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Evidence for an involvement of acetylcholine in self-stimulation of the prefrontal cortex in the rat.

The effects of injections of antagonists of muscarinic and nicotinic receptors on self-stimulation of the prefrontal cortex in the rat were studied. The results of this investigation suggest that acetylcholine is involved in self-stimulation of the prefrontal cortex through activation of muscarinic receptors, and also suggest a possible interaction between acetylcholine and dopamine in mediating self-stimulation of this area of the brain.

Acetylcholine↗

Stimulation of rat medial or sulcal prefrontal cortex during passive avoidance learning selectively influences retention performance.

Low-level unilateral electrical stimulation was delivered during passive avoidance learning through a bipolar electrode to the prefrontal cortex of the adult albino rat. No brain stimulation was applied during a retention test measured 24 h later. Ventromedial prefrontal cortex stimulation produced retention impairment over and above that observed with chronic electrode implantation. Sulcal cortex stimulation, in contrast, actually attenuated the retention deficit produced by chronic implantation in the sulcal cortex. Stimulation of an afferent common to both prefrontal regions, the dorsomedial thalamus, resulted in retention disruption, but stimulation of another common afferent, the locus coeruleus, did not. Acquisition of the inhibitory response was not affected by stimulation of any of the above brain regions. The present results demonstrate, again, that the functional role in memory of particular brain regions can be dissected by low-level electrical stimulation. The functional separation of rat sulcal and medial cortices revealed by the effects of stimulation suggests that these prefrontal subfields subserve different functions in the information storage process.

Animals↗

Characterization of 5-hydroxytryptamine3 receptors in the medial prefrontal cortex: a microiontophoretic study.

The microiontophoretic application of the selective 5-hydroxytryptamine3 (5-HT3) agonist 2-methylserotonin suppresses medial prefrontal cortex cell firing. This effect is blocked by the 5-HT3 antagonists BRL 43694 and ICS205930, but not by metergoline or (+/-)-pindolol. Continuous microiontophoretic administration of magnesium chloride or the gamma-aminobutyric acidA antagonist SR 95103 did not alter 2-methylserotonin's suppressant action, suggesting that this effect is direct. Our results suggest that 5-HT3 receptors have a functional role in the medial prefrontal cortex.

Animals↗

An in vivo study of the prefrontal cortex of schizophrenic patients at different stages of illness via phosphorus magnetic resonance spectroscopy.

BACKGROUND: In this study, phospholipid metabolism of cell membranes, high-energy phosphate metabolism, and intracellular free magnesium concentration in the prefrontal cortex of first-episode drug-naive schizophrenic patients and medicated schizophrenic patients at different stages of illness were compared with those of controls. METHODS: Localized in vivo phosphorus 31 magnetic resonance spectra of the left dorsolateral prefrontal cortex of 11 drug-native, eight newly diagnosed medicated, and 10 chronic medicated patients with schizophrenia were compared with controls of similar gender, education, parental education, and handedness. RESULTS: Significantly decreased levels of phosphomonoesters in drug-native, newly diagnosed medicated, and chronic medicated patients and significantly increased levels of phosphodiesters in drug-native patients were observed when compared with controls. There were no significant differences in the levels of high-energy phosphate metabolites between the groups except for a significant decrease in the inorganic orthophosphate levels of newly diagnosed medicated patients. A significant increase in the intracellular free magnesium concentration was observed in drug-naive, newly diagnosed medicated, and chronic medicated patients compared with controls. There were no correlations between the patients' negative and positive symptoms and the observed phosphorus-containing metabolites. CONCLUSIONS: A reduction in precursors of membrane phospholipid are observed during the early and chronic stages of the schizophrenia illness, and breakdown products of membrane phospholipids are increased at the early stage of illness before medication treatment.

Adolescent↗

Effect of stress on prefrontal cortex function.

Stress is the major epigenetic factor that contributes to the etiology, pathophysiology, and treatment outcome of most psychiatric disorders. Understanding the mechanisms by which stress contributes to these processes can have important implications for improving therapeutic outcome. Considering that a dysfunctional prefrontal cortex has been implicated in many psychiatric disorders, such as schizophrenia and mood disorders, delineating mechanisms by which stress affects prefrontal cortex (PFC) function is critical to our understanding of the role of stress in influencing the disease process. This paper will review recent mechanistic information about the effects of stress on dopamine and glutamate neurotransmission in the PFC.

Humans↗

The role of the left prefrontal cortex in verbal processing: semantic processing or willed action?

