, rats were fed an FC enriched diet or a control diet and five weeks later infused with vehicle or Aβ42 into the lateral ventricle. Ten weeks post-infusion Aβ42-rats fed the FC diet showed increased membrane n3 PUFA and phosphatidylcholine content while they did not show the reductions in exploratory behavior or in choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT) immunoreactivity that were seen in Aβ42-rats fed the control diet. We conclude that FC protects the cholinergic system against Aβ42-induced toxicity and speculate that the effects of FC on membrane formation and composition might be supportive for this protective effect. Based on these data a long-term intervention study was started in the prodromal stages of AD (NTR1705, LipiDiDiet, EU FP7).

in the NHP were performed following iv bolus and infusion treatment with SAM-760 designed to maintain steady state drug exposure throughout the experiment. Human PET RO was evaluated at approximately tmax and 24 or 48h following oral treatment with a single dose of SAM-760. All animal study procedures conducted were approved by an institutional review committee (IACUC). Results: [C] GSK215083 produced reproducible test-retest values in both species (NHP: caudate 1⁄4 15.0 6 6.8%, putamen 1⁄4 12.1 6 7.3%; human: caudate 1⁄4 19.8 6 10.6%, putamen 1⁄4 16.6 6 12.7%). In the NHP, SAM760 treatment produced exposure dependent RO in the striatum, with a complete blockade of the receptor at free drug plasma exposures of > 10 nM. Human RO studies with SAM-760 demonstrated RO within the striatum of > 70% following treatment with a single oral dose of 60 mg. Conclusions: The PET radiotracer [C]GSK215083 demonstrated robust test-retest reliability within striatal structures for both species. Characterization of the RO: exposure relationship for SAM-760 in NHP and human striatum demonstrated that high levels of RO can be achieved at clinically relevant drug exposures. These studies provide support for dose selection for the further development of SAM-760 as a potential treatment for the cognitive deficits associated with Alzheimer’s disease.

The effect of supplementation with the omega 3 polyunsaturated fatty acid (n3 PUFA) docosahexaenoic acid (DHA) on membrane composition and amyloid-β₁₋₄₂ (Aβ₄₂) secretion was studied in human amyloid-β protein precursor-transfected Chinese Hamster Ovary (CHO) cells. Twenty-four hour incubation with a range of DHA concentrations resulted in a dose-dependent increase in membrane DHA and eicosapentaenoic acid content and a decrease in arachidonic acid content. In addition, DHA supplementation caused a dose-dependent reduction in the secreted Aβ₄₂ levels and resulted in a 4-8 fold decrease in extracellular prostaglandin E₂ (PGE₂) levels. Tocopherol, which was added to DHA to prevent oxidation, may have contributed to the effect of DHA, since it slightly decreased extracellular Aβ₄₂ and PGE₂ levels when given alone. The addition of selective COX2 inhibitors Celebrex and curcumin to the culture medium resulted in a significant and comparable inhibition of PGE₂ release, but did not inhibit Aβ₄₂ secretion, and even significantly increased Aβ₄₂ production in this cell system. Together, the present data show that, whereas both DHA and COX2 inhibitors may reduce PGE₂ production, only DHA in the presence of tocopherol significantly reduced Aβ₄₂ production and concurrently changed membrane lipid composition in CHO cells. It is concluded that in this in vitro setting DHA reduced Aβ₄₂ secretion through membrane-related, but not PGE₂-related mechanisms.

