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Results for “Prefrontal Cortex”

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PubMed1991

Stimulation in prefrontal cortex inhibits conditioned increase in blood pressure and avoidance bar pressing in rats.

In our previous work, it was established that stimulation in a precisely defined area of the prefrontal cortex and in nucleus accumbens inhibits motor and cardiovascular components of the defence reaction elicited by stimulation in hypothalamus or amygdala, but it did not inhibit operant appetitive bar pressing. In the present investigations it was shown that electrical stimulation in the same area of prefrontal cortex and in the nucleus accumbens inhibited blood pressure increases elicited by a conditioned sound. In another set of experiments it was also shown that it inhibited bar pressing developed with Sidman's schedule. It is therefore concluded that inhibition originating in the described region of the prefrontal cortex is specifically addressed to motor and cardiovascular components motivated by fear or aggression.

Animals↗

PubMed2006

Lack of enhanced effect of antipsychotics combined with fluvoxamine on acetylcholine release in rat prefrontal cortex.

We have shown that coadministration of sulpiride and fluvoxamine preferentially increases the release of dopamine in the prefrontal cortex. To study the possible role of the cortical cholinergic system in this effect, we combined several other antipsychotic drugs with fluvoxamine and examined the effects on acetylcholine release in rat prefrontal cortex. Risperidone and clozapine significantly increased the release of acetylcholine but sulpiride did not, and fluvoxamine did not enhance the effects of the antipsychotics. These results further support the previous suggestion that the cortical dopamine system plays an important role in the effects of antipsychotic drugs administered in combination with fluvoxamine.

Acetylcholine↗

PubMed2000

Effects of prefrontal cortex microinjection of neurotensin-(8-13) on midbrain dopamine and non-dopamine cell firing.

Effects of prefrontal cortex microinjections of 0.3 and 3 nmol/0.5 microl of neurotensin-(8-13) on the firing rate of midbrain dopamine and non-dopamine cells were studied in urethane-anesthetized rats. Neurotensin produced an increase in firing in 14 of 26 dopamine cells tested, an effect that peaked between 15 and 20 min after the injection at both doses. On the other hand, a majority of non-dopamine cells (7/10) tested with the higher dose of neurotensin showed a statistically significant decrease in firing when compared to saline, an effect that also peaked between 15 and 20 min. These results show that prefrontal cortex neurotensin can modulate both dopamine and non-dopamine neurotransmission in the ventral midbrain.

Action Potentials↗

PubMed1999

Immunohistochemical localization of the cell adhesion molecules Thy-1 and L1 in the human prefrontal cortex patients with schizophrenia, bipolar disorder, and depression.

L1 and Thy-1 are members of the immunoglobulin (Ig) superfamily of cell adhesion molecules (CAMs) that are vital for normal neural development. Abnormalities in CAM expression could lead to the histological abnormalities that have previously been described in the frontal cortex of patients with schizophrenia. A postmortem immunohistochemical study of L1 and Thy-1 in the normal human prefrontal cortex revealed positive immunostaining of axons in all layers of the cortex. Quantifying the intensity of immunostaining in the prefrontal cortex of patients with schizophrenia, bipolar disorder and depression failed to reveal any significant differences when compared to that of normal controls.

Adult↗

PubMed1999

Idazoxan preferentially increases dopamine output in the rat medial prefrontal cortex at the nerve terminal level.

The effects of the alpha2-adrenoceptor antagonist idazoxan on extracellular concentrations of dopamine in major dopaminergic terminal regions in the brain were investigated by means of microdialysis in freely moving rats. Systemic administration of idazoxan markedly increased dopamine output in the medial prefrontal cortex, whereas it failed to affect dopamine efflux in the striatum or in the nucleus accumbens. Local perfusion of idazoxan via reversed dialysis markedly enhanced dopamine efflux in cortical but not subcortical areas, in which dopamine output was but little affected. Infusion of idazoxan into the ventral tegmental area did not alter the dopamine efflux in the medial prefrontal cortex. Moreover, the increase in cortical dopamine efflux induced by systemic administration of idazoxan was unaffected by tetrodotoxin perfusion of the ventral tegmental area. These data show that the alpha2-adrenoceptor antagonist idazoxan preferentially increases basal dopamine output in the medial prefrontal cortex through a local mechanism, an effect which appears largely independent of dopaminergic neuronal activity. An enhanced output of cortical dopamine may contribute to the purported augmentation by alpha2-adrenoceptor antagonists of the therapeutic effects of both antidepressant and antipsychotic drugs.

