Neuroanatomical changes in the adult rat brain after neonatal lesion of the medial prefrontal cortex

After neonatal lesions of the medial prefrontal cortex (mPFC) the lesion cavity are considerably replaced by neuronal tissue ("filled-in-tissue"). This is accompanied by sparing of some behavioral functions related to the mPFC, while others are deteriorated. We here investigated the neuroanatomical integration of the filled-in-tissue. Bilateral neonatal (postnatal day 7) excitotoxic lesions were induced by microinjection of ibotenate into the mPFC. Immunohistochemical staining for the neuronal marker NeuN and the glia cell marker GFAP in adult rats confirmed that the filled-in-tissue consists of neuronal tissue with disturbed lamination but without reactive gliosis. The afferents to the mPFC were marginally altered as shown by almost normal distribution of retrogradely labeled cells in regions projecting to the mPFC after injection of the retrograde tract tracer fluorogold into the filled-in-tissue. Although virtually no transport was found after injection of the anterograde tracer Phaseolus vulgaris leucoagglutinin into the filled-in-tissue, injections of fluorogold into the nucleus accumbens and mediodorsal thalamus revealed that neurons of the filled-in-tissue project at least to the nucleus accumbens. Additionally, after neonatal mPFC lesions the density of parvalbumin-immunoreactive, presumably GABAergic interneurons, was increased in the amygdala and hippocampus and myelin sheaths were reduced in several cortical and subcortical regions as shown by goldchloride staining. Together, these findings indicate restored anatomical connectivities of the filled-in-tissue that might be responsible for the sparing of behavioral function in some mPFC related tasks, but may also explain disturbed function as a consequence of faulty information transfer between subcortical regions and the filled-in-tissue of the mPFC.     

Behavioral and morphological alterations following neonatal excitotoxic lesions of the medial prefrontal cortex in rats

The prefrontal cortex (PFC) is essential for executive functions in mammals. Damage of the developing PFC may partly be compensated over time, but may also lead to structural and functional deficits due to neurodevelopmental disturbances. The present study investigated the effects of excitotoxic lesions of the medial PFC (mPFC) in neonatal rats on brain morphology, myelination and behavior. Neonatal lesions were induced with ibotenate on postnatal day (pd) 7 and all animals were tested pre- and postpubertally for prepulse inhibition (PPI) of the acoustic startle reflex (ASR), locomotor activity and food preference. Furthermore, adult rats were tested for apomorphine sensitivity of PPI and for their performance in a progressive ratio operant response task. Neonatally lesioned animals showed a reduced volume of the mPFC, enlarged ventricles and a deficient myelination in some projection areas of the mPFC, including the thalamus, hippocampus, nucleus accumbens (NAC) and amygdala. PPI was enhanced in lesioned rats when tested as juveniles, but PPI-deficits induced by the dopamine receptor agonist apomorphine were exacerbated in adult rats after neonatal mPFC lesion. Furthermore, the break point in a progressive ratio task was lower in lesioned animals, whereas the total number of lever presses was initially increased, indicating an impulsive response of rats for food reward under a progressive ratio schedule after neonatal mPFC lesion. No effects were found on food preference and open field performance. These data support the hypothesis that neonatal mPFC lesions lead to disruptions of neurodevelopmental processes in a cortico-limbic-striatal network, which are manifested in adult animals as morphological and behavioral disturbances.     

Effects of neonatal lesions of the medial prefrontal cortex on adult rat behaviour

While prefrontal lesions in rodents serve as models for frontal lobe syndromes, neonatal lesions are considered as models for disconnection syndromes, such as schizophrenia. We investigated the effect of neonatal lesions of the rat medial prefrontal cortex (mPFC) together with pubertal dexamethasone-challenge on adult rat behaviour and on apomorphine-induced behavioural changes. Adult lesions were used as controls. Rats with neonatal (postnatal day 7) or adult excitotoxic lesions or sham-lesions of the mPFC were tested 9 weeks after surgery. At postnatal day 49 one group of neonatal operated rats were systemically injected with the glucocorticoid receptor agonist dexamethasone (20 mg/kg), in order to simulate stress-induced glucocorticoid receptor activation. Working memory and perseveration was tested in T-maze tasks (continuous delayed alternation and reversal learning). Additionally, locomotor activity and prepulse inhibition (PPI) of startle was tested with and without apomorphine-treatment. Brain tissue damage was assessed using Nissl-staining and parvalbumine-immunocytochemistry. Pronounced thinning of the prelimbic-infralimbic subregion of the mPFC accompanied by altered cytoarchitecture and reduced number of parvalbumine-immunopositive neurones was found after neonatal lesions while adult lesions resulted in loss of neurones accompanied by gliosis. Neonatal lesions increased perseveration in the T-maze tasks and enhanced PPI, while adult lesions induced a working memory deficit. This differential behavioural outcome presumably reflects neurodevelopmentally induced alterations in neuronal circuits after neonatal lesions versus damage to mPFC alone after adult lesions. Dexamethasone-injection at day 49 did not alter behaviour in these tasks. Motor activity was not affected by neonatal or adult lesions but dexamethasone reduced apomorphine-induced hyperlocomotion.     

