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PubMed2004

The atypical antipsychotic quetiapine increases both noradrenaline and dopamine release in the rat prefrontal cortex.

Quetiapine is a novel atypical antipsychotic drug with multi-receptorial affinity. Using in vivo microdialysis, we investigated if quetiapine modulates extracellular noradrenaline and dopamine in brain areas generally believed to be involved in the pathophysiology of schizophrenia and in the action of antipsychotic drugs. Quetiapine (5, 10 and 20 mg/kg, i.p.) increased levels of noradrenaline in both the prefrontal cortex and the caudate nucleus, while it increased dopamine levels mainly in the prefrontal cortex. It is argued that the marked increase of dopaminergic transmission in the prefrontal cortex induced by quetiapine might be relevant to its therapeutical action.

Animals↗

PubMed1989

Adrenergic receptors in aging and Alzheimer's disease: increased beta 2-receptors in prefrontal cortex and hippocampus.

Loss of pigmented noradrenergic locus ceruleus neurons occurs in Alzheimer's disease (AD) and, to a lesser extent, in aging. We studied beta-adrenergic receptors and their subtypes, beta 1 and beta 2, by the specific binding of 125I-pindolol to particulate membrane preparations from prefrontal cortex, hippocampus, putamen, and cerebellum and to sections from frontal cortex by in vitro autoradiography. In prefrontal cortex from controls, numbers of total beta- and beta 2-adrenoceptors did not significantly correlate with age, but number of beta 1-adrenoceptors showed a weak but significant negative correlation. Binding in tissue particulate preparations to total beta-receptors did not reveal significant differences in samples from prefrontal cortex between AD subjects and age-matched controls. However, beta 1-adrenoceptors were decreased and beta 2-adrenoceptors were increased in number by approximately 30-50% in AD subjects. Thus, the relative ratio of beta 1-/beta 2-receptors was decreased in AD. Binding by in vitro receptor autoradiography performed in a subset of samples of frontal cortex also showed beta 2-adrenoceptors, and less consistently total beta- and beta 1-receptors, to be increased significantly in number in cortical laminae II, III, IV, and V of tissue sections from AD subjects. In these subjects, number of locus ceruleus cells and norepinephrine concentrations in putamen and frontal cortex were markedly reduced compared with values in controls. In the hippocampus, total beta- and both beta 2- and beta 1-adrenoceptors were increased in number in AD. In contrast, in the putamen, where beta 1-receptors predominate, total beta- and beta 1-receptors were significantly decreased in number with no consistent change in content of beta 2-receptors in AD. There were no significant changes in the cerebellum. Specific pindolol binding was not affected by interval between death and sampling of tissue at autopsy. Our results indicate selective changes in number of beta-receptors in AD. These changes in the cortex and hippocampus suggest receptor upregulation in response to noradrenergic deafferentation from the locus ceruleus or may simply reflect glial proliferation in AD.

Aged↗

PubMed1989

Selectivity of the hippocampal projection to the prelimbic area of the prefrontal cortex in the rat.

Afferent connections of the medial and lateral prefrontal cortex of the rat arising from the hippocampal formation were investigated using iontophoretic application of the fluorescent tracer, Fluoro-gold. Our results demonstrate that the projection which originates in the temporal part of the CA1 hippocampal field and in the prosubiculum is restricted to the prelimbic area of the prefrontal cortex.

Animals↗

PubMed2002

Effects of quinolinic acid-induced lesions of the orbital prefrontal cortex on inter-temporal choice: a quantitative analysis.

RATIONALE: Lesions of the orbital prefrontal cortex (OPFC) can cause pathologically impulsive behaviour in humans. Inter-temporal choice behaviour (choice between reinforcers differing in size and delay) has been proposed as a model of "impulsive choice" in animals. OBJECTIVE: A quantitative method was used to analyse inter-temporal choice in rats with lesions of the OPFC and sham-lesioned control rats. METHODS: Under halothane anaesthesia, rats received injections of the excitotoxin quinolinate into the OPFC (0.1 M, 0.5 micro l; two injections in each hemisphere), or sham lesions (injections of the vehicle). They were trained to press two levers (A and B) for sucrose reinforcement (0.6 M) in discrete-trials schedules. In free-choice trials, a press on A resulted in delivery of 50 micro l of the sucrose solution after a delay d (A); a press on B resulted in delivery of 100 micro l of the same solution after a delay d (B). d (B) was increased progressively across successive blocks of six trials in each session, while d (A) was manipulated systematically across phases of the experiment. The indifference delay, d (B(50)) (value of d (B) corresponding to 50% choice of B) was estimated for each rat in each phase. Linear functions of d (B(50)) versus d (A) were derived, and the parameters of the function compared between the groups. The locations of the lesions were verified histologically at the end of the experiment. RESULTS: In both groups, d (B(50)) increased linearly with d (A) ( r(2)>0.98 in each case). The slope of the function was significantly steeper in the lesioned group than the sham-lesioned group, whereas the intercept did not differ significantly between the groups. The brains of the lesioned rats showed extensive atrophy/gliosis of the OPFC, with sparing of the dorsolateral prefrontal cortex. CONCLUSIONS: The results indicate that lesions of the OPFC can alter inter-temporal choice, either promoting or suppressing "impulsive choice", depending upon the relative sizes and delays of the two choice alternatives. Theoretical analysis based on a quantitative model of inter-temporal choice indicates that the pattern of effect of the OPFC lesion is likely to reflect two actions: (i) an increase in the rate of time discounting; (ii) an increase in sensitivity to the ratio of the sizes of two reinforcers.