Adrenergic alpha-Antagonists↗

PubMed1997

Dual role of substance P/GABA axons in cortical neurotransmission: synaptic triads on pyramidal cell spines and basket-like innervation of layer II-III calbindin interneurons in primate prefrontal cortex.

In spite of accumulating evidence on the potent neuromodulatory, neuroprotective, trophic and memory-enhancing effects of the neuropeptide substance P (SP) in the cerebral cortex, the excitatory or inhibitory nature of the cortical SP innervation remains unclear and the postsynaptic targets of SP fibers are not defined. To obtain further insight into these issues, we have examined SP-containing axons and their postsynaptic targets in the prefrontal cortex of adult monkeys with single- and double label immunocytochemistry combined with light and correlated electron microscopy. SP fibers in the primate prefrontal cortex, unlike those in the rat cortex, preferentially innervate cortical layers I, II and upper layer III. Our results demonstrate for the first time that all SP-immunoreactive boutons in all cortical layers contain GABA. Of the entire sample of SP boutons, 53% synapse on dendritic shafts, 39% on dendritic spines and 8% on cell bodies. Another new finding is that synapse-forming SP boutons, in addition to their known innervation of pyramidal cells, form pericellular baskets around interneurons in layers II and upper III, a subpopulation of which contains calbindin D28k. Finally, the study also revealed that SP boutons frequently participate in 'synaptic triads' with spines which receive another (asymmetric, putatively excitatory amino acid-utilizing) synapse. Our findings indicate that SP/GABA axons in the primate prefrontal cortex modulate excitatory amino acid-mediated neurotransmission and control feed-forward disinhibitory GABAergic circuits in supragranular cortical layers.

Animals↗

PubMed2004

Age-dependent reductions in the level of glial fibrillary acidic protein in the prefrontal cortex in major depression.

The density of glial cells is reduced in certain layers of the dorsolateral prefrontal cortex in major depressive disorder (MDD). Moreover, there are reductions in the packing density of glial fibrillary acidic protein (GFAP) immunoreactive astrocytes in the same cortical layers in younger subjects with MDD. The objective of the present study was to test if the level of GFAP is preferentially decreased in younger subjects with MDD, and whether GFAP levels are correlated with the age of onset of depression. Post-mortem brain tissue punches from dorsolateral prefrontal cortex were collected from 15 subjects with MDD and 15 age-matched psychiatrically normal control subjects. Western blots were performed on gels containing duplicated samples from both subjects of each matched pair, and on gels containing samples at different ages from either the MDD or the control group. The GFAP level was calculated as the ratio of the optical density of GFAP bands to actin bands in subjects with MDD and nonpsychiatric controls. Levels of GFAP were significantly lower in subjects with MDD as compared to controls and this decrease was most prominent in subjects less than 60 years old at the time of death. In the MDD group, GFAP levels were positively correlated with age at the time of death and show a trend toward correlation with the age of onset of depression. These findings indicate that a decrease in levels of GFAP may contribute to the pathophysiology of MDD, particularly in subjects of relatively young age.

Adult↗

PubMed1997

Evidence for N-methyl-D-aspartate receptor-mediated increase in norepinephrine utilization in the prefrontal cortex of unanesthetized rats.

Local injection of N-methyl-D-aspartate (NMDA; 10-20 nmol/rat) into the prefrontal cortex of conscious rats caused a dose-related and an NMDA antagonist-reversible facilitation of norepinephrine (NE) disappearance in the cortical region during 35 min after inhibition of tyrosine hydroxylase. Destruction of ascending NE neurons by bilateral application of 6-hydroxydopamine into the superior cerebellar peduncle failed to affect [3H]N-(1-[2-thienyl]cyclohexyl)piperidine binding to the NMDA receptor-associated ion channel in the prefrontal cortex. These results indicate that, under unanesthetized conditions, the prefrontal NE neurons may be under glutamatergic facilitatory control mediated by the NMDA receptors which are located on the non-NE systems in the frontal cortex.

2-Amino-5-phosphonovalerate↗

PubMed1991

Single doses of methamphetamine cause changes in the density of dendritic spines in the prefrontal cortex of gerbils (Meriones unguiculatus).

Single doses of methamphetamine (25 mg/kg) were administered to adult gerbils. All detectable spines were counted along defined segments of basal, apical and lateral dendrites of Golgi-impregnated pyramidal cells in the medial prefrontal cortex (layers III and V) and the parietal cortex (layer V). These two areas were selected because previous investigations had shown methamphetamine-induced neurotoxicity in prefrontal cortex but not in parietal cortex. The frequencies of dendritic spines in methamphetamine-treated gerbils were found to be significantly increased in the prefrontal cortex, while no significant change was found in the parietal cortex.