Sparing of function in rats with early prefrontal cortex lesions

Previous work has shown that medial frontal lesions in adult rats produce deficits on spatial reversals, delayed responses, and active avoidance, whereas more ventrolateral (orbital) lesions have little effect on these tasks. These findings were confirmed. However, when lesions were made at 2, 5 or 9 days of age, rats tested as adults showed dramatic sparing of function on all these tasks, whereas similar lesions inflicted at 35 or 40 days of age produced deficits on delayed responses and spatial reversals. Orbital frontal lesions failed to significantly alter behavior on any task at any age. The effects of the neonatal lesions are in striking contrast to the effects of juvenile or adult lesions, even though the infant lesions were considerably larger. Histological analysis revealed no retrograde degeneration in the dorsomedial thalamic nucleus of the rats operated in infancy unless the lesions were so large that the adjacent caudate-putamen was also damaged. The contrast between these results, and results obtained after similar lesions in adults may indicate the growth of sustaining collaterals after the infant lesions which might be involved in the observed behavioral sparing.     

Sulpiride alleviates the attentional impairments of rats with medial prefrontal cortex lesions

Recent studies have shown that medial prefrontal cortex (mPFC) lesions impair performance on a number of rodent tests of attention. Although this evidence clearly suggests a role for the rat mPFC in attentional functions, it is unclear whether subcortical changes associated with mPFC lesions might also be relevant to the neuropsychological deficits observed. Given the ample evidence suggesting increased dopaminergic mechanisms in the basal ganglia following mPFC lesions, we investigated the effects of dopamine receptor agonists and antagonists on the attentional deficits associated with mPFC lesions. Rats trained on a five-choice reaction time task received either complete mPFC lesions or lesions restricted to its ventral subregions, the prelimbic and infralimbic cortices (PRL-IL). Compared with sham-operated rats, animals in both the lesioned groups were impaired at responding correctly to the visual targets, although this deficit was more marked in mPFC-lesioned rats. In addition, both lesions were associated with increased perseverative responding. The accuracy deficits of rats with mPFC lesions were alleviated by systemic administration of the dopamine D2 receptor antagonist sulpiride. In contrast, rats with PRL-IL damage were not affected and control rats were impaired by sulpiride. Administration of either the dopamine D1 receptor antagonist SCH 23390 or of pre-synaptic doses of apomorphine had similar, albeit non-significant effects. Higher doses of any of these drugs non-specifically impaired performance. These results extend previous findings of attentional impairments in rats with mPFC lesions and are compatible with recent hypotheses concerning the role of dopaminergic dysregulation in the pathogenesis of schizophrenia.     

Effects of medial prefrontal cortex cytotoxic lesions in mice

Mice (C57BL/6J strain, females) with cytotoxic lesions of the medial wall of the prefrontal cortex were given a battery of tests to assess emotional, species-typical, cognitive, motor and other behaviours. Lesioned mice showed a profile of reduced anxiety, both on a plus-maze, and a similar, novel test, the successive alleys. There was no evidence, however, for attenuation of anxiety in tests of hyponeophagia, and lesioned mice, like controls, preferred the black to the white area of an enclosed alley. Their locomotor activity tended to be higher than that of the controls, particularly when the test surroundings were novel or relatively so. Species-typical behaviours were similar to those of control mice, except lesioned mice displaced ('burrowed') less food pellets from a tube in their home cage. They were not impaired at learning a spatial Y-maze reference memory task, which is profoundly affected by cytotoxic hippocampal lesions in the same strain, or at learning a multi-trial passive avoidance test. Their strength and co-ordination in motor performance tests was also normal. The results show that cytotoxic medial prefrontal cortex lesions in mice produce a clear but restricted anxiolytic action. The marked reduction in burrowing, in the absence of any detectable impairment of motor ability, demonstrates the sensitivity of this behavioural index.     