Animals↗

PubMed2006

Electrolytic lesions of the medial prefrontal cortex do not interfere with long-term memory of extinction of conditioned fear.

Lesion studies indicate that rats without the medial prefrontal cortex (mPFC) have difficulty recalling fear extinction acquired the previous day. Several electrophysiological studies have also supported this observation by demonstrating that extinction-related increases in neuronal activity in the mPFC participate in expression of fear extinction. However, a more recent study has shown that fear extinction can be recalled, in certain circumstances, without mPFC potentiation, suggesting contribution of other circuits. Here, we examined this possibility in rats that were subjected to auditory fear conditioning, extinction training, and extinction retention test 7 d later. Electrolytic lesions were made in the mPFC, the motor cortex (MO), the dorsal septum (SEP), or the mediodorsal thalamus (MD), because of their potential participation in conditioned fear inhibition; combined lesions including the mPFC with the MO, SEP, or MD were also made. The lesions were made either 1 wk before conditioning or 1 d after extinction training. All rats normally extinguished their conditioned freezing behavior during extinction training and did not display any return of this behavior during the retention test. These data reveal that the mPFC is not required for the acquisition, the expression, or the retrieval of extinction memories but do not exclude the possibility that the mPFC normally participates in these processes.

Acoustic Stimulation↗

PubMedDate not supplied

Effect of corticotropin releasing factor receptor 1 antagonist on extracellular norepinephrine, dopamine and serotonin in hippocampus and prefrontal cortex of rats in vivo.

Corticotropin releasing factor (CRF) is a major mediator of adaptive responsiveness to stress. We measured changes in extracellular concentrations of catecholamine and indoleamines in freely moving rats in response to administration of CRF1 antagonist CP-154,526 by using in vivo microdialysis. Dialysis probes were placed stereotaxically in either the hippocampus or the prefrontal cortex. We examined the response in the hippocampus or the prefrontal cortex to 32.0 mg/kg i.p. administration of CP-154,526. CP-154,526 reduced the extracellular concentration of norepinephrine (NE) from 30 min to 180 min and 5-hydroxytryptamine (5-HT) from 30 min to 60 min after injection in the hippocampus. CP-154,526 did not remarkably change dopamine (DA). There were no significant differences between CP-154,526 and vehicle in NE, 5-HT and DA in the prefrontal cortex. The present results indicate that CRF1 receptor antagonist produced a decrease in dialysate concentration of NE and 5-HT, but not DA, in the hippocampus. These results suggest that the CRH-1 receptor antagonist suppresses the release of NE and 5-HT in the hippocampus.

Animals↗

PubMed2006

Bilateral activation of the prefrontal cortex after strategic semantic cognitive training.

The prefrontal cortex (PFC) has been implicated in the ability to apply semantic organizational strategies during verbal encoding and episodic learning. However, there has been no direct evidence demonstrating which specific areas in the PFC are engaged after cognitive training using semantic organizational strategies in healthy adult human subjects. In this study, we investigated the effects of semantic strategic training on brain activity and changes in behavioral performance, after cognitive training, using functional MRI (fMRI). There was a significant activation in bilateral dorsolateral prefrontal (DLPF) and orbitofrontal (OFC) areas after cognitive training. These results demonstrate the engagement of bilateral DLPF and OFC cortex during strategic memory processes, particularly when mobilization and effort of effective use of strategies are required. The functional adaptations observed here may also shed light on some of the processes underlying recovery with cognitive rehabilitation in patient populations with brain injury.

