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Limited collateralization of neurons in the rat prefrontal cortex that project to the nucleus accumbens.

The specificity and selectiveness of a neuronal message depends in part on the number of recipient neurons that simultaneously receive this message. Hence, projections involved in higher order cognitive processes might be expected to exhibit a lower degree of collateralization than projections that mediate more basic brain functions. This study sought to determine the degree to which neurons projecting from the prefrontal cortex to the nucleus accumbens collateralize to major cortical and subcortical regions: the contralateral prefrontal cortex, the basolateral amygdala or the ventral tegmental area. Fluoro-Gold and cholera toxin-b were used to label prefrontal cortex neurons that project to these targets, and the proportion of neurons singly and dually labeled by immunofluorescence for these tracers was determined. The prefrontal cortex neurons projecting to these regions exhibited a partially complementary laminar distribution. Furthermore, of the neurons projecting to the nucleus accumbens, 13% sent a collateralized projection to the contralateral prefrontal cortex, 7% collateralized to the basolateral amygdala, and 3% sent a branched projection to the ventral tegmental area. No differences were observed in the degree of collateralization of neurons in superficial versus deep layers.Thus, the degree of collateralization of corticoaccumbens neurons was overall limited, but significantly greater to a cortical target than to subcortical regions. These branching patterns provide anatomical substrates for temporal and spatial coordination of activity in limbic circuits.

Amygdala↗

SCH 23390 in the prefrontal cortex enhances the effect of apomorphine on prepulse inhibition of rats.

The aim of this study was to investigate the role of dopaminergic activity in the prefrontal cortex in the regulation of prepulse inhibition (PPI) of acoustic startle. Rats were instrumented with permanent indwelling cannulas into the prefrontal cortex region and tested at least one week after surgery using a randomized sequence, repeated-measures protocol. Doses of apomorphine (0.1 mg/kg subcutaneously, s.c.) and MK-801 (0.03 mg/kg s.c.) were obtained from preliminary dose-response studies. Intracerebral injection of 0.5 microg/side of the dopamine D1 receptor antagonist, SCH 23390, significantly enhanced the disruptive effect of apomorphine on PPI, but had no effect on its own or on startle amplitude or habituation. Furthermore, the effect of SCH 23390 on PPI was not seen with a lower dose (0.2 microg/side) or in combination with the NMDA receptor antagonist, MK-801. These data confirm and extend previous reports on the importance of dopaminergic innervation of the prefrontal cortex in the regulation of PPI. It is suggested that apomorphine treatment directly or indirectly activates dopamine D1 receptors in the prefrontal cortex to inhibit its own action on PPI elsewhere in the brain, presumably in the nucleus accumbens. Antagonism of this inhibitory component by SCH 23390 therefore leads to a larger disruption of PPI.

Acoustic Stimulation↗

The postnatal maturation of dopamine innervation in the prefrontal cortex of gerbils (Meriones unguiculatus) is sensitive to an early single dose of methamphetamine. A quantitative immunocytochemical study.

Dopamine (DA)-immunoreactivity was investigated in the prefrontal cortex (PFC) of 90 day old adult male gerbils (Meriones unguiculatus) after they had received a single dose of either methamphetamine (50 mg/kg; i.p.) or saline at the age of postnatal day 14. For that purpose, a selective and sensitive antibody directed against glutaraldehyde-conjugated dopamine was applied. All detectable fragments of dopamine-immunoreactive fibres were identified in consecutive frontal sections of the pregenual prefrontal cortex, and their total numbers and total length were determined in the medial (mPFC) and orbital prefrontal cortex (oPFC). The results indicate that a single application of methamphetamine during early postnatal development caused a significant and severe restraint of the subsequent maturation of the prefrontal dopamine-innervation. Although, on postnatal day 14, the total dopamine-immunoreactivity had only attained about 4% (mPFC) and 7% (oPFC) of the regular adult values, this solitary pharmacological challenge entailed final adult innervation densities which were about 38% (mPFC) and 50% (oPFC) below those of the controls. Considering the pivotal role which mesoprefrontal dopaminergic afferents play in morphogenesis and regular functioning, the present results are discussed with current understanding of structural and functional plasticity during maturation of the prefrontal cortex.

