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PubMed1996

Alterations in locomotor activity after microinjections of GBR-12909, selective dopamine antagonists or neurotensin into the medial prefrontal cortex.

It has been postulated that increased dopamine (DA) activity in the medial prefrontal cortex (mPFC) exerts an inhibitory influence over DA release in the nucleus accumbens and, thus, also over locomotor activity. Experiments were designed to examine the role of mPFC DA and neurotensin (NT), a neuropeptide which interacts with DA, in spontaneous locomotor activity. LS/IBG mice were injected bilaterally with either GBR-12909, a selective DA uptake blocker, the DA D1 receptor antagonist R-(+)-SCH-23390, the DA D2 receptor antagonist epidepride, NT or a combination of drugs. GBR-12909 produced a U-shaped dose-response curve with a maximum inhibition of 47% of control. Postmortem tissue levels of DA, 5-hydroxytryptamine, norepinephrine and their major metabolites were determined after microinjections of GBR-12909. Tissue levels of these compounds were not significantly affected by GBR-12909. However, the ratios of homovanilic acid/DA and homovanilic acid + 3,4-dihyroxyphenylacetic acid/DA were significantly decreased, whereas the 5-hydroxyindoleacetic acid/5-hydroxytryptamine ratio was not affected by GBR-12909, suggesting a selective effect on DAergic processes. By itself, R-(+)-SCH-23390 had no effect on locomotor activity except at a very high dose which caused locomotor inhibition (49% of control). Epidepride caused a dose-dependent inhibition of locomotor activity with a maximum inhibition of 49% of control. When coinjected with an inhibitory dose of GBR-12909, both epidepride and R-(+)-SCH-23390 attenuated the GBR-12909 effect in a dose-dependent manner. A broad range of doses of NT was found to have no consistent effect on locomotor activity. However, when coinjected with an inhibitory dose of GBR-12909, NT attenuated the GBR-12909-induced inhibition in a dose-dependent manner. The results suggest that stimulation of DA receptors in the mPFC, both DA D1 and DA D2 receptors mediates locomotor inhibition. Furthermore, stimulation of NT receptors appears to antagonize the effects of DA.

Analysis of Variance↗

PubMed2001

Ethanol reduces rCFB activation of left dorsolateral prefrontal cortex during a verbal fluency task.

In a previous study in normal subjects (Wendt et al., 1994), using a reversing checkerboard as activation stimulus, we found that the coupling between local neuronal activity and regional cerebral blood flow was preserved following ethanol, and that a right-sided occipital activation response seen during sobriety became symmetrical during inebriation. In the present study we investigated if ethanol has a detrimental effect also on the activation of the left dorsolateral prefrontal cortex found in normals during verbal fluency. Measurements of regional cerebral blood flow in 20 healthy, young, male, right-handed volunteers during rest and verbal fluency were made during sobriety and inebriation (0.06% blood alcohol concentration) with a 1-week interval. We found a decrease in word production during inebriation. The normal activation within the frontotemporal part of the left dorsolateral prefrontal cortext was preserved during inebriation. The activation of this region seems thus to be robust to the effects of ethanol. During inebriation no activation response to the word fluency test was found in the anterior prefrontal part of the dorsolateral prefrontal cortex. This region is important for working, temporal, and short-term memory functions, processes that are affected by ethanol. Hemispheric functioning and specialization seem to be adversely affected by ethanol, regardless of which hemisphere is most involved while sober.

Adult↗

PubMed2006

Repeated maternal separation of male Wistar rats alters glutamate receptor expression in the hippocampus but not the prefrontal cortex.

