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PubMed2005

Unchanged packing density but altered size of neurofilament immunoreactive neurons in the prefrontal cortex in schizophrenia and major depression.

Morphometric changes in the general population of Nissl-stained neurons in area 9 of the dorsolateral prefrontal cortex have been reported in major depressive disorder (MDD) and schizophrenia. These alterations include lamina-specific reductions in the packing density of neuronal somata in MDD, increases or reductions in the density of neuronal somata in schizophrenia, and reductions in average size of neuronal somata in both MDD and schizophrenia. These changes are prominent in deep layer III, where pyramidal excitatory neurons establishing cortico-cortical association connections are localized. To test whether deep layer III pyramidal neurons are differentially affected in MDD or schizophrenia, an antibody was used that labels both phosphorylated and non-phosphorylated forms of the 200 kD neurofilament protein (NF200) in pyramidal cells of layer III in area 9. The packing density and somal size of NF200-immunoreactive (IR) pyramidal neurons were measured in area 9 in 13 subjects with nonpsychotic MDD, 11 subjects with schizophrenia and 13 psychiatrically normal controls. Analysis of covariance did not reveal a difference in packing density among groups. However, the mean size of NF200-IR somata was significantly larger in subjects with schizophrenia than in controls. These results indicate that this neuronal subpopulation does not contribute to the smaller average size of neuronal somata in layer III of prefrontal cortical area 9 in schizophrenia or MDD. In addition, the enlarged somal size in schizophrenia as compared to controls suggests that NF200 neurons may contribute differentially to unique cognitive disturbances present in schizophrenia and not in MDD subjects.

Adult↗

PubMed2002

Extracellular glutamate levels in prefrontal cortex during the expression of associative responses to cocaine related stimuli.

We conducted studies to examine the potential role of glutamate in the prefrontal cortex (PFC) during conditioned responses to stimuli (flashing light and metronome) previously associated with cocaine administration. During training, PAIRED subjects received cocaine injections (15 mg/kg) during stimuli sessions while UNPAIRED subjects received saline injections (but received cocaine in the home cage an hour later). We showed previously that PAIRED subjects exhibit conditioned locomotion when tested with the stimuli alone. In this study, we further demonstrated that the expression of behavioral sensitization in response to cocaine challenge is under conditioned control in PAIRED subjects. Then, we used microdialysis to examine extracellular levels of glutamate in the PFC in response to presentation of the conditioned stimuli alone and challenge with cocaine in the presence of the conditioned stimuli. Although PAIRED subjects demonstrated conditioned locomotion and conditioned control of sensitization during the microdialysis experiment, PFC glutamate levels were unaltered during the tests and did not differ between the PAIRED and UNPAIRED subjects.

Acoustic Stimulation↗

PubMed2000

Mood effects of repetitive transcranial magnetic stimulation of left prefrontal cortex in healthy volunteers.

This study investigated the effect of high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) of the left prefrontal cortex (LPFC) on mood in a sham-controlled crossover design. Twenty-five healthy male subjects received HF-rTMS of the LPFC in real and sham conditions. Forty trains (frequency 20 Hz, stimulation intensity 100% of individual motor threshold, train duration 2 s, intertrain interval 28 s) were applied in each session. Mood change from baseline was measured with five visual analog scales (VAS) for sadness, anxiety, happiness, tiredness and pain/discomfort. We were unable to demonstrate significant mood changes from baseline on visual analog scales after either sham or real stimulation of LPFC. There is insufficient evidence to support the general conclusion that HF-rTMS of LPFC has mood effects in healthy volunteers. Future studies should be sham-controlled, have larger sample sizes, and strictly stimulate one single region per session in order to exclude interaction effects with the previous stimulation.

Adult↗

PubMed1997

Effects of cholinergic drug infusions into the dorsal part of the medial prefrontal cortex on delayed conditional discrimination performance in the rat.