Behavioural effects of neonatal lesions of the medial prefrontal cortex and subchronic pubertal treatment with phencyclidine of adult rats

According to the neurodevelopmental hypothesis of schizophrenia, early brain damage renders the brain vulnerable to adverse effects during puberty, which precipitate the disease in young adults. Animal models can be used to test this hypothesis. We investigated the potentially independent or interactive effects of neonatal (postnatal day 7) excitotoxic lesions of the rat medial prefrontal cortex (mPFC) and subchronic pubertal phencyclidine (PCP)-treatment on adult rat behaviour. Sham-lesioned (vehicle-injection) and naive (unoperated) rats served as controls. On postnatal days 42-48 rats were systemically injected with 5 mg/kg PCP or vehicle twice daily. Behavioural testing started at postnatal day 70. Rats were tested for locomotor activity (open field), anxiety (elevated plus maze), social behaviour (conditioned place preference for cage-mates), reward-related operant behaviour [progressive ratio (PR)] and spatial learning (four-arm baited eight-arm radial maze task). Nissl-stained sections revealed considerable regeneration of much of the lesioned tissue in the mPFC, however, with disturbed cytoarchitecture. Locomotor activity was increased by neonatal lesions but reduced after pubertal PCP-treatment. Neonatal lesions alone increased operant behaviour in the PR-test and reduced anxiety in the elevated plus maze. In contrast, PCP-treatment disturbed social behaviour while neonatal lesions had no effect. Different aspects of leaning and memory in the radial maze task were independently disturbed after neonatal lesions and PCP-treatment. Neonatal lesions and pubertal PCP-treatment differentially affected adult rat behaviour and no interactions were found.     

Lateralized effects of medial prefrontal cortex lesions on neuroendocrine and autonomic stress responses in rats.

The medial prefrontal cortex (mPFC) is highly activated by stress and modulates neuroendocrine and autonomic function. Dopaminergic inputs to mPFC facilitate coping ability and demonstrate considerable hemispheric functional lateralization. The present study investigated the potentially lateralized regulation of stress responses at the level of mPFC output neurons, using ibotenic acid lesions. Neuroendocrine function was assessed by plasma corticosterone increases in response to acute or repeated 20 min restraint stress. The primary index of autonomic activation was gastric ulcer development during a separate cold restraint stress. Restraint-induced defecation was also monitored. Plasma corticosterone levels were markedly lower in response to repeated versus acute restraint stress. In acutely restrained animals, right or bilateral, but not left mPFC lesions, decreased prestress corticosterone levels, whereas in repeatedly restrained rats, the same lesions significantly reduced the peak stress-induced corticosterone response. Stress ulcer development (after a single cold restraint stress) was greatly reduced by either right or bilateral mPFC lesions but was unaffected by left lesions. Restraint-induced defecation was elevated in animals with left mPFC lesions. Finally, a left-biased asymmetry in adrenal gland weights was observed across animals, which was unaffected by mPFC lesions. The results suggest that mPFC output neurons demonstrate an intrinsic right brain specialization in both neuroendocrine and autonomic activation. Such findings may be particularly relevant to clinical depression which is associated with both disturbances in stress regulatory systems and hemispheric imbalances in prefrontal function.     

Dissociation of item and order spatial memory in rats following medial prefrontal cortex lesions

In order to test whether there is a correspondence in function of prefrontal cortex in rats and humans, rats with medial prefrontal cortex lesions were tested for item and order memory for a list of items (spatial locations in a maze). Results indicate that for order memory rats with medial prefrontal cortex lesions cannot remember the order of presentation of four or eight specific spatial locations. This inability to remember order information can be seen even when animals with lesions have to remember only two spatial locations, can self-order the sequence of four or eight spatial locations, or have been presented with the same study phase on every trial. In contrast, for item memory animals with medial prefrontal cortex lesions retain the first item of the list in the variable study phase situation and remember all the items of the list in a constant study phase situation. However, there are also deficits for the last items within a list in the variable study phase situation for both win-stay and win-shift procedures. This deficit might be a function of an impairment in the utilization of appropriate temporal strategies, which normally would facilitate recognition memory in the win-stay and win-shift tasks. In general, the data suggest a partial, but not complete, dissociation of item-order memory. Furthermore, the data suggest that the medial prefrontal cortex is involved in temporal structuring of information.     

