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PubMed2004

Effects of acute and chronic buspirone on impulsive choice and efflux of 5-HT and dopamine in hippocampus, nucleus accumbens and prefrontal cortex.

RATIONALE: Reduced central serotonin (5-HT) activity has been associated with impulsive choice behaviour, but there is no consensus about the precise nature of these effects. Behavioural and neurochemical effects of 5-HT(1A) agonists such as buspirone depend critically on the dose and the duration of treatment. We thus undertook a parametric study of the effects of acute and chronic buspirone on the performance on a test of delayed gratification, as well as on the efflux of serotonin and dopamine (DA) in cortical and subcortical regions in rats. OBJECTIVES: Three experiments examined (i) the effects of acute buspirone on impulsive choice and how such effects were modified by prior chronic exposure to buspirone; (ii) the effects of chronic buspirone on impulsive choice; (iii) the effects on impulsive choice of a selective 5-HT(1A) antagonist, WAY-100635 tested alone and in combination with buspirone; (iv) the effects of chronic and acute buspirone on 5-HT and DA efflux in anaesthetised rats. METHODS: In experiment 1, rats previously trained on the delayed gratification task were tested with acute buspirone (0.5, 1 and 2 mg/kg). The same rats were then treated with chronic buspirone (1 mg/kg/day) over the next 65 days, and the effects of acute buspirone (1 mg/kg) re-determined at 20, 45 and 65 days of chronic treatment. In experiment 2, two groups of rats trained on the delayed gratification task were treated either with saline or buspirone (1 mg/kg/day) continually for 65 days before being tested with acute buspirone (1 mg/kg), WAY-100635 (0.08 mg/kg), or a combination of the two drugs. In experiment 3, rats received the same regimen of buspirone dosing as in experiment 2, before receiving in-vivo microdialysis for 5-HT and DA in the ventral hippocampus, nucleus accumbens and medial prefrontal cortex. RESULTS: Acute buspirone dose dependently increased the choice for the small, immediate reinforcer (impulsive choice) but the effects of 1 mg/kg were reversed on chronic administration of buspirone. This increased choice of the large, delayed reinforcer, which was not accompanied by any changes in baseline (non-drugged) performance, was blocked by the 5-HT(1A) receptor antagonist WAY-100635. The chronic buspirone regimen did not alter buspirone-evoked reductions in 5-HT efflux in hippocampus but did lead to a differential effect of acute buspirone in medial prefrontal cortex, with the chronic buspirone and saline groups exhibiting decreases and increases in efflux, respectively. There were no systematic changes in DA efflux under any condition. CONCLUSIONS: These findings show that the effects of acute buspirone on impulsive choice are reversed following chronic treatment and are mediated by 5-HT(1A) receptors, and suggest, in addition, that the behavioural effects may involve changes in 5-HT functioning in medial prefrontal cortex.

Analysis of Variance↗

PubMed2002

Comparative analysis of group II metabotropic glutamate receptor immunoreactivity in Brodmann's area 46 of the dorsolateral prefrontal cortex from patients with schizophrenia and normal subjects.

Glutamate is the primary excitatory neurotransmitter in the mammalian central nervous system, and a key neurotransmitter in prefrontal cortical function. Converging lines of evidence implicate prefrontal cortical dysfunction in the neurobiology of schizophrenia. Thus, aberrant glutamate neurotransmission may underlie schizophrenia and other complex disorders of behavior. Group II metabotropic receptors (mGluRs) are important modulators of glutamatergic and non-glutamatergic neurotransmission. Moreover, in an animal model, an agonist for group II mGluRs has been shown to reverse the behavioral, locomotor, and cognitive effects of the psychotomimetic drug phencyclidine. Accordingly, group II mGluRs constitute attractive targets for the pharmacotherapeutics and study of schizophrenia. Using immunocytochemistry and Western immunoblotting, we compared the localization and levels of group II mGluRs in Brodmann's area 46 of the dorsolateral prefrontal cortex from patients with schizophrenia and normal subjects. Consistent with previous reports, we found that immunolabeling of group II mGluRs is prominent in Brodmann's area 46. The majority of labeling was present on axon terminals distributed in a lamina-specific fashion. No apparent difference in the cellular localization or laminar distribution of immunoreactive group II mGluRs was noted between the two diagnostic groups. Similarly, the levels of receptor immunoreactivity determined by quantitative Western immunoblotting were comparable between schizophrenic patients and normal subjects. We conclude that while the function of group II mGluRs in Brodmann's area 46 of dorsolateral prefrontal cortex may be altered in patients with schizophrenia, this is not evident at the level of protein expression using an antibody against mGluR2 and mGluR3.

