Medial prefrontal transection enhances social interaction: I: Behavioral studies

Brain Research 887 (2000) 7–15www.elsevier.com/ locate /bres

Research report

Medial prefrontal transection enhances social interactionI: Behavioral studies

*Luis E. Gonzalez , Maria Rujano, Sonia Tucci, Daniel Paredes, Elizabeth Silva,German Alba, Luis Hernandez

Laboratory of Behavioral Physiology, Department of Physiology, School of Medicine, Los Andes University, Merida, Venezuela

Accepted 29 August 2000

Abstract

Behavioral effects of a medial prefrontal cortex (MPFC) transection were assessed in animal tests of anxiety. Social investigation andplus-maze open arm exploration increased in MPFC damaged animals relative to sham ones. MPFC lesions prevented D-amphetamine (2mg/kg, i.p.) induced social investigation decrease and exaggerated general locomotion increase. Diazepam (1 mg/kg, i.p.) and MPFCsynergistically increased open arm exploration on a second (repeated) plus-maze trial. These results suggest that the MPFC would beimplicated in a generalized mechanism of warning enabling emission of appropriate responses to anxiogenic stimuli. Although, this lesiondid not modify motor activity itself, the pattern of the motor activation induced by amphetamine was altered. The role of the MPFC areasin the behavioral response associated with fear is discussed. 2000 Elsevier Science B.V. All rights reserved.

Theme: Neural basis of behaviour

Topic: Motivation and emotion

Keywords: Anxiety; Prefrontal cortex; Amphetamines; Benzodiazepines; Animal model

1. Introduction action test. A single plus-maze trial (Experiment 3)allowed a comparative study, in which an independent

It has been proposed that reciprocal neural circuits group of animals are confronted with a novel situation.linking the MPFC, the extended amygdala and the hypo- Because it has been previously found that systemicthalamus are directly involved in fear processing and the administration of amphetamine decreases social interactionbehavioral response to stress in rats [16,20,30]. In support [40] we assessed whether or not MPFC damage suppressesof this hypothesis, Fos protein has been selectively induced amphetamine effect. To compare the behavioral changesin the MPFC, amygdala, lateral septum and hypothalamus induced by amphetamines [25,40] additional behavioralin anxiety related situations but not in many other types of parameters (rearing and self-grooming) were scored inbehavioral activation [8,43]. Moreover, positron emission control and lesioned animals (Experiment 2).tomography studies have shown that the MPFC is con- Finally, systemic administration of benzodiazepinessistently activated during anxiety [18,19,36,52]. does not evoke anxiolytic effect in the plus-maze in mice

Although marked effects on social behavior have been or rats with a 5 min previous experience in this testnoted [6,45], to the best of our knowledge the social [10,31,37]. However, lesions of subcortical structuresinteraction test of anxiety has not been used to discriminate interconnected to the MPFC such as the amygdala [12] andeffects of MPFC lesions on anxiety. This study evaluates hypothalamus [13] restate sensitivity to the anxiolyticthe effect of a surgical MPFC lesion in the social inter- effect of benzodiazepines in this test. On the basis of these

observations it was tested whether or not MPFC transec-tion might abolish the typical loss of benzodiazepine effect*Corresponding author. Tel.: 158-74-403-110; fax: 158-74-638-304.

E-mail address: [email protected] (L.E. Gonzalez). on the plus-maze second trial. Thereby, MPFC damaged

0006-8993/00/$ – see front matter 2000 Elsevier Science B.V. All rights reserved.PI I : S0006-8993( 00 )02931-0

8 L.E. Gonzalez et al. / Brain Research 887 (2000) 7 –15

rats were treated with benzodiazepines or vehicle and 1900 h. Animals were anesthetized by co-administration oftested on a repeated trial of the elevated plus-maze ketamine and penthothal (110 and 10 mg/k i.p., respec-(Experiment 4). tively) and positioned in a stereotaxic frame (David-Kopf

Instruments). The skull was exposed and the incisor baradjusted such that bregma and lambda were at the same

2. Materials and methods height. To lesion the MPFC a knife blade was positioned at2.5 mm anterior to bregma. The sharp pointed tip of a

2.1. Animals and surgery 3-mm wide scalp blade was lowered 7.0 mm below durasuch that each side of the blade extended to a maximum of