Synaptic rearrangements in medial prefrontal cortex of haloperidol-treated rats

The effects of daily administration of haloperidol for 16 weeks on the structure of layer VI in medial prefrontal cortex of rat was performed at the light and electron microscopic levels. At the light microscopic level, no difference in either the size or the density of neurons was observed. At the electron microscopic level, the mean dendritic calibre of haloperidol-treated rats was twice that observed in control animals, but this was due to a selective loss of small-calibre dendritic profiles. Rats treated with neuroleptic also showed a reduction in axon terminals with asymmetric postsynaptic membrane specializations, which, in control animals, were preferentially associated with small-calibre dendritic profiles. These small-calibre dendritic profiles were found to be spines rather than small terminal dendritic shafts. An increase in axon terminals showing no membrane specialization on larger dendritic profiles also occurred in rats treated daily with the neuroleptic. The data suggest the possibility that haloperidol may have induced a relocation of asymmetric terminals from resorbed spinous processes to larger dendritic branches with the concomitant loss of their postsynaptic membrane specialization.     

Comparative behavioral changes in postpubertal rats after neonatal excitotoxic lesions of the ventral hippocampus and the prefrontal cortex

The neonatal ventral hippocampal (nVH) and the neonatal prefrontal cortex (nPFC) lesions in rats have been used as models to test the hypothesis that early neurodevelopmental abnormalities lead to behavioral changes putatively linked to schizophrenia. We investigated the role of the nVH and the nPFC lesions on behavioral characteristics related to locomotor behaviors, social interaction, and grooming. Bilateral ibotenic acid lesions of the VH, the PFC, or both were made in neonatal Sprague-Dawley rats (postnatal day 7, P7) and their behaviors studied at P35 and P60. No significant differences in any of the behaviors were observed between sham animals and rats with ibotenic acid lesions at P35. Postpubertally (at P60), the spontaneous locomotor activity of nVH-lesioned rats was significantly enhanced compared to the sham controls; however, this hyperactivity was reversed by nVH and nPFC double lesions. Neonatal PFC lesion alone did not alter spontaneous activity, although a trend of increased activity was observed. The duration of grooming was significantly decreased in rats with neonatal lesions of the VH. Similar to the data on locomotion, nVH plus nPFC lesion normalized the grooming behavior. Lesion of the PFC alone was without any significant effect on grooming behavior. Neonatal VH-lesioned animals spent less time in active social interaction, and this effect persisted even in nVH plus nPFC-lesioned animals. By itself, nPFC lesion did not alter social behavior. These data suggest that subtle developmental aberrations within PFC caused by nVH lesions, rather than the lesion of PFC itself, may contribute to some of the behavioral changes seen in the nVH-lesioned rats.     

Stimulus specific deficit on visual reversal learning after lesions of medial prefrontal cortex in the mouse

Tests of executive abilities, such as discrimination reversal and attentional set shifting, are sensitive to prefrontal cortex (PFC) damage in primates. The purpose of the present study was to use a primate reversal task to determine if PFC in the mouse is involved in similar cognitive functions. Mice with lesions of medial PFC and Sham operated control animals were trained on a series of visual problems in a computer-automated touchscreen apparatus using stimuli that varied in either pattern (lines) or luminance (black-white). PFC-lesioned mice learned to discriminate both sets of stimuli as readily as controls, but displayed a stimulus specific (pattern only) deficit on the reversal task. Analysis of error patterns on the line reversal suggests the deficit exhibited by PFC-lesioned mice was related to stimulus specific aspects of visual attention, rather than perseveration. These results demonstrate that medial PFC may play a role in control of directed attention and provide further evidence that the touchscreen procedure can be a useful tool for examining functional similarities in brain regions of very diverse species.     