Stress early in life puts the individual at a greater risk for developing mental disorders in adulthood. The animal model of maternal separation involves daily removal of pups from their mother over the early postnatal period and leads to several behavioral deficits in adults. Since this period corresponds to a time of extensive developmental changes in the glutamatergic system, glutamate receptor mRNA expression was studied in the hippocampus and prefrontal cortex. Male Wistar rats were either separated from their mother for 15 min (MS15 or 'handling') or 360 min (MS360) once a day from pnd 1-21 and glutamate receptor expression levels were measured at 25 weeks of age using real-time RT-PCR analysis. A third group of animal facility reared (AFR) rats was included as a control for the handling group. In the hippocampus, mRNA expression of NMDA NR2B and AMPA GluR1 and GluR2 receptors was significantly lower in MS360 rats relative to MS15. In addition, expression of the glutamate transporter GLAST was increased in MS360 relative to MS15. No differences were observed for AFR rats relative to MS15, which indicates that the hippocampal effects were not a result of handling or maternal care. For the prefrontal cortex, no difference in mRNA expression was observed for NMDA NR2A and NR2B or AMPA GluR1 and GluR2. These findings suggest that prolonged maternal separation produces neuroadaptive changes in the hippocampus that may, at least partially, account for the behavioral deficits previously observed in this animal model.

Analysis of Variance↗

PubMed1991

Haloperidol attenuates conditioned place preferences produced by electrical stimulation of the medial prefrontal cortex.

A Conditioned Place Preference test procedure [Ettenberg and Duvauchelle (13)] was used to investigate the effects of dopamine antagonist challenge on the rewarding properties of medial prefrontal cortex (MPFC) electrical stimulation. Rats exhibited strong preferences for the side of a two-compartment test apparatus in which they experienced sessions of experimenter-administered 0.5-s trains of MPFC sine-wave 60-Hz stimulation. Pretreatment with the neuroleptic dopamine antagonist drug, haloperidol (0.0, 0.15, or 0.3 mg/kg IP), resulted in a dose-dependent reduction in the magnitude of observed place preferences. Preference tests were conducted 24 hours after drug-conditioning trials and, hence, were not subject to motoric or other nonspecific actions of the neuroleptic treatments. In a control experiment, haloperidol did not block the place aversions produced by dorsomedial tegmental stimulation. Animals can, therefore, recall place-associations formed in the presence of haloperidol, a result which challenges "state-dependent learning" explanations of the drug's actions. Together, these results are consistent with the view that dopamine neurotransmission is involved in the rewarding consequences of electrical stimulation in the medial prefrontal cortex.

Animals↗

PubMed2006

Alteration in kinase activity but not in protein levels of protein kinase B and glycogen synthase kinase-3beta in ventral prefrontal cortex of depressed suicide victims.

BACKGROUND: Past studies in the neurobiology of suicide have reported alterations in serotonin and downstream effectors, such as Akt/protein kinase B. In this study, we aimed to examine possible abnormality in the Akt/glycogen synthase kinase-3beta (GSK-3beta) axis of depressed suicide victims' brains. METHODS: Twenty suicide victims and 20 drug-free non-suicide subjects were included for a postmortem study. The ventral prefrontal cortex area (BA'11) was used, and antemortem diagnoses of major depression disorder (MDD) (DSM-IV) were made from Institution's records. The protein levels of GSK-3alpha/beta and Akt-1 were assayed with the Western blot method, and the kinase activity of Akt and GSK-3alpha/beta were determined by phosphorylation of specific substrates. RESULTS: There was no change either in GSK-3alpha/beta and Akt-1 protein levels or in lithium-inhibitable total GSK-3alpha/beta enzyme activity of the ventral prefrontal cortex. The enzyme activity of Akt decreased significantly [analysis of variance (ANOVA): F(3,36)=5.372; p= .003], whereas GSK-3beta activity increased significantly [ANOVA: F(3,36)=8.567; p= .002] in depressed suicide victims and non-suicide subjects but not in non-depressed suicide victims. CONCLUSIONS: This study indicated that the activity rather than the protein levels of Akt and GSK-3beta was altered. The alteration was associated with MDD rather than with suicide per se.

Adult↗

PubMed2001

Acute increases in monoamine release in the rat prefrontal cortex by the mGlu2/3 agonist LY379268 are similar in profile to risperidone, not locally mediated, and can be elicited in the presence of uptake blockade.