Male Wistar rats weighing 250–300 g were single 1.5 mm lateral to the midsagital suture (see Fig. 1).housed with food and water ad libitum, and the room Sham-operated had a craniotomy and the longitudinal sinustemperature was kept at 228C. Lights were on from 0700 to was cut. In both type of surgical procedure, bleeding from

Fig. 1. Diagrammatic representation of (A) rat brain sagital section showing the lines of transection and bregma (T and B, respectively) and (B) coronalsections (2.5 mm anterior to Bregma) through the rat brain showing the target area (shaded) of the MPFC. Animals with track knife outside of this targetarea were excluded from statistical analysis. (C) Photomicrograph of a typical horizontal brain section stained for hematoxylin-eosin showing the extent ofmechanical damage and gliosis 10 days after surgery. Level: frontal pole 3-mm depth from dura. Bar 0.5 mm.

L.E. Gonzalez et al. / Brain Research 887 (2000) 7 –15 9

Fig. 1. (continued)

sinus was stopped by pressing over the area for about 1 line crossing and rears using a computational timer /coun-min. Animals were allowed to recover for 10 days prior to ter apparatus.behavioral testing.

2.3.2. The plus-mazeThe plus-maze was made of wood and consisted of two2.2. Drugs

opposite open arms 50310 cm, and two opposite armsenclosed by 40 cm high walls. The arms were connectedDiazepam and D-amphetamine sulphate (Sigma, St.by a 10310 cm central square, and thus the maze formed aLouis, MO, USA) were prepared in 0.9% sodium chloride‘plus’ shape. The maze was elevated 50 cm above thesolution. A drop of Tween 80 was added to disolvefloor. A closed circuit TV camera was vertically mounteddiazepam.over the maze and the behavior was scored from a monitorin an adjacent room. All scores were directly entered into

2.3. Apparatus an IBM computer. Changes in the % of time spent on theopen arms indicate changes in anxiety [34] whereas the

2.3.1. The social interaction test arena number of closed arm entries is the best measure ofThe social interaction test arena was a wooden box general activity in the maze [4,11]. Testing took place in a

60360 cm, with 35 cm high walls and was lit by low light room lit by dim light (,50 lux) from a light source(50 lux). A camera was vertically mounted above the arena directly above the plus-maze.and the rats were observed on a monitor in an adjacentroom. Test sessions were also video recorded for sub- 2.4. Behavioral testingsequent analysis. The arena was divided into nine squares

2of 20 cm each by placing a grid over the video screen. An Testing took place randomly for condition or treatmentobserver blind to the drug treatment scored the number of between 08:00 and 12:00 h.


2.4.1. The social interaction test 2.6. HistologyRats were tested under low light, unfamiliar test con-

ditions for anxiogenic or anxiolytic effects [9]. A day prior At the end of the behavioural testing all animals wereto testing, operated animals were weighed and allocated to overdosed with chloroform and the brains perfused in-pairs; the partners were non-operated, untreated rats of tracardially with 0.9% saline followed by 4% formalde-similar weight, which had been singly housed for the same hyde solution. Brains were removed from the skull andlength of time as the operated animals. Both animals of a fixed with paraffin. Coronal 25 mm microtome sections,pair were placed in low light (50 lux) in the social stained by hematoxylin-eosin, were performed to evaluateinteraction arena for a 5-min period. An observer blind to the position and extensions of the lesion [33]. To furtherrat condition scored the time spent in social interaction. visualize the extension of the mechanical damage andBehaviors were only scored when initiated by the operated gliosis, preliminary studies included horizontal brain sec-animal and consisted of sniffing, following, allogrooming, tions (Fig. 1C).wrestling, biting and kicking. A surgical scar on the headallowed the scorer to distinguish the operated animals from

2.7. Statisticstheir partner.

Behavioral scores from experiments 1 and 3 were2.4.2. Elevated plus-mazeanalyzed by Student t-tests. Data from experiments 2 and 4Each rat was placed in the central square of the plus-were subjected to analyses of variance with drug andmaze facing a closed arm and its behavior observed for 5lesion as independent factors (Two-way ANOVA). Themin by an observer blind to the treatment. The number ofsignificance obtained by Newman-Keuls’ post-hoc test isentries onto open and closed arms and the times spent inshown in the figures.open and closed arms and in the central square were

scored. The arena was thoroughly wiped with damp tissueafter each trial.