Diminished serotonergic innervation of adult medial prefrontal cortex after 6-OHDA lesions in the newborn rat

The development of the serotonergic (5HT) and dopaminergic (DA) systems may contribute to the onset of psychotic disorders during late adolescence and early adulthood. Previous studies in our laboratory have suggested that these systems may compete for functional territory on neurons during development, as lesions of the serotonergic system at postnatal day 5 (P5) result in an increase in the density of dopaminergic fibers in rat medial prefrontal cortex (mPFC). In the present study, the dopaminergic system of P5 rats was lesioned with intracisternal injections of 6-hydroxydopamine (6-OHDA). Quantification of serotonin-immunoreactivity (5HT-IR) in mPFC at adulthood (P70) revealed a significant decrease in fiber density within layers II and III of the Cg3 subdivision of mPFC in lesioned rats compared to sham controls. We propose that the decrease in serotonergic fibers in mPFC in response to a neonatal depletion of dopamine may be due to the loss of a trophic effect of this system on 5HT neurons and/or fibers during development. Taken together with previous findings, our data suggest that there may be an "inverse trophic" relationship between the cortical DA and 5HT systems whereby dopamine facilitates the ingrowth of 5HT fibers, while serotonin suppresses the ingrowth of DA fibers. We present a model based on neurotrophic interactions at the cortical and brainstem levels that could potentially explain these unexpected results.     

Effects of medial prefrontal cortex lesions in rats on the what-where-when memory of a fear conditioning event

Previous animal studies have defined the ability to remember the details of what, where, and when of an event as an episodic-like memory to be used to model episodic memory in humans. Numerous findings indicate that the hippocampal-frontal cortical circuitry plays a major part in its neural mechanism. Researchers have intensively studied roles of diverse hippocampus sub-regions using animal models. By contrast, the impact of prefrontal cortex lesions on episodic-like memory in animals is still unknown. Here we show that Wistar rats with bilateral medial prefrontal cortex lesions failed to use the temporal-contextual information to retrieve memory of a fear-conditioning event, indicating impairments in their episodic-like memory. Subsequent experiments excluded alternative interpretations that the manipulation impaired the fear-conditioning per se, or interfered with the sensory preconditioning process. We concluded that damages in this area might impair temporal information processing, or interfere with integrating temporal and contextual elements of fear-conditioning events to form a conjunctive entity. These findings can help understand how the medial prefrontal cortex contributes to episodic-like memory.     

Noradrenaline depletion blocks behavioral sparing and alters cortical morphogenesis after neonatal frontal cortex damage in rats.

The possibility that cortical noradrenaline (NA) is necessary for sparing of function that occurs after neonatal frontal cortex damage was examined. Spatial localization by rats with frontal cortex damage on postnatal day 7 (P7) was better than that by rats with similar damage sustained as adults. The sparing was abolished in rats depleted of cortical NA by means of neonatal 6-hydroxydopamine (6HDA) administration. The blockade of sparing in the P7 frontal operates was associated with a smaller brain, thinner cortex, and reduced cortical dendritic branching relative to saline-treated P7 frontal operates. NA depletion alone in unoperated rats did not affect spatial learning but did reduce brain size and dendritic branching. Rats with frontal lesions on P4 did not show sparing of spatial localization, and 6HDA administration had no additional behavioral effect. Overall, these data are consistent with the notion that NA has some general function in maintaining some forms of plasticity in posterior cortex.     

Effect of excitotoxic lesions of rat medial prefrontal cortex on spatial memory

The involvement of medial prefrontal cortex (mPFC) in spatial learning was examined in two memory tasks using spatial components, the Morris water maze and the three-panel runway. Using the Morris water maze task, with an invisible platform, the effects of NMDA mPFC lesions were assessed in a procedure reflecting spatial learning and memory, including a spatial reversal. In the three-panel runway, a delayed matching-to-position procedure was used in which rats were required to find food at the end of the runway after passing through one of three panel gates set into four barriers spaced equally apart along the maze. In addition, mPFC lesions were assessed behaviorally in two behavioral tests known to be sensitive to mPFC dysfunction: the food hoarding paradigm and spontaneous locomotion in the open field. Consistent with the documented effects of mPFC damage, NMDA mPFC lesions impaired food hoarding behavior and increased spontaneous exploratory locomotion. In the Morris water maze and the three-panel runway, mPFC-lesioned rats showed relatively few effects, supporting the conclusion that the damage inflicted to the mPFC had no consequence for the processing of spatial information. However, mPFC lesioned animals showed slower acquisition during both the training trial in the three-panel runway and the reversal training in the Morris water maze. These results suggest that spatial memory did not depend on mPFC integrity in the Morris water maze and the three-panel runway experiments, and address the issue of deficits induced by mPFC lesions in memory tasks dependent on non-mnemonic processes such as attentional processes and/or a reduced behavioral flexibility to environmental changes.     