Animals↗

Possible involvement of medial prefrontal cortex in amphetamine-induced sensitization of mesolimbic dopamine function.

We examined the role of the dopamine projection to the medial prefrontal cortex in amphetamine-induced sensitization of meso-nucleus accumbens dopamine function. In the first experiment, male rats received bilateral microinfusions either of 6-hydroxydopamine or of vehicle (sham) into prefrontal cortex. Six weeks later animals from both groups were injected once daily for 5 consecutive days with either amphetamine or saline. Two days after the last daily injection, all the animals were each implanted with a voltammetric electrode into nucleus accumbens. Increases in dopamine-dependent electrochemical signals elicited by amphetamine were monitored 3-4 days later using chronoamperometry. The results showed that amphetamine stimulates dopamine efflux to a greater extent in the nucleus accumbens of lesioned than of sham-lesioned animals. Furthermore, of the animals with prefrontal cortical lesions, amphetamine-induced dopamine efflux was greater in animals previously treated with the drug than in animals with no prior drug experience. In a second experiment, sensitization to the acute locomotor-stimulant effect of amphetamine was examined in prefrontal cortex-lesioned and sham-lesioned animals. The locomotor response of all animals to a test dose of amphetamine was first monitored and then on each of the subsequent 5 days, lesioned and sham-lesioned animals received an injection either of amphetamine or of saline. Five and then 13 days later, the locomotor response of all animals to the test dose of amphetamine was again measured. The results of this study showed that prefrontal cortex-lesioned animals were less responsive to the first amphetamine injection than sham-lesioned animals. However, after repeated daily administration, the acute locomotor response of lesioned animals to amphetamine was significantly greater than that of sham-lesioned animals with the same drug history. These findings are generally consistent with evidence from other sources suggesting that the dopamine input to medial prefrontal cortex exerts an indirect, inhibitory influence on mesolimbic dopamine transmission. They also suggest that long-term changes to a dopamine-sensitive mechanism in prefrontal cortex may contribute to the development of stimulant-induced sensitization of mesolimbic dopamine function.

Amphetamine↗

Relation between the prefrontal cortex and cerebro-cerebellar functions: evidence from the results of stabilometrical indexes.

The relation between prefrontal cortex and cerebro-cerebellar functions of 50 normal healthy elderly people was examined. The function of the prefrontal cortex was measured by means of a letter fluency test and the Digit Cancellation Test (D-CAT, a test for the assessment of attention). Two indexes of postural tremor measured by the stabilometer were employed for the indication of cerebello-thalamo-cortical circuit functions. The results of groups consisting of participants showing higher or lower scores than the mean of the norm on the stabilometer index measurements were compared with their D-CAT and letter fluency test performances. The results showed that 2 indexes of cerebello-thalamo-cortical circuit functions related to the attention function while the relation to the language function was rather weak. The results of the behavioral measures demonstrated a mutual relation between prefrontal cortex and cerebello-thalamo-cortical circuit functions and strongly suggest the notion that the human brain functions as a system, which includes neocortex, subcortex, and cerebellum.

Aged↗

Inhibitory control and affective processing in the prefrontal cortex: neuropsychological studies in the common marmoset.

The orbitofrontal cortex has been ascribed a role in the inhibitory control, as well as in the emotional control, of behaviour. While damage to the orbitofrontal cortex in humans and non-human primates can cause inflexibility, impulsiveness and emotional disturbance, the relationship between these effects are unclear. Excitotoxic lesion studies in marmosets comparing the effects of cell loss within specific regions of the prefrontal cortex on performance of a range of behavioural tests reveal that mechanisms of response inhibition are not unique to the orbitofrontal cortex. Instead they are present in distinct cognitive domains for lowerorder as well as higher-order processing throughout the prefrontal cortex. Thus, the lateral prefrontal cortex is involved in the selection and control of action based upon higher-order rules while the orbitofrontal and medial prefrontal cortex may be involved in different but complementary forms of lower-order rule learning, their roles dissociable, as a result of their differential contribution to different types of associative learning.

