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PubMed2006

Chronic fluoxetine treatment increases the expression of PSA-NCAM in the medial prefrontal cortex.

Recent hypotheses suggest that changes in neuronal structure and connectivity may underlie the etiology of depression. The medial prefrontal cortex (mPFC) is affected by depression and shows neuronal remodeling during adulthood. This plasticity may be mediated by the polysialylated form of the neural cell adhesion molecule (PSA-NCAM), which is intensely expressed in the adult mPFC. As the expression of PSA-NCAM is increased by serotonin in other cerebral regions, antidepressants acting on serotonin reuptake may influence PSA-NCAM expression and thus counteract the effects of depression by modulating neuronal structural plasticity. Using immunohistochemistry, we have studied the relationship between serotoninergic fibers and PSA-NCAM expressing neurons in the adult rat mPFC and the expression of serotonin receptors in these cells. The effects of fluoxetine treatment for 14 days on mPFC PSA-NCAM expression have also been analyzed. Although serotoninergic fibers usually do not contact PSA-NCAM immunoreactive neurons, most of these cells express 5-HT3 receptors. In general, chronic fluoxetine treatment induces significant increases in the number of PSA-NCAM immunoreactive neurons and in neuropil immunostaining and coadministration of the 5-HT3 antagonist ondansetron blocks the effects of fluoxetine on PSA-NCAM expression. These results indicate that fluoxetine, acting through 5-HT3 receptors, can modulate PSA-NCAM expression in the mPFC. This modulation may mediate the structural plasticity of this cortical region and opens new perspectives on the study of the molecular bases of depression.

Analysis of Variance↗

PubMed2000

Characterization of the decision-making deficit of patients with ventromedial prefrontal cortex lesions.

On a gambling task that models real-life decisions, patients with bilateral lesions of the ventromedial prefrontal cortex (VM) opt for choices that yield high immediate gains in spite of higher future losses. In this study, we addressed three possibilities that may account for this behaviour: (i) hypersensitivity to reward; (ii) insensitivity to punishment; and (iii) insensitivity to future consequences, such that behaviour is always guided by immediate prospects. For this purpose, we designed a variant of the original gambling task in which the advantageous decks yielded high immediate punishment but even higher future reward. The disadvantageous decks yielded low immediate punishment but even lower future reward. We measured the skin conductance responses (SCRs) of subjects after they had received a reward or punishment. Patients with VM lesions opted for the disadvantageous decks in both the original and variant versions of the gambling task. The SCRs of VM lesion patients after they had received a reward or punishment were not significantly different from those of controls. In a second experiment, we investigated whether increasing the delayed punishment in the disadvantageous decks of the original task or decreasing the delayed reward in the disadvantageous decks of the variant task would shift the behaviour of VM lesion patients towards an advantageous strategy. Both manipulations failed to shift the behaviour of VM lesion patients away from the disadvantageous decks. These results suggest that patients with VM lesions are insensitive to future consequences, positive or negative, and are primarily guided by immediate prospects. This 'myopia for the future' in VM lesion patients persists in the face of severe adverse consequences, i.e. rising future punishment or declining future reward.

Adult↗

PubMed1994

Effects of local application of dopaminergic drugs into the dorsal part of the medial prefrontal cortex of rats in a delayed matching to position task: comparison with local cholinergic blockade.