Our recent work (Cartmell et al., Journal of Neurochemistry, 75 (2000) 1147-1154) demonstrated that systemic injection of the potent, selective mGlu2/3 receptor agonist, LY379268, acutely increased extracellular levels of dopamine, its metabolites DOPAC and HVA, and the 5-HT metabolite, 5-HIAA, in rat medial prefrontal cortex (mPFC). Here, we compared the acute effects of LY379268 with those of clozapine and risperidone (atypical antipsychotics) on extracellular levels of both dopamine and 5-HT in the mPFC of freely-moving rats. Uptake blockers were included to minimize metabolism of monoamines near the probe area. One hour after injection, LY379268 (10 mg/kg s.c.), clozapine (10 mg/kg s.c.) or risperidone (1 mg/kg s.c.) maximally increased dopamine by 224, 257 and 234% of basal levels. These effects were followed by maximal increases in DOPAC and HVA levels 2 to 3.5 hours after administration. LY379268, at 3 and 10 mg/kg s.c., and risperidone (1 mg/kg s.c.) also increased dialysate 5-HT to 169, 179 and 140% of basal levels and 5-HIAA to 144, 154 and 121% of basal levels, respectively. These neurochemical changes in the mPFC could not be mimicked when LY379268 (3 or 30 microM) was administered locally via the microdialysis probe. These data demonstrate that increases in extracellular monoamines in the rat prefrontal cortex evoked acutely by the mGlu2/3 agonist, LY379268, are similar in profile to risperidone, not locally mediated, and can be elicited in the presence of uptake blockade.

Amino Acids↗

PubMed2000

D-amphetamine facilitation of morris water task performance is blocked by eticlopride and correlated with increased dopamine synthesis in the prefrontal cortex.

The effect of posttraining D-amphetamine on Morris water task (MWT) performance was analyzed in this study by training rats using a single training trial per day procedure. In addition to acquisition latency, learning was assessed by a probe trial given 24 h after the last training trial. Rats given immediate post-trial D-amphetamine demonstrated improved performance over saline rats on both acquisition and the probe trial. An analysis of the mechanisms underlying facilitation revealed that eticlopride (a D2 antagonist) blocked D-amphetamine's facilitatory effects on the probe trial and dopamine synthesis was increased in the medial prefrontal cortex in the D-amphetamine group relative to controls. These results show that chronic administration of posttraining D-amphetamine facilitated MWT performance, and this facilitation may be mediated by the dopaminergic system and dopamine synthesis in the prefrontal cortex.

Animals↗

PubMed1999

Amphetamine-induced glutamate efflux in the rat ventral tegmental area is prevented by MK-801, SCH 23390, and ibotenic acid lesions of the prefrontal cortex.

We showed previously that amphetamine challenge produces a delayed increase in glutamate efflux in the ventral tegmental area of both naive and chronic amphetamine-treated rats. The present study examined the mechanisms underlying this response. The NMDA receptor antagonist MK-801 (0.1 mg/kg, i.p.) or the D1 dopamine receptor antagonist SCH 23390 (0.1 mg/kg, i.p.), given 30 min before acute amphetamine (5 mg/kg, i.p.), prevented amphetamine-induced glutamate efflux. Neither antagonist by itself altered glutamate efflux. Ibotenic acid lesions of the prefrontal cortex similarly prevented amphetamine-induced glutamate efflux, while producing a trend toward decreased basal glutamate levels (82.8% of sham group). Previous work has shown that the doses of NMDA and D1 receptor antagonists used in this study prevent the induction of behavioral sensitization when coadministered repeatedly with amphetamine, and that identical prefrontal cortex lesions performed before repeated amphetamine prevent the induction of ambulatory sensitization. Thus, treatments that prevent acute amphetamine from elevating glutamate efflux in the ventral tegmental area also prevent repeated amphetamine from eliciting behavioral sensitization. These findings suggest that repeated elevation of glutamate levels during a chronic amphetamine regimen may contribute to the cascade of neuroadaptations within the ventral tegmental area that enables the induction of sensitization.

Amphetamine↗

PubMed2001

N-methyl-D-aspartic acid receptor expression in the dorsolateral prefrontal cortex of elderly patients with schizophrenia.