3. Results2.5. Allocation to experimental groups

3.1. HistologyExcept for experiments 3 and 4, different sets of rats

were allocated to each experiment. Numbers in brackets The stereotaxic knife cut produced lesions of uniformcorrespond to animals with correct lesion location. size and comparable volumes. Data from animals with

predominant damage on the left (n54: two from experi-2.5.1. Experiment 1 ment 1 and two from experiment 2) and right (n52, from

Effect of the MPFC lesion on the behavior in the social experiments 3 and 4) sides were excluded from the study.interaction test. Rats were allocated to sham (n59) and The corpus callosum and nucleus accumbens were sparedMPFC lesion (n59) groups. in all the animals included in the study. Fig. 1A shows a

diagram of the lesion target area.

2.5.2. Experiment 2Effect of amphetamine (2 mg /kg) on the behavior in the

3.2. Experiment 1social interaction test. Rats were allocated to the followinggroups: sham1vehicle (n58); sham1amphetamine (n58);

Rats with MPFC lesions significantly spent more time inMPFC lesion1vehicle (n57); MPFC lesion1amphetaminesocial interaction than controls (P,0.002, Fig. 2). No(n57).significant difference in locomotor activity was observed,see Fig. 2. MPFC damaged rats increased social interaction

2.5.3. Experiment 3 by displaying extensive social investigation (sniffing,Effect of the MPFC lesion on the behavior in the allogrooming, and following). Aggressive behavioral fea-

plus-maze. Rats were allocated to sham (n510) and MPFC tures (wrestling, biting and kicking) were not observed.lesion (n510) groups.

2.5.4. Experiment 4 3.3. Experiment 2Effect of diazepam (1 mg /kg) on the behavior in a

plus-maze second trial. Rats tested on experiment 3 were The effect of amphetamine on time spent in socialretested in the plus-maze apparatus for 5 min. Animals interaction varied depending on whether the animal brainwere allocated to the following groups: sham1vehicle was intact or transected [drug3lesion, F(1,26)54.85, P,

(n55); sham1diazepam 1 mg/kg (n55); MPFC lesion1 0.01; lesion, F(1,26)516.67, P,0.0001; drug, F(1,26)5vehicle (n55); MPFC lesion1diazepam 1 mg/kg (n55). 3.47, P,0.074]. Thus, systemic administration of amphet-


Fig. 2. Mean (6S.E.M.) time (s) spent in social interaction by rats withmedial prefrontal cortex lesions and sham in low light unfamiliar testcondition. Unpaired t-test: T(16)53.7, **P,0.002. There was no differ-ence in locomotor activity [T(16)50.3, P50.1].

amine decreased the time spent in social interaction insham but not in MPFC damaged (Fig. 3A). As in experi-ment 1, MPFC damaged rats increased social interactionexclusively at the expense of social investigation.

Amphetamine increased locomotor activity [F(1,26)516.3, P,0.0001] see Fig. 3B. However, this effect wasgreater in lesioned than in sham animals and there was asignificant drug3lesion interaction [F(1,26)53.34, P,

0.05]. However, the lesion itself had no effect onlocomotor activity [F(1,26)51.6, NS].

There were effects of the lesions [F(1,26)513.59, P,

0.001], and drug treatment [F(1,26)55.81, P,0.02] onnumber of rearing and there was significant drug3lesion

Fig. 3. Behavioral measures in the social interaction test by MPFC andinteraction [F(1,26)54.7, P,0.05]. However, post-hoc sham rats after IP injections of saline or d-amphetamine (2 mg/kg) in lowanalysis showed that rearing only increased in sham but light, unfamiliar test conditions. (A) Mean (6S.E.M.) time (s) spent innot in lesioned rats following amphetamine administration. social interaction. Sham-amphetamine and lesion-vehicle groups differ

significantly from sham-vehicle (*P,0.05 and 0.01, respectively). (B)In contrast, only the drug factor was significant for timeMean (6S.E.M.) number of line crossing. *P,0.05 sham-amphetaminespent in self-grooming [F(1,26)516.97, P,0.0001],vs. sham-vehicle. **P,0.001 lesioned-amphetamine vs. sham-vehicle

whereas the lesion and drug3lesion factors were not and lesioned-vehicle. (C) Mean (6S.E.M.) number of rearing. *P,0.01significant [F(1,26)50.01, NS and F(1,26)50.1, NS, sham-amphetamine vs. sham vehicle. (D) Mean (6S.E.M.) time spentrespectively]. Post-hoc analysis showed that amphetamine grooming. *P,0.05 both groups (sham and lesioned) amphetamines

groups vs. their controls.abolished self-grooming in both lesioned and sham animalsto the same extent.

