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PubMed2002

Brief communication: how much larger is the relative volume of area 10 of the prefrontal cortex in humans?

It has long been thought that the prefrontal cerebral cortex has been greatly expanded in the human brain. Semendeferi et al. ([2001] Am. J. Phys. Anthropol. 114:224-241) showed that Brodmann's area 10 is relatively larger in the human compared to pongid brains. The question is: how much larger relatively is it? Using their data, it can be shown that the relative increase for human prefrontal area 10 is only 6% larger. Looking at the data base of neural structures provided by Stephan et al. ([1981] Folia Primatol. (Basel) 35:1-29), it is apparent that 6% is a relatively low residual value from a predicted value based on allometric considerations between total brain weight and any given neural structure. When this small increase is combined with their earlier findings on area 13 of prefrontal cortex (Semendeferi et al. [1997] J. Hum. Evol. 32:375-388), it appears that the prefrontal cortex in humans is not some 200% larger as claimed by some researchers (Deacon [1997] Symbolic Species, New York: W.W. Norton; cf. Holloway [1998] Am Sci 86:184-186), and that the findings of Semendeferi et al. ([2001] Am. J. Phys. Anthropol. 114:224-241) are in agreement with the earlier work (Semendeferi and Damasio [2000] J. Hum. Evol. 38:317-332; Semendeferi et al. [1997] J. Hum. Evol. 32:375-388), showing that the human frontal lobe volume is what would be expected for a primate of its brain size. While the prefrontal cortex may have increased relatively in Homo sapiens, the increase is likely to have been far less than currently believed.

Humans↗

PubMed2003

Flibanserin, a potential antidepressant drug, lowers 5-HT and raises dopamine and noradrenaline in the rat prefrontal cortex dialysate: role of 5-HT(1A) receptors.

(1) Using in vivo intracerebral microdialysis in conscious, freely moving rats, we examined the effect of flibanserin, a potential antidepressant drug with high affinity for human 5-HT(1A) receptors and four-50-fold lower affinity for 5-HT(2A) and D(4) receptors, on basal extracellular concentrations of serotonin (5-hydroxytryptamine, 5-HT), dopamine (DA) and noradrenaline (NA) in selected regions of the rat brain. (2) Flibanserin at 3 and 10 mg kg(-1) significantly reduced extracellular 5-HT in the prefrontal cortex (by 30 and 45%) and dorsal raphe (35 and 44%), but had no effect on extracellular 5-HT in the ventral hippocampus. The 3 and 10 mg kg(-1) doses raised extracellular NA to a similar extent in the prefrontal cortex (47 and 50%). In all, 10 mg kg(-1) raised extracellular DA in the prefrontal cortex (63%) whereas 3 mg kg(-1) had no significant effect. (3) Pretreatment with the selective 5-HT(1A) receptor antagonist WAY100,635 (0.3 mg kg(-1)) 30 min before 10 mg kg(-1) flibanserin completely antagonized the latter's effects on extracellular 5-HT, DA and NA in the prefrontal cortex. WAY100,635 by itself had no effect on cortical extracellular monoamines. (4) The results show that the stimulation of 5-HT(1A) receptors plays a major role in the effect of flibanserin on brain extracellular 5-HT, DA and NA.

Animals↗

PubMed1994

Stress-induced activation of prefrontal cortex dopamine turnover: blockade by lesions of the amygdala.

Stress consistently has been found to activate peripheral and central catecholamine systems. Dopamine (DA) turnover in the prefrontal cortex is especially sensitive to stress produced by relatively mild footshock, conditioned fear, or exposure to a novel cage. Because lesions of the central nucleus of the amygdala block the effects of both stress and fear in many experimental paradigms, the present study evaluated whether such lesions would block stress-induced increases in prefrontal dopamine turnover using either mild footshock or novelty as stressors. In Experiment 1 electrolytic lesions of the central nucleus of the amygdala attenuated the increase in the dopamine metabolite homovanillic acid (HVA) in the prefrontal cortex evaluated in post-mortem tissue normally produced by footshock. In Experiment 2 similar lesions attenuated the increase in dopamine turnover in the prefrontal cortex using a different stressor, novelty, and a different measure of dopamine turnover, DOPAC/DA ratios. These data provide further evidence for the critical role of the amygdala in stress.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1982

Reduction of dopamine utilization in the prefrontal cortex but not in the nucleus accumbens after selective destruction of noradrenergic fibers innervating the ventral tegmental area in the rat.

