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Middle-latency auditory evoked potentials (MAEPs) were recorded in controls and patients with focal lesions in dorsolateral prefrontal cortex. Unilateral prefrontal lesions increased the amplitude of the Pa component of the MAEP beginning at 25-35 ms poststimulus. The data suggest that prefrontal cortex exerts early inhibitory modulation of input to primary auditory cortex in humans.
When the anteromedial hypothalamus is stimulated with a chronically implanted electrode in conscious cats, negative emotional behaviors such as restlessness and escape occur during stimulation and ventricular extrasystoles occur in rapid succession immediately after the end of stimulation. It has been shown in the lightly anesthetized cat that the activity of the sympathetic nervous system becomes predominant during stimulation of the anteromedial hypothalamus thereby causing the rises in blood pressure and heart rate. However, immediately after the cessation of the stimulation, this 'sympathetic dominant' state was observed to be switched to the 'parasympathetic dominant' state with falls in blood pressure and heart rate which was very frequently followed by the appearance of the ventricular extrasystoles (Poststimulus Arrhythmia: PSA). The purpose of this experiment was to examine how the electric and pharmacological stimulation of the prefrontal cortex modulate the rise in the blood pressure and heart rate and PSA caused by electric stimulation of the anteromedial hypothalamus. When the prefrontal cortex was electrically stimulated simultaneously with stimulation of the anteromedial hypothalamus in 24 lightly anesthetized cats, PSA was inhibited or facilitated or remained unchanged depending on the site of stimulation in the prefrontal cortex. When dopamine or noradrenaline was microinjected into the site of prefrontal cortex where PSA was inhibited, PSA was suppressed and this effect was blocked by microinjection of haloperidol or phenoxybenzamine, respectively. Dopamine was ineffective when injected in the site where PSA was facilitated; PSA was facilitated by microinjection of noradrenaline and this effect was inhibited by microinjection of propranolol. Although changes in blood pressure and heart rate were observed when the inhibition or facilitation of PSA was elicited by prefrontal injection of noradrenaline, no changes in cardiovascular parameters occurred when dopamine injection caused the inhibition of PSA. These results suggest (1) that activation of the dopamine receptor or alpha adrenoceptor in the prefrontal cortex is involved in the inhibition of PSA, and activation of beta adrenoceptor is concerned with facilitation of PSA and (2) that the mechanisms of dopamine receptor mediated inhibition of PSA appear to be different from those of inhibition of PSA by activation of the alpha adrenoceptor in the prefrontal cortex.
It has been demonstrated that cocaine HCl lowers thresholds for and increases rates of medial forebrain bundle intracranial self-stimulation. The influence of cocaine on prefrontal cortex self-stimulation was assessed in the present experiment. The prefrontal cortex was chosen because evidence indicates that the neuroanatomical and pharmacological substrate for intracranial self-stimulation at this site may differ from the substrate for medial forebrain bundle self-stimulation. Cocaine significantly decreased train-duration thresholds and increased the rate of prefrontal cortex self-stimulation. It was concluded that cocaine facilitates both prefrontal cortex and medial forebrain bundle self-stimulation, perhaps by influencing neural activity in the mesocorticolimbic dopamine system. However, the role of dopamine in cocaine's effects at both sites remains speculative.