Adult↗

PubMed2005

Serotonergic modulation of prefrontal cortex during negative feedback in probabilistic reversal learning.

This study used functional magnetic resonance imaging to examine the effects of acute tryptophan (TRP) depletion (ATD), a well-recognized method for inducing transient cerebral serotonin depletion, on brain activity during probabilistic reversal learning. Twelve healthy male volunteers received a TRP-depleting drink or a balanced amino-acid drink (placebo) in a double-blind crossover design. At 5 h after drink ingestion, subjects were scanned while performing a probabilistic reversal learning task and while viewing a flashing checkerboard. The probabilistic reversal learning task enabled the separate examination of the effects of ATD on behavioral reversal following negative feedback and negative feedback per se that was not followed by behavioral adaptation. Consistent with previous findings, behavioral reversal was accompanied by significant signal change in the right ventrolateral prefrontal cortex (PFC) and the dorsomedial prefrontal cortex. ATD enhanced reversal-related signal change in the dorsomedial PFC, but did not modulate the ventrolateral PFC response. The ATD-induced signal change in the dorsomedial PFC during behavioral reversal learning extended to trials where subjects received negative feedback but did not change their behavior. These data suggest that ATD affects reversal learning and the processing of aversive signals by modulation of the dorsomedial PFC.

Adolescent↗

PubMed1989

Pharmacological profile of nicotinic acetylcholine receptors in the rat prefrontal cortex: an electrophysiological study in a slice preparation.

The specificity of nicotinic receptors in the neocortex has been questioned previously because: (i) electrophysiological responses to nicotine could not be blocked by nicotinic antagonists, and (ii) the effect of nicotine was not mimicked by acetylcholine. In the present study, the presence of functional nicotinic receptors in rat neocortex has been assessed in a slice preparation of prefrontal cortex, using evoked field potential and unit recordings. Nicotine and the nicotinic agonists, dimethylphenylpiperazinium, cytisine, acetylthiocholine, applied by iontophoresis, produced an increase in the negative wave of field potentials, reflecting an increased excitability of cortical neurons. This effect was blocked by the selective probe for neuronal nicotinic receptors Toxin F (1.4 microM in the perfusion medium) and by dihydro-beta-erythroidine (100 microM). Alpha-bungarotoxin, the blocker of skeletal muscle acetylcholine receptor had no effect. Iontophoretically applied acetylcholine, muscarine and pilocarpine, on the other hand, produced a decrease in the field potential amplitude, which was blocked by atropine and scopolamine (1-10 microM). In the presence of eserine (10 microM), the muscarinic effect of acetylcholine was dramatically altered, leading to the development of a nicotinic response sensitive to Toxin F. Thus, the physiological activation of nicotinic receptors in rat prefrontal cortex appears to require higher concentrations of acetylcholine than do muscarinic receptors. Our results show that: (i) the rat prefrontal cortex possesses functional nicotinic receptors with a pharmacological profile clearly distinct from muscle receptors, and (ii) a nicotinic effect of acetylcholine can be revealed when its degradation by acetylcholinesterase is inhibited.

Acetylcholine↗

PubMed2001

Effects of slow rTMS at the right dorsolateral prefrontal cortex on EEG asymmetry and mood.

In a sham-controlled design (n = 12), slow repetitive transcranial magnetic stimulation (rTMS) was applied to the right dorsolateral prefrontal cortex for 20 min, and the subsequent effects on mood and the EEG spectrum were investigated, Analysis revealed a significant left hemisphere increase in EEG theta activity at 25-35 and 55-65 min after stimulation. In addition, participants reported significant decrease in anxiety immediately after stimulation, as well as 35 and 65 min after rTMS. These findings indicate that reductions in anxiety after slow rTMS at the right dorsolateral prefrontal cortex are associated with a contralateral increase in theta activity.