Animals↗

PubMed2000

Massive impairment in executive functions with partial preservation of other cognitive functions: the case of a young patient with severe degeneration of the prefrontal cortex.

Historical bases for the special role of the prefrontal cortex are outlined and the case of a 27-year-old woman with massive bilateral prefrontal damage of unknown etiology is then described. Frontal lobe degeneration was repeatedly examined with magnetic resonance imaging and fluoro-deoxy-D-glucose-positron emission tomography and was found to include both orbital and dorsolateral aspects of the frontal lobes. While the degeneration initially measured was limited to portions of the orbital, medial and dorsolateral parts of both frontal lobes, with right-sided predominance, a second brain scan 15 months later revealed massive shrinkage of both frontal lobes, together with additional involvement of the posterior association cortices. The patient had completed her high-school education and had superior verbal long-term memory, normal short-term memory, and normal priming, but manifested grossly deficient scores in various frontal lobe-sensitive tests. Though a number of neurological examinations were performed, no plausible cause for the damage was established.

Adult↗

PubMed2001

Immunohistochemical localization of phosphorylated glial fibrillary acidic protein in the prefrontal cortex and hippocampus from patients with schizophrenia, bipolar disorder, and depression.

Increasingly, abnormalities of glial cell function have been implicated in pathological studies of the major mental illnesses (schizophrenia, bipolar disorder, and major depression). In a recent proteomic study, four isoforms of astrocytic glial fibrillary acidic protein (GFAP) were decreased in one or more of these diseases. In the current study, we sought to determine the immunohistochemical localization of phosphorylated GFAP (pGFAP) in the prefrontal cortex and hippocampus and to describe possible disease-related changes in the distribution of pGFAP containing astrocytes. In the prefrontal cortex, interlaminar astrocytes in layer I and stellate astrocytes in layers II and VI were labeled. Labeled cells were also present adjacent to blood vessels in the gyral white matter and in underlying white matter generally. In the hippocampus, labeled cells were present in the polymorphic layer of the dentate gyrus. In the prefrontal cortex, schizophrenia and major depression were characterized by decreased labeling of astrocytes adjacent to blood vessels. There were no significant differences between the diagnostic groups in the other prefrontal layers or in the hippocampus. These results suggest that reduced numbers or functional regulation of pGFAP containing astrocytes occurs in schizophrenia and major depression. The mechanism by which this deficit occurs is not known, but it may adversely effect the regulation of neuronal metabolism, communication, and response to injury.

Adult↗

PubMed1999

Withdrawal from repeated amphetamine administration reduces NMDAR1 expression in the rat substantia nigra, nucleus accumbens and medial prefrontal cortex.

Glutamate plays a critical role in neuroadaptations induced by drugs of abuse. This study determined whether expression of the NMDAR1 subunit of the NMDA receptor is altered by repeated amphetamine administration. We quantified NMDAR1 mRNA (using in situ hybridization with 35S-labelled oligonucleotide probes) and immunolabelling (using immunocytochemistry with 35S-labelled secondary antibodies) in rat ventral midbrain, nucleus accumbens and prefrontal cortex after 3 or 14 days of withdrawal from five daily injections of saline or amphetamine sulphate (5 mg/kg/day). No changes in NMDAR1 expression were observed after 3 days of withdrawal, whereas significant decreases were observed in all regions after 14 days. NMDAR1 mRNA levels in midbrain were too low for reliable quantification, but immunolabelling was decreased significantly in intermediate and caudal portions of the substantia nigra. This may indicate a reduction in excitatory drive to substantia nigra dopaminergic neurons. In the nucleus accumbens, there were significant decreases in NMDAR1 mRNA levels (74.8 +/- 7. 7% of control, P < 0.05) and immunolabelling (76.7 +/- 4.4%, P < 0. 05). This may account for previously-reported decreases in the electrophysiological responsiveness of nucleus accumbens neurons to NMDA after chronic amphetamine treatment, and contribute to dysregulation of goal-directed behaviour. In prefrontal cortex, there was a significant decrease in NMDAR1 mRNA levels (76.1 +/- 7. 1%, P < 0.05) and a trend towards decreased immunolabelling (89.5 +/- 7.0%). This may indicate decreased neuronal excitability within prefrontal cortex. A resultant decrease in activity of excitatory prefrontal cortical projections to nucleus accumbens or midbrain could synergize with local decreases in NMDAR1 to further reduce neuronal excitability in these latter regions.