The reinforcing efficacy of cocaine is thought to involve, at least in part, mesocortical dopaminergic (DA) neurons. Rats will self-administer cocaine applied directly into the medial prefrontal cortex but not into nucleus accumbens or the ventral tegmental area (Goeders & Smith, 1983). The present experiments were conducted to assess whether lesions of prefrontal cortex (mesocortical DA target regions) attenuate the reinforcing properties of systemically administered cocaine. Male Sprague-Dawley rats were anesthetized, and one of three subfields (medial, orbital, or precentral) of the prefrontal cortex was removed by aspiration or no brain injury was done (sham operates). In four experiments the rats were tested on conditioned place preference (CPP), conditioned taste aversion (saccharin conditioned stimulus, cocaine unconditioned stimulus), general activity in the running wheel and open field, and food-reinforced spatial alternation in the T-maze. Sham operates demonstrated a cocaine-induced place preference, rats with medial frontal lesions showed a cocaine-induced place aversion, and other operates showed neither a conditioned place preference nor an aversion. The results of this experiment suggest that lesions of the DA projection fields of the prefrontal cortex in the rat reduce the positive reinforcing properties of systemically injected cocaine. In the second experiment, all subjects showed a conditioned taste aversion of equal magnitude. This suggests that whereas the positive reinforcing properties were affected differentially by prefrontal cortex lesions, the aversive properties were not affected. In Experiment 3 there were no lesion-induced differences in activity in either the running wheel or the open field. Therefore, changes in motor activity cannot account for the CPP data. In the final experiment, the medial frontal operates were impaired relative to the precentral and sham operates on learning to alternate choices in the T-maze, but the orbital frontal operates' performance was not different from that of any other group. This suggests that a general disruption of all reinforcement mechanisms did not occur following these lesions. Instead, these results indicate that mesocortical DA projection regions are involved with mediating the reinforcing properties of cocaine and that there is a separate system mediating the aversive properties of cocaine.
A large body of empirical evidence supports the notion of a critical role of the prefrontal cortex in the temporal organization of goal-directed behavioral sequences. The key element of that role is the bridging of cross-temporal contingencies of behavior, in other words, the adjustment of the actions of the organism to temporally distant events and objectives. By the analysis of lesion effects, neuroelectrical phenomena, and metabolic activity we are led to conclude that the prefrontal cortex subserves at least three cognitive functions that allow the mediation of cross-temporal contingencies and, thereby, the formation of temporally extended structures of behavior: short-term memory, preparatory set, and control of interference. The three have a somewhat different topographic representation within the prefrontal cortex and thus the principle of its functional heterogeneity is upheld. However, all three sustain the supraordinate role of the prefrontal cortex in the temporal integration of behavior.
Using the technique of perfusion microdialysis combined with a small-bore liquid chromatography system we have measured the basal and drug-induced fluxes of extracellular dopamine in the medial prefrontal cortex of chloral hydrate-anesthetized rats and have compared our findings in the cortex to that observed in the striatum. The results were as follows. (1) At a flow rate of 2 microliter/min, the basal level of dopamine in the medial prefrontal cortex was 0.28 +/- 0.1 (n = 32) fmol/microliter perfusate, which was nearly an order of magnitude less than that obtained from the striatum. (2) alpha-Methyl-para-tyrosine (150 mg/kg i.v.) significantly decreased the extracellular levels of striatal and cortical dopamine. The magnitude and duration of the responses were similar in both regions. (3) Local perfusion with 30 mM K+ had a more profound effect on dopamine release in the striatum than in the medial prefrontal cortex. The K(+)-induced release in both regions was significantly attenuated in the absence of Ca2+. (4) The anxiogenic beta carboline FG 7142 (15 mg/kg, i.p.) enhanced the release of cortical dopamine by about 50% while it was without an effect in the striatum. (5) Amphetamine (1 mg/kg, i.v.) significantly elevated, while reserpine (5 mg/kg, i.p.) rapidly attenuated, the dopamine level in the medial prefrontal cortex. These studies demonstrate that perfusion microdialysis, in conjunction with small-bore liquid chromatography with electrochemical detection, can be used to measure the basal release of dopamine in the rat medial prefrontal cortex and that the dopamine release process in this region, as has been shown in the striatum, is sensitive to stimulation conditions and pharmacological manipulations.(ABSTRACT TRUNCATED AT 250 WORDS)
The competitive NMDA (N-methyl-D-aspartate) receptor antagonist, CPP (3(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid), microinjected into the medial prefrontal cortex of rats, induces a unique behavioral syndrome termed 'darting', characterized by rapid leaping across an open field arena. In addition, CPP induces generalized hyperactivity when microinjected into the medial prefrontal cortex, nucleus accumbens, and caudate nucleus. Polyamine modulation of the NMDA receptor was tested at the medial prefrontal cortex microinjection site in this behavioral paradigm. The polyamine spermidine, and its diamine precursor, putrescine, blocked CPP-induced darting behavior, as well as CPP-induced hyperactivity, at doses which did not decrease locomotor activity when administered alone. The putative polyamine antagonists, ifenprodil and diethylenetriamine, did not prevent spermidine from inhibiting CPP-induced darting. These results suggest that polyamines, presumably by acting as positive allosteric modulators of the NMDA receptor, can inhibit the CPP-induced behavioral syndrome at the prefrontal cortex site.