Animals↗

Effects of conditioned fear stress on 5-HT release in the rat prefrontal cortex.

The effects of conditioned fear stress (CFS) on 5-HT release in the medial prefrontal cortex were studied by in vivo microdialysis. CFS (exposure to an environment in which foot-shock had been delivered previously) induced a marked suppression of motility-that is, freezing behavior. The extracellular concentration of 5-HT in the medial prefrontal cortex increased during this freezing behavior, but no significant changes were observed in the concentration of its metabolite, 5-HIAA. The increased 5-HT concentration returned to pretreatment levels when the animals were returned to their home cages. Diazepam (0.5 mg/kg, intraperitoneally) reduced the CFS-induced freezing behavior and prevented the increases in extracellular 5-HT levels. A 5-HT3 receptor antagonist, tropisetron (10 and 100 micrograms/kg), also inhibited both the CFS-induced increase in 5-HT release and the freezing behavior. These findings suggest that there is a relationship between anxiety and 5-HT release in the prefrontal cortex and that the 5-HT3 receptor antagonist tropisetron might have anxiolytic properties.

Animals↗

Involvement of the nucleus accumbens and medial prefrontal cortex in the expression of conditioned hyperactivity to a cocaine-associated environment in rats.

This study examined the roles of the nucleus accumbens (NAc), medial prefrontal cortex, basolateral amygdala, and ventral subiculum of the hippocampus in the expression of Pavlovian conditioned hyperactivity responses to cocaine-related stimuli. This was accomplished by pharmacologically inhibiting these regions prior to drug-free tests for conditioned hyperactivity in an environment previously associated with cocaine. The results indicate that conditioned hyperactivity could be disrupted by infusions of the GABA-B agonist, baclofen (0.2 nmol/0.5 microl/side) into the NAc, or completely blocked by infusions of the GABA-A agonist, muscimol (0.1 and 0.2 nmol/0.5 microl/side) into the medial prefrontal cortex. In contrast, conditioned hyperactivity was unaffected by pharmacological inhibition of the basolateral amygdala, the ventral subiculum, or sites dorsal to the NAc or prefrontal cortex. These findings suggest that the NAc and the prefrontal cortex are crucial elements of the neural circuitry underlying the expression of Pavlovian conditioned responses to cocaine-related stimuli.

Amygdala↗

Aripiprazole increases dopamine but not noradrenaline and serotonin levels in the mouse prefrontal cortex.

Aripiprazole, a novel atypical antipsychotic drug, can significantly increase dopamine (DA) levels in the prefrontal cortex of rats, but only at low doses below 1mg/kg. The aim of the present work was to test the effect of aripiprazole (0, 0.1, 0.3, 3 and 30 mg/kg, i.p.) on extracellular levels of monoamines in the prefrontal cortex of freely moving C57BL/6J mice. Concurrent horizontal locomotor activity was also assessed. Aripiprazole produced a significant increase in dialysate DA levels after the administration of a low dose of 0.3mg/kg. Lower (0.1 mg/kg) or higher (3 and 30 mg/kg) doses failed to affect extracellular levels of DA. In addition, none of the doses tested in the present study produced significant changes in extracellular levels of noradrenaline (NA) and serotonin (5-HT). For the sake of comparison, clozapine (0, 3 and 10 mg/kg, s.c.) was also tested under similar conditions. Clozapine produced a dose-dependent increase in both dialysate DA and NA levels without affecting extracellular 5-HT. Locomotor activity was significantly decreased by both clozapine and aripiprazole. These data further support the hypothesis that selective activation of dopaminergic neurotransmission in the prefrontal cortex may contribute to the therapeutic efficacy of aripiprazole.