Lesions of the medial prefrontal cortex (mPFC) disrupt performance in a variety of delay tasks, which suggests that the mPFC supports short-term memory processes. The putative involvement of the dopaminergic innervation of the mPFC in these mnemonic processes was investigated by evaluating the effects of local infusions of dopaminergic drugs into the mPFC of rats in an operant delayed-matching-to-position (DMTP) task. Trained animals were provided with bilateral guide cannulae aimed at the dorsal part of the mPFC. Two separate groups of rats were tested after microinfusion of several doses of either the dopamine agonist apomorphine (APO) or the dopamine antagonist cis-flupenthixol (FLU). In addition, all animals were tested after infusion of several doses of the muscarinic antagonist scopolamine (SCO). Animals were tested 0 and 135 min after each infusion. At the 0 min interval, neither APO nor FLU affected accuracy of DMTP performance, while both drugs dose-dependently increased response latencies and decreased nosepoke frequencies. At the 135 min interval, APO had almost no effect, whereas the effects of FLU were very prominent. A number of animals no longer responded after infusion of the highest doses of FLU and those that did showed a delay-independent decrease in response accuracy. In contrast, SCO infusions into the mPFC induced a dose- and delay-dependent deterioration of DMTP performance. Taken together, these results support a direct involvement of the rat mPFC in short-term memory processes, although they implicate cholinergic rather than dopaminergic mechanisms in this function.

Animals↗

PubMed2006

Medial prefrontal cortex NMDA receptors and nitric oxide modulate the parasympathetic component of the baroreflex.

The ventral portion of the medial prefrontal cortex (vMPFC) is involved in the modulation of the parasympathetic component of the baroreflex. In the present study, we verified the effect of blockade of vMPFC glutamatergic receptors and nitric oxide synthases (NOS) on the parasympathetic component of baroreflex in awake rats. Bilateral microinjection of the non-selective ionotropic glutamate antagonist kynurenic acid (KYN) into the vMPFC caused a shift of the threshold of reflex bradycardia toward higher pressures in response to increases in mean arterial pressure (MAP) caused by intravenous infusion of phenylephrine, thus indicating a tonic facilitatory influence action of vMPFC glutamate receptors on the parasympathetic component of the baroreflex. The effect of blockade of vMPFC-NMDA receptors by AP7 was similar to that observed after KYN, suggesting mediation via NMDA receptors. Pretreatment with the NOS inhibitor L-NAME or the specific neural NOS (nNOS) N(omega)-propyl-l-arginine microinjected in the vMPFC caused a shift of the reflex threshold toward higher pressures that was similar to that observed after blockade of NMDA receptors, thus indicating participation of the NO/NMDA-receptor pathway in the vMPFC modulation of the parasympathetic component of the baroreflex. In conclusion, our data indicate that glutamatergic neurotransmission in the vMPFC has a tonic facilitatory influence on the parasympathetic component of the baroreflex. Because local treatment with either the nNOS inhibitor N(omega)-propyl-l-arginine or the specific NMDA antagonist AP7 had similar effects on the baroreflex, it is also suggested that this modulation involves an NMDA-NO interaction within the vMPFC.

2-Amino-5-phosphonovalerate↗

PubMed2002

5-HT(1A) and 5-HT(2A) receptors minimally contribute to clozapine-induced acetylcholine release in rat medial prefrontal cortex.

The atypical antipsychotic drugs (APDs) clozapine, olanzapine, risperidone, and ziprasidone preferentially increase dopamine (DA) release in rat medial prefrontal cortex (mPFC). These effects have been shown to depend upon potent 5-HT(2A) relative to weak D(2) antagonism, and 5-HT(1A) agonism as well. Atypical APDs also increase acetylcholine (ACh) release in the mPFC, but not the nucleus accumbens (NAC) or striatum (STR), whereas typical APDs such as haloperidol, S(-)-sulpiride and thioridazine do not produce either effect in the mPFC. This study examined the role of 5-HT(1A) agonism, 5-HT(2A) and D(2) antagonism, and the combination thereof, in the ability of clozapine to increase ACh release in rat mPFC. R(+)-8-OH-DPAT (0.2 mg/kg), a 5-HT(1A) agonist, WAY100635 (0.2-0.5 mg/kg), a 5-HT(1A) antagonist, and DOI (0.6-2.5 mg/kg), a 5-HT(2A/2C) agonist, increased ACh release in the mPFC, whereas M100907 (0.03-1 mg/kg), a 5-HT(2A) antagonist, did not. DOI (2.5 mg/kg) and M100907 (0.1 mg/kg) had no effect on ACh release in the NAC or STR. WAY100635 and M100907 inhibited the ability of R(+)-8-OH-DPAT and DOI, respectively, to increase ACh release in the mPFC. WAY100635, which inhibits clozapine-induced DA release in the mPFC, failed to inhibit clozapine (20 mg/kg)-induced ACh release in that region. Similarly, the combination of M100907 and haloperidol (0.1 mg/kg), which enhances DA release in the mPFC, failed to increase ACh release in that region. These results suggest that 5-HT(1A) agonism and 5-HT(2A) antagonism, as well as DA release, contribute minimally to the ability of clozapine, and perhaps other atypical APDs, to increase ACh release in the mPFC.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1996