It is worth noting that number of rears and time spent inself-grooming from lesioned and sham animals were 3.5. Experiment 4similar (Figs. 3C and D).

The effect of diazepam on percentage of time spent onthe open arms varied depending on whether the animal

3.4. Experiment 3 brain was intact or transected [drug3lesion, F(1,16)53.39,P,0.04; lesion, F(1,16)56.23, P,0.02; drug, F(1,16)5

Rats with MPFC lesions significantly spent more per- 4.03, P,0.061, see Fig. 4]. Further analysis showed thatcentage of time on the open arms (P,0.001) and made MPFC lesioned rats did not differ from the sham group inmore entries to the open arms (P,0.01) than sham rats this measure. However, only MPFC lesioned rats increased(Fig. 4A). No significant difference in closed arm entries the percentage of time spent on open arms as compared towas observed (Table 1). sham-vehicle group following administration of diazepam.


was confirmed that the lesion produced a primary changein anxiety measures, which does not depend on a particularmotor activity pattern. Lesioned animals reduced openarms exploration as did sham ones in the second trial ofthe elevated plus-maze. This implies that MPFC transectedrats conserved their ability for spatial discrimination andfor changing exploratory strategy.

Increased social behavior in rats following MPFClesions have been reported elsewhere [6,23]. However, abehavioral analysis on anxiety related measures in thesocial interaction test was lacking. The increase in socialinteraction reported here was at the expense of socialinvestigation and not related to augmented aggression.

The results in the plus-maze trial 1 confirm the be-havioral pattern observed in the social interaction test.MPFC transected animals explore the open arms more thancontrols without altering the entries to closed arms, whichis considered the best measure of locomotion on this model[4,11]. During a plus-maze trial rodents progressivelyreduce open arm exploration due to their natural aversionto open spaces [12,13,17,38,46]. Therefore, the animalidentifies and avoids an anxiogenic area. In contrast, socialinteraction increases as a function of familiarity with theFig. 4. Mean (6S.E.M.) time (s) spent on, and number of entries onto,arena that becomes less aversive over the time [9,35].open arms of the elevated plus-maze by MPFC and sham rats. (A) TRIAL

1, there was a significant difference between groups [% time open: T(18) The fact that MPFC transections selectively decrease3.2, **P,0.005; % number open: T(18)52.7, *P,0.01]; (B) TRIAL 2, anxiety as measured by tests whose situational arrange-after IP injections of saline or diazepam (1 mg/kg). *P,0.01 lesioned-

ments serve distinct cognitive processes suggests that thediazepam vs. sham-vehicle group.MPFC transections primarily altered the general emotionalresponse. Further support for this view comes from theNo effects were observed in other plus-maze measures (seeplus-maze second trial experiment. In this test situationFig. 4B and Table 1).both sham and MPFC transected animals learned to avoidthe open arms. However, MPFC transected animals sig-nificantly differed from sham-vehicle group when treated4. Discussionwith diazepam. This indicates that MPFC lesions facilitatethe anxiolytic effects of benzodiazepines.MPFC transection reduced anxiety as measured by the

Neuroanatomical studies have shown reciprocal con-social interaction and elevated plus-maze tests. In bothnections between the amygdala, hypothalamus and MPFCmodels, the lesion did not modify motor activity measures.[1,21,28,41,42,49]. Lesions in the basolateral amygdalaFollowing systemic administration of amphetamine, ratsand dorsomedial hypothalamus increased sensitivity towith MPFC lesions increased locomotor activity but theiranxiolytic effects of chlordiazepoxide on the second trial inlevels of social interaction did not decrease. Therefore, itthe plus-maze [12,13]. It is believe that both of thesestructures are part of a larger neural circuitry that includes

Table 1 other forebrain (cingulate cortex, MPFC and septum) andMean (6S.E.M.) number of entries onto closed arms of the plus-maze by

midbrain (periaqueductal gray, VTA, locus coeruleus,rats with medial prefrontal cortex lesions (L) and sham (S). On trial 2raphe nuclei) structures [3,15,20,21,30]. If the anxietyanimals were IP injected with vehicle (V) or diazepam 1 mg/kg (DZP).