The present study was made to determine the role of the noradrenergic (NA) neurons which innervate the ventral tegmental area (VTA) in the regulation of VTA dopaminergic (DA) neurons projecting to the prefrontal cortex and the nucleus accumbens. For this purpose, a 6-hydroxydopamine lesion was made in benztropine pretreated rats medially just above the decussatio of the pedunculus cerebellaris superior in order to specifically destroy the NA fibers innervating the VTA without affecting those projecting to the prefrontal cortex. Seven days later the ratio of DOPAC and DA levels was estimated in the prefrontal cortex and the nucleus accumbens and used as an index of DA utilization. In the lesioned rats the DOPAC/DA ratio was significantly decreased in the prefrontal cortex but not in the nucleus accumbens. These results suggest that the NA neurons which innervate the VTA exert a specific tonic excitatory influence on the mesocortico-prefrontal DA neurons.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1993

Effects of cocaine and footshock stress on extracellular dopamine levels in the medial prefrontal cortex.

The interaction between cocaine and footshock stress was evaluated by determining changes in extracellular dopamine and metabolite levels by in vivo microdialysis in the medial prefrontal cortex. In the first experiment, rats were given one of three treatments: no pretreatment (naive); or five daily injections of cocaine (15 mg/kg, i.p.); or daily saline. Six to seven days later, animals had a microdialysis probe implanted into the medial prefrontal cortex and an acute 20-min footshock stress (0.45 mA/200 ms per s) or sham shock was delivered. The results showed that acute footshock in daily saline pretreated rats increased medial prefrontal cortex extracellular dopamine concentrations to 203% of baseline levels. In rats pretreated with daily cocaine, this stress-induced response was completely abolished and extracellular dopamine was reduced 38% below baseline levels by 100 min post-shock. Naive animals showed a response to footshock that was intermediate between cocaine and saline pretreated rats (156% of baseline). In the second experiment, rats were given either no pretreatment (naive) or five daily 20-min footshock treatments (as above) or daily sham shock. Six to seven days later, an acute cocaine or saline injection was given. In daily sham-pretreated rats, extracellular dopamine levels were increased to 500% of baseline in response to acute cocaine. Pretreatment with daily footshock significantly reduced the response to acute cocaine (216% of baseline). Naive rats showed an intermediate increase that was not significantly different from footshock-pretreated animals (265% of baseline). Locomotor activity measured concurrently with dialysis showed a non-significant trend towards enhanced activity in daily footshock animals.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗

PubMed1994

[The dopaminergic and serotoninergic components of the self-stimulation reaction of the lateral hypothalamus in rats with disruption of the medial prefrontal cortex].

Amphetamine (1 mg/kg) promoted a pedal self-stimulation of lateral hypothalamus of Wistar rats in the Skinner box. An unipolar lesion of medical prefrontal cortex with kainic acid 10-14 days prior to an experiment did not prevent the facilitating effect of amphetamine on self-stimulation, though the levels of hypothalamic noradrenaline and dopamine are 43% and 4.5-fold decreased respectively, the hypothalamic serotonin concentration not changing. Lysergic acid diethylamid (10 mkg/kg) did not influence on self-stimulation response in rats with damaged medial prefrontal cortex, but after preliminary administration prevented the stimulating effect of amphetamine on self-stimulation of lateral hypothalamus. The data are discussed from the point of view of a hypothesis that the phenomenon obtained is associated with the presence of a hypothalamic autoregulatory dopaminergic system providing the realization of self-stimulation. However, it does not exclude that the modulating influence of medial prefrontal cortex on lateral hypothalamus is connected with not only dopaminergic but with serotoninergic axons too.

Amphetamine↗

PubMed2003

Involvement of the prefrontal cortex but not the dorsal hippocampus in the attention-enhancing effects of nicotine in rats.