Effects of bilateral infusions of cholinergic drugs into the dorsal part of the medial prefrontal cortex (dmPFC) on performance in a delayed conditional discrimination (DCD) task were examined in rats. Scopolamine dose-dependently impaired performance. No delay-dependent effect was found indicating that scopolamine did not specifically affect working memory (WM). Physostigmine alone induced a slight improvement of DCD performance independent of delay and co-administration of physostigmine with scopolamine attenuated the scopolamine-induced impairment of DCD performance. Infusion of the muscarinic M2 antagonist AQRA-471, the M3 antagonist 4-DAMP and the mixed M1-M3 antagonist UH-AH 37 did not affect performance in the DCD task, suggesting that the effect of scopolamine is not mediated by a single muscarinic receptor subtype. The results furthermore indicate that the cholinergic system in the dmPFC does not play a specific role in WM processes in the DCD task. Furthermore, the results suggest that the dmPFC cholinergic system plays a role in the attentional processes involved in the DCD task.

Animals↗

PubMed2006

Amygdala input monosynaptically innervates parvalbumin immunoreactive local circuit neurons in rat medial prefrontal cortex.

The projection from the basolateral nucleus of the amygdala (BLA) conveys information about the affective significance of sensory stimuli to the medial prefrontal cortex (mPFC). By using an anterograde tract-tracing procedure combined with immunocytochemistry and correlated light/electron microscopical examination, labeled BLA afferents to layers 2-6 of the rat mPFC are shown to establish asymmetrical synaptic contacts, not only with dendritic spines (approximately 95.7% of targets innervated), but also with the aspiny dendritic shafts and somata of multipolar parvalbumin immunopositive (PV+) neurons. A population of PV- dendritic shafts was also innervated. Labeled BLA synaptic input to identified PV+ structures occurred in layers 2-6 of mPFC. The results indicate that labeled BLA afferents predominantly contact the spiny processes of presumed pyramidal cells and also provide a direct and specific innervation to a sub-population of local circuit neurons in mPFC containing PV. Since PV+ cells include two significant classes of fast-spiking GABAergic inhibitory interneuron (basket and axo-axonic cells), these novel observations indicate that the amygdalocortical pathway in the rat has the ability to directly influence functionally strategic 'feed-forward' inhibitory mechanisms at the first stage of processing amygdalocortical information.

Afferent Pathways↗

PubMed2003

Functional disconnection of the medial prefrontal cortex and subthalamic nucleus in attentional performance: evidence for corticosubthalamic interaction.

The present study used a disconnection procedure to test whether the medial prefrontal cortex (mPFC) and the subthalamic nucleus (STN) were functional components in a common neural system that controlled continuous performance in a test of sustained and divided visual attention. Animals with disconnected lesions of the mPFC and STN in contralateral hemispheres were severely impaired in several aspects of performance, including discriminative accuracy, increased perseveration, and slowed response latencies during postoperative testing. These deficits persisted throughout the entire experimental test period. Increasing the stimulus duration alleviated the accuracy deficit but failed to improve speed of responding or reduce perseverative responses. These deficits were in marked contrast to animals with combined mPFC and STN lesions made on the ipsilateral side, which produced behavior not different from that of sham controls. Rats with unilateral lesions of either structure alone were also impaired in terms of accuracy and perseveration. These data suggest that some of the deficits observed after bilateral STN lesions (attention and perseveration) may be attributable to a disrupted corticosubthalamic projection. This study provides direct evidence that performance in tasks that require optimal attentional and executive control relies on a corticosubthalamic interaction within the neural circuitry of the basal ganglia.

Animals↗

PubMed1996

Rapid sampling of extracellular dopamine in the rat prefrontal cortex during food consumption, handling and exposure to novelty.

We report the effects of physiological stimuli on extracellular dopamine (DA) in the medial prefrontal cortex (PFC) of the rat determined on-line in dialysates obtained every 5.5 min. The detection limit for DA was 0.03-0.1 pg/5 microl injection using a conventional HPLC set-up. Basal levels in PFC were at the detection limit, therefore 3 microM nomifensine was included in the Ringer perfusion fluid, producing readily detectable DA levels of 0.9 pg/injection. Perfusion with 3 microM TTX for 30 min decreased DA within 11 min to 10% of control. The routine use of rapid sampling of extracellular DA was applied to study cortical DA release in relation to behaviour. Exposure to a novel environment for 5.5 min led to an increase to 135%. Presentation of a food pellet to food-deprived rats resulted in a rapid increase to 150% within 5.5 min, which lasted 30-40 min, which is 10-20 min more than the time spent eating. Handling the rat for 5.5 min increased DA in PFC within 5.5 min to 160% and in 11 min to 190% of control followed by a 25-min period of a 50% increase, probably reflecting increased arousal. The results suggest that emotional arousal is a common denominator of increased cortical DA release and that responses are graded depending on the intensity of the stimulus.