This study was designed to test the various proposed explanations (semantic processing, willed action, production of a spoken response) for the unilateral activation of the left prefrontal cortex noted in PET studies of verbal processing. Twenty subjects underwent 15O-water PET scans while undertaking a lexical task (detecting the letter 'a' in visually presented words) and a semantic task (categorizing nouns into living/non-living). The semantic task resulted in a significant unilateral left dorsolateral prefrontal activation. This finding suggests that the left inferior prefrontal cortex is the anatomical region involved in 'working with meaning', and that the activation does not reflect willed action, is not task-specific and is not attributable to the requirements of a spoken response.

Adult↗

Stimulation-induced release of coexistent transmitters in the prefrontal cortex: an in vivo microdialysis study of dopamine and neurotensin release.

Extracellular fluid levels of dopamine and neurotensin in the rat prefrontal cortex were measured using in vivo microdialysis. Electrical stimulation of the median forebrain bundle resulted in increased release of both dopamine and neurotensin from the prefrontal cortex. Thus, stimulation of neurons in which dopamine and neurotensin are colocalized can evoke the in vivo release of both substances.

Animals↗

Dorsomedial prefrontal cortex resolves response conflict in rats.

The capacity for goal-directed behavior requires not only the encoding of the response-outcome relationship but also the ability to resolve conflict induced by competing responses. Recent neuroimaging studies have identified the prefrontal cortex as critical for resolving conflict between competing responses. At present, however, much of this evidence is indirect, and the necessity of dorsomedial prefrontal cortex (dmPFC) function for the resolution of conflict in goal-directed behavior has not been assessed. Here, we develop a rodent paradigm to investigate response conflict caused by the concurrent activation of a correct and incorrect response. In this paradigm, the outcome of one response also acts as a discriminative stimulus signaling that the other response is correct. Whereas rats with a functional dmPFC are able to resolve this conflict, inactivation of dmPFC using an infusion of muscimol produced a deficit by selectively interfering with their ability to inhibit the incorrect, competing response.

Animals↗

D1/D5 dopamine receptor activation differentially modulates rapidly inactivating and persistent sodium currents in prefrontal cortex pyramidal neurons.

Dopamine (DA) is a well established modulator of prefrontal cortex (PFC) function, yet the cellular mechanisms by which DA exerts its effects in this region are controversial. A major point of contention is the consequence of D(1) DA receptor activation. Several studies have argued that D(1) receptors enhance the excitability of PFC pyramidal neurons by augmenting voltage-dependent Na(+) currents, particularly persistent Na(+) currents. However, this conjecture is based on indirect evidence. To provide a direct test of this hypothesis, we combined voltage-clamp studies of acutely isolated layer V-VI prefrontal pyramidal neurons with single-cell RT-PCR profiling. Contrary to prediction, the activation of D(1) or D(5) DA receptors consistently suppressed rapidly inactivating Na(+) currents in identified corticostriatal pyramidal neurons. This modulation was attenuated by a D(1)/D(5) receptor antagonist, mimicked by a cAMP analog, and blocked by a protein kinase A (PKA) inhibitor. In the same cells the persistent component of the Na(+) current was unaffected by D(1)/D(5) receptor activation-suggesting that rapidly inactivating and persistent Na(+) currents arise in part from different channels. Single-cell RT-PCR profiling showed that pyramidal neurons coexpressed three alpha-subunit mRNAs (Nav1.1, 1.2, and 1.6) that code for the Na(+) channel pore. In neurons from Nav1.6 null mice the persistent Na(+) currents were significantly smaller than in wild-type neurons. Moreover, the residual persistent currents in these mutant neurons-which are attributable to Nav1.1/1.2 channels-were reduced significantly by PKA activation. These results argue that D(1)/D(5) DA receptor activation reduces the rapidly inactivating component of Na(+) current in PFC pyramidal neurons arising from Nav1.1/1.2 Na(+) channels but does not modulate effectively the persistent component of the Na(+) current that is attributable to Nav1.6 Na(+) channels.

Animals↗

Rapid increase in PKA activity during long-term potentiation in the hippocampal afferent fibre system to the prefrontal cortex in vivo.

The purpose of the present study was to examine whether cAMP-dependent protein kinase (PKA) was implicated in the process of long-term potentiation (LTP) in the hippocampal afferent fibre system to the prefrontal cortex in vivo. Using a biochemical approach, we measured PKA activity at different times after induction of LTP. We show that there is an NMDA receptor-dependent increase in PKA activity in the prefrontal cortex, only at five minutes after LTP induction. These data demonstrate a role of PKA in the induction and not the expression of cortical LTP and suggest that if PKA is involved in the late phase of LTP, it does not appear to be a persistent activation.