Prepulse inhibition of the startle reflex has been used as an animal model for the information processing deficits found in some types of schizophrenia. These deficits may be mediated by hypersensitive dopaminergic systems. In the present study, the effects of subchronic d -amphetamine administration [2 mg/kg intraperitoneally (IP)] on prepulse and gap inhibition of the startle reflex were compared to the effects of acute amphetamine and saline administration on startle inhibition. Results of three experiments are reported. The first two experiments were used to select prestimulus parameters sensitive to tem stimulus intensity on the other hand, and prestimulus parameters sensitive to temporal aspects of stimulus processing on the other hand. Because schizophrenics have problems with the temporal sequencing of information, prestimulus inhibition of the startle reflex was expected to be more pronounced when prestimulus processing depended predominantly upon temporal factors. Results supported this hypothesis, although the effects of d -amphetamine were found at near detection threshold duration only. Subchronic amphetamine had no effect on the neuronal mechanisms underlying inhibition of the startle reflex by prestimuli. The results also suggested that a careful selection of duration and intensity of the prestimulus may increase the sensitivity of the prestimulus-startle paradigm for the effects of drugs, for example.

Background: Alzheimer’s disease (AD) is characterized by memory loss as a consequence of reduced neurotransmission. Functional deterioration of neuronal components, especially membrane linked components like receptors, is thought to play a significant role. Indeed, deterioration of the cholinergic system is found already early in AD pathogenesis and involves reduction of acetylcholine levels but also reductions in acetylcholine receptors, in particular muscarinic M1 receptors. Former study has shown that membrane-targeted multi-nutrient intervention could increase agonist binding to muscarinic M1 receptors in rats, indicative for enhanced cholinergic neurotransmission. Methods: The current study set out to detect effects of single nutrient and nutrient combinations on receptor agonist binding in neuronal cells. To this end pheochromocytoma cells were incubated with individual nutrients from specific nutrient classes (PUFA’s, nucleotides, phospholipids, B-vitamins and antioxidants) or combinations of nutrients from different classes for 24 hours. Thereafter, a flex-station was used to measure agonist induced changes in membrane potential. In untreated cells it was shown that agonists induced dose-dependent changes in membrane potential. Sub-optimal doses of agonists were then applied to the supplemented cells. Results: The results show that cells incubated with single nutrients or combinations of 2 showed a minor change in membrane potential (approx. 2% increase compared to control). Cells incubated with combinations of nutrients from 3 classes showed an increase of approximately 20% while combining 4 classes resulted in a roughly 40% increase in membrane potential change. The combination of nutrients from all classes into one supplementation resulted in a 60% increase compared to untreated cells. Conclusions: Together, these results show that incubation with nutrients resulted in greater agonist-induced changes in membrane potential, suggesting stronger receptor stimulation. Moreover, agonistinduced changes in membrane potential were especially enhanced in cells incubated with specific combinations of nutrient classes. These results demonstrate that specific combinations of nutrients can effectively enhance receptor functioning and might offer an effective means to improve neurotransmission.

Contains fulltext : 53169.pdf (Publisher’s version ) (Closed access) High dietary cholesterol and low dietary docosahexaenoic acid (DHA) intake are risk factors for Alzheimer's disease (AD). However, it is unclear how these components influence the course of the disease. We investigated the effects of dietary lipids on beta-amyloid deposition and blood circulation in the brains of 18-month-old APP/PS1 mice. Starting at 6 months of age, mice were fed a regular rodent chow, a Typical Western Diet (TWD) containing 1% cholesterol, or a diet with a high (0.5%) level of DHA for 12 months. Relative cerebral blood volume (rCBV) and flow (CBF) were determined with (2)H MR spectroscopy and gradient echo contrast enhanced MRI. Deposition of beta-amyloid was visualized in fixed brain tissue with immunohistochemistry. The TWD diet increased plaque burden in the dentate gyrus of the hippocampus, but did not significantly reduce rCBV. In contrast, the DHA-enriched diet increased rCBV without changing blood flow indicating a larger circulation in the brain probably due to vasodilatation and decreased the amount of vascular beta-amyloid deposition. Together, our results indicate that the long-term intake of dietary lipids can impact both brain circulation and beta-amyloid deposition, and support the involvement of hemodynamic changes in the development of AD.