OBJECTIVE: The N-methyl-D-aspartic acid (NMDA) class of glutamate receptors has received attention in the pathophysiology of schizophrenia because of the similarity between some schizophrenic symptoms and symptoms caused by NMDA antagonists. To determine if NMDA receptor abnormalities were present at the mRNA level, expression of NMDA receptor (NR) subunits NR(1), NR(2A), and NR(2B) was measured in specimens from the dorsolateral prefrontal cortex and the occipital cortex of elderly patients with schizophrenia and normal elderly subjects. METHOD: Postmortem specimens from antemortem assessed and diagnosed elderly patients with schizophrenia (N=26) were compared with those from a neuropathologically and neuropsychiatrically normal elderly comparison group (N=13) and from patients with Alzheimer's disease (N=10). The mRNA expression of the NR(1), NR(2A), and NR(2B) subunits and of postsynaptic density 95 (PSD-95), a protein associated with postsynaptic NMDA receptors, was studied with quantitative real-time reverse transcriptase polymerase chain reaction. RESULTS: Expression of NR(1) and NR(2A) but not NR(2B) subunits was higher in the dorsolateral prefrontal cortex and the occipital cortex of patients with schizophrenia than in the normal and Alzheimer's disease groups. In contrast, NR(1) expression was significantly lower in the Alzheimer's disease group. Occipital cortex expression of PSD-95 was higher in the schizophrenic subjects and correlated strongly with the expression of NR(2A) and NR(2B) in both cortical regions and with expression of NR(1) in the occipital cortex. These results were not influenced by neuroleptic exposure history, postmortem interval, or age of the subject. CONCLUSIONS: NMDA receptor subunits are abnormally expressed in elderly patients with schizophrenia. The disproportionate expression of the NR(1) and NR(2A) subunits relative to NR(2B) expression may have implications for the pathophysiology of schizophrenia and the sensitivity of schizophrenic patients to glutamate and glutamatergic drugs.

Actins↗

PubMed2004

Left inferior prefrontal cortex activity reflects inhibitory rather than facilitatory priming.

Functional neuroimaging has demonstrated reduced activation correlated with behavioral priming effects, a finding generally interpreted in terms of facilitated retrieval of target items in the context of related primes. Without a neutral prime, however, one cannot separate facilitatory effects of related primes from inhibitory effects of unrelated primes. Here we report an auditory semantic priming paradigm with congruent (''The boy bounced the BALL''), neutral (''The next item is BALL''), and incongruent (''Pasta is my favorite kind of BALL'') sentence trials. As previously reported, reduced left inferior prefrontal cortex activation was observed for congruent relative to incongruent trials; however, the neutral condition allowed us to show that the effect arose from increased activation in the incongruent condition rather than reduced activation for congruent trials. Our results suggest that the left inferior prefrontal cortex inhibits interference from prepotent representations in order to select a task-appropriate target, and is consistent with its broader role in behavioral inhibition.

Adolescent↗

PubMed2002

Proton magnetic resonance spectroscopy (1H MRS) in schizophrenia: investigation of the right and left hippocampus, thalamus, and prefrontal cortex.

Single voxel proton magnetic resonance spectroscopy (1H MRS) was used to study the metabolites N-acetylaspartate (NAA), choline (CHO), and myo-inositol (ml) in order to test a neurodegenerative hypothesis in schizophrenia (decrease of NAA, increase of CHO, and increase of ml) and a cerebral asymmetry of these metabolites. 1H MRS was performed in 17 schizophrenia patients and 14 healthy subjects in three cerebral areas highly involved in the pathophysiology of schizophrenia (the prefrontal cortex, the thalamus, and the hippocampus). The ratio amplitudes between metabolites and creatine plus phosphocreatine (Cr) were determined. No difference in the metabolites existed between patients and healthy subjects. However, relationships were noted between NAA/Cr and age in the thalami of the schizophrenia patients (r = -0.37; p = 0.14) and healthy subjects (r = -0.52; p = 0.05). A significant correlation was observed between NAA/Cr and age of onset of illness in the hippocampi of schizophrenia patients (r = -0.59; p < 0.05). Moreover, NAA/Cr was lower in the right than in the left prefrontal cortex in both schizophrenia patients and healthy subjects. There was no relationship between the metabolites and duration of illness or dose of antipsychotics. These findings might suggest a neurodegenerative process in the hippocampi of schizophrenia patients with late onset of illness, and the NAA/Cr ratio could be a marker of aging in the thalami.