Supersensitivity to the reinforcing effects of cocaine following 6-hydroxydopamine lesions to the medial prefrontal cortex in rats

The effects of neurotoxic lesions to the medial prefrontal cortex on both the acquisition and maintenance of intravenous cocaine self-administration were examined. In one experiment, acquisition of intravenous cocaine self-administration (0.25, 0.5 or 1.0 mg/kg/infusion) was measured in separate groups of rats 14 days following either a sham or 6-hydroxydopamine lesion to the medial prefrontal cortex. For sham rats, the 1.0 and 0.5 mg/kg dose supported reliable self-administration as indicated by discriminative responding. These rats reliably chose a lever that resulted in the delivery of these doses of cocaine over an inactive lever. Reinforced response rates were reduced when 0.25 mg/kg was the available dose and there was a loss of discriminative responding for some of the rats suggesting that it was close to threshold for self-administration. For rats that sustained a 70% depletion of dopamine in the medial prefrontal cortex, the dose-response curve was an inverse function across the entire dose range tested. In contrast to the data from the control rats, lesioned rats had a high rate of reinforced responses and demonstrated good discrimination for all doses including 0.25 mg/kg/infusion, suggesting a supersensitive response to the initial reward effect of cocaine. Another group of rats was first screened for reliable cocaine self-administration (0.5 mg/kg/infusion) and then subjected to either the prefrontal cortical 6-hydroxydopamine or sham lesion. Dose-response curves for cocaine self-administration were compared 14 days following the infusions. The lesioned rats responded reliably for low doses of cocaine that were unable to maintain responding in sham rats. These data support the hypothesis that the medial prefrontal cortex plays an important role in cocaine self-administration.     

Comparison of the effects of neonatal and adult medial prefrontal cortex lesions on food hoarding and spatial delayed alternation

Performance in food hoarding, a species-typical task, and spatial delayed alternation, a learning task, was investigated in male rats with bilateral medial prefrontal cortex (mPFC) lesions sustained in adulthood or at the age of 6 days. Animals with adult mPFC lesions hoarded significantly fewer food pellets than their controls. The mPFC lesion effect on hoarding behaviour of the neonatally operated rats was unclear because of the unexpectedly low hoarding score of their controls. In the spatial delayed alternation task, the animals with mPFC lesions in adulthood exhibited a permanent deficit, while the animals with neonatal mPFC lesions showed no significant deficits. It is concluded that a bilateral lesion in adulthood, mainly affecting the frontal area 2 and the dorsal anterior cingulate area of the mPFC, results in a permanent deficit in food hoarding and spatial delayed alternation performance, whereas a similarly restricted mPFC lesion at the age of 6 days shows a complete sparing of the spatial delayed alternation task performance.     

Pressor effects of electrical stimulation of medial prefrontal cortex in unanesthetized rats

The medial prefrontal cortex (MPFC) is involved in central nervous system (CNS)-mediated cardiovascular modulation. We compared the cardiovascular effects of electrical stimulation (EE) of the MPFC in unanesthetized rats to those observed after stimulation of the same area in urethane-anesthetized rats. Electrical stimulation (35, 106, 177, 247, 318, and 389 microA rms/10 sec, 60-Hz sine wave) of the MPFC of urethane-anesthetized rats caused depressor responses of stimulus-related intensity. The cardiovascular response to electrical stimulation of the MPFC in unanesthetized rats was characterized by stimulus-related pressor responses. No significant heart rate changes were observed during the EE period in any case. The pressor response to electrical stimulation (106 microA rms/10 sec, 60-Hz sine wave) of the MPFC was not affected by intravenous pretreatment with the vasopressin antagonist dTyr(CH(2))(5)(Me)AVP (50 microg/kg, intravenously), by hypophysectomy, or by intravenous pretreatment with the angiotensin II antagonist losartan (1 mg/kg, intravenously). The pressor response was blocked by intravenous pretreatment with the ganglionic blocker mecamylamine (2 mg/kg, intravenously) but was not affected by adrenal demedullation, thus suggesting involvement of the neural component of the sympathetic nervous system without a major involvement of its hormonal component. Our results confirmed the occurrence of depressor responses after electrical stimulation of the MPFC in urethane-anesthetized rats and evidenced that only pressor responses are observed after its stimulation in unanesthetized rats. The fact that the pressor response to the stimulation of the MPFC was blocked by a ganglioplegic suggests that the MPFC has functional excitatory actions over the sympathetic nervous system.