The present study assessed the influence of dietary lipids on accumulation of amyloid beta-peptide (Abeta) in the brain. Seven experimental diets with varying n-6/n-3-ratio, saturated and polyunsaturated fatty acid and cholesterol contents were fed to transgenic APPswe/PS1dE9 mice for 3-4 months beginning at a young adult age (6 months). Hippocampal Abeta levels were determined with ELISA and plaque load by using immunocytochemistry. A typical Western diet with 40% saturated fatty acids and 1% of cholesterol increased, while diets supplemented with docosahexaenoic acid (DHA) decreased Abeta levels compared to regular (soy oil based) diet. DHA diet also decreased the number of activated microglia in hippocampus and increased exploratory activity of transgenic mice, but did not improve their spatial learning in the water maze. The favorable effect of DHA on Abeta production was verified in two different cell lines. Regulation of dietary lipid intake may offer a new tool to reduce the risk of Alzheimer's disease at the population level.

Prior behavioral history in operant conditioning paradigms may induce impulsive-like responding as shown in rats. Little is known to what extent behavioral history influences subsequent behavior in mice, therefore the present study investigated the effects of lever-pressing under a fixed-ratio 5 schedule of reinforcement on subsequent differential-reinforcement-of-low-rate (DRL) 36 s performance in wild type mice compared to the behavior of 5-HT 1B receptor knockout mice. Acquisition of both autoshaping and fixed-ratio 5 training was faster in 5-HT1B receptor knockout compared to wild type mice. Nevertheless, in the DRL 36 s procedure no differences were observed between genotypes. Both wild type and 5-HT 1B receptor knockout mice displayed premature or impulsive-like responding in the DRL 36 s procedure, for example a peak location of responses around 20 s and high rates of responding. Taken together, the present data suggest that impulsive-like responding in the DRL 36 s procedure in mice depends on prior behavioral history.

The putative discriminative stimulus of the 5-HT3 receptor antagonists ondansetron and ( dl )-11-[(2-methyl-1H-imidazol-1-yl)methyl]-4,5,6,7,10,11,12-octahydroazepinol[3,2,1-jk]-carbazol-12-one hydrochloride (DU122932), and of the 5-HT3 receptor agonists 2-methyl-5-HT and 3,4-dichlorophenylbiguanide (3,4DCPB) were investigated in a standard two-lever, food-reinforced drug–saline discrimination procedure with groups of rats (N=10 per group). In three groups of rats after 80 sessions with training doses ranging from 0.1 to 4.0 mg/kg po, stimulus control by ondansetron, DU122932 and 2-methyl-5-HT was still absent. The same 30 animals thereafter rapidly learned to discriminate chlordiazepoxide (CDP) from vehicle. In three other groups of rats, stimulus control by CDP was first established. Then, the vehicle was gradually (from 0.1 to 2.0 mg/kg po) replaced by either ondansetron, DU122932 or 2-methyl-5-HT. Finally, the dose of CDP was gradually decreased. In all three groups, stimulus control disappeared. A seventh group was trained to discriminate 3,4DCPB (5.0 mg/kg po) from saline. When training was not successful, dose and route were changed but discrimination was not attained. It is concluded that in the rat, using the classical two lever discrimination procedure, the 5-HT3 receptor ligands ondansetron, DU122932, 2-methyl-5-HT and 3,4DCPB are incapable of producing an internal state that can act as a stimulus to control responding.