Adult↗

PubMed1997

Selective dopamine depletion within the medial prefrontal cortex induces anxiogenic-like effects in rats placed on the elevated plus maze.

The objective of this study was to investigate if selective dopamine depletion within the medial prefrontal cortex modifies the anxiety state in rats. Anxiety was evaluated by using the elevated plus maze test, an anxiety model. Dopamine depletion in the medial prefrontal cortex (79% vs. controls) induced a significantly lower preference to stay on open arms together with a reliably lower frequency of open arm entries, as well as a significant increase of percent time spent on closed arms. Although locomotion was also significantly reduced, protected head-dipping and protected stretched attend, novel "ethologically derived" indices of anxiety, were reliably enhanced. Taken together, the results are indicative of enhanced anxiety level despite hypomotility. The findings confirm that prefrontocortical dopamine activation is necessary for coping with an anxiogenic challenge, allowing the animal to display adaptive exploratory responses in a fear-inducing environment.

Animals↗

PubMed2004

Neural representation of vocalizations in the primate ventrolateral prefrontal cortex.

In this study, we examined the role of the ventrolateral prefrontal cortex in encoding communication stimuli. Specifically, we recorded single-unit responses from the ventrolateral prefrontal cortext (vlPFC) in awake behaving rhesus macaques in response to species-specific vocalizations. We determined the selectivity of vlPFC cells for 10 types of rhesus vocalizations and also asked what types of vocalizations cluster together in the neuronal response. The data from the present study demonstrate that vlPFC auditory neurons respond to a variety of species-specific vocalizations from a previously characterized library. Most vlPFC neurons responded to two to five vocalizations, while a small percentage of cells responded either selectively to a particular vocalization type or nonselectively to most auditory stimuli tested. Use of information theoretic approaches to examine vocalization tuning indicates that on average, vlPFC neurons encode information about one or two vocalizations. Further analysis of the types of vocalizations that vlPFC cells typically respond to using hierarchical cluster analysis suggests that the responses of vlPFC cells to multiple vocalizations is not based strictly on the call's function or meaning but may be due to other features including acoustic morphology. These data are consistent with a role for the primate vlPFC in assessing distinctive acoustic features.

Animals↗

PubMed2006

Catecholaminergic neurons in medullary nuclei are among the post-synaptic targets of descending projections from infralimbic area 25 of the rat medial prefrontal cortex.

The infralimbic (IL) 'visceromotor' area of the rat medial prefrontal cortex projects to strategic subcortical nuclei involved in autonomic functions. Central among these targets are the nucleus tractus solitarius (NTS) and the rostral ventrolateral medulla (rVLM). By combining tract-tracing using the anterograde tracer biotinylated dextran amine (BDA) with immunolabeling for tyrosine hydroxylase (TH; an enzyme marker of catecholaminergic neurons), a limited proportion of BDA-labeled IL axonal boutons in the NTS and rVLM was found to be closely associated with TH immunopositive (+) target structures. Such structural appositions were mainly located proximally over the labeled dendritic arbors of identified TH+ neurons. Quantitative ultrastructural examination revealed that in NTS, TH+ dendritic shafts comprised 7.0% of the overall post-synaptic target population innervated by BDA-labeled IL boutons, whereas TH+ dendritic spines represented 1.25% of targets. In rVLM, TH+ shafts represented 9.0% and TH+ spines 2.5% of IL targets. Labeled IL boutons established exclusively asymmetric Gray Type 1 (presumed excitatory) synaptic junctions. The results indicate that subpopulations of catecholaminergic neurons in the NTS and rVLM are among the spectrum of post-synaptic neurons monosynaptically innervated by descending 'excitatory' input from IL cortex. Such connectivity, albeit restricted, identifies the potential direct influence of IL cortex on the processing and distribution of cardiovascular, respiratory and related autonomic information by catecholaminergic neurons in the NTS and VLM of the rat.

Afferent Pathways↗

PubMed1980

Neuronal activity in the monkey dorsolateral prefrontal cortex during a discrimination task with delay.