Dopamine receptors in the medial prefrontal cortex influence ethanol and sucrose-reinforced responding.

This study tested the role of dopamine receptors in the medial prefrontal cortex (mPFC) in the onset, maintenance, and termination of ethanol and sucrose-reinforced responding. Two groups of Long Evans rats were trained to lever press on a fixed-ratio 4 schedule of reinforcement with 10% ethanol (n = 10) or 5% sucrose (n = 5) presented as the reinforcer. After implantation of injector guide cannulae, the D2/3 agonist quinpirole and the D2 antagonist raclopride were administered bilaterally into the mPFC before behavioral sessions. During control conditions, sucrose reinforcement maintained a 2-fold greater number of responses per session than did ethanol reinforcement. Quinpirole (10.0 micrograms/microliter) reduced total ethanol-reinforced responses by delaying response onset and decreasing the duration of responding, but had no effect on response maintenance (i.e., response rate). A higher dose of quinpirole (20.0 micrograms/microliter) decreased total sucrose responses by simultaneously decreasing duration and response rate, without altering response latency. Thus, the effects of quinpirole on ethanol and sucrose-reinforced responding were similar on response total and duration, but differential on response latency and rate. Raclopride (0.05 and 1.0 microgram/microliter) decreased total ethanol responding and rate, but doses as much as 400-fold greater (20.0 micrograms/microliter) did not alter sucrose response totals. Raclopride alone had no effect on response latency or duration measures in either reinforcement condition. Coadministration of raclopride blocked the quinpirole-induced increase in response latency (ethanol reinforcement) and decrease in response rate (sucrose reinforcement), but had no effect on other response measures. These data are consistent with the interpretation that D2 and D3 receptors in the mPFC are differentially involved in ethanol and sucrose response onset and maintenance, but similarly involved in response termination. However, differences in baseline response parameters and group size may have contributed to the observed effects.

Animals↗

PubMed1993

Topography of serotonin neurons in the dorsal raphe nucleus that send axon collaterals to the rat prefrontal cortex and nucleus accumbens.

