Medial prefrontal transection enhances social interaction II: Neurochemical studies

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1 Brain Research 887 (2000) locate/ bres Research report Medial prefrontal transection enhances social interaction II: Neurochemical studies * Sonia Tucci, Quilianio Contreras, Ximena Paez, Luis Gonzalez, Pedro Rada, Luis Hernandez Laboratory of Behavioral Physiology, Department of Physiology, School of Medicine, Los Andes University, Merida, Venezuela Accepted 29 August 2000 Abstract Medial prefrontal cortex (MPFC) transection enhances social interaction in an open arena test. Social interaction enhances dopaminergic activity in the nucleus accumbens (NAC). In the present set of experiments, microdialysis probes were implanted in the NAC, and glutamate, g-aminobutyric acid (GABA) and dopamine (DA) were measured during electrical stimulation of the MPFC, after coronal transection caudal to the MPFC and after a systemic injection of amphetamine in transected rats. Electrical stimulation of the MPFC caused a transient enhancement of glutamate release in the NAC, no change in GABA levels and a long lasting increase in DA levels. Medial prefrontal transection did not change basal glutamate or GABA levels in the NAC, but increased basal DA levels. Amphetamine administration decreased GABA levels in medial prefrontal transected rats, had no effect on glutamate and increased DA levels more than in controls. The experiments suggest that glutamatergic activity in the accumbens decreases dopamine release. Medial prefrontal transection reduces glutamatergic tone and enhances dopamine release, which probably decreases GABAergic activity in the NAC. Presumably, GABA inhibition in the NAC enhances social interaction Elsevier Science B.V. All rights reserved. Theme: Neurotransmitters, modulators, transporters and receptors Topic: Interactions between neurotransmitters Keywords: Microdialysis; Electric stimulation; Micellar electrokinetic chromatography; Prefrontal cortex; Nucleus accumbens; GABA glutamate dopamine interaction 1. Introduction the NAC [16]. In addition, the glutamatergic corticoaccumbens neurons and the GABAergic NAC neurons A coronal transection, separating the medial prefrontal receive dopaminergic terminals that project from the cortex (MPFC) from the basal ganglia, enhances social ventral tegmental area (VTA) to the MPFC [1] and the interaction [5]. This result suggested that nerve impulses NAC [24]. Therefore, MPFC, NAC and VTA are intimatefrom the MPFC modulate social interaction. Several brain ly connected and they might concert to modulate social areas receive connections from the MPFC, and those areas interaction. might be involved in social interaction [15]. Specifically, it Pharmacological evidence suggests that the dopahas been reported that there is an increase in dopaminergic minergic, GABAergic and glutamatergic systems control transmission in the nucleus accumbens (NAC) septi during social interaction. Systemic injections of amphetamine, a social interaction [14]. This nucleus receives glutamatergic dopaminergic agonist, and PCP, a glutamatergic antagonist, projections from the MPFC [26] and these neurons, in turn, decrease social interaction [21]. Injections of GABAergic make synaptic contact with GABAergic neurons located in agonists increase social interaction [3].Therefore, increases in social interaction due to MPFC transection might have, as their neurochemical basis, dopamine (DA), glutamate *Corresponding author. Address for correspondence: Departamento de and GABA changes in the prefrontal cortex, NAC and Fisiologıa, Apartado de correos 109, 5101-A Merida, Venezuela. Tel.: ; fax: VTA. address: tuccis@ula.ve (S. Tucci). In this report, we used brain microdialysis, micellar / 00/ $ see front matter 2000 Elsevier Science B.V. All rights reserved. PII: S (00)

2 260 S. Tucci et al. / Brain Research 887 (2000) electrokinetic chromatography (MEKC) with laser-induced guide shaft. The inlet tube of the microdialysis probe was fluorescence detection (CZE LIFD) and high-performance connected to a syringe that was loaded with artificial liquid chromatography with electrochemical detection cerebrospinal fluid (136 mm NaCl, 3.7 mm KCl, 1.2 mm (HPLC ED) to measure extracellular GABA, glutamate, CaCl 2, 1 mm MgCl2 and 10 mm NaHCO 3, at ph 7.4), and DA and its metabolites in the NAC of rats during which was delivered at a flow-rate of 1 ml/ min. Sample electrical stimulation (ES) of the MPFC, after coronal collection started 14 h after insertion of the probe. transection caudal to the MPFC and after amphetamine administration in both normal and transected rats Experiments 2. Material and methods Experiment 1: microdialysis during electrical stimulation (ES) 2.1. Subjects For glutamate and GABA analysis, samples were collected every 30 s (500 nl) into hematocrit tubes and stored Male albino rats of the Wistar strain and weighing in a humid chamber to minimize evaporation [19]. After between 250 and 300 g were individually housed in wire the first five samples, five animals received electrical cages with water and food ad libitum. The room tempera- stimulation for 2 min and eight additional samples were ture was 238C and the dark:light cycle was 12:12 h. collected, four during the stimulation and four after stimulation. A