This study was designed to characterize the response of a select population of prefrontal cortex neurons to exogenous and endogenous dopaminergic influences. Of particular interest were neurons with efferent projections to the ventral tegmental area (VTA) which are part of a reciprocal innervation between the prefrontal cortex and the VTA. Extracellular single unit recording techniques were used to determine the response of cortical neurons to electrical stimulation of the VTA in chloral hydrate anesthetized rats. The neurons were selected on the basis of their electrophysiological characteristics (large amplitude with positive initial deflection) and were classified as to whether or not they were antidromically activated from the VTA. Apomorphine (25 micrograms/kg, IV) significantly reduced the spontaneous activity of both the antidromically identified and the unidentified prefrontal cortex neurons. The apomorphine (25 micrograms/kg, IV) response was antagonized by cis-flupentixol (1.0 mg/kg, IV) in both antidromically identified and unidentified cortical neurons. Stimulation of the VTA also induced a synaptically mediated inhibition of the cortical neuron spontaneous activity. The orthodromic VTA stimulus-evoked inhibition was antagonized by cis-flupentixol (1.0 mg/kg, IV) for both the antidromically identified and the unidentified neurons (63 and 71% of the neurons respectively). The results indicate that a select population of prefrontal cortex neurons respond specifically to exogenous and endogenous dopaminergic influences and that the response is independent of efferent projections to the VTA.
The prefrontal cortex (PFC) is critical for temporal organization of behavior. It mediates cross-temporal sensorimotor contingencies, integrating motor action (including speech) with recent sensory information. It performs this role through cooperation of 2 cognitive functions represented in its dorsolateral areas: short-term memory (STM) and preparatory set. Supporting data have been obtained from monkeys performing delay tasks, which epitomize the principle of cross-temporal contingency. In a given trial, the animal performs an act contingent on a sensory cue given a few seconds or minutes earlier. During the delay between cue and response, cells in dorsolateral PFC show sustained activation. Two cell categories can be identified in tasks in which cue and response are spatially separate. Cells of the first participate in STM: Their activation tends to diminish as the delay progresses; in some, the activation level depends on the particular cue received. Similar cells are found elsewhere in the cortex. Cells of the second category seem to take part in preparation of motor response: Their activation tends to increase in anticipation of it and may be attuned to the particular movement the cue calls for. This cell type is rare outside of the frontal cortex. The temporally integrative function of the PFC is probably based on local interactions between "memory" and "motor-set" cells, as well as on neural associations between PFC and posterior cortical areas.
Morphometric analysis of medial prefrontal cortex (layer VI) of rats treated daily with amphetamine in a dose of 2.5 mg/kg during 3 weeks was performed on the electron microscopic level. The efficacy of the amphetamine dosage was tested on behavioral observation. Synapses on dendritic shafts and spines were studied. The density of axo-dendritic synapses increase on 74%, while the density of synapses on spine's neck decreased on 53%. Most synaptic parameters measured in axo-dendritic (1) and axo-spinous (2) synapses increased significantly under the influence of 2.5 mg/kg dose of AMPH: area of presynaptic terminal increased on 35% (1) and 21% (2), length of postsynaptic density increased on 13% (1) and 12% (2), area of spine increase on 25%. But the density of synaptic vesicles near the active zone decrease (1-on 16.5%, 2-on 20%).