Animals↗

Dissociations in dopamine release in medial prefrontal cortex and ventral striatum during the acquisition and extinction of classical aversive conditioning in the rat.

Dual perfusion in vivo brain microdialysis was used to monitor extracellular levels of dopamine in the medial prefrontal cortex and ventral striatum during the acquisition and extinction of a classical aversive conditioning paradigm in rats. The main finding was a dissociation in the pattern of release in the two brain areas. The first stimulus-footshock pairing elicited large increases in cortical dopamine over baseline levels that were much greater than the increases elicited by different stimuli of equivalent salience that were unpaired with footshock. In contrast, dopamine levels in ventral striatum were unchanged under these conditions. Over the next two pairings, there was a decline in the cortical response and an increase in the response in ventral striatum. The first presentation of the aversive conditioned stimulus in a separate context elicited the largest response in ventral striatum. Post-conditioning, the cortical response to the conditioned stimulus was smaller than that elicited by the initial stimulus-footshock pairing and was equivalent in magnitude to that elicited by stimuli unpaired with footshock. Over the final two conditioned stimuli presentations, in the absence of the footshock reinforcer (extinction), responses declined in both brain areas. Simultaneous monitoring of behaviour indicated that the neurochemical events were accompanied by effective aversive learning, as indexed by conditioned freezing responses. The data are discussed in terms of the hypothesis that medial prefrontal cortex is especially engaged during novel circumstances which may, potentially, require new learning, whilst ventral striatal dopamine more closely follows the expression of conditioned responding during learning and extinction.

Animals↗

Peptidase inhibitors potentiate the effects of neurotensin and neuromedin N on self-stimulation of the medial prefrontal cortex.

The purpose of this study was to examine the possible role of endogenous peptidases in the inhibition of intracranial self-stimulation (ICSS) produced by injections of neurotensin (NT) and neuromedin N (NN) into the medial prefrontal cortex (MPC) of the rat. We studied the effects on ICSS of the MPC of the administration of thiorphan and bestatin, two specific inhibitors of the peptidases that inactivate NT and NN respectively. Microinjections into MPC of thiorphan (10 micrograms) and bestatin (25 micrograms) potentiated in inhibition of ICSS produced by the intracortical administration of NT (10 nmol) and NN (20 nmol) respectively. This potentiation affected both the amplitude and the duration of the inhibition of ICSS produced by the neuropeptides. Our data indicate that endogenous peptidases are involved in the inactivation of NT and NN in the prefrontal cortex.

Animals↗

Auditory memory cells in dorsolateral prefrontal cortex.

The activity of single neurons was recorded extracellularly from dorsolateral prefrontal cortex (DPC) of monkeys during the performance of a cross-modal audio-visual short-term memory task. Cells in DPC show sustained elevated firing levels (higher than spontaneous discharge) during the retention of the auditory stimulus. In some cells this elevated firing was significantly different depending on the particular auditory memorandum of each trial. These results support the notion that DPC participates in auditory short-term memory and the integration of auditory and visual information for prospective action.

Animals↗

Induction of c-fos mRNA in rat medial prefrontal cortex by antipsychotic drugs: role of dopamine D2 and D3 receptors.

The present studies compared the effects of acute and chronic administration of haloperidol or clozapine on c-fos mRNA expression in the rat medial prefrontal cortex. Acute administration of clozapine, but not haloperidol robustly increased c-fos mRNA expression in the infralimbic and prelimbic cortex of the rat. Even though most c-fos mRNA-expressing neurons in the clozapine- treated animals were localized in deep cortical layers, labeled neurons were found organized into several cell bridges connecting the superficial and deep layers of the cortex. After chronic treatment with clozapine, c-fos mRNA was reduced by approximately 60% of that seen acutely; however, the columns of c-fos mRNA expressing neurons did not show the same magnitude of tolerance. Haloperidol had no significant effect even after chronic treatment. We examined further the role of dopamine D2 versus D3 receptors in c-fos gene induction in the infralimbic cortex by studying the acute effects of remoxipride and U-99194A. Remoxipride, a selective D2 antagonist in vitro, induced c-fos mRNA at very low doses and lost its ability to alter c-fos mRNA at higher doses. Interestingly, U-99194A, an antagonist with 20-fold selectivity for D3 over D2 receptors, also produced greater induction of c-fos mRNA at lower doses. We hypothesize that blockade of D3 receptors may enhance c-fos gene expression in the medial prefrontal cortex but that of D2 receptors may prevent the same.