Animals↗

PubMedDate not supplied

NMDA receptor-dependent processes in the medial prefrontal cortex are important for acquisition and the early stage of consolidation during trace, but not delay eyeblink conditioning.

Permanent lesions in the medial prefrontal cortex (mPFC) affect acquisition of conditioned responses (CRs) during trace eyeblink conditioning and retention of remotely acquired CRs. To clarify further roles of the mPFC in this type of learning, we investigated the participation of the mPFC in mnemonic processes both during and after daily conditioning using local microinfusion of the GABA(A) receptor agonist muscimol or the NMDA receptor antagonist APV into the rat mPFC. Muscimol infusions into the mPFC before daily conditioning significantly retarded CR acquisition and reduced CR expression if applied after sufficient learning. APV infusion also impaired acquisition of CRs, but not expression of well-learned CRs. When infusions were made immediately after daily conditioning, acquisition of the CR was partially impaired in both the muscimol and APV infusion groups. In contrast, rats that received muscimol infusions 3 h after daily conditioning exhibited improvement in their CR performance comparable to that of the control group. Both the pre- and post-conditioning infusion of muscimol had no effect on acquisition in the delay paradigm. These results suggest that the mPFC participates in both acquisition of a CR and the early stage of consolidation of memory in trace, but not delay eyeblink conditioning by NMDA receptor-mediated operations.

Animals↗

PubMed2004

Semantic processing of Chinese in left inferior prefrontal cortex studied with reversible words.

This study utilized fast event-related fMRI with reversible words to examine the role of left inferior prefrontal cortex (PFC) in semantic processing of Chinese. As a special linguistic phenomenon in Chinese, a reversible word is a two-character word (AB) that, when read from right to left (BA), opposite to the normal left to right reading direction, is also a real word. The two words, AB and BA, can have very different meanings. Fourteen native Chinese saw a reversible word (BA) and were asked to read it backward silently to obtain the meaning of AB, defined as the target meaning. They then saw two test words and decided which of the two was semantically related to the target meaning. Activity in a subregion of BA47 was found to be modulated by the extent to which irrelevant semantic activation of the distractor word BA interfered with semantic retrieval of the target word AB. This finding demonstrated the involvement of the left inferior PFC in the control processes of semantic retrieval in Chinese. In addition, comparing conditions using reversible with that using nonreversible words, we found evidence suggesting a semantic/phonological functional subdivision in left inferior PFC, consistent with that in English.

Adult↗

PubMed2005

Medial prefrontal cortex control of the paraventricular hypothalamic nucleus response to psychological stress: possible role of the bed nucleus of the stria terminalis.

The medial prefrontal cortex (mPFC) has been strongly implicated in control of the paraventricular nucleus of the hypothalamus (PVN) response to stress. Because of the paucity of direct projections from the mPFC to the PVN, we sought to investigate possible brain regions that might act as a relay between the two during psychological stress. Bilateral ibotenic acid lesions of the rat mPFC enhanced the number of Fos-immunoreactive cells seen in the PVN after exposure to the psychological stressor, air puff. Altered neuronal recruitment was seen in only one of the candidate relay populations examined, the ventral bed nucleus of the stria terminalis (vBNST). Furthermore, bilateral ibotenic acid lesions of the BNST caused a significant attenuation of the PVN response to air puff. To better characterize the structural relationships between the mPFC and PVN, retrograde tracing studies were conducted examining Fos expression in cells retrogradely labeled with cholera toxin b subunit (CTb) from the PVN and the BNST. Results obtained were consistent with an important role for both the mPFC and BNST in the mpPVN CRF cell response to air puff. We suggest a set of connections whereby a direct PVN projection from the ipsilateral vBNST is involved in the mpPVN response to air puff and this may, in turn, be modulated by an indirect projection from the mPFC to the BNST.

Animals↗

PubMed2000

Enhanced and impaired attentional performance after infusion of D1 dopaminergic receptor agents into rat prefrontal cortex.