Ninety-nine single neuron activities of the dorsolateral prefrontal cortex of 3 monkeys were recorded during performance of a Konorski task. Green or red lights were presented successively with a separation of fixed delay interval. The monkey responded as soon as the second stimulus was presented. If the two stimuli were color-matched, the 'YES' lever press was rewarded; if the two stimuli were not, the 'NO' lever press was rewarded. In the second task, after paired color stimuli, a tone pip was presented as the 'GO' signal for lever presses. During sample and matching periods 50 neurons increased their discharge rates and 10 decreased. In 86% of increasing type neurons rate increase occurred during both periods. During auditory GO periods, 27 neurons increased their rates and 11 decreased. Discharge peak was before or at the moment of hold key release. In 60% of these neurons were also observed the rate changes to sample and matching stimuli. Differential activations between left and right levers were found in 20%. It was suggested that the prefrontal cortex is related to a sensorial attention mechanism to the visual stimulus which enables correct choice of the behavior to be rewarded.

Animals↗

PubMed1997

M1 acetylcholine receptor stimulation increases the extracellular concentrations of glutamate and GABA in the medial prefrontal cortex of the rat.

The present study was undertaken to examine the effects of different muscarinic receptor agonists on glutamate and GABA concentrations in the medial prefrontal cortex of the rat. In vivo perfusions were made in the conscious rat using a concentric push-pull cannulae system. Amino acid concentrations in samples were determined by HPLC with fluorometric detection. The intracortical perfusion of arecoline, a M1-M2 muscarinic receptor agonist, produced a significant increase in extracellular [GLU] and [GABA]. McN-A-343, a M1 muscarinic receptor agonist, but not the M2 muscarinic receptor agonist, oxotremorine, produced a significant increase in extracellular [GLU] and [GABA]. The effects of McN-A-343 on extracellular [GLU] and [GABA] were blocked by pirenzepine, a M1 muscarinic receptor antagonist. These results suggest that M1 muscarinic receptor stimulation increases the extracellular concentrations of GLU and GABA in the medial prefrontal cortex of the rat.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗

PubMed2005

Representation of attitudinal knowledge: role of prefrontal cortex, amygdala and parahippocampal gyrus.

It has been proposed that behavior is influenced by representations of different types of knowledge: action representations, event knowledge, attitudes and stereotypes. Attitudes (representations of a concept or object and its emotional evaluation) allow us to respond quickly to a given stimulus. In this study, we explored the representation and inhibition of attitudes. We show that right dorsolateral prefrontal cortex mediates negative attitudes whereas left ventrolateral prefrontal cortex mediates positive attitudes. Parahippocampal regions and amygdala mediate evaluative processing. Furthermore, anxiety modulates right dorsolateral prefrontal activation during negative attitude processing. Inhibition of negative attitudes activates left orbitofrontal cortex: a region that when damaged is associated with socially inappropriate behavior in patients. Inhibition of positive attitudes activates a brain system involving right inferior frontal gyrus and bilateral anterior cingulate. Thus, we show that there are dissociable networks for the representation and inhibition of attitudes.

Adult↗

PubMed1993

Topography of pyramidal neuron intrinsic connections in macaque monkey prefrontal cortex (areas 9 and 46).

An understanding of the normal organization of prefrontal cortex is essential to the recognition of pathology underlying human behavioral disorders believed to depend on this region. We have therefore studied the pattern of intrinsic intra- and interlaminar pyramidal neuron connectivity in prefrontal areas 9 and 46 (of Walker) in macaque monkey cerebral cortex (anterior to the arcuate sulcus between the principal sulcus and midline). We made focal (200-400 microns) injections of biocytin and mapped the pattern of orthogradely transported label. Injections made into the superficial layers label wide-ranging lateral projections within the same areas of prefrontal cortex. Projections local to such small injections form a narrow band of terminals in layers 1-3 (200-400 microns wide, 2-4 mm long) centered on the injection site. Collateral fibers spread orthogonal to this terminal band, making frequent bifurcations, to establish a series of parallel bands of terminals with uninnervated bands between, spaced regularly across the cortex (center to center 500-600 microns). The entire pattern of terminal label is stripe-like, with occasional narrower interbands and crosslinks between the bands, and can extend over 7-8 mm across the cortex. These projections arise from pyramidal neurons in layers 2, 3, and 5 and terminate in layers 1-3. The stripe-like pattern contrasts with patch-like patterns in other cortical regions (V1, V2, V4, motor, somatosensory) and is smaller in scale than stripe-like zones of corticocortical afferent terminals to this region, reported to be 300-750 microns wide and spaced 1.0-1.5 mm center to center.