Animals↗

Dopamine and noradrenaline efflux in the prefrontal cortex in the light and dark period: effects of novelty and handling and comparison to the nucleus accumbens.

We used on-line microdialysis measurements of dopamine and noradrenaline extracellular concentrations in the medial prefrontal cortex of awake, freely moving rats during the dark and the light period of the day to study whether (i) basal efflux would be higher in the active, dark period than in the inactive, light period; (ii) the activation induced by environmental stimuli would be dependent on these conditions. When determined one day after cannula placement, noradrenaline and dopamine levels were higher during the dark. Maximal relative increases induced by novelty and handling were 150% and 175-200%, respectively, and were very similar in the light and the dark, but the net increases were higher in the dark. Separate groups were tested one week after cannula placement to ensure recovery of possibly disturbed circadian rhythms. While basal levels in the dark were now approximately twice those in the light, the maximal relative and net increases after both novelty and handling were very similar. Basal levels of dopamine in the nucleus accumbens (one day after cannula placement) were not different in the light or dark, but were increased by novelty and handling to about 130% only in the light period, not in the dark. Thus, in the prefrontal cortex, dopamine strongly resembles noradrenaline, in that basal efflux was state dependent, whereas activation by stimuli was not. In the nucleus accumbens, basal dopamine efflux was not state dependent, but activation by stimuli was. These results suggest that there are differential effects of circadian phase on basal activity and responsiveness of the mesolimbic vs the mesocortical dopamine system.

Animals↗

Dissecting contributions of prefrontal cortex and fusiform face area to face working memory.

Interactions between prefrontal cortex (PFC) and stimulus-specific visual cortical association areas are hypothesized to mediate visual working memory in behaving monkeys. To clarify the roles for homologous regions in humans, event-related fMRI was used to assess neural activity in PFC and fusiform face area (FFA) of subjects performing a delay-recognition task for faces. In both PFC and FFA, activity increased parametrically with memory load during encoding and maintenance of face stimuli, despite quantitative differences in the magnitude of activation. Moreover, timing differences in PFC and FFA activation during memory encoding and retrieval implied a context dependence in the flow of neural information. These results support existing neurophysiological models of visual working memory developed in the nonhuman primate.

Adult↗

Impairment in a discrimination reversal task after D1 receptor blockade in the pigeon "prefrontal cortex".

Dopamine (DA) is known to modulate cognitive functions of the prefrontal cortex (PFC) of mammals, especially via D1 receptor mechanisms. Like the PFC, the neostriatum caudolaterale (NCL) of birds is characterized by dopaminergic input, and NLC and PFC lesions cause similar deficits. The significance of DA in a color discrimination reversal was assessed by evaluating the effects of bilateral infusions of the D1 receptor antagonist SCH 23390 into the NCL of pigeons (Columba livia). Reversal deficits were qualitatively similar to those in mammals. At a low dose, perseveration occurred predominantly to the incorrect stimulus. Higher doses caused additional spatial perseveration. The data demonstrate, for the first time, that D1 receptor mechanisms in the NCL of pigeons contribute substantially to its function in cognitive processes. Thus, the avian NCL and mammalian PFC could represent functionally equivalent neural networks under control of the DA system.

Animals↗

Lysergic acid diethylamide and [-]-2,5-dimethoxy-4-methylamphetamine increase extracellular glutamate in rat prefrontal cortex.

The ability of hallucinogens to increase extracellular glutamate in the prefrontal cortex (PFC) was assessed by in vivo microdialysis. The hallucinogen lysergic acid diethylamide (LSD; 0.1 mg/kg, i.p.) caused a time-dependent increase in PFC glutamate that was blocked by the 5-HT(2A) antagonist M100907 (0.05 mg/kg, i.p.). Similarly, the 5-HT(2A/C) agonist [-]-2,5-dimethoxy-4-methylamphetamine (DOM; 0.6 mg/kg, i.p.), which is a phenethylamine hallucinogen, increased glutamate to 206% above saline-treated controls. When LSD (10 microM) was directly applied to the PFC by reverse dialysis, a rapid increase in PFC glutamate levels was observed. Glutamate levels in the PFC remained elevated after the drug infusion was discontinued. These data provide direct evidence in vivo for the hypothesis that an enhanced release of glutamate is a common mechanism in the action of hallucinogens.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