Diverse physiological actions have been reported for 5-hydroxytryptamine (5-HT, serotonin) in the medial prefrontal cortex (MPFC) and the nucleus accumbens (Acb) suggesting that the 5-HT innervation of these forebrain areas may be derived from different populations of neurons. We examined this possibility by mapping the distribution of 5-HT-immunoreactive (ir) and non-5-HT-ir neurons containing retrograde labeling following injections of different tracers into both these target regions. The analysis was focused in the dorsal raphe nucleus (DRN) of the midbrain, since 5-HT pathways to the MPFC and Acb primarily originate from this area. Volume microinjections of the fluorescent retrograde tracer, Fluoro-Gold (FG), were placed into the MPFC and microinjections of cholera toxin B subunit coupled to 15 nm gold particles (CT-Au) were placed into the Acb of the same animal. Sections through the DRN containing retrogradely labeled neurons were further processed for immunofluorescent localization of 5-HT using a rhodamine marker. Neurons retrogradely labeled from the Acb were greater in number overall than those projecting to the MPFC. In addition, Acb-projecting neurons extended into the lateral wings of the DRN, whereas MPFC-projecting neurons were more restricted to the midline. Both groups of retrogradely labeled neurons, however, were more numerous in the caudal aspect of the dorsal raphe nucleus and were scattered amongst 5-HT immunoreactive perikarya. Of 783 +/- 69 CT-Au labeled cells, 15% also contained the FG label and 11% contained FG and 5-HT immunoreactivity. Of 613 +/- 48 FG labeled cells, 24% also contained the CT-Au label and 21% were also immunoreactive to 5-HT. The results suggest a more prominent input to the Acb from both 5-HT-ir and non-5-HT-ir neurons in the caudal aspect of the DRN and further indicate that while most 5-HT-ir and non-5-HT-ir neurons project differentially to both forebrain regions, a few cells also show collateralization to the MPFC and Acb. Such collateralization of single serotonergic neurons to divergent targets may integrate cognitive and motor activities in response to pharmacological manipulations of ascending serotonergic pathways.

Animals↗

PubMed1972

Some hypotheses concerning the functional organization of prefrontal cortex.

The paper deals with systematization of the behavioral disorders after partial prefrontal lesions. It is assumed that depending on the localization of lesions two disorders may be discerned: impairment of drive inhibition (meaning by this only preservative but not protective drives) land of motor-act inhibition. The first deficit leads to the disinhibition of no-go responses in Pavlovian differentiation, the second one to the disorder of R1-R2 differentiation due to the difficulty of switching from one response to the other. Different parts of the prefrontal cortex are engaged in directional response and nondirectional response differentiation. It is posltulated that drive inhibition depends on the limbo-prefrontal system, whereas motor-act inhibition depends on the premotor-prefrontal system for manipulatory responses and the caudate-prefrontal system for locomotor responses.

Animals↗

PubMed1999

Chronic (-) deprenyl administration alters dendritic morphology of layer III pyramidal neurons in the prefrontal cortex of adult Bonnett monkeys.

Chronic (-) deprenyl (0.2 mg/kg, b.wt; for 25 days) treatment induced alterations in the dendritic morphology of prefrontal cortical neurons in adult Bonnett monkeys were evaluated in the present study. The branching points and intersections in apical and basal dendrites were studied up to a distance of 400 and 200 micrometers, respectively, in Golgi impregnated layer III pyramidal neurons of the prefrontal cortex. Our results revealed a significant (p<0.001) increase in the number of branching points and intersections in both apical and basal dendrites in (-) deprenyl treated monkeys compared to controls. Such an enriched dendritic arborization in prefrontal cortical neurons may be responsible for the enhancement of cognitive functions in Alzheimer disease patients following (-) deprenyl treatment.

Analysis of Variance↗

PubMed1990

Comparison of the effects of cocaine and other inhibitors of dopamine uptake in rat striatum, nucleus accumbens, olfactory tubercle, and medial prefrontal cortex.

It is thought that inhibition of dopamine reuptake into neurons may play a major role in the mechanisms by which cocaine produces its reinforcing effects. The striatum, while rich in dopamine terminals, is not implicated in drug reinforcement, whereas the mesolimbic dopamine pathway appears to play a primary role. It is therefore possible that the properties and drug sensitivities of the dopamine uptake systems in the nigrostriatal, mesolimbic, and mesocortical tracts differ. The effects of cocaine, GBR 12909, amfonelic acid, and methylphenidate on dopamine uptake in the striatum, nucleus accumbens, olfactory tubercle, and medial prefrontal cortex were examined. Over 80% of the dopamine uptake in each of the 4 regions was sodium-dependent and exhibited Km values of approximately 100 nM. Cocaine, GBR 12909, amfonelic acid, and methylphenidate each biphasically inhibited uptake in the striatum, nucleus accumbens and olfactory tubercle with GBR 12909 and amfonelic acid being approximately 50-fold more potent than cocaine or methylphenidate. In the medial prefrontal cortex, cocaine and GBR 12909 could inhibit only about 40% of the [3H]dopamine uptake. There are similarities in the properties and drug sensitivities of the dopamine uptake systems in brain areas which are implicated in drug reinforcement and those which are not.