Animals↗

PubMed2003

A comparison of the effects of loxapine with ziprasidone and thioridazine on the release of dopamine and acetylcholine in the prefrontal cortex and nucleus accumbens.

RATIONALE: Atypical, but not typical, antipsychotic drugs (APDs), produce preferential increases in dopamine (DA) and acetylcholine (ACh) release in rat medial prefrontal cortex (mPFC) compared to the nucleus accumbens (NAC). The increase in DA release has been attributed, in part, to their greater serotonin (5-HT)(2A) relative to D(2) receptor occupancy, while the basis for the increase in ACh has not yet been determined. Loxapine, a dibenzoxazepine congener of clozapine, is generally considered to be a typical APD because it produces significant extrapyramidal symptoms (EPS) in humans, at generally recommended clinical doses (60-100 mg/day), and catalepsy in rodents, although several studies have found it to be effective at lower doses which do not produce significant EPS. Moreover, loxapine, like its congener clozapine, has higher affinity for serotonin (5-HT)(2A) than dopamine D(2) receptors, in vitro, suggesting the possibility it could be an atypical APD with clozapine-like potential. OBJECTIVES: The purpose of this study was to compare the effects of loxapine on DA and ACh release in the mPFC and NAC with those of ziprasidone, a novel atypical APD, and thioridazine, which is generally classified as a typical APD. RESULTS: Loxapine, 0.03-10 mg/kg, increased prefrontal dopamine release with the magnitude of this increase exceeding that in the NAC, at all doses, other than the 10 mg/kg dose. The effect of loxapine (0.3 mg/kg) on DA release in the prefrontal cortex was attenuated by WAY 100635 (0.2 mg/kg), a 5-HT(1A) antagonist, as is the case for other atypical APDs. Ziprasidone (0.1-3 mg/kg) also preferentially increased DA release in the mPFC compared to NAC. Thioridazine (5 and 20 mg/kg) did not increase DA release in either the mPFC or NAC. Loxapine (3 mg/kg) and ziprasidone (1 and 3 mg/kg), but not thioridazine (10 and 20 mg/kg), significantly increased cortical ACh release. CONCLUSION: Loxapine has effects on cortical and NAC DA and ACh release which are comparable to those of known atypical APDs. Ziprasidone and thioridazine have effects on cortical DA and ACh characteristic of atypical and typical APDs, respectively. It is concluded that further clinical studies of the atypical APD properties of loxapine are indicated.

Acetylcholine↗

PubMed2004

Spatial and temporal dissociation in prefrontal cortex during action execution.

It is widely accepted that dorsolateral prefrontal cortex (DLPFC) is activated at the time of action generation in humans. However, the previous functional neuroimaging studies that have supported this hypothesis temporally integrated brain dynamics and therefore could not demonstrate when DLPFC underwent activation relative to the emergence of voluntary behavior. Data that are time-locked to the instant of voluntary action execution do not reveal DLPFC activation at that moment. Rather, activated foci are seen at the frontal poles. We investigated this apparent conundrum through three differentially constrained experiments, utilizing functional magnetic resonance imaging to identify those prefrontal areas exhibiting functional change at the moment of spontaneous action execution. We observed profound functional dissociation between anterior and dorsolateral regions, compatible with their involvement at different points during the temporal evolution of action: bilaterally the frontal poles activated at the moment of execution, while simultaneously (and relative to a prior activation state) left DLPFC 'deactivated.'

Adult↗

PubMed2004

Perinatal flunitrazepam exposure causes persistent alteration of parvalbumin-immunoreactive interneuron localization in rat prefrontal cortex.