Adult↗

PubMed2006

Neural correlates of memory retrieval in the prefrontal cortex.

Working memory includes short-term representations of information that were recently experienced or retrieved from long-term representations of sensory stimuli. Evidence is presented here that working memory activates the same dorsolateral prefrontal cortex neurons that: (a) maintained recently perceived visual stimuli; and (b) retrieved visual stimuli from long-term memory (LTM). Single neuron activity was recorded in the dorsolateral prefrontal cortex while trained monkeys discriminated between two orientated lines shown sequentially, separated by a fixed interstimulus interval. This visual task required the monkey to compare the orientation of the second line with the memory trace of the first and to decide the relative orientation of the second. When the behavioural task required the monkey to maintain in working memory a first stimulus that continually changed from trial to trial, the discharge in these cells was related to the parameters--the orientation--of the memorized item. Then, what the monkey had to recall from memory was manipulated by switching to another task in which the first stimulus was not shown, and had to be retrieved from LTM. The discharge rates of the same neurons also varied depending on the parameters of the memorized stimuli, and their response was progressively delayed as the monkey performed the task. These results suggest that working memory activates dorsolateral prefrontal cortex neurons that maintain parametrical visual information in short-term and LTM, and that the contents of working memory cannot be limited to what has recently happened in the sensory environment.

Action Potentials↗

PubMed1986

Cholinergic induction of seizures in the rat prefrontal cortex.

Intracerebral microinjection of the cholinergic agonist, carbachol, into the medial prefrontal cortex of the rat, induced a profound behavioral syndrome consisting of repetitive, stereotyped forepaw treading in an upright posture. Electroencephalographic analysis revealed multiple bursts of sharp waves, 200-300 microV, accompanying the carbachol-elicited motor behavior. Pretreatment with intraperitoneal doses of three anticonvulsant drugs, clonazepam, diazepam, and pentobarbital, blocked the manifestation of the motor behavior. These observations suggest that activation of cholinergically innervated regions of the rat medial prefrontal cortex induces an atypical form of seizures.

Animals↗

PubMed2006

A dynamical model of event-related FMRI signals in prefrontal cortex: predictions for schizophrenia.

Two different models of the topographical and functional organization of the prefrontal cortex have been proposed: organization-by-stimulus-domain, and organization-by-process. The present work utilizes an integrate-and-fire network to model fMRI data on short term memory in order to understand data obtained in topologically different parts of the prefrontal cortex during working memory tasks. We explicitly model the mechanisms that underly working memory-related activity during the execution of delay tasks. It is shown that the effects of neuromodulation by dopamine of the synaptic processes utilized in the neurons in the model leads to experimental predictions of the effects of manipulations of dopamine on working memory.

Brain Mapping↗

PubMed2005

cAMP and extracellular signal-regulated kinase signaling in response to d-amphetamine and methylphenidate in the prefrontal cortex in vivo: role of beta 1-adrenoceptors.

d-Amphetamine and methylphenidate are widely used in the treatment of attention-deficit/hyperactivity disorder. Both drugs increase extracellular norepinephrine and dopamine in the prefrontal cortex, where they are believed to exert their therapeutic effects. However, the molecular mechanisms underlying their action are poorly understood. To investigate the intracellular signaling pathways activated by d-amphetamine and methylphenidate in the prefrontal cortex in vivo in mice, we measured the cAMP-dependent Ser845 phosphorylation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor GluR1 subunit and the active form of extracellular signal-regulated kinase (ERK). Administration of d-amphetamine (5-10 mg/kg) or methylphenidate (10-20 mg/kg) increased phosphorylation of GluR1. Basal and d-amphetamine-induced GluR1 phosphorylation was reduced by propranolol, a general beta-adrenoceptor antagonist, and betaxolol, a beta1-antagonist, but not by (+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol (ICI-118,515), a beta2-antagonist. The effect of methylphenidate was also blocked by propranolol and betaxolol. The d-amphetamine effect was slightly potentiated by prazosin, an alpha1-adrenoceptor antagonist, and mimicked by yohimbine, an alpha2 antagonist. Blockade of dopamine or N-methyl-d-aspartate (NMDA) receptors or serotonin depletion had no effect on d-amphetamine-induced GluR1 phosphorylation. d-amphetamine but not methylphenidate increased ERK phosphorylation. This effect required multiple signaling pathways because it was blocked by beta1- and alpha1-adrenoceptor antagonists, by dizocilpine maleate (MK801), an NMDA antagonist, and by serotonin depletion. In contrast, blockade of dopamine receptors had no effect on d-amphetamine-induced ERK phosphorylation. Propranolol and betaxolol increased the hyperlocomotion produced by d-amphetamine and methylphenidate. Thus, both d-amphetamine and methylphenidate potently activate the cAMP pathway in the prefrontal cortex through beta1-adrenergic receptors. This activation could have behavioral consequences and contribute to the treatment of attention-deficit/hyperactivity disorder.