The role in spatial divided and sustained attention of D1 and D2-like dopamine (DA) receptors in the rat prelimbic medial prefrontal cortex (mPFC) was investigated in a five-choice serial reaction time task. Rats were trained to detect brief flashes of light (0.5-0.25 sec) presented randomly in a spatial array of five apertures. When performance stabilized, animals received bilateral microinfusions of either the D1 DA receptor antagonist SCH 23390, the D1 DA receptor agonist SKF 38393, or the D2 DA antagonist sulpiride into the mPFC. Rats were divided into two groups, with low (<75% correct) and high (>75%) baseline levels of accuracy. Infusions of the D2 receptor antagonist sulpiride had no significant effect on any task variable. SCH 23390 (0.3 microg) selectively impaired the accuracy of attentional performance in rats in the high baseline condition. By contrast, SKF 38393 (0.06 microg) enhanced the accuracy of attentional performance in the low baseline condition, a lower dose (0.03 microg) also increasing the speed of making correct responses. Finally, the beneficial effects of SKF-383893 on choice accuracy were antagonized by SCH 23390 (1.0 microg). The results provide apparently the first demonstration of enhanced cognitive function after local administration of a D1 receptor agonist to the mPFC and suggest dissociable roles of D1 and D2 DA receptors of the mPFC in modulating attentional function.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed2005

Lesions of medial prefrontal cortex disrupt the acquisition but not the expression of goal-directed learning.

Several studies have established that pretraining lesions of the medial prefrontal cortex (mPFC) render instrumental actions insensitive to devaluation of the instrumental outcome and degradation of the action-outcome contingency. Nevertheless, it remains to be assessed whether the involvement of the mPFC in goal-directed action is limited to the acquisition or to the expression of the action-outcome association in performance. The current series of experiments investigated this issue by comparing the effects of mPFC lesions made either before or after initial training using sensitivity to outcome devaluation as an assay of goal-directed performance. Whereas pretraining lesions left performance insensitive to outcome devaluation, posttraining lesions spared this effect. To determine whether the effect of mPFC lesions on outcome devaluation was the result of a more fundamental deficit in response selection, experiment 2 assessed the impact of pretraining and posttraining lesions on the ability of the instrumental outcome to selectively reinstate the performance of its associated action after a period of extinction. Although both lesions attenuated the magnitude of instrumental reinstatement generally, they left intact the ability of the instrumental outcome to influence response selection. Experiment 3 investigated the relationship between the outcome-selective devaluation and reinstatement effects and found evidence that these effects are both behaviorally and neurally dissociable at the level of the mPFC. These results indicate that the mPFC is selectively involved in the acquisition, but not the permanent storage or expression, of action-outcome associations in instrumental conditioning.

Animals↗

PubMed2005

Mediodorsal thalamic afferents to layer III of the rat prefrontal cortex: synaptic relationships to subclasses of interneurons.

The mediodorsal nucleus of the thalamus (MD) represents the main subcortical structure that projects to the prefrontal cortex (PFC) and it regulates key aspects of the cognitive functions of this region. Within the PFC, GABA local circuit neurons shape the activity patterns and hence the "memory fields" of pyramidal cells. Although the connections between the MD and PFC are well established, the ultrastructural relationships between projecting fibers from the MD and different subclasses of GABA cells in the PFC are not known. In order to address this issue in the rat, we examined MD axons labeled by tract-tracing in combination with immunogold-silver to identify different calcium-binding proteins localized within separate populations of interneurons. Electron micrographic examination of PFC sections from these animals revealed that MD terminals made primarily asymmetric synapses onto dendritic spines and less commonly onto dendritic shafts. Most of the dendrites receiving MD synaptic input were immunoreactive for parvalbumin (ParV), whereas MD synapses onto dendrites labeled for calretinin or calbindin were less frequent. We also observed that some MD terminals were themselves immunoreactive for calcium-binding proteins, again more commonly for ParV. These results suggest that the MD exerts a dual influence on PFC pyramidal cells: direct inputs onto spines and an indirect influence mediated via synapses onto each subclass of interneurons. The apparent preferential input to ParV cells endows MD afferents with a strong indirect inhibitory influence on pyramidal neuron activity by virtue of ParV cell synapses onto soma, proximal dendrites, and axon initial segments.

Afferent Pathways↗

PubMed1994

Anatomical and electrophysiological evidence for an excitatory amino acid pathway from the thalamic mediodorsal nucleus to the prefrontal cortex in the rat.