Morphometric analysis of Medial prefrontal cortex (layer VI) of rats treated daily with haloperidol in a dose of 0.1 mg/kg during 3 weeks was performed on the electron microscopic level. The efficacy of the haloperidol dosage was tested on the amphetamine psychosis model. Synapses on dendritic shafts and dendritic spines were studied. The density of synapses on dendritic shafts increased on 51%, while on spine's neck it decreased on 19%. There were significant changes of some synaptic parameters only in axo-dendritic synapses: area of presynaptic terminal decreased on 13% (p less than 0.05), length of postsynaptic density decreased on 15% (p less than 0.05), but the density of synaptic vesicles near the active zone increased on 10% (p less than 0.05).
The effect of the anxiogenic beta-carboline methyl-beta-carboline-3-carboxyamide (FG 7142) on dopamine release in prefrontal cortex and striatum in the awake freely moving rat was determined using the technique of microdialysis. FG 7142 (25 mg/kg, i.p.) caused a time-dependent increase in dopamine release in prefrontal cortex which was statistically significantly greater than the response to vehicle administration. Dopamine release in striatum was unaltered by FG 7142. Pretreatment of animals with the benzodiazepine antagonist Ro 15-1788 (30 mg/kg, i.p., 15 min prior to FG 7142 administration) completely abolished the increase in dopamine release caused by FG 7142 in prefrontal cortex. These data indicate that the anxiogenic benzodiazepine inverse agonist FG 7142 can selectively increase dopamine release in prefrontal cortex, and that this effect appears to be mediated via the gamma-aminobutyric acid/benzodiazepine receptor complex.
The effects of prefrontal cortical dopamine depletion on subcortical dopamine function in the rat were examined. 6-Hydroxydopamine lesions of the dopaminergic innervation of the prefrontal cortex did not alter concentrations of dopamine or its metabolite 3,4-dihydroxyphenylacetic acid in either the striatum or nucleus accumbens. Similarly, the activity of the catecholamine biosynthetic enzyme tyrosine hydroxylase in the striatal complex was not changed in animals with prefrontal cortical lesions. Animals sustaining neurotoxic lesions of the prefrontal cortex were challenged with haloperidol in order to activate submaximally tyrosine hydroxylase activity. The magnitude of the haloperidol-induced increase in enzyme activity in the nucleus accumbens was significantly greater in lesioned subjects than in control animals. These data suggest that lesions of the prefrontal cortical dopamine innervation do not result in significant alterations in basal dopaminergic function in the striatal complex. However, lesions of the dopaminergic innervation of the prefrontal cortex significantly increase the responsiveness of mesolimbic dopamine afferents to pharmacological challenge.
The effect of chronic administration of spiroperidol, a dopaminergic antagonist, on self-stimulation of the prefrontal cortex was investigated. When spiroperidol was administered either before or after daily self-stimulation tests for 9 days, self-stimulation rates were significantly elevated for several weeks following withdrawal of the drug. Self-stimulation of the nucleus accumbens, supracallosal bundle, and other forebrain sites was not altered, suggesting that the increased self-stimulation of the prefrontal cortex was not due to increased motor activity. Self-stimulation of the prefrontal cortex was also facilitated by chronic administration of d-amphetamine whereas self-stimulation of the supracallosal bundle was suppressed and self stimulation of the nucleus accumbens was unchanged. The results suggest that dopamine modulates self-stimulation of the prefrontal cortex. Additionally, the effects of chronic spiroperidol on self-stimulation of this structure may model the therapeutic effects of neuroleptics in humans.