The latent inhibition (LI) phenomenon refers to the retardation in learning of an association between a stimulus and a consequence if that stimulus had been previously experienced without consequence. An earlier study demonstrated that the benzodiazepine receptor agonist chlordiazepoxide (CDP), when administered before the phase of preexposure to the to-be-conditioned stimulus, impaired animals' ability to develop LI. The present study was designed to investigate the effect of the anxiogenic drugs pentylenetetrazole (PTZ) and the benzodiazepine partial inverse agonist Ro15-4513 on LI. Both anxiogenics, in contrast to CDP, are known for their GABA inhibitory action. The effects produced by the combined administration of a GABAergic function facilitator and inhibitor (CDP/PTZ and CDP/Ro15-4513) were also investigated. Both anxiogenic drugs led to an attenuation of LI, and, similarly to CDP, this attenuation was exclusively due to their administration prior to the preexposure stage of the experiment. However, this effect was abolished when anxiolytic and anxiogenic drugs were administered together, suggesting a pharmacological rather than behavioral summation of effects. These data also demonstrate the bidirectional GABAergic modulation of the LI phenomenon: both increased and decreased GABA A receptor activation led to reduced LI, thereby suggesting that an optimal receptor activation level is necessary for the normal establishment of LI.

Publisher Summary This chapter discusses a direct comparison of prefrontal cortex (PFC) and hippocampal area (HPC) by presenting selected results of a series of recent experiments pertaining possible dissociable roles of PFC and HPC in a variety of rat models of learning, memory, and attention. Data pertaining to the involvement of the PFC and the HPC in different cognitive processes in rats shows that indeed both the PFC and the HPC of the rat are essential brain structures for learning, memory, and attention processes. However, even though lesions of these structures have been shown to disrupt performance of similar if not the same behavioral paradigms, this is not to say that their roles in these processes are similar; both qualitative and quantitative differences in lesion effects can be obtained with direct comparisons, using adequate behavioral procedures. Results of such comparisons show that lesions of the HPC disrupt spatial learning, working memory and selective attention, whereas lesions of the PFC disrupt working memory, behavioral flexibility, and sustained attention.

Publisher Summary This chapter describes the role of the prefrontal cortex of the rat in learning and decision making. Depending on the authors reviews of prefrontal cortex (PFC) functions in rats have provided lists of behavioral deficiencies following damage of the PFC. They include deficient performance in various delay-type tasks, spatial tasks, inhibition, attention, along with abnormalities in social behavior. When rats with PFC damage are examined for their spatial learning skills in a Morris water maze, no impairments in spatial learning could be detected; however, when the task was changed from an allocentric one to a visual-cued one, rats with damage of the medial PFC were initially impaired. It is assumed that with prefrontal damage, it was more difficult to shift between tasks with different task demands. Evidence supporting this assumption has been obtained, when rats are trained either in a cheeseboard task, or a visual-cued version of that task. Transient inactivation of the medial PFC did not interfere with task acquisition. However, such an inactivation impaired learning when the rats were switched from one version of the task to the other one. It is tempting to relate these findings with the well-known deficiencies described in humans with PFC damage.

The prefrontal cortex has traditionally been implicated in a variety of cognitive processes, including memory, attention and decision making. The detection of effects of prefrontal cortex lesions on attention has been shown to depend on the procedure used to assess the attentional process. We therefore investigated the effects of lesions of the prefrontal cortex in two different visual attention tasks, i.e. a three-choice serial reaction time task involving sustained and divided attention processes and a visual timing task involving sustained attention and response inhibition processes. In two rat strains that are frequently used in behavioural analysis, i.e. albino Wistar rats and pigmented Lister Hooded rats, lesions of the medial prefrontal cortex caused a deterioration of performance in both tasks, although the effect lasted much longer in the visual timing task. This latter task proved to be especially sensitive to detect the consequences of medial prefrontal cortex lesions, consisting of a loss of both attention control and response inhibition. In both attention tasks, Wistar rats performed less accurate and made more anticipatory responses than Listers. Strain differences could not entirely be attributed to possible visual deficits in albinos, which was also evident when locomotor activity in an open field and food-motivated behaviour in a hoarding paradigm were assessed. Due to slower habituation rates, Lister rats were more active and displayed little food hoarding behaviour. In Wistar rats, hoarding was disrupted by medial prefrontal cortex lesions, showing the effectiveness of the lesion. The results indicate that, although different rat strains provide different baseline levels of behaviour for testing lesion- or drug-induced behavioural changes, lesions of the medial prefrontal cortex do not only disrupt sustained attention processes, but also induce a strong impairment in response inhibition in both Wistar and Lister rats.