Adult↗

PubMed2001

Hippocampal-prefrontocortical circuits: PKA inhibition in the prefrontal cortex impairs delayed nonmatching in the radial maze in rats.

Recent findings implicate the prefrontal cortex (PFC) and, in particular, frontocortical dopamine acting at D1-like receptors, in working memory. However, the mechanisms underlying this function of dopamine remain unknown. The present studies evaluated the hypothesis that dopamine contributes to working memory through its action on the 2nd messenger cyclic 3',5'-adenosine monophosphate (cAMP) and cAMP-dependent protein kinase (PKA). Thus, rats were trained to perform random foraging or delayed (30 min) nonmatching-to-position (delayed win-shift) tasks on the radial maze. With hippocampal output to the frontal cortex disconnected by injecting lidocaine (20 microg/0.5 microl) unilaterally into the ventral subiculum, contralateral frontocortical injections of lidocaine (20 microg/0.5 microl) or the D1-like dopamine receptor antagonist SCH 23390 (0.5 microg/0.5 microl) impaired delayed win-shift but not random foraging, replicating previous findings. In similarly disconnected rats, frontocortical injections of the PKA inhibitor Rp-cAMPS (5.0 and 10.0, but not 1.0, microg/0.5 microl) selectively impaired delayed nonmatching-to-position. Results suggest that activation of the cAMP-PKA pathway by dopamine acting at D1-like receptors in the frontal cortex is necessary for working memory.

Animals↗

PubMed2004

Object recognition impairment in Fmr1 knockout mice is reversed by amphetamine: involvement of dopamine in the medial prefrontal cortex.

Fragile X syndrome is an X-linked form of mental retardation including, among others, symptoms such as stereotypic behaviour, hyperactivity, hyperarousal, and cognitive deficits. We hypothesized that hyperactivity and/or compromised attentional, cognitive functions may lead to impaired performance in cognitive tasks in Fmr1 knockout mice, the most widely used animal model of fragile X syndrome, and suggested that psychostimulant treatment may improve performance by acting on one or both components. Since hyperactivity and cognitive functions have been suggested to depend on striatal and prefrontal cortex dopaminergic dysfunction, we assessed whether amphetamine produced beneficial, positive effects by acting on dopaminergic corticostriatal systems. Our results show that Fmr1 knockout mice are not able to discriminate between a familiar object and a novel one in the object recognition test, thus showing a clear-cut cognitive impairment that, to date, has been difficult to demonstrate in other cognitive tasks. Amphetamine improved performance of Fmr1 knockout mice, leading to enhanced ability to discriminate novel versus familiar objects, without significantly affecting locomotor activity. In agreement with behavioural data, amphetamine produced a greater increase in dopamine release in the prefrontal cortex of Fmr1 knockout compared with the wild-type mice, while a weak striatal dopaminergic response was observed in Fmr1 knockout mice. Our data support the view that the psychostimulant ameliorates performance in Fmr1 knockout mice by improving merely cognitive functions through its action on prefrontal cortical dopamine, irrespective of its action on motor hyperactivity. These results indicate that prefrontal cortical dopamine plays a major role in cognitive impairments characterizing Fmr1 knockout mice, thus pointing to an important aetiological factor in the fragile X syndrome.

Amphetamine↗

PubMed2006

Transient and selective overexpression of dopamine D2 receptors in the striatum causes persistent abnormalities in prefrontal cortex functioning.

Increased activity of D2 receptors (D2Rs) in the striatum has been linked to the pathophysiology of schizophrenia. To determine directly the behavioral and physiological consequences of increased D2R function in the striatum, we generated mice with reversibly increased levels of D2Rs restricted to the striatum. D2 transgenic mice exhibit selective cognitive impairments in working memory tasks and behavioral flexibility without more general cognitive deficits. The deficit in the working memory task persists even after the transgene has been switched off, indicating that it results not from continued overexpression of D2Rs but from excess expression during development. To determine the effects that may mediate the observed cognitive deficits, we analyzed the prefrontal cortex, the brain structure mainly associated with working memory. We found that D2R overexpression in the striatum impacts dopamine levels, rates of dopamine turnover, and activation of D1 receptors in the prefrontal cortex, measures that are critical for working memory.