RATIONALE: Nicotine can enhance attentional performance in humans, a property that may be of therapeutic utility. OBJECTIVES: To identify brain sites mediating nicotine-induced attentional enhancement. METHODS: Nicotine (0, 1, 2, 4 and 8 microg) was injected bilaterally into the dorsal hippocampus and the prelimbic area of the prefrontal cortex, brain sites implicated in cognitive functions, of rats performing the five-choice serial reaction time task (5-CSRTT). This rodent model of attention required the detection of light stimuli presented randomly in one of five locations during 30-min sessions. Systemically administered nicotine (0.1 and 0.2 mg/kg SC) was tested alongside local injections as a positive control. RESULTS: Nicotine (SC) enhanced response accuracy, reduced omission errors and shortened response latency. Nicotine injected into the dorsal hippocampus had no effect on any measure of performance except a slight decrease in latency in some animals at lower doses. By contrast, local injections of nicotine into the prefrontal cortex caused a dose-related increase in accuracy, the measure most closely reflecting stimulus detection and attention. Nicotine also increased omission errors selectively in the first 10 min of sessions and slightly reduced premature responding in the intertrial interval. No effects on response latency were observed. CONCLUSIONS: The results implicate the prefrontal cortex, but not the dorsal hippocampus, in the attention-enhancing effects of nicotine. The targeting of nicotinic receptor subtypes expressed in the prefrontal cortex may be of particular benefit for the treatment of chronic disease states characterised by attentional dysfunction.

Animals↗

PubMed1988

The dopaminergic innervation of monkey prefrontal cortex: a tyrosine hydroxylase immunohistochemical study.

The distribution of tyrosine hydroxylase (TH)-immunoreactive fibers was characterized immunohistochemically in the prefrontal cortical regions of both Old World cynomolgus monkeys (Macaca fascicularis) and New World squirrel monkeys (Saimiri sciureus). In both species, differences in the density and/or laminar distribution of TH-labeled fibers were detected both across and within almost every prefrontal cytoarchitectonic region. In cynomolgus monkeys, areas 9 and 24 had the greatest density of TH-labeled fibers, areas 11, 12, 13 and 25 were of intermediate density, and areas 10 and 46 had the lowest density of immunoreactive fibers. Differences in fiber density within many of these regions were also consistently observed. On a laminar basis, the distribution of labeled fibers in a given area of cynomolgus prefrontal cortex was systematically related to the overall fiber density of that area. For example, in the lightly innervated fundus of the principal sulcus (area 46), labeled fibers were primarily present in layer I and layers V-VI, whereas in area 9, the most densely innervated region, TH-labeled fibers were present in all cortical layers. Similar regional differences in the density and laminar distribution of TH-immunoreactive fibers were also present in squirrel monkey prefrontal cortex. In previous studies, we have analyzed the regional and laminar distributions of fibers immunoreactive for TH and dopamine-beta-hydroxylase (DBH), a specific marker for noradrenergic cortical fibers, in multiple areas of cortex from both normal and locus ceruleus-lesioned animals. These comparisons, which have been confirmed in the present report, indicate that anti-TH and anti-DBH label distinct populations of axons in monkey neocortex, which presumably are dopaminergic and noradrenergic, respectively. Thus, the distribution of TH immunoreactivity described in the present report suggests that dopaminergic fibers are distributed in a very heterogeneous fashion in monkey prefrontal cortex. The distinctive innervation patterns exhibited by these fibers reveal the regions and layers that may be the principle sites of action of dopamine in exerting its effects on prefrontal cortical function.

Animals↗

PubMed1998

Effect of antipsychotic drugs on extracellular serotonin levels in rat medial prefrontal cortex and nucleus accumbens.