There was not significant difference between groups [Trial 1: T(18)51.6, depends on neuronal circuits interconnecting these struc-P50.1; Trial 2: F(3,16)51.1, P50.4] tures, damage of any component of this circuitry would

impair processing and reduce expression of anxiety orTrial Condition No. of closed arm entrieswould facilitate inhibition of this neuronal system byMean SDMdiazepam and other CNS depressants.

1 S 9.4 60.7 The finding that lesion did not alter locomotor measuresL 7.7 60.9

is also consistent with previous studies [24,26]. Animalswith large MPFC lesions not only were similar to controls2 S1V 10.4 61.4

S1DZP 10 61.1 in their swimming performance and escape latency duringL1V 13 62.0 the spatial training phase but learned to locate the hiddenL1DZP 8.8 61.9 platform of the water maze equally fast to controls [7].


Our results show that D-amphetamine enhanced century. These patients did not have motor alterations andlocomotor activity in lesioned rats but did not change the intellectual capability as measured by conventional testsocial investigation time. Neonatal excitotoxic lesions of of intelligence was slightly affected. In contrast, theirthe MPFC enhance sensitivity to the amphetamine-induced emotional life was profoundly touched showing lack oflocomotion [14]. Additional destruction of the nucleus drives or lack of inhibitions [27,48]. Similarly, patientsaccumbens blocked amphetamine-induced locomotion in with traumatic injuries involving prefrontal structuresMPFC damaged rats, suggesting that this action depended scored well on perception, language, memory and in-upon the integrity of the nucleus acumbens [51]. In the telligence. However, they had difficulty reassuming a taskaccompanying paper we reported that MPFC enhanced after a delay, exhibited lack of control and their socialamphetamine-induced dopamine release in the nucleus behavior was inappropriate. Detailed analysis on specialaccumbens, which may underlay amphetamine-induced tasks also revealed that these patients were resistant tolocomotion [47]. modify established behaviors when facing changes of

The level of vertical activity measured as number of contingencies [39,41,42]. Recently, Tucker et al. [48] haverearing was not different between sham and lesioned suggested that MPFC dorsomedial and ventral lesionsanimals. However, D-amphetamine increased rearing in produce apathy and disinhibition, respectively.sham but not in MPFC lesioned animals. Thus, lesioned Cutting across MPFC should interrupt monoaminergicanimals showed an altered motor response pattern to projections impairing generalized mechanisms of warningamphetamines. [44,45,53]. As a result the animal exhibits behavioral

It has been reported that dorsal MPFC lesions enhance disinhibition in tasks where warning and caution should betimidity and conditioned fear in the rat [22,23,32]. Also, in play. Studies in monkeys and humans support this viewJinks and McGregor [26] suggested that lesions in pre- [39,48,50]. In contrast, lesion in dorsal or other discreetlimbic and infralimbic cortex enhanced anxiety as mea- areas within the MPFC would not interrupt most fiberssured by the elevated plus-maze and a modified open field. passing through, thus, preserving functional input toIt is possible that restricted lesions of these areas within anterior prefrontal areas.the MPFC could lead to anxiogenic instead of anxiolytic In summary, MPFC transections have reliable effects oneffects. However there are many controversial data that anxiety measures, which do not depend on general motorpreclude this conclusion. For instance, dorsal MPFC lesion activity changes or alterations in particular cognitive tasks,had no effect in the elevated plus-maze, prepulse inhibition suggesting a crucial role of the MPFC in the emotionalor two-way active avoidance [29]. Furthermore, this lesion response to threatening stimuli.did not alter the incidence of freezing in a box associatedwith shock, increased activity in a novel open field,increased time ‘in contact’ with other rats and did not Acknowledgementsinduce neo-phobia [22,23,29]. Rats with ventral prefrontaldamage showed significantly step-down shorter latencies in CONICIT G-97000820 and CDCHT-ULA M-653-9903-a passive avoidance test, exhibited a significantly lower A grants support this research. The authors are grateful forshock-induced respiratory quotient relative to controls [26] the expert assistance of Dr. Carlos E. Mendoza, De-and reduced several other autonomic responses to an- ´partamento de Histologıa, Universidad de los Andes,xiogenic stimuli [15] similar to humans with injures in this Merida, Venezuela.region [2,5]. Morgan and LeDoux [30] have suggested afunctional dissociation between dorsal and ventral aspectsof the MPFC on the basis that dorsal but not ventral