Background: Folate, vitamin B-12, and vitamin B-6 are essential nutritional components in one-carbon metabolism and are required for methylation capacity. The availability of these vitamins may therefore modify methylation of phosphatidylethanolamine (PE) to phosphatidylcholine (PC) by PE-N-methyltransferase (PEMT) in the liver. It has been suggested that PC synthesis by PEMT plays an important role in the transport of polyunsaturated fatty acids (PUFAs) like docosahexaenoic acid (DHA) from the liver to plasma and possibly other tissues. We hypothesized that if B-vitamin supplementation enhances PEMT activity, then supplementation could also increase the concentration of plasma levels of PUFAs such as DHA. To test this hypothesis, we determined the effect of varying the combined dietary intake of these three B-vitamins on plasma DHA concentration in rats. Methods: In a first experiment, plasma DHA and plasma homocysteine concentrations were measured in rats that had consumed a B-vitamin-poor diet for 4 weeks after which they were either continued on the B-vitamin-poor diet or switched to a B-vitamin-enriched diet for another 4 weeks. In a second experiment, plasma DHA and plasma homocysteine concentrations were measured in rats after feeding them one of four diets with varying levels of B-vitamins for 4 weeks. The diets provided 0% (poor), 100% (normal), 400% (enriched), and 1600% (high) of the laboratory rodent requirements for each of the three B-vitamins. Results: Plasma DHA concentration was higher in rats fed the B-vitamin-enriched diet than in rats that were continued on the B-vitamin-poor diet (P = 0.005; experiment A). Varying dietary B-vitamin intake from deficient to supra-physiologic resulted in a non-linear dose-dependent trend for increasing plasma DHA (P = 0.027; experiment B). Plasma DHA was lowest in rats consuming the B-vitamin-poor diet (P > 0.05 vs. normal, P 0.05 vs. enriched). B-vitamin deficiency significantly increased plasma total homocysteine but increasing intake above normal did not significantly reduce it. Nevertheless, in both experiments plasma DHA was inversely correlated with plasma total homocysteine. Conclusion: These data demonstrate that dietary folate, vitamin B-12, and vitamin B-6 intake can influence plasma concentration of DHA., Nutricia Advanced Medical Nutrition, Danone Research

Lesions of the medial prefrontal cortex (mPFC) disrupt performance in a variety of delay tasks, which suggests that the mPFC supports short-term memory processes. The putative involvement of the dopaminergic innervation of the mPFC in these mnemonic processes was investigated by evaluating the effects of local infusions of dopaminergic drugs into the mPFC of rats in an operant delayed-matching-to-position (DMTP) task. Trained animals were provided with bilateral guide cannulae aimed at the dorsal part of the mPFC. Two separate groups of rats were tested after microinfusion of several doses of either the dopamine agonist apomorphine (APO) or the dopamine antagonist cis-flupenthixol (FLU). In addition, all animals were tested after infusion of several doses of the muscarinic antagonist scopolamine (SCO). Animals were tested 0 and 135 min after each infusion. At the 0 min interval, neither APO nor FLU affected accuracy of DMTP performance, while both drugs dose-dependently increased response latencies and decreased nosepoke frequencies. At the 135 min interval, APO had almost no effect, whereas the effects of FLU were very prominent. A number of animals no longer responded after infusion of the highest doses of FLU and those that did showed a delay-independent decrease in response accuracy. In contrast, SCO infusions into the mPFC induced a dose- and delay-dependent deterioration of DMTP performance. Taken together, these results support a direct involvement of the rat mPFC in short-term memory processes, although they implicate cholinergic rather than dopaminergic mechanisms in this function.