Animals↗

Sensitivity of prefrontal cortex to changes in target probability: a functional MRI study.

Electrophysiological studies suggest sensitivity of the prefrontal cortex to changes in the probability of an event. The purpose of this study was to determine if subregions of the prefrontal cortex respond differentially to changes in target probabilities using functional magnetic resonance imaging (fMRI). Ten right-handed adults were scanned using a gradient-echo, echo planar imaging sequence during performance of an oddball paradigm. Subjects were instructed to respond to any letter but "X". The frequency of targets (i.e., any letter but X) varied across trials. The results showed that dorsal prefrontal regions were active during infrequent events and ventral prefrontal regions were active during frequent events. Further, we observed an inverse relation between the dorsal and ventral prefrontal regions such that when activity in dorsal prefrontal regions increased, activity in ventral prefrontal regions decreased, and vice versa. This finding may index competing cognitive processes or capacity limitations. Most importantly, these findings taken as a whole suggest that any simple theory of prefrontal cortex function must take into account the sensitivity of this region to changes in target probability.

Adolescent↗

Neurons expressing calcium-binding proteins in the prefrontal cortex in schizophrenia.

Increased neuronal density, cortical thinning, and alterations of GABAergic interneurons in the prefrontal cortex have been associated with the pathophysiology of schizophrenia. This study used antibodies directed against the calcium-binding proteins, calretinin (CR), parvalbumin (PV), and calbindin (CB) to compare the relative density of subpopulations of GABAergic interneurons in BA9 of the prefrontal cortex from six subjects with schizophrenia and six control subjects matched for age, gender, and postmortem interval. The relative density of interneurons expressing CR, PV, or CB did not differ significantly between subjects with schizophrenia and control subjects. In addition, no change in somal size of immunoreactive (IR) neurons or cortical thickness was observed between the two groups. This study supports previous reports consistently demonstrating no change in the relative density of interneurons expressing CR in the dorsolateral prefrontal cortex in schizophrenia but does not support previous inconsistent findings that the relative density of interneurons expressing PV and CB might be altered in this disorder.

Adult↗

Insensitivity to future consequences following damage to human prefrontal cortex.

Following damage to the ventromedial prefrontal cortex, humans develop a defect in real-life decision-making, which contrasts with otherwise normal intellectual functions. Currently, there is no neuropsychological probe to detect in the laboratory, and the cognitive and neural mechanisms responsible for this defect have resisted explanation. Here, using a novel task which simulates real-life decision-making in the way it factors uncertainty of premises and outcomes, as well as reward and punishment, we find that prefrontal patients, unlike controls, are oblivious to the future consequences of their actions, and seem to be guided by immediate prospects only. This finding offers, for the first time, the possibility of detecting these patients' elusive impairment in the laboratory, measuring it, and investigating its possible causes.

Adult↗

Effects of dopamine depletions in the medial prefrontal cortex on active avoidance and escape in the rat.

Dopamine systems have been implicated in the performance of avoidance behavior, and the dopaminergic innervation of medial prefrontal cortex is known to be responsive to stressful stimuli. In the present investigation, injections of 6-hydroxydopamine were used to produce moderate depletions of dopamine in the medial prefrontal cortex of rats trained to perform an active avoidance/escape task. In this task, 0.5 mA shock was presented for 5 s every 30 s, and the rat could escape shock presentation, or avoid the shock for 30 s, by pressing a lever. Depletion of dopamine in the medial prefrontal cortex did not affect total number of responses, and did not impair avoidance responding (i.e. responding when the shock was off), and in fact dopamine-depleted animals tended to make slightly more avoidance responses than control animals. Prefrontal dopamine depletions did result in a significant decrease in the number of escape responses (i.e. responding to terminate shock when the shock was on). Moreover, dopamine depletions significantly decreased response efficiency, which is an index of the reduction of shock time produced per lever pressing response. Previous work has indicated that dopamine antagonists and accumbens dopamine depletions have dramatic effects on avoidance behavior; thus, the present results indicate that prefrontal cortex dopamine depletions do not mimic the effects of interference with subcortical dopamine systems. The selective effects of dopamine depletions on escape behavior in the present study suggest that rats with medial prefrontal dopamine depletions have an impairment in the ability to respond appropriately to the direct presentation of footshock.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Asymmetry of interhemispheric responses evoked in the prefrontal cortex of the rat.