Amperozide, clozapine, olanzapine and risperidone are more potent serotonin (5-hydroxytryptamine, 5-HT)2A receptor antagonists than dopamine D2-like receptor antagonists. Haloperidol and S(-)-sulpiride are potent or selective dopamine D2-like receptor antagonists and lack 5-HT2A receptor antagonist properties. We studied the effect of these five proven antipsychotic drugs and one putative (amperozide) antipsychotic drug on extracellular 5-HT levels in the medial prefrontal cortex and the nucleus accumbens of awake, freely-moving rats, using in vivo microdialysis with dual probe implantation. Risperidone (1 mg/kg) and clozapine (20 mg/kg) significantly increased extracellular 5-HT levels in the medial prefrontal cortex and the nucleus accumbens, respectively. Amperozide (2 and 10 mg/kg) significantly increased extracellular 5-HT levels in both regions. Olanzapine (1 and 10 mg/kg), S(-)-sulpiride (10 and 25 mg/kg), haloperidol (0.1 and 1 mg/kg) and the selective 5-HT2A receptor antagonist MDL-100,907 (1 mg/kg) had no significant effect on extracellular 5-HT levels in either region. Thus, the ability to increase extracellular 5-HT levels in the medial prefrontal cortex and the nucleus accumbens by these antipsychotic drugs is not directly related to their affinity for 5-HT2A receptors since olanzapine and MDL-100,907 had no significant effect on extracellular 5-HT levels. A variety of mechanisms other than those involving 5-HT2A receptors, e.g., reuptake inhibition (amperozide) and blockade of alpha2-adrenoceptors (clozapine), may contribute to the ability to increase extracellular 5-HT levels in the brain. The increase in extracellular 5-HT levels in the medial prefrontal cortex or nucleus accumbens following amperozide, clozapine, or risperidone administration may not be related to the effect on psychotic symptoms but could be related to effects on other types of psychopathology such as depression, negative symptoms, or cognition.

Animals↗

PubMed1999

Effects of cocaine on dopamine in subregions of the rat prefrontal cortex and their efferents to subterritories of the nucleus accumbens.

The present study sought to investigate the contributions of the ventral prelimbic/infralimbic cortices and shell subterritory of the nucleus accumbens as well as the dorsal prelimbic/anterior cingulate cortices and core subregion of the nucleus accumbens to the acute systemic effects of cocaine (20 mg/kg i.p.) on both locomotor activity and simultaneous dialysate dopamine levels using a dual-probe microdialysis design. Basal dopamine levels were significantly higher in the ventral medial prefrontal cortex compared with the dorsal medial prefrontal cortex and higher concentrations of dopamine were also observed in the core of the nucleus accumbens compared with its shell counterpart. Cocaine produced a significant decrease in dopamine levels in both the ventral and dorsal medial prefrontal cortices. In contrast, cocaine significantly increased dialysate dopamine in the shell of the nucleus accumbens, whereas only a slight increase in dopamine was observed in the core subregion of the nucleus accumbens. A significant negative relationship between dopamine levels in the ventral and dorsal medial prefrontal cortices and dialysate dopamine concentrations in the shell and core of the nucleus accumbens was observed. Finally, in both the ventral and dorsal medial prefrontal cortices, the magnitude of the locomotor response to cocaine was inversely related to dialysate dopamine levels. In contrast, the magnitude of the locomotor response to cocaine became progressively larger as dopamine levels increased in the shell of the nucleus accumbens. These results show a dissociation in the pattern of dopamine release in subterritories of both the medial prefrontal cortex and nucleus accumbens in response to the acute systemic administration of cocaine.

Animals↗

PubMed2006

Selective increases in the cytokine, TNFalpha, in the prefrontal cortex of PCP-treated rats and human schizophrenic subjects: influence of antipsychotic drugs.

The psychotomimetic drug phencyclidine (PCP) induces symptoms closely related to those of schizophrenia in humans. In order to test the hypothesis that cytokines may be involved in the aetiology and treatment of schizophrenia, this study investigated the levels of cytokine mRNAs in rat brain after acute and chronic administration of PCP, in the presence and absence of antipsychotic drugs. The levels of the mRNAs encoding TNF, IL-2, IL-6, TGF 1, 2, 3, IL-3 and GM-CSF were measured in the prefrontal cortex, cortex, hippocampus, ventral and dorsal striatum regions of male hooded Long Evans rats after acute drug administration. Antipsychotic drugs and PCP significantly reduced the levels of TNF in the prefrontal cortex compared to vehicle-treated animals, whilst other cytokines remained unchanged. In addition, significant reductions in the levels of TNF mRNA in the prefrontal cortex still occurred 24h after acute PCP administration. However, levels of TNF mRNA were restored to control values after chronic PCP treatment, whereas increased expression was detected in animals co-administered with haloperidol. Levels of TNF mRNA were also found to be significantly increased in the prefrontal cortex of schizophrenic subjects. The relationship between TNF levels and schizophrenia are discussed.