This study was undertaken to identify the neurotransmitter of the projection from the thalamic mediodorsal nucleus (MD) to the prefrontal cortex (PFC) using both retrograde transport of D-[3H]aspartate and electrophysiological approaches in the rat. Unilateral microinjections of D-[3H]aspartate performed into the prelimbic area of the PFC resulted in dense labelling of numerous cells in the ipsilateral MD. Excitatory responses were observed in PFC neurons after electrical stimulation of the MD. However, since cortical neurons project to the MD, these excitatory responses could have resulted either from the activation of the MD-PFC pathway and/or from the activation of recurrent collaterals of antidromically driven cortico-thalamic fibres. The conduction time of each of these two reciprocal pathways was determined by antidromic activation. Short latency excitatory responses resulted from activation of the MD-PFC pathway. They were predominantly observed in PFC neurons located in layer III and evoked at low frequency stimulation (0.3-1 Hz). These excitatory responses disappeared or were replaced by longer latency responses when higher frequency stimulations (3-10 Hz) were used. MD-evoked responses were blocked by the iontophoretic application of the AMPA receptor antagonist CNQX into the PFC. These results indicate that the MD-PFC pathway utilizes glutamate and/or aspartate as the neurotransmitter and that its activation induces excitation in PFC neurons through AMPA receptors. Even though the local application of the NMDA receptor antagonist APV was ineffective, a contribution of these receptors in MD-PFC transmission cannot be excluded.

2-Amino-5-phosphonovalerate↗

PubMed2003

Electrophysiological evidence for convergence of inputs from the medial prefrontal cortex and lateral habenula on single neurons in the dorsal raphe nucleus.

Neuronal projections to the dorsal raphe nucleus (DRN) from the medial prefrontal cortex (mPFC) and lateral habenula nucleus (LHb) provide the two key routes by which information processed by mood regulatory, cortico-limbic-striatal circuits input into the 5-HT system. These two projections may converge as it appears that both activate local GABAergic neurons to inhibit 5-HT neurons in the DRN. Here we have tested this hypothesis by measuring the effect of stimulation of the mPFC and LHb on the activity of 5-HT and non-5-HT, putative gamma-amino butyric acid (GABA) neurons in the DRN using extracellular recordings in anaesthetized rats. A total of 119 5-HT neurons (regular, slow firing, broad spike width) and 21 non-5-HT, putative GABA neurons (fast-firing, narrow spike width) were tested. Electrical stimulation of the mPFC or LHb caused a poststimulus inhibition (30 ms latency) of 101/119 5-HT neurons, of which 61 (60%) were inhibited by both the mPFC and LHb. Electrical stimulation of the mPFC or LHb also caused a short latency (12-20 ms) poststimulus facilitation of 10/21 non-5-HT neurons, of which 5 (50%) were activated by both the mPFC and LHb. These data indicate that a significant number of 5-HT neurons and non-5-HT neurons in the DRN are influenced by both the mPFC and LHb. Moreover, the data are compatible with the hypothesis and that there is a convergence of mPFC and LHb inputs on local circuit GABAergic neurons in the DRN which in turn inhibit the activity of 5-HT neurons.

Animals↗

PubMed1993

Cellular distribution of dopamine D1 and D2 receptors in rat medial prefrontal cortex.