Adenylyl Cyclases↗

PubMed1986

No change in neostriatal D-2 dopamine receptors after NMDA lesions of rat prefrontal cortex.

D-2 dopamine receptor function in rat nucleus accumbens and anterior corpus striatum was examined 6-8 days following N-methyl-D-aspartate lesions confined to medial prefrontal cortex. Lesions failed to alter the affinity or density of D-2 receptors labelled by [3H]spiperone in membrane preparations of both subcortical areas. Locomotor activity and stereotyped behaviours induced by the D-2 agonist, LY-171555, were also not significantly altered in lesioned animals. These results suggest that D-2 dopamine receptors of nucleus accumbens and anterior corpus striatum are not localized on corticofugal afferents from medial prefrontal cortex.

Animals↗

PubMed2004

Prefrontal cortex and decision making in a mixed-strategy game.

In a multi-agent environment, where the outcomes of one's actions change dynamically because they are related to the behavior of other beings, it becomes difficult to make an optimal decision about how to act. Although game theory provides normative solutions for decision making in groups, how such decision-making strategies are altered by experience is poorly understood. These adaptive processes might resemble reinforcement learning algorithms, which provide a general framework for finding optimal strategies in a dynamic environment. Here we investigated the role of prefrontal cortex (PFC) in dynamic decision making in monkeys. As in reinforcement learning, the animal's choice during a competitive game was biased by its choice and reward history, as well as by the strategies of its opponent. Furthermore, neurons in the dorsolateral prefrontal cortex (DLPFC) encoded the animal's past decisions and payoffs, as well as the conjunction between the two, providing signals necessary to update the estimates of expected reward. Thus, PFC might have a key role in optimizing decision-making strategies.

Animals↗

PubMed2006

Acute exhaustive exercise does not alter lipid peroxidation levels and antioxidant enzyme activities in rat hippocampus, prefrontal cortex and striatum.

Although regular physical exercise is beneficial to the body, it is well known that exhaustive exercise causes oxidative stress in muscle. Recent studies suggest that regular moderate physical exercise has the beneficial effects on brain. However, there is little information regarding whether or not exhaustive exercise could generate oxidative stress in brain and the findings are conflicting. The aim of this study was to investigate the effects of exhaustive exercise on thiobarbituric acid reactive substances, as an indicator of lipid peroxidation, in the hippocampus, prefrontal cortex and striatum. Additionally we examined antioxidant enzymes activities, superoxide dismutase and glutathione peroxidase, to assess the effects of reactive oxygen species. Exhaustive exercise did not change superoxide dismutase and glutathione peroxidase enzyme activities and thiobarbituric acid reactive substances levels neither immediately (0 min) nor at 3, 6, 12, 24 and 48 h after the cessation of exercise in the brain. These results indicate that acute exhaustive exercise may not cause significant lipid peroxidation in the hippocampus, prefrontal cortex and striatum during the post-exercise period.

Animals↗

PubMed1996

Age-related changes in diurnal acetylcholine release in the prefrontal cortex of male rats as measured by microdialysis.

Extracellular levels of acetylcholine in the prefrontal cortex were measured using the micro-dialysis method in freely moving young (three to four months old) and old (23 to 24 months old) male rats over a period of 24 h to examine the effect of aging on prefrontal acetylcholine release. Prefrontal acetylcholine release during a 24 h period exhibited a diurnal variation with higher levels during the dark cycle than during the light cycle in young rats but not in old rats. In addition, prefrontal acetylcholine release was closely associated with spontaneous activity in young rats but not in old rats. The present study suggests that aging reduces diurnal changes in the prefrontal acetylcholine release and that there is a cross-correlation between the prefrontal acetylcholine release and spontaneous locomotor activity in male rats.

Acetylcholine↗