Interhemispheric responses of anesthetized rats were evoked in the prefrontal cortex of both cerebral hemispheres by electric stimulation of the homologous contralateral cortical region. Fatigability of interhemispheric responses to repetitive stimulation was lower in the right prefrontal cortex. Besides, responses recorded in the right hemisphere exhibited greater amplitude increments to double-shock stimulation. No significant differences in rheobase, chronaxie, and threshold current were observed when comparing responsiveness of both prefrontal cortices to single stimuli. Results suggest that brain lateralization in the rat could depend, in part, on synaptic functional asymmetries of the prefrontal cortex.

Animals↗

Desipramine attenuates working memory impairments induced by partial loss of catecholamines in the rat medial prefrontal cortex.

RATIONALE: The density of tyrosine hydroxylase-immunoreactive (TH-IR) axons in the prefrontal cortex of schizophrenic subjects may be reduced by as much as 50% in the deep cortical layers (Am J Psychiatry 156:1580-1589, 1999). Previously, we demonstrated that approximately 60% loss of TH-IR axons in the rat medial prefrontal cortex (mPFC) decreases local basal and stress-evoked extracellular dopamine (DA) concentrations, suggesting that moderate loss of DA axons in the mPFC is sufficient to alter the neurochemical activity of the remaining DA neurons (Neuroscience 93:497-505, 1999). OBJECTIVES: To further assess the functional consequences of partial mPFC DA depletion, we examined the effects of 6-hydroxydopamine lesions of the rat mPFC on behavior in a T-maze delayed-response task. We also assessed whether chronic administration of the norepinephrine (NE) uptake inhibitor, desipramine (DMI), attenuates lesion-induced deficits in T-maze performance. Previous research indicates that inhibition of NE transport in the mPFC results in a concomitant increase in extracellular DA and NE. RESULTS: Moderate loss of mPFC DA and NE (approximately 50 and 10% loss, respectively) was sufficient to impair delayed-response behavior, in part due to an increase in perseverative responding. Chronic DMI treatment (3 mg/kg delivered via osmotic pumps) impaired performance of control rats but attenuated the deficits in delayed-response behavior in rats previously sustaining loss of mPFC DA and NE (approximately 75 and 35% loss, respectively). CONCLUSION: These data suggest that moderate loss of DA and NE in the prefrontal cortex is sufficient to impair cognitive function, and these behavioral effects are attenuated by inhibition of the NE transporter.

3,4-Dihydroxyphenylacetic Acid↗

Response durations encode nociceptive stimulus intensity in the rat medial prefrontal cortex.

We examined whether the medial prefrontal cortex (mPFC) encodes nociceptive stimulus intensity by applying mechanical pressure stimulation, for 2 s at 50, 100, or 300 g constant force (gf) to the tails of urethane-anesthetized rats. In a total of 1208 neurons sampled, 242 (20.0%) were responsive to mechanical stimuli. One hundred thirteen of the 242 (46.7%) were mechanical high threshold neurons (nociceptive specific neurons, NS; threshold >or=100 gf), and 35 (14.5%) exhibited a graded increase in excitator responses to a stepwise increase in stimulus intensity (wide dynamic range-like neurons, WDR-L). These 148 response discharges persisted during stimulation followed by post-stimulus discharges. The nociceptive response duration of NS neurons, but not discharge frequency, was reduced dose-dependently by intraventricular injection of morphine (0.3, and 30 microg/3 microl). Different doses of morphine may set the stimulus intensity at relatively different brain activity levels. Thus, the NS neurons used the response duration as a sensory transduction code. In WDR-L neurons, the response duration, but not always the firing frequency, was linearly related to stimulus intensity. The WDR-L neurons in the mPFC encoded stimulus intensity with response duration, although the coding method is not likely to be the same as that of sensory discriminating WDR cells in the primary somatosensory cortex. Both types of mPFC neurons encode nociceptive (absolute or relative) stimulus intensity and transform the information into the temporal duration of the next stage of pain-related modulation in animal behavior.