Adult↗

PubMed1999

Interactions of prefrontal cortex in relation to awareness in sensory learning.

In an associative learning paradigm, human subjects could be divided based on whether they were aware that one tone predicted a visual event and another did not. Only aware subjects acquired a differential behavioral response to the tones. Regional cerebral blood flow in left prefrontal cortex showed learning-related changes only in aware subjects. Left prefrontal cortex also showed changes in functional connectivity with contralateral prefrontal cortex, sensory association cortices, and cerebellum. Several of the interacting areas correlated with aware subjects' behavior. These results suggest cerebral processes underlying awareness are mediated through interactions of large-scale neurocognitive systems.

Acoustic Stimulation↗

PubMed2000

Postnatal development of the basal forebrain cholinergic projections to the medial prefrontal cortex in mice.

The postnatal development of basal forebrain cholinergic projections to the medial prefrontal cortex in mice was analyzed by means of the double labeling track-tracing study. The tracer was injected into the medial prefrontal cortex of mice, on the day of birth (P0) to 60 days after birth. The total number of basal forebrain neurons increased from P4 to P8, and began to decrease until P13 (52.9% vs. the maximal average (P8)). After P13, the mean average remains stable up to P60. On the other hand, differential pattern of frontocortical projections of the anterior, intermediate, and posterior regions can be observed.

Acetylcholinesterase↗

PubMed1991

Neuronal activity related to saccadic eye movements in the monkey's dorsolateral prefrontal cortex.

1. Single-neuron activity was recorded from the prefrontal cortex of monkeys performing saccadic eye movements in oculomotor delayed-response (ODR) and visually guided saccade (VGS) tasks. In the ODR task the monkey was required to maintain fixation of a central spot throughout the 0.5-s cue and 3.0-s delay before making a saccadic eye movement in the dark to one of four or eight locations where the visual cue had been presented. The same locations were used for targets in the VGS tasks; however, unlike the ODR task, saccades in the VGS tasks were visually guided. 2. Among 434 neurons recorded from prefrontal cortex within and surrounding the principal sulcus (PS), 147 changed their discharge rates in relation to saccadic eye movements in the ODR task. Their response latencies relative to saccade initiation were distributed between -192 and 460-ms, with 22% exhibiting presaccadic activity and 78% exhibiting only postsaccadic activity. Among PS neurons with presaccadic activity, 53% also had postsaccadic activity when the monkey made saccadic eye movements opposite to the directions for which the presaccadic activity was observed. 3. Almost all (97%) PS neurons with presaccadic activity were directionally selective. The best direction and tuning specificity of each neuron were estimated from parameters used to fit a Gaussian tuning curve function. The best direction for 62% of the neurons with presaccadic activity was toward the contralateral visual field, with the remaining neurons having best directions toward the ipsilateral field (23%) or along the vertical meridian (15%). 4. Most postsaccadic activity of PS neurons (92%) was also directionally selective. The best direction for 48% of these neurons was toward the contralateral visual field, with the remaining neurons having best directions toward the ipsilateral field (36%) or along the vertical meridian (16%). Eighteen percent of the neurons with postsaccadic activity showed a reciprocal response pattern: excitatory responses occurred for one set of saccade directions, whereas inhibitory responses occurred for roughly the opposite set of directions. 5. Sixty PS neurons with saccade-related activity in the ODR task were also examined in a VGS task. Forty of these neurons showed highly similar profiles of directional specificity and response magnitude in both tasks, 13 showed saccade-related activity only in the ODR task, and 7 changed their response characteristics between the ODR and VGS tasks.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2001

Differential environment alters ontogeny of dopamine innervation of the orbital prefrontal cortex in gerbils.