The relative distribution and cellular localization of the dopamine D1 and D2 receptor subtypes were assessed in frozen sections of rat medial prefrontal cortex (mPFC). The D1 and D2 receptor binding sites were labeled with the selective high-affinity antagonists SCH 23390 and N-(p-aminophenethyl)-spiperone (NAPS), respectively, coupled to either Bodipy or Texas red fluorophores. Under the incubation conditions employed, kinetic, competition, and selectivity studies showed that these modified ligands retained pharmacological selectivity. Optimal binding fluorescence was at 100 nM of each ligand, and fluorescence increased linearly from 1 to 15 min of incubation at 2 degrees C. NAPS-Texas red binding fluorescence was inhibited with 10 nM quinpirole (D2 agonist), but not 10 nM SKF 38393 (D1 agonist), while SCH 23390-Texas red binding was inhibited with SKF 38393, but not quinpirole. The localization of dopamine receptor binding was assessed in montages constructed from low-magnification photomicrographs through the depth of the cortex, or in corresponding high-magnification photomicrographs. Cells showing D1- or D2-like receptor binding fluorescence were present in layers II-VI, with the highest density observed in layers V and VI. The addition of mianserin (100 nM, 5-HT2 antagonist) to incubated sections slightly reduced the numbers of labeled cells in each cortical layer, but retained the preferential localization to the deeper layers. Two separate observations supported the idea that the fluorescently coupled ligands were localized to neuronal cell bodies. First, receptor labeling with the fluorescently coupled ligands co-localized almost exclusively to cells in the cortical mantle showing neuron-specific enolase immunoreactivity. Second, a comparison of the cell size distribution taken from adjacent Nissl-stained sections with the size of cells showing D1- or D2-like receptor binding fluorescence revealed complete overlapping of fluorescence with neuronal cell bodies. In mPFC layer VI, the size of cells showing D1-like receptor binding fluorescence was 77.8 +/- 5.1 microns2, similar to non-pyramidal neurons, while that for D2-like receptor binding fluorescence was 108.2 +/- 4.5 microns2, consistent with both large interneurons and small pyramidal cells. Only a small percentage of cells showing D1- or D2-like receptor binding overlapped in size with glia, but this occurred almost exclusively within the white matter region below the cortical mantle. These findings are consistent with the hypothesis that the D1 and D2 receptor subtypes are found on different populations of neurons, although some overlap probably occurs.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2006

GABAergic neurons immunoreactive for calcium binding proteins are reduced in the prefrontal cortex in major depression.

Post-mortem morphometric studies report reductions in the average density and size of cortical neurons in the dorsolateral prefrontal cortex (dlPFC) and orbitofrontal cortex (ORB) in major depressive disorder (MDD). The contribution of specific neuronal phenotypes to this general pathology in depression is still unclear. Post-mortem sections from the dlPFC and ORB regions of 14 subjects with MDD and 11 controls were immunostained to visualize calbindin-immunoreactive (CB-IR) and parvalbumin-immunoreactive (PV-IR) presumptive GABAergic neurons. A three-dimensional cell counting probe was used to assess the cell packing density and size of CB-IR neurons in layers II+IIIa and PV-IR neurons in layers III-VI. The density of CB-IR neurons was significantly reduced by 50% in depression in the dlPFC and there was a trend toward reduction in the ORB. The size of CB-IR somata was significantly decreased (18%) in depression in the dlPFC with a trend toward reduction in the ORB. In contrast, there was no difference in the density of PV-IR neurons between the depressed and control groups in the dlPFC. The size of PV-IR neuronal soma was unchanged in depressed compared to control subjects in either dlPFC or ORB. In depression, subpopulations of GABAergic neurons may be affected differently in dlPFC and ORB. A significant reduction in the density and size of GABAergic interneurons immunoreactive for calcium binding proteins was found predominantly in the dlPFC region. These cellular changes are consistent with recent neuroimaging studies revealing a reduction in the cortical levels of GABA in depression.

Adult↗

PubMed2002

A model of prefrontal cortex dopaminergic modulation during the delayed alternation task.

Working memory performance is modulated by the level of dopamine (DA) D1 receptors stimulation in the prefrontal cortex (PFC). This modulation is exerted at different time scales. Injection of D1 agonists/antagonists exerts a long-lasting influence (several minutes or hours) on PFC pyramidal neurons. In contrast, during performance of a cognitive task, the duration of the postsynaptic effect of phasic DA release is short lasting. The functional relationships of these two time scales of DA modulation remain poorly understood. Here we propose a model that combines these two time scales of DA modulation on a prefrontal neural network. The model links the cellular and behavioral levels during performance of the delayed alternation task. The network, which represents the activity of deep-layer pyramidal neurons with intrinsic neuronal properties, exhibits two stable states of activity that can be switched on and off by excitatory inputs from long-distance cortical areas arriving in superficial layers. These stable states allow PFC neurons to maintain representations during the delay period. The role of an increase of DA receptors stimulation is to restrict inputs arriving on the prefrontal network. The model explains how the level of working memory performance follows an inverted U-shape with an increased stimulation of DA D1 receptors. The model predicts that (1) D1 receptor agonists increase perseverations, (2) D1 antagonists increase distractability, and (3) the duration of the postsynaptic effect of phasic DA release in the PFC is adjusted to the delay period of the task. These results show how the precise duration of the postsynaptic effect of phasic DA release influences behavioral performance during a simple cognitive task.

Dopamine↗