Animals↗

PubMed1999

Nicotinic receptors in the rat prefrontal cortex: increase in glutamate release and facilitation of mediodorsal thalamo-cortical transmission.

The modulatory influence of nicotinic acetylcholine receptor (nAChRs) on thalamocortical transmission was characterized in the prelimbic area (PrL) of the rat prefrontal cortex. In the first experiment, rats received a unilateral excitotoxic lesion centred on the mediodorsal thalamic nucleus (MD), and were sacrificed 1 week later. The lesion resulted in a 40% reduction of 3H-nicotine autoradiographic labelling in the ipsilateral prefrontal cortex, particularly in areas that are innervated by the MD. Electrophysiological experiments were subsequently performed in non-lesioned anaesthetized animals, in order to study modulation of short- and long-latency responses of PrL neurons evoked by electrical stimulation of the MD. The short-latency responses result from activation of the MD-PrL pathway and are mediated via AMPA-type glutamatergic receptors, whereas the long-latency responses reflect activation of the recurrent collaterals of cortical pyramidal neurons, Iontophoretic application of nicotinic agonists (nicotine, DMPP) facilitated both types of response. Local application of the nAChR antagonists dihydro-beta-erythroidine, mecamylamine and methyllycaconitine, prevented both kinds of facilitation. Finally, intracerebral microdialysis experiments were performed in order to test for nicotinic modulation of extracellular glutamate concentrations in the PrL. Direct application of nicotine via the dialysis probe increased glutamate levels in a dose-dependent manner. This effect was blocked by local perfusion of dihydro-beta-erythroidine. These findings therefore provide anatomical and functional evidence for nAChR-mediated modulation of thalamocortical input to the prefrontal cortex. Such a mechanism may be relevant to the cognitive effects of nicotine and nicotinic antagonists.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1993

Effects of metabolic perturbation on plasma homovanillic acid in schizophrenia. Relationship to prefrontal cortex volume.

OBJECTIVE: Several recent hypotheses suggest that deficits in normal prefrontal cortical inhibition of subcortical dopamine activity result in dysregulated dopamine function and may contribute to the pathophysiology of schizophrenia. These effects seem to be more consistently demonstrable during stressful perturbation of the dopamine system, as opposed to during the resting state. We have developed a novel paradigm involving infusion of the glucose analog, 2-deoxyglucose (2DG), to examine the effects of perturbation on the dopamine metabolite, plasma homovanillic acid (HVA), in schizophrenics and healthy controls. DESIGN: Pharmacologic doses of 2DG (50 mg/kg) and placebo were infused in a double-blind manner. 2-Deoxyglucose-induced effects on plasma HVA were related to magnetic resonance imaging-derived prefrontal cortex volumes. SUBJECTS: Schizophrenic outpatients (N = 18) and healthy volunteers (N = 11) participated in the study. RESULTS: Schizophrenic patients, as compared with controls, had significantly greater 2DG-induced plasma HVA elevations. These effects were observed in subgroups of neuroleptic-free and neuroleptic-treated patients. Other neuroendocrine (plasma cortisol), physiologic (heart rate, diastolic blood pressure, temperature) and behavioral (self-ratings of stress, fatigue) variables were significantly effected by 2DG but did not differeniate schizophrenics and controls suggesting that the effects on plasma HVA may be relatively specific. Magnetic resonance imaging-derived volumes of the prefrontal cortex were significantly and inversely correlated to 2DG-related peak changes in plasma HVA levels in the schizophrenics. CONCLUSION: These data support the hypothesis that schizophrenia is associated with abnormal regulation of dopamine and that this deficit may be related to reduced frontal cortical inhibitory influences.

Adult↗

PubMed1984

The prefrontal cortex of a prosimian (Galago senegalensis) is reached by efferent neurons originating in the nucleus basalis of Meynert.

Efferent projections from the basal forebrain to the prefrontal cortex of the lesser bush baby (Galago senegalensis) were traced with the retrograde horseradish peroxidase technique. Different areas of the prefrontal cortex of six bush babies were injected with small amounts of horseradish peroxidase. The entire basal forebrain was then screened for labeled neurons. Following all six injections, many retrogradely labeled neurons could be detected in the nucleus basalis of Meynert. These results indicate a strong innervation of the bush baby's prefrontal cortex by the nucleus basalis of Meynert. The observed projections seem comparable in strength and topography to those found in another primate species, the rhesus monkey. Anatomical and functional implications of these projections in the bush baby are discussed and related to findings in other primates and species of other orders.