Animals↗

PubMed1985

Postnatal volumetric development of the prefrontal cortex in the rat.

The medial and orbital parts of the prefrontal cortex (PFC) increase in volume during the first weeks of postnatal life. At the end of this period, however, the volumes of both parts of the PFC reach a significantly higher value than in adulthood. Subsequently the volumes decrease until the adult volume is attained. The three subareas of the medial PFC (i.e., the medial precentral area, the dorsal anterior cingulate, and the prelimbic area) reach a maximum volume around day 24, while the two orbital PFC subareas (i.e., the dorsal and ventral agranular insular areas) attain their maximum value around day 30. The differences found in the growth pattern of the five PFC subareas, which are innervated by specific subnuclei of the mediodorsal nucleus of the thalamus, suggest a role of these subnuclei in the PFC development.

Aging↗

PubMed1982

Subcortical influences upon prefrontal cortex of the cat.

Extracellular unit recordings were obtained from the prefrontal cortex (CPF) of free-moving cats with the head fixed. The prevailing effect produced by electrical stimulation of dorsal amygdala (AD) and N. medialis dorsalis thalami (DM) was a decrease in the spontaneous activity of CPF neurons, while lateral hypothalamus (HL) stimulation produced an increase. Concurrent electrical stimulation of HL and DM, and HL and AD produces suppression of the effect induced by HL single stimulation. Basal amygdala (AB) and DM simultaneous stimulation produces suppression of DM single stimulation.

Amygdala↗

PubMed1976

Functional development of prefrontal cortex in rats continues into adolescence.

Bilateral removal of the sulcal prefrontal cortex in rats at 60 days of age and older results in aphagia and adipsia, but removal of this area before 60 days of age does not affect food or water regulation. Apparently the development of the role of this neocortical region in feeding and drinking continues well beyond the time of weaning in the rat.

Age Factors↗

PubMedDate not supplied

Firing characteristics of deep layer neurons in prefrontal cortex in rats performing spatial working memory tasks.

Single cells were recorded with 'tetrodes' in regions of the rat medial prefrontal cortex, including those which are targets of hippocampal afferents, while rats were performing three different behavioral tasks: (i) an eight-arm radial maze, spatial working memory task, (ii) a figure-eight track, delayed spatial alternation task, and (iii) a random food search task in a square chamber. Among 187 recorded units, very few exhibited any evidence of place-specific firing on any of the behavioral tasks, except to the extent that different spatial locations were related to distinct phases of the task. Furthermore, no prefrontal unit showed unambiguous spatially dependent delay activity that might mediate working memory for spatial locations. Rather, the cells exhibited diverse correlates that were generally associated with the behavioral requirements of performing the task. This included firing related to intertrial intervals, onset or end of trials, selection of specific arms on the eight-arm radial maze, delay periods, approach to or departure from goals, and selection of paths on the figure-eight track. Although a small number of cells showed similar behavioral correlates across tasks, the majority of cells showed no consistent correlate when recorded across multiple tasks. Furthermore, some units did not exhibit altered firing patterns in any of the three tasks, while others showed changes in firing that were not consistently related to specific behaviors or task components. These results are in agreement with previous lesion and behavioral studies in rats that suggest a prefrontal cortical role in encoding 'rules' (i.e. structural features) or behavioral sequences within a task but not in encoding allocentric spatial information. Given that the hippocampal projection to this cortical region is capable of undergoing LTP, our data lead to the hypothesis that the role of this projection is not to impose spatial representations upon prefrontal activity, but to provide a mechanism for learning the spatial context in which particular behaviors are appropriate.