Grass S11 stimulator provided square pulses 2.2. Surgery of 0.35 ms duration, 145 Hz frequency and 45 V for electrical stimulation. The pulses were passed through a Under ketamine (Ketalar, 50 mg/ kg i.p.; Parke Davis) stimulus isolation unit and were delivered through an and sodium thiopental (10 mg/ kg i.p.; Abbot) anesthesia, a electrical swivel joint. guide shaft made of a 10-mm long, 21 gauge stainless steel For analysis of DA and its metabolites, samples were tubing was stereotaxically implanted above the accumbens collected every 20 min. When the chemicals in four shell (NAC-S) of 25 rats. With the level skull, the consecutive samples showed less than 10% variation, four coordinates for NAC-S were 0.7 mm lateral (L), 4.0 mm animals received electrical stimulation and then four more ventral (V) and 1.2 mm anterior (A) with respect to the samples were collected. midsagital suture (L), the surface of the skull (V) and bregma (A) [18]. In nine rats bearing a NAC-S guide shaft, a nichrome wire (250 mm diameter), insulated except at the Experiment 2: bilateral frontal coronal transection cross-sectional area of the tip and connected to an Am- experiment phenol microconnector, was implanted in the ipsilateral For glutamate and GABA analysis, the samples were prefrontal cortex at the coordinates 0.5 mm L, 4.0 mm V collected every 5 min (5 ml). In all groups (four rats were and 2.0 mm A. A stainless steel ground electrode was fixed operated upon and four rats received a sham operation) to the skull. In eight rats bearing a NAC-S guide shaft, a four baseline samples were taken. Then, an i.p. injection of medial frontal coronal transection was performed, introtional amphetamine (2 mg/kg) was administered and six addi- ducing and retiring a 3-mm wide blade at the coordinates samples were collected. 2.5 mm A and 7.0 mm V. Eight rats bearing a guide shaft For analysis of DA and its metabolites, four samples were sham-operated (craniotomy without performing the were collected every 20 min (20 ml). Then, all rats (four bilateral coronal frontal transection, but disrupting the dura rats were operated upon and four received a sham opera- and damaging the saggital sinus). tion) received an i.p. injection of amphetamine (2 mg/kg) and five additional samples were collected Microdialysis The microdialysis probe was made of a concentric 2.5. Glutamate and GABA analysis fused-silica polyimide covered capillary tubing (150 mm OD375 mm ID) in 26 gauge stainless-steel tubing. A Derivatization procedure cellulose hollow fiber was plugged with epoxy at one end Each sample was mixed in a 5:1:1 ratio with 20 mm and attached inside the 26 gauge tube with 3 mm of carbonate buffer, ph 9.4, and 2.57 mm fluorescein iso- cellulose exposed. This cellulose tube had a 13,000 thiocyanate isomer I (FITC) in acetone. A blank solution molecular-weight cut-off, and its permeability data have 26 (ACSF) and 5310 M glutamate and GABA standard been reported elsewhere [6]. One week after surgery, the solutions were derivatized using the same protocol. The animals were placed in a 32-cm high, 30 cm diameter mixtures were placed in a water-saturated chamber for 24 cylindrical Plexiglass cage and a probe was inserted. The h in the dark. Then, the mixtures were diluted fivefold with microdialysis probe protruded 5 mm from the tip of the water and injected into the CZE LIFD instrument.

3 S. Tucci et al. / Brain Research 887 (2000) Capillary zone electrophoresis instrument compared by a t-test. To compare neurotransmitter levels The CZE system is a colinear instrument, model R2D2 between transected and sham rats, data were subjected to a (Meridialysis, Merida, Venezuela), which has been de- mixed two-way ANOVA, with time and treatment as the scribed elsewhere [7,8]. Briefly, a 3 mw Argon ion laser repeated measures and independent factors, respectively. beam was tuned to 488 nm and reflected by a dichroic Concentrations at specific time points were compared by mirror centered at 510 nm. The laser beam was focused by t-tests. means of a 0.85 NA objective on the window of the capillary. The window was located 38 cm from the anodic end of a 48-cm long, 26 mm bore fused-silica capillary that 3. Results was filled with buffer. Fluorescence was measured by the objective, and stray radiation was attenuated by a high pass 3.1. Experiment 1: electrical stimulation of the medial filter, centered at 520 nm and a notch filter, centered at 488 prefrontal cortex nm. The fluorescence was focused on a R1477 multialkali photomultiplier (PMT). The current of the PMT was Electrical stimulation of the MPFC increased glutamate converted to voltage by a voltage follower and fed to a and DA in the accumbens shell dialysates. Fig. 1A shows computer. The electropherograms were acquired and ana- the variations in glutamate and GABA concentrations in lyzed by means of a pentium II computer and ONICE the extracellular space of the NAC-S during and after software (Dialdemo, Merida, Venezuela) electrical stimulation of the prefrontal cortex. Electrical stimulation elicited an immediate significant increase on Micellar electrokinetic chromatography (MEKC) glutamate that lasted one sample and then returned to basal Micellar electrokinetic chromatography analysis con- levels (F12, ; P,0.05). GABA variations were not sisted of injecting