Referenceslesions of the MPFC increased fear reactivity duringacquisition of conditioned fear. Collectively, these studies

[1] D.G. Amaral, J.L. Price, Amygdalo-cortical projections in thesuggest, in fact, that ventral but not dorsal damage of the monkey (Macaca fascicularis), J. Comp. Neurol. 230 (1984) 465–MPFC may reduce some types of anxiety. In this respect, 496.lesions of the ventral MPFC probably produces more [2] A. Bechara, D. Tranel, H. Damasio, A.R. Damasio, Failure to

respond autonomically to anticipated future outcomes followingdamage along the dorsoventral axis of the MPFC and,damage to prefrontal cortex, Cereb. Cortex 6 (1996) 215–225.therefore, behavioral effect of ventral MPFC lesion may

[3] M.J. Christie, L.B. James, P.M. Beart, An excitatory amino acidresemble those of the large lesion seen in the present study. projection from rat prefrontal cortex to periaqueductal gray, Brain

Monkeys with anterior cingulate cortex lesions loss their Res. Bull. 16 (1986) 127–129.fear and timidity toward humans or co-specifics increasing [4] A.P. Cruz, F. Frei, F.G. Graeff, Ethopharmacological analysis of rat

behavior on the elevated plus-maze, Pharmacol. Biochem. Behav. 49interactive and exploratory behavior [50]. To reduce(1994) 171–176.emotional response in patients with obsessive compulsive

[5] A.R. Damasio, D. Tranel, H. Damasio, Individuals with sociopathicdisorder, generalized anxiety or pain, prefrontal psycho- behavior caused by frontal damage fail to respond autonomically tosurgery (lobotomy, leukotomy, tractotomy, cingulotomy, social stimuli, Behav. Brain Res. 41 (1990) 81–94.and capsulotomy) was extensively practiced for over half a [6] J.P. de Bruin, H.G. van Oyen, N. Van de Poll, Behavioural changes


following lesions of the orbital prefrontal cortex in male rats, Behav. dopamine system: behavioral and neurochemical evidence, Psycho-Brain Res. 10 (1983) 209–232. pharmacology (Berl.) 138 (1998) 89–95.

[7] J.P. de Bruin, F. Sanchez-Santed, R.P. Heinsbroek, A. Donker, P. [26] A.L. Jinks, I.S. McGregor, Modulation of anxiety-related behavioursPostmes, A behavioural analysis of rats with damage to the medial following lesions of the prelimbic or infralimbic cortex in the rat,prefrontal cortex using the Morris water maze: evidence for be- Brain Res. 772 (1997) 181–190.havioural flexibility, but not for impaired spatial navigation, Brain [27] E. Kandel, J. Schwartz, T. Jessel (Eds.), The Principles of NeuralRes. 652 (1994) 323–333. Science, 3rd Edition, Elsevier, Amsterdam, 1991.

[8] G.E. Duncan, D.J. Knapp, G.R. Breese, Neuroanatomical characteri- [28] J.E. Krettek, J.L. Price, Projections from the amygdaloid complex tozation of Fos induction in rat behavioral models of anxiety, Brain the cerebral cortex and thalamus in the rat and cat, J. Comp. Neurol.Res. 713 (1996) 79–91. 172 (1977) 687–722.

[9] S.E. File, The use of social interaction as a method for detecting [29] L. Lacroix, L.M. Broersen, I. Weiner, J. Feldon, The effects ofanxiolytic activity of chlordiazepoxide-like drugs, J. Neurosci. excitotoxic lesion of the medial prefrontal cortex on latent inhibi-Methods 2 (1980) 219–238. tion, prepulse inhibition, food hoarding, elevated plus maze, active

[10] S.E. File, One-trial tolerance to the anxiolytic effects of chlor- avoidance and locomotor activity in the rat, Neuroscience 84 (1998)diazepoxide in the plus-maze, Psychopharmacology (Berl.) 100 431–442.(1990) 281–282. [30] J.E. LeDoux, Brain mechanisms of emotion and emotional learning,