Action Potentials↗

Dopamine release in the prefrontal cortex during stress is reduced by the local activation of glutamate receptors.

Using microdialysis, we investigated the effects of the ionotropic glutamatergic agonists N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) on the stress-induced dopamine release in the prefrontal cortex of the freely moving rat. Handling-stress during 40 min increased extracellular dopamine by 195% and dopamine metabolites dihydroxyphenilacetic acid (DOPAC) by 120% and homovallinic acid (HVA) by 155% of baseline, but it did not modify extracellular glutamate, in the prefrontal cortex. Both NMDA (100 microM) and AMPA (20 microM), perfused through the microdialysis probe in the prefrontal cortex simultaneously to stress, significantly reduced the stress-induced dopamine release. These same doses or lower doses of NMDA (20 and 100 microM) and AMPA (1 and 20 microM) did not significantly modify basal dopamine release in the prefrontal cortex, but higher doses of these glutamatergic agonists significantly decreased (NMDA 500 microM) or increased (AMPA 100 microM) basal dopamine release in this area of the brain. These results show that the local activation of prefrontal glutamatergic ionotropic receptors reduces the stress-induced dopamine release in the prefrontal cortex of the rat.

3,4-Dihydroxyphenylacetic Acid↗

Postsynaptic 5-hydroxytryptamine(1A) receptor activation increases in vivo dopamine release in rat prefrontal cortex.

5-Hydroxytryptamine (5-HT) plays a role in the regulation of 3, 4-dihydroxyphenylethylamine (dopamine) neurons in the brain, but the precise mechanism of regulation by 5-HT(1A) receptors of dopamine release has not been defined. The present study describes the effect of 5-¿3-[[(2S)-1,4-benzodioxan-2ylmethyl]amino]propoxy¿-1, 3-benzodioxole HCl (MKC-242), a highly potent and selective 5-HT(1A) receptor agonist, on dopamine release in the prefrontal cortex using microdialysis in the freely moving rat. Subcutaneous injection of MKC-242 (0.3 - 1.0 mg kg(-1)) increased extracellular levels of dopamine in the prefrontal cortex. The effect of MKC-242 in the prefrontal cortex was antagonized by pretreatment with the selective 5-HT(1A) receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohe xanecarboxamide (WAY100635; 1 mg kg(-1), i.p.). Local application of WAY100635 (10 microM) via a microdialysis probe antagonized the effect of systemic MKC-242 in an increasing dopamine release, and locally infused 8-hydroxy-2-(di-n-propylamino)tetralin (10 microM) increased dopamine release in the prefrontal cortex. MKC-242 increased cortical dopamine release in the rats pretreated with 5, 7-dihydroxytryptamine (150 microgram, i.c.v.) that caused an almost complete reduction in cortical 5-HT content. The effect of MKC-242 to increase dopamine release was also observed in the hippocampus, but not in the striatum or nucleus accumbens. Fluoxetine, a selective serotonin reuptake inhibitor, increased dopamine release in the prefrontal cortex, but not in the nucleus accumbens, while buspirone, a 5-HT(1A) receptor agonist, increased dopamine release in both brain regions. The present results indicate that activation of postsynaptic 5-HT(1A) receptors increases dopamine release in a brain region-specific manner.

5,7-Dihydroxytryptamine↗