In the present study, the influence of postnatal environmental conditions on the structural ontogeny of the orbital prefrontal cortex of adult gerbils (Meriones unguiculatus) was examined. The animals were bred and reared either isolated in standard laboratory cages or grouped in an object-filled environment. At the age of postnatal day 90, dopamine fibers were stained immunocytochemically and innervation density was determined in the orbital prefrontal cortex. By comparison, restricted rearing produced a restraint of the subsequent maturation of orbital prefrontal dopamine innervation, leading to adult fiber densities that were approximately 38% below those in seminaturally reared gerbils. Results are discussed in terms of activity-dependent postnatal maturation of the cortex and adaptive neuroplasticity with regard to previously published data concerning diminished dopamine innervation in the medial prefrontal cortex (Winterfeld et al. [1998]

Animals↗

PubMed2006

Metabolic alterations in the dorsolateral prefrontal cortex after treatment with high-frequency repetitive transcranial magnetic stimulation in patients with unipolar major depression.

Neuroimaging studies suggest a specific role of anterior cingulate cortex (ACC) and left dorsolateral prefrontal cortex (DLPFC) in major depression. Stimulation of the latter by means of repetitive transcranial magnetic stimulation (rTMS) as an antidepressant intervention has increasingly been investigated in the past. The objective of the present study was to examine in vivo neurochemical alterations in both brain regions in 17 patients with unipolar major depression before and after 10 days of high-frequency (20Hz) rTMS of the left DLPFC using 3-tesla proton magnetic resonance spectroscopy. Six out of seventeen patients were treatment responders, defined as a 50% reduction of the Hamilton depression rating scale. No neurochemical alterations in the ACC were detected after rTMS. As compared to the non-responders, responders had lower baseline concentrations of DLPFC glutamate which increased after successful rTMS. Correspondingly, besides a correlation between clinical improvement and an increase in glutamate concentration, an interaction between glutamate concentration changes and stimulation intensity was observed. Our results indicate that metabolic, state-dependent changes within the left DLPFC in major depressive disorder involve the glutamate system and can be reversed in a dose-dependent manner by rTMS.

Adult↗

PubMed2003

Increased stress vulnerability after a prefrontal cortex lesion in female rats.

Neuroimaging studies in patients suffering from affective disorders have shown decreased volume and reduced regional cerebral blood flow in multiple areas of the prefrontal cortex, including the medial prefrontal cortex and the orbitofrontal cortex. This aberrant brain activity is among other things attributed to chronic stress. Affective disorders occur more often in women than in men. In the current experiment, female mPFC-lesioned and non-lesioned rats were subjected to 3 weeks of chronic unpredictable stress in order to determine the role of the mPFC in dealing with chronic stress, and the consequences of mPFC damage for coping with consecutive stressful events. mPFC damage in female rats intensified the stress-induced activation of the dorsomedial nucleus of the hypothalamus and the paraventricular nucleus of the hypothalamus as measured with Fos expression changes and markedly increased plasma catecholamine levels after 3 weeks of unpredictable stress. Additionally, an mPFC lesion significantly reduced the time of appearance of stress-induced behavioral changes in the open field. Altogether, mPFC dysfunction affects the way female rats react to chronic stress, it not only increased the activation of brain regions involved in neuroendocrine and autonomic responses to stress but it also significantly reduced the time of onset of behavioral changes.

Animals↗

PubMed1994

Induction of errors in a delayed response task by repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex.

We used repetitive transcranial magnetic stimulation to study the function of the dorsolateral frontal cortex in a delayed response task in 10 normal volunteers. Unilateral stimulation of right or left prefrontal cortex during the delay period between instruction and execution cues led to a significantly greater number of response errors than stimulation of motor cortex or in unstimulated trials. Repetitive transcranial stimulation of appropriate intensity and frequency seems to disrupt the function of mnemonic cells in the prefrontal cortex and is useful for the study of the role of the prefrontal cortex in short-term motor memory.

Adult↗