Animals↗

PubMed1992

Neuromedin N decreases self-stimulation of the medial prefrontal cortex.

Intracerebral microinjections of neurotensin (NT) decrease intracranial self-stimulation (ICSS) of the medial prefrontal cortex (MPC) in the rat. This effect could be due to the ability of NT to bind dopamine. To test this hypothesis we studied the effects of intracerebral microinjections of neuromedin N, a natural NT analogue that does not bind dopamine, on ICSS of the rat MPC. Unilateral microinjections of neuromedin N into the MPC at doses of 2.5, 5, 10, 20 and 40 nmol produced a dose-related decrease in ICSS of the ipsilateral MPC. ICSS of the contralateral MPC, used as a control, was not affected by the microinjections. These results suggest that the inhibitory effect of NT on ICSS is independent of NT-dopamine binding. Because neuromedin N is also present in the MPC, these results also suggest a possible neuromodulatory role of this neuropeptide on ICSS of the prefrontal cortex.

Animals↗

PubMed2004

The role of the human ventromedial prefrontal cortex in memory for contextual information.

There is a growing body of evidence that the ventromedial prefrontal cortex (VMPFC) is implicated in the new learning of visual items. Little is known, however, as to the involvement of that portion of the prefrontal cortex in the learning of temporal and spatial relationship of those items. The aim of the present study, therefore, was to investigate the role of the VMPFC in memory for temporal and spatial order. Patients who had undergone surgery of the anterior communicating artery aneurysm, and normal control subjects (C), participated in the study. The patients were subdivided into three groups: with resection of the left (LGR+) or right (RGR+) gyrus rectus, and without such a resection (GR-). Subjects were presented with two memory tests: a temporal order (TO) test and a spatial order (SO) test. In the TO test, the LGR+ and RGR+ groups performed worse than the C group, while the GR- group did not differ significantly from the C group. In the SO test, the LGR+ and RGR+ groups did not differ significantly from the C and GR- groups. However, the trend appears to be the same for both tests, although only the TO test provides statistically significant group differences. Our results thus suggest that the VMPFC is involved in memory for contextual information. Together with previous findings, the data suggest that the learning of the relationship between items as well as the learning of those items are mediated by overlapping areas of the VMPFC.

Aneurysm, Ruptured↗

PubMed2006

Effect of metabotropic glutamate receptor 3 genotype on N-acetylaspartate measures in the dorsolateral prefrontal cortex.

OBJECTIVE: This study was carried out to confirm prior evidence of an effect of a single nucleotide polymorphism (SNP) in the metabotropic glutamate receptor 3 (GRM3) gene (a putative risk factor for schizophrenia) on measures of N-acetylaspartate in healthy comparison subjects. METHOD: Fifty-four carefully screened healthy volunteers genotyped at SNP rs6465084 underwent magnetic resonance spectroscopic imaging (MRSI) at 3 T and selected neuropsychological testing. RESULTS: The A/A genotype group exhibited a significant reduction of N-acetylaspartate/creatine levels in the right dorsolateral prefrontal cortex compared to the G carriers. A tendency in the same direction was seen in the left dorsolateral prefrontal cortex and in the white matter adjacent to the prefrontal cortex. CONCLUSIONS: These findings provide further evidence that GRM3 affects prefrontal function and that variation in GRM3, monitored by SNP rs6465084, affects GRM3 function.

Aspartic Acid↗

PubMedDate not supplied

Aging, prefrontal cortex, and amino acid neurotransmitters: differential effects produced by electrical stimulation.

The purpose of the present study was to investigate the effects of electrical stimulation on the in vivo release of amino acid neurotransmitters in the prefrontal cortex of young (3-4 months) and aged (27-30 months) rats. In vivo push-pull perfusions were performed in the conscious animal. The levels of aspartate, glutamate, and glycine were analyzed by HPLC-fluorimetric detection. Electrical stimulation of the medial prefrontal cortex at the intensity of 0.3 mA produced a significant increase in the levels of aspartate, glutamate, and glycine in young but not aged rats. However, at the intensity of 0.6 mA, a significant delayed increase of these same amino acids was produced in the aged rats. These results support the existence of a differential effect of electrical stimulation on amino acid neurotransmitters in the prefrontal cortex of young and aged rats.

Aging↗