Action Potentials↗

PubMed2005

Organization of multisynaptic inputs from prefrontal cortex to primary motor cortex as revealed by retrograde transneuronal transport of rabies virus.

The organization of multisynaptic projections from the prefrontal cortex to the primary motor cortex (MI) was examined in macaque monkeys by retrograde transneuronal transport of rabies virus. In the first series of experiments, the virus was injected into the MI forelimb region, and the time-dependent distribution patterns of transsynaptic labeling were analyzed in the frontal lobe with various survivals (2-4 d). Two days after the viral injection, neuronal labeling emerged in the caudal aspects of the nonprimary motor-related areas that are known to project to the MI directly. At the same time, the motor thalamus contained labeled neurons. On the third day, cortical labeling extended into the rostral motor-related areas and, also, prearcuate area 8. Moreover, a number of labeled neurons were located in the internal pallidum and the cerebellar nuclei. At the 4 d postinjection period, neuronal labeling occurred widely in prefrontal areas as well as in the putamen and the cerebellar cortex. In the second series of experiments, the viral injection was made into the MI hindlimb region, and the distribution pattern of prefrontal labeling on the fourth day was compared with that in the forelimb-injection case. The labeled neurons in each prefrontal area were much fewer in the hindlimb-injection case than in the forelimb-injection case. Whereas ventral area 46 was most densely labeled from the forelimb region, only sparse labeling from the hindlimb region was observed in this prefrontal area. The present results suggest the importance of ventral area 46 in the cognitive control of forelimb movements.

Animals↗

PubMed2005

Neuroprotective activity of proproten in rats with experimental local photothrombosis of the prefrontal cortex.

Proproten (ultralow doses of antibodies to S100 protein) exhibited neuroprotective activity in rats with experimental photochemical thrombosis of the prefrontal cortex. Proproten was more potent than standard neuroprotectors piracetam and vinpocetine in alleviating the signs of memory disorders produced by ischemic injury. Pathomorphological study of the damaged area confirmed the neuroprotective effect of Proproten.

Animals↗

PubMed2000

The alpha-2A-adrenoceptor agonist, guanfacine, increases regional cerebral blood flow in dorsolateral prefrontal cortex of monkeys performing a spatial working memory task.

Research indicates that norepinephrine enhances the working memory functions of the prefrontal cortex (PFC) through actions at post-synaptic, alpha-2A adrenoceptors. The current study examined the effects of the alpha-2A adrenoreceptor agonist, guanfacine (0.7 mg/kg, i.m.), compared to saline on SPECT measures of regional cerebral blood flow (rCBF) in monkeys performing a spatial working memory task. Animals were infused with the SPECT blood flow tracer, Tcm-99m ECD, through an indwelling intravenous catheter while performing the working memory task. Guanfacine treatment significantly improved cognitive performance of the working memory task, and significantly increased rCBF values in the dorsolateral PFC, the brain region most tightly associated with performance of spatial working memory tasks. In contrast, guanfacine had no significant effect on rCBF in the superior temporal cortex, an auditory association area unrelated to task performance. These data are consistent with the hypothesis that alpha-2A adrenoceptor stimulation preferentially enhances functioning of the PFC.

Adrenergic alpha-2 Receptor Agonists↗

PubMed2004

Relationship between changes in rat behavior and integral biochemical indexes determined by laser correlation spectroscopy after photothrombosis of the prefrontal cortex.

Experiments on rats showed that Noopept improved retention and retrieval of conditioned passive avoidance response after phototrombosis of the prefrontal cortex (a procedure impairing retention of memory traces). The impairment of mnesic functions was accompanied by changes in integral biochemical indexes of the plasma determined by laser correlation spectroscopy. Treatment of behavioral disorders with Noopepet normalized biochemical indexes.

Animals↗