It is well documented that latent inhibition (LI), i.e. slower conditioning to a stimulus that had been repeatedly pre-exposed without consequences, compared to a non-pre-exposed stimulus, is prevented by amphetamine. Recently, we found that the effects of amphetamine on LI, as assessed in an off-baseline conditioned emotional response (CER) procedure, depend on the nature of the pre-exposed stimulus, irrespective of reinforcer intensity. Because these results contrast with a recent finding that a reduction in reinforcer intensity reversed amphetamine-induced attenuation of LI in an on-baseline CER procedure, the present study investigated the effects of amphetamine on LI as a function of the nature of the pre-exposed stimuli and shock intensity, using an on-baseline CER procedure. The effects of amphetamine on post-shock suppression of drinking as well as on activity, were monitored throughout the stages of the CER procedure. Experiment 1 used a 5 s steady light as the pre-exposed and conditioned stimulus, and two shock intensities in conditioning, and Experiment 2 used a 10 s flashing light and two shock intensities. Amphetamine disrupted LI with a steady light at both low and high shock intensities, but failed to disrupt LI with a flashing light at both shock intensities. In addition, the drug disrupted LI in Experiment 3, which increased the duration of the steady light to 10 s and used only low shock intensity, but failed to affect LI in Experiment 4 which used the flashing light on the background of darkness or of light, and only high shock intensity. The effects of amphetamine on LI were not related to its effects on behavioural suppression after footshock, or on activity.

Latent inhibition is a measure of retarded conditioning to a previously presented nonreinforced stimulus that is impaired in schizophrenic patients and in rats treated with amphetamine. In terms of neural substrates, latent inhibition depends on the integrity of the nucleus accumbens and the inputs to this structure from the hippocampal formation and adjacent cortical areas. Since another major source of input to the nucleus accumbens is the medial prefrontal cortex, and there are numerous demonstrations that manipulations of this region can modify ventral striatal dopamine, we investigated the effects of N-methyl-D-aspartate lesion to the medial prefrontal cortex on latent inhibition, assessed in an off-baseline conditioned emotional response procedure in rats licking for water. In addition, the effects of the medial prefrontal cortex lesion were assessed on a battery of tasks potentially sensitive to medial prefrontal cortex damage, including spontaneous and amphetamine-induced activity, elevated plus maze exploration, food hoarding, prepulse inhibition, and active avoidance. The lesion decreased hoarding behaviour and increased spontaneous exploratory activity in the open field, while exerting only mild effects on amphetamine-induced activity. Prepulse inhibition, exploration of the elevated plus maze, and the acquisition of two-way active avoidance were unaffected by the lesion. Likewise, latent inhibition was left intact following the lesion, suggesting that neither the destruction of the intrinsic cells of the medial prefrontal cortex nor any potential lesion-induced changes in subcortical dopamine, affect latent inhibition.

Impaired ability to ‘gate out’ sensory and cognitive information is considered to be a central feature of schizophrenia and is manifested, among others, in disrupted prepulse inhibition (PPI) and latent inhibition (LI). The present study investigated in rats the effects of increasing or decreasing dopamine (DA) receptor activation within the medial prefrontal cortex (mPFC) by local administration of the indirect DA receptor agonist amphetamine (AMPH; 10.0 μg/side) or the DA antagonist cis -flupenthixol (FLU; 12.0 μg/side) on PPI and LI as well as on systemic AMPH-induced activity. The effects of intra-mPFC apomorphine (APO; 10.0 μg/side) on PPI were also tested. AMPH infusions decreased systemic AMPH-induced increase in locomotor activity in the open field, whereas FLU infusion was ineffective. Both infusions had no effect on LI and PPI. However, APO infusions induced a disruption of PPI. These results provide additional evidence that the mPFC is a component of the neural circuitry mediating PPI but plays no role in LI. In addition, they show that the behavioral outcomes produced by DA receptor activation/blockade in the mPFC of the rat cannot be explained by postulating a simple reciprocal relationship between the cortical and subcortical DA systems.