Unilateral partial ablations in the medial prefrontal cortex of six squirrel monkeys led to fiber degeneration which followed cingulate and uncinate routes to the hippocampal region. Degenerating fibers were observed primarily in the alvear, but also in the perforant, bundle. Preterminal and terminal debris was seen on basket cells of the stratum oriens and pyramidal cells within the sratum pyramidalis of CA1-3. Since the prefrontal cortex has been shown to receive convergent sensory inputs from both external and internal milieu, this projection may represent the anatomical substrate for the essential influence of this information on the hippocampus proper, and also explain data which show the prefrontal cortex and hippocampus to be integrally related to mechanisms of learning and memory behavior.
The magnitude and duration of release of monoamines evoked by local applications of potassium were measured in vivo in the medial prefrontal cortex using high-speed chronoamperometry. Typical electrochemical signals reflecting released of electroactive species ranging from 0.5 to 3.0 microM and lasting 90-120 s were detected at a variety of dorsal-ventral and anterior-posterior electrode placements in the medial prefrontal cortex. The magnitude of the reduction current measured following the oxidation reaction suggests a contribution of both serotonin and dopamine to the electrochemical signal, dopamine serving as the predominant monoamine in the medial prefrontal cortex proper and serotonin appearing to predominant in the more posterior regions of the frontal cortex. This conclusion was reinforced by the fact that unilateral 6-hydroxydopamine lesions of ascending dopamine fibers almost completely abolished electrochemical signals in the ipsilateral but not in the contralateral medial prefrontal cortex. The present study provides an in vivo characterization of monoamine release in the mesocortical dopamine terminal field, where it has been suggested that psychomotor stimulants may produce some of their positive reinforcing effects.
Following horseradish peroxidase (HRP) injections into different areas within the prefrontal cortex (PFC) of the cat, labeled neurons were found in the cingulate and insular cortex. These results demonstrate that the cat's prefrontal cortex is reached directly from these cortical regions, and that the observed cortical projections are similar to those detected in the monkey's prefrontal cortex.
We have analyzed the cortical and subcortical afferent connections of the medial prefrontal cortex (MPF) in the cat with the specific aim of characterizing subregional variations of afferent connectivity. Thirteen tracer deposits were placed at restricted loci within a cortical district extending from the proreal to the subgenual gyrus. The distribution throughout the forebrain of retrogradely labeled neurons was then analyzed. Within the thalamus, retrogradely labeled neurons were most numerous in the mediodorsal nucleus and in the ventral complex. The projection from each region exhibited continuous topography such that more medial thalamic neurons were labeled by tracer from more ventral and posterior cortical deposits. Marked retrograde labeling without any sign of topographic order occurred in a narrow medioventral sector of the lateroposterior nucleus. Several additional thalamic nuclei contained small numbers of labeled neurons. In a subset of nuclei closely affiliated with the limbic system (the parataenial, paraventricular, reuniens, and basal ventromedial nuclei), retrograde labeling occurred exclusively after deposits at extremely ventral and posterior cortical sites. Within the amygdala, retrogradely labeled neurons occupied the anterior basomedial nucleus, the posterior basolateral nucleus, and a narrow strip of the lateral nucleus immediately adjoining the basolateral nucleus. The number of labeled neurons was greater after more ventral deposits. Very ventral deposits resulted in extensive labeling of the cortical amygdala. Within the cerebral cortex, the distribution of labeled neurons depended on the location of the tracer deposit. Comparatively dorsal deposits produced prominent retrograde transport to the anterior and posterior cingulate areas, to the agranular insula, and to lateral prefrontal cortex. Comparatively ventral deposits gave rise to prominent labeling of the hippocampal subiculum, various parahippocampal areas, and prepiriform cortex. On the basis of afferent connections, it is possible to divide the cat's medial prefrontal cortex into an infralimbic component, MPFil, marked by strong afferents from prepiriform cortex and the cortical amygdala, and a dorsal component, MPFd, without afferents from these structures. Further, within MPFd, it is possible to define an axis, running from ventral and posterior to dorsal and anterior levels, along which limbic afferents gradually become weaker and projections from cortical association areas gradually become stronger.