each of the three solutions, blank, statistically significant (F12, ; NS). Fig. 1B shows standard and sample by the hydrodynamic method. A the variations in dopamine concentrations in the extracellusuction of 210 p.s.i. (1 p.s.i Pa) was applied for lar space of the NAC-S after electrical stimulation of the 1 s at the cathodic end of the capillary, while the anodic prefrontal cortex. Electrical stimulation elicited a signifiend was immersed in the mixture reservoir. Then, the anodic end was transferred to the buffer reservoir and a high voltage was applied using a cathode and an anode made of platinum iridium wire. The running buffer was 80 mm sodium dodecyl sulfate (SDS), 80 mm borate, 1% acetonitrile. A high-voltage power supply supplied 26 kv between the anode and the cathode for 15 min. After each run, the capillary was rinsed with 1 M sodium hydroxide solution for 1 min, 18 mv pure water for 1 min and borate SDS buffer for 3 min Analysis of DA and its metabolites Samples were analyzed by HPLC ED. The HPLC system consisted of a Waters 510 pump connected to a model 1725 Rheodyne valve equipped with a 20-ml loop. The chemicals were separated in an ODS, 3 mm particle, 3.2 mm bore, 10 cm long Brownlee column. They were detected in a Waters 464 electrochemical detector on a glassy carbon electrode set at 705 mv with respect to a Ag AgCl reference electrode. 3,4-Dihydroxyphenylacetic acid (DOPAC), dopamine (DA) and homovanillic acid (HVA) were measured by comparison of the peak heights of the samples with the peak height of standards Statistical analysis In both experiments, data were subjected to one-way ANOVA for repeated measures followed by Newman- Keuls post-hoc test. In experiment 2, the mean of the basal data (four basal measures for each rat) were calculated and Fig. 1. (A) Extracellular levels of glutamate (black squares, **P,0.01, post-hoc test) and GABA (open circles) before, during (black bar) and after electrical stimulation. (B) Extracellular concentrations of dopamine before, during (black line) and after electrical stimulation.

4 262 S. Tucci et al. / Brain Research 887 (2000) cant increase of dopamine that lasted for 1 h and then Systemic amphetamine administration decreased in the last sample (F7, ; P,0.05). Administration of amphetamine to the sham-operated DOPAC and HVA showed a slight increase after the group increased DA release in the accumbens shell. electrical stimulation that was not statistically significant Amphetamine elicited a 250% increase in DA levels that (data not shown). In summary, electrical stimulation of the lasted for four samples (80 min) and then returned to basal MPFC increased extracellular concentrations of glutamate levels (F8, ; P,0.0001). In the medial prefrontal and DA. GABA, DOPAC and HVA did not change transected group, amphetamine administration elicited a significantly. 650% increase in DA levels that lasted for 100 min (F8, ; P,0.0001). The difference between the 3.2. Experiment 2 sham-operated and the medial prefrontal transected group was statistically significant (time3treatment, F ; 8, Medial prefrontal cortex coronal transection P,0.0001; treatment factor F1,65128; P,0.0001). Fig. Medial prefrontal transection increased NAC-S basal 2A shows the variations in extracellular DA concentrations levels of dopamine. Frontal transected rats had 4.36 pg/ 20 after the administration of amphetamine. ml60.3 and sham operated rats had 2.22 pg/ 20 ml Amphetamine administration to the sham-operated This difference was statistically significant (t ; P, group elicited an immediate 30% decrease in DOPAC , Fig. 2A). Basal levels of DOPAC, HVA, glutamate levels that also lasted for 100 min (F8, ; P, and GABA were not different when the MPFC transected ). Amphetamine administration to the prefrontal rats were compared to sham-operated rats. transected group elicited an immediate 50% decrease in DOPAC levels that lasted for all samples collected (100 min) (F8, ; P,0.0001).The difference between the sham-operated and transected groups was statistically significant (time3treatment, F8, ; P,0.001; treatment factor F1, ; P,0.005). Fig. 2B shows the variations in DOPAC concentrations in the extracellular space of the NAC-S after the administration of amphetamine. HVA levels did not change. In summary, lesioned rats showed higher basal levels of DA. Amphetamine administration produced a greater increase in DA levels and a greater decrease in DOPAC levels in the prefrontal transected group than in the shamoperated group. Fig. 3A shows the variations in GABA concentration in the extracellular space of the NAC-S after the administration of amphetamine. In the sham-operated group, amphetamine elicited a significant increase in GABA levels that lasted for two samples (10 min) and then returned to basal levels (F9, ; P,0.005). Administration of amphetamine to the medial prefrontal transected group decreased GABA release in the accumbens shell. This decrease lasted for three samples (15 min) and then returned to basal levels (F9, ; P,0.05). The difference between the sham and transected groups was statistically significant (time3treatment, F9, ; P,0.005; treatment factor F1, ; P,0.005). Glutamate concentrations in the extracellular space showed no statistically significant variation after the administration of amphetamine in both Fig. 