GABA regulates proliferation via GABAA receptors during development of the neocortex. We recently demonstrated that the endogenous GABAA receptor modulator allopregnanolone plays a role in regulating normal neurodevelopment in prefrontal cortex. Benzodiazepine exposure during early development produces marked behavioral changes in adult rats. To determine if exposure to benzodiazepines during development alters GABAergic interneurons in prefrontal cortex (PFC), rat pups were exposed to flunitrazepam (2.5 mg/kg) on postnatal day (P) 2 and assayed for parvalbumin- and calbindin-immunoreactivity on P80. The ratio of parvalbumin labeled cells in deep vs. superficial layers increased five-fold; calbindin-immunoreactivity and total cell number were not altered. These data are consistent with altered distribution of a subset of interneurons after benzodiazepine exposure and suggest a role for GABAA receptor modulation in normal development of GABAergic systems in PFC.

Animals↗

PubMed2005

Thickness of ventromedial prefrontal cortex in humans is correlated with extinction memory.

The ventromedial prefrontal cortex (vmPFC) has been implicated in fear extinction [Phelps, E. A., Delgado, M. R., Nearing, K. I. & Ledoux, J. E. (2004) Neuron 43, 897-905; Herry, C. & Garcia, R. (2003) Behav. Brain Res. 146, 89-96]. Here, we test the hypothesis that the cortical thickness of vmPFC regions is associated with how well healthy humans retain their extinction memory a day after having been conditioned and then extinguished. Fourteen participants underwent a 2-day fear conditioning and extinction protocol. The conditioned stimuli (CSs) were pictures of virtual lights, and the unconditioned stimulus (US) was an electric shock. On day 1, participants received 5 CS+US pairings (conditioning), followed by 10 CS trials with no US (extinction). On day 2, the CS was presented alone to test for extinction memory. Skin conductance response (SCR) was the behavioral index of conditioning and extinction. Participants underwent MRI scans to obtain structural images, from which cortical thickness was measured. We performed a vertex-based analysis across the entire cortical surface and a region-of-interest analysis of a priori hypothesized territories to measure cortical thickness and map correlations between this measure and SCR. We found significant, direct correlation between thickness of the vmPFC, specifically medial orbitofrontal cortex, and extinction retention. That is, thicker medial orbitofrontal cortex was associated with lower SCR to the conditioned stimulus during extinction recall (i.e., greater extinction memory). These results suggest that the size of the vmPFC might explain individual differences in the ability to modulate fear among humans.

Adult↗

PubMed1994

Spatial selectivity of go/no-go neurons in monkey prefrontal cortex.

We examined single-unit activity in the inferior prefrontal cortex during a visual go/no-go discrimination task under maintained visual fixation. The monkeys had to base their response on either the color, shape, or position of a discriminative cue, and the relevant task condition was indicated by the color of the fixation spot. We analyzed the spatial selectivity of 128 go/no-go neurons showing a marked differential cue-period activity that depended on whether the stimulus signaled a go or no-go response. Most of these neurons (n = 106, 83%) showed asymmetry between their responses to stimuli in the contralateral and ipsilateral visual fields. Seventy-seven of these neurons had a contralateral preferential field, and 29 had an ipsilateral preferential field. These results show that in many inferior prefrontal neurons a degree of differentiation in their responses to go and no-go stimuli depends on the cue positions, and that the coding of behavioral meaning is carried out mainly in the contralateral hemisphere.

Animals↗

PubMed2002

Alterations in MAP2 immunocytochemistry in areas 9 and 32 of schizophrenic prefrontal cortex.

A variety of lines of converging evidence implicate the prefrontal cortex (PFC) in schizophrenia. Studies employing Nissl stains have suggested that PFC dendrites may be atrophic in schizophrenia; however, Nissl stains do not reveal dendrites. We employed MAP2 immunocytochemistry, which stains dendrites to examine cortical layers III and V in two areas of the PFC (areas 9 and 32). Occipital cortex (area 17) was examined as a control region. Tissues from seven schizophrenics and seven non-psychiatric controls were examined. Immunostaining was quantitated by area fraction analysis. MAP2 area fraction was decreased in both layers in both regions of PFC, but not in occipital cortex. Area 9 exhibited a 42% reduction in layer V and a 36% reduction in layer III. Area 32 exhibited a 31% reduction in layer V and a 36% reduction in layer III. Neither region exhibited a significant change in the density of pyramidal cells. These data are consistent with the hypothesis of a schizophrenia-associated decrease in dendritic material in the PFC.

Adult↗