Amphetamine↗

PubMed2006

Identification of neurotransmitter receptor genes involved in alcohol self-administration in the rat prefrontal cortex, hippocampus and amygdala.

About half of the risk to develop alcoholism is related to genetic background and it is well known that alcohol consumption is highly individualized. In this study, we investigated how individual alcohol consumption behaviour in Wistar rats correlated with mRNA expression of 20 genes in the prefrontal cortex, hippocampus and amygdala. We found that the long-term alcohol consumption of an individual could be estimated by the mean of its consumption on Day 2 and 3. This short exposure minimized changes in gene expression induced by alcohol itself. We found a positive correlation in the prefrontal cortex of GABA(A) alpha5 (r=0.96), GABA(B1) (r=0.96), AMPA GluR1 (r=0.93), 5-HT(3A) (r=0.93) and the alpha adrenoceptors (alpha(1A)r=1.00, alpha(1B)r=0.93, alpha(2A)r=0.93) with consumption. In the hippocampus, we found negative correlations with the NMDA NR2A subunit (r=-0.86), the alpha(1A) adrenoceptor (r=-0.89) and the glucocorticoid receptor (r=-0.86). Finally, in the amygdala there was a negative correlation to NMDA NR2A (r= -0.79) and a positive correlation with serotonin 5-HT(2C) (r=0.79). In conclusion, we have used qPCR to identify specific genes in the brain that correlated to alcohol self-administration of an individual animal. This study suggests that alcohol consumption in the early stages of acquisition depends on the genetic background of the individual and that the prefrontal cortex is particularly important in this behaviour.

Alcohol Drinking↗

PubMed2005

Repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex and cortical excitability in patients with major depressive disorder.

Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex is a relatively non-invasive technique with putative therapeutic effects in major depression. However, the exact neurophysiological basis of these effects needs further clarification. Therefore, we studied the impact of ten daily sessions of left, dorsolateral prefrontal rTMS on motor cortical excitability, as revealed by transcranial magnetic stimulation-elicited motor-evoked potentials in 30 patients. As compared to the non-responders, responders (33%) showed changes in parameters pointing towards a reduced cortical excitability. These results suggest that repetitive transcranial magnetic stimulation of the dorsolateral, prefrontal cortex may have inhibitory effects on motor cortical neuronal excitability in patients with major depressive disorder. Furthermore, measurement of motor cortical excitability may be a useful tool for investigating and monitoring inhibitory brain effects of antidepressant stimulation techniques like rTMS.

Adult↗

PubMed2000

Differential postnatal development of catecholamine and serotonin inputs to identified neurons in prefrontal cortex of rhesus monkey.

The monoaminergic innervation of cerebral cortex has long been implicated in its development. Methods now exist to examine catecholamine and serotonin inputs to identified neurons in the cerebral cortex. We have quantified such inputs on pyramidal and nonpyramidal cells in prefrontal cortex of rhesus monkeys ranging in age from 2 weeks to 10 years. Individual layer III neurons were filled with Lucifer yellow and double-immunostained with axons containing either tyrosine hydroxylase (TH) or 5-hydroxytryptamine (5-HT). The filled cells were reconstructed, and putative appositions between the axons and dendritic spines and shafts were quantified at high magnification using light microscopy. The density of catecholamine appositions on pyramidal neurons matures slowly, reaching only half the adult level by 6 months of age and thereafter rising gradually to adult levels by 2 years of age. By contrast, the density of serotonin appositions on pyramidal cells reaches the adult level before the second week after birth. The average adult pyramidal neuron in layer III of area 9m receives three times stronger input from catecholaminergic than from serotoninergic axons. The overall density of both inputs to interneurons does not appear to change during postnatal development. Selective changes in the TH innervation of pyramidal cells against a backdrop of constant TH innervation of interneurons suggest that the balance between excitation and inhibition may change developmentally in the prefrontal cortex. By contrast, 5-HT innervation of both types of neurons remains relatively constant over the age range studied.

Aging↗

PubMed2004

Serotonergic regulation of membrane potential in developing rat prefrontal cortex: coordinated expression of 5-hydroxytryptamine (5-HT)1A, 5-HT2A, and 5-HT7 receptors.