[11] S.E. File, Behavioural detection of anxiolytic action, in: J.M. Elliot, Curr. Opin. Neurobiol. 2 (1992) 191–197.D.J. Heal, C.A. Marsden (Eds.), Experimental Approaches to [31] R.G. Lister, The use of a plus-maze to measure anxiety in theAnxiety and Depression, John Wiley, Chichester, UK, 1992, pp. mouse, Psychopharmacology (Berl.) 92 (1987) 180–185.25–44. [32] M.A. Morgan, J.E. LeDoux, Differential contribution of dorsal and

[12] S.E. File, L.E. Gonzalez, R. Gallant, Role of the basolateral nucleus ventral medial prefrontal cortex to the acquisition and extinction ofof the amygdala in the formation of a phobia, Neuropsychophar- conditioned fear in rats, Behav. Neurosci. 109 (1995) 681–688.macology 19 (1998) 397–405. [33] G. Paxinos, C. Watson, The Rat Brain in Stereotaxic Coordinates,

[13] S.E. File, L.E. Gonzalez, R. Gallant, Role of the dorsomedial Academic Press, Sydney, 1982.hypothalamus in mediating the response to benzodiazepines on trial [34] S. Pellow, P.H. Chopin, S.E. File, M. Briley, Validation of open:2 in the elevated plus-maze test of anxiety, Neuropsychopharmacol- closed arm entries in an elevated plus-maze as a measure of anxietyogy 21 (1999) 312–320. in the rat, J. Neurosci. Methods 14 (1985) 149–167.

[14] G. Flores, G.K. Wood, J.J. Liang, R. Quirion, L.K. Srivastava, [35] R.J. Primus, C.K. Kellogg, Pubertal-related changes influence theEnhanced amphetamine sensitivity and increased expression of development of environment-related social interaction in the maledopamine D2 receptors in postpubertal rats after neonatal excitotox- rat, Dev. Psychobiol. 22 (1989) 633–643.ic lesions of the medial prefrontal cortex, J. Neurosci. 16 (1996) [36] M. Reivich, R. Gur, A. Alavi, Positron emission tomographic7366–7375. studies of sensory stimuli, cognitive processes and anxiety, Hum.

[15] R.J. Frysztak, E.J. Neafsey, The effect of medial frontal cortex Neurobiol. 2 (1983) 25–33.lesions on cardiovascular conditioned emotional responses in the rat, [37] R.J. Rodgers, J.K. Shepherd, Influence of prior maze experience onBrain Res. 643 (1994) 181–193. behaviour and response to diazepam in the elevated plus-maze and

[16] L.E. Goldstein, A.M. Rasmusson, B.S. Bunney, R.H. Roth, Role of light /dark tests of anxiety in mice, Psychopharmacology (Berl.) 113the amygdala in the coordination of behavioral, neuroendocrine, and (1993) 237–242.prefrontal cortical monoamine responses to psychological stress in [38] R.J. Rodgers, N.J. Johnson, J.C. Cole, C.V. Dewar, G.R. Kidd, P.H.the rat, J. Neurosci. 16 (1996) 4787–4798. Kimpson, Plus-maze retest profile in mice: importance of initial

[17] L.E. Gonzalez, S.E. File, A 5-min experience in the elevated stages of trail 1 and response to post-trail cholinergic receptorplus-maze alters the state of the benzodiazepine receptor in the blockade, Pharmacol. Biochem. Behav. 54 (1996) 41–50.dorsal raphe nucleus, J. Neurosci. 17 (1997) 1505–1511. [39] E.T. Rolls, J. Hornak, D. Wade, J. McGrath, Emotion-related

[18] L.A. Gottschalk, M.S. Buchsbaum, J.C. Gillin, J. Wu, C.A. learning in patients with social and emotional changes associatedReynolds, D.B. Herrera, Positron-emission tomographic studies of with frontal lobe damage, J. Neurol. Neurosurg. Psychiatry 57the relationship of cerebral glucose metabolism and the magnitude (1994) 1518–1524.of anxiety and hostility experienced during dreaming and waking, J. [40] F. Sams-Dodd, Effect of continuous D-amphetamine andNeuropsychiatry Clin. Neurosci. 3 (1991) 131–142. phencyclidine administration on social behavior, stereotyped be-