The developing prefrontal cortex receives a dense serotonergic innervation, yet little is known about the actions of serotonin [5-Hydroxytryptamine (5-HT)] in this region during development. Here, we examined the developmental regulation of 5-HT receptors controlling the excitability of pyramidal neurons of this region. Using whole-cell recordings in in vitro brain slices, we identified a dramatic shift in the effects of 5-HT on membrane potential during the postnatal developmental period. In slices derived from young animals [postnatal day (P) 6 to P19], administration of 5-HT elicits a robust depolarization of layer V pyramidal neurons, which gradually shifts to a hyperpolarization commencing during the third postnatal week. This progression is the result of coordinated changes in the function of 5-HT7 and 5-HT2A receptors, which mediate different aspects of the depolarization, and of 5-HT1A receptors, which signal the late developing hyperpolarization. The loss of the 5-HT7 receptor-mediated depolarization and the appearance of the 5-HT1A receptor-mediated hyperpolarization appears to reflect changes in receptor expression. In contrast, the decline in the 5-HT2A receptor depolarization with increasing age was associated with changes in the effectiveness with which these receptors could elicit a membrane depolarization, rather than loss of the receptors per se. Together, these results outline coordinated changes in the serotonergic regulation of cortical excitability at a time of extensive synaptic development and thus suggest a key role for these receptor subtypes in the postnatal development of the prefrontal cortex.

Age Factors↗

PubMed2005

Serotonergic regulation of calcium-activated potassium currents in rodent prefrontal cortex.

In spite of a growing understanding of the actions of 5-hydroxytryptamine (5-HT) in the prefrontal cortex, the specific cellular mechanism used by 5-HT in this region remains poorly understood. Previous studies have shown that 5-HT inhibits the after hyper-polarization that follows a burst of spikes in pyramidal neurons. In the present study, we have used whole cell recordings in rat and mouse brain slices to re-examine this phenomenon with special emphasis on identifying the 5-HT receptor subtypes mediating this effect. Layer V pyramidal neurons display complex after hyper-polarizations that are mediated predominantly by calcium-activated potassium channels and involve two distinct currents known as medium after hyper-polarizating current and slow after hyper-polarizating current (I(sAHP)). Administration of 5-HT reduced the current underlying these after hyper-polarizations by selectively inhibiting I(sAHP). Pharmacological analysis of this response indicates that the main receptor responsible for this inhibition belongs to the 5-HT(2A) subtype. Thus, alpha-methyl-5-HT and 2,5-dimethoxy-4-bromoamphetamine (DOB) mimic the effect of 5-HT and the effect of these agonists is blocked by MDL 100 907. Similarly, administration of alpha-methyl-5-HT is without effect in slices derived from 5-HT(2A) receptor knockout mice. However, 5-HT(2A) receptor blockade only partially suppressed the ability of 5-HT to inhibit I(sAHP). This suggests the involvement of at least one more receptor subtype in this response. Consistent with this idea, administration of 5-carboxyamido-tryptamine, an agonist exhibiting no detectable affinity for 5-HT(2A) receptors, was also capable of suppressing I(sAHP). These results identify 5-HT(2A) receptors as being primarily involved in mediating the 5-HT-induced inhibition of I(sAHP) in prefrontal cortex, while also recognizing a contribution by an additional 5-HT receptor subtype.

Animals↗

PubMed2000

Imipramine and phenelzine decrease glutamate overflow in the prefrontal cortex--a possible mechanism of neuroprotection in major depression?

Antidepressant drugs have been used for decades, but the neurobiological substrate of their efficacy is not completely understood. Although these drugs have well-established effects on monoamines, evidence is emerging that they may also affect other neurotransmitter systems. It has been shown that treatment with a wide range of antidepressants changes the binding characteristics of the N-methyl-D-aspartate type of glutamate receptor. This change is delayed and occurs only in the cortex. The mechanism that triggers it is unknown. We hypothesized that N-methyl-D-aspartate receptor alterations may be due to changes in the dynamics of cortical excitatory amino acid release. Such changes are of particular interest in areas such as the prefrontal cortex, a region involved in stress responses and affected in major depression. We investigated the effects of two antidepressants with different modes of action, imipramine and phenelzine, on glutamate and aspartate outflow in rat prefrontal cortex and striatum. We showed that antidepressants significantly decreased stimulated glutamate outflow. The effect had a rapid onset, was sustained during chronic administration and was only seen in the prefrontal cortex. This change may initiate receptor alterations. Furthermore, if antidepressants can dampen states of hyperglutamatergic activity and the subsequent excitotoxicity, their chronic use may have a considerable neuroprotective potential in major depression.

Animals↗