[19] L.A. Gottschalk, M.S. Buchsbaum, J.C. Gillin, J. Wu, C.A. havior and locomotor activity in rats, Neuropsychopharmacology 19Reynolds, D.B. Herrera, The effect of anxiety and hostility in silent (1998) 18–25.mentation on localized cerebral glucose metabolism, Compr. Psychi- [41] S.R. Sesack, V.M. Pickel, Prefrontal cortical efferents in the ratatry 33 (1992) 52–59. synapse on unlabeled neuronal targets of catecholamine terminals in

[20] F.G. Graeff, Minor tranquilizers and brain defense systems, Braz. J. the nucleus accumbens septi and on dopamine neurons in the ventralMed. Biol. Res. 14 (1981) 239–265. tegmental area, J. Comp. Neurol. 320 (1992) 145–16041.

[21] H.J. Groenewegen, Organization of the afferent connections of the [42] T. Shallice, P.W. Burgess, Deficits in strategy application followingmediodorsal thalamic nucleus in the rat, related to the mediodorsal- frontal lobe damage in man, Brain 114 (Pt. 2) (1991) 727–741.prefrontal topography, Neuroscience 24 (1988) 379–431. [43] M.C. Silveira, G. Sandner, F.G. Graeff, Induction of Fos immuno-

[22] R.R. Holson, Mesial prefrontal cortical lesions and timidity in rats. I. reactivity in the brain by exposure to the elevated plus-maze, Behav.Reactivity to aversive stimuli, Physiol. Behav. 37 (1986) 221–230. Brain Res. 56 (1993) 115–118.

[23] R.R. Holson, C. Walker, Mesial prefrontal cortical lesions and [44] C.J. Stam, J.P. de Bruin, A.M. van Haelst, J. van der Gugten, A.timidity in rats. II. Reactivity to novel stimuli, Physiol. Behav. 37 Kalsbeek, Influence of the mesocortical dopaminergic system on(1986) 231–238. activity, food hoarding, social-agonistic behavior, and spatial de-

[24] G.E. Jaskiw, D.R. Weinberger, Ibotenic acid lesions of the medial layed alternation in male rats, Behav. Neurosci. 103 (1989) 24–35.prefrontal cortex potentiate FG-7142-induced attenuation of ex- [45] J.W. Tidey, K.A. Miczek, Social defeat stress selectively altersploratory activity in the rat, Pharmacol. Biochem. Behav. 36 (1990) mesocorticolimbic dopamine release: an in vivo microdialysis study,695–697. Brain Res. 721 (1996) 140–149.

[25] J.D. Jentsch, A. Tran, J.R. Taylor, R.H. Roth, Prefrontal cortical [46] D. Treit, J. Menard, C. Royan, Anxiogenic stimuli in the elevatedinvolvement in phencyclidine-induced activation of the mesolimbic plus maze, Pharmacol. Biochem. Behav. 44 (1993) 463–469.


[47] S. Tucci, Q. Contreras, X. Paez, L. Gonzalez, P. Rada, L. Her- structures compete for behavioral expression? Evidence from am-nandez, Medial prefrontal transection enhances social interaction: II. phetamine-induced behavior, microdialysis, and caudate-accumbensNeurochemical studies. Submitted to Brain Research, 2000. lesions in medial frontal cortex damaged rats, Brain Res. 576 (1992)

[48] D.M. Tucker, P. Luu, K.H. Pribram, Social and emotional self- 1–11.regulation, Ann. NY Acad. Sci. 769 (1995) 213–239. [52] J.C. Wu, M.S. Buchsbaum, T.G. Hershey, E. Hazlett, N. Sicotte, J.C.

[49] S.R. Vincent, T. Hokfelt, L.R. Skirboll, J.Y. Wu, Hypothalamic Johnson, PET in generalized anxiety disorder, Biol. Psychiatry 29gamma-aminobutyric acid neurons project to the neocortex, Science (1991) 1181–1199.220 (1983) 1309–1311. [53] M. Yoshioka, M. Matsumoto, H. Togashi, H. Saito, Effects of

[50] A.A. Ward, The cingular gyrus: Area 24, J. Neurophysiology 11 conditioned fear stress on 5-HT release in the rat prefrontal cortex,(1948) 13–23. Pharmacol. Biochem. Behav. 51 (1995) 515–519.

[51] I.Q. Whishaw, D. Fiorino, G. Mittleman, E. Castaneda, Do forebrain

Documents

Medial prefrontal transection enhances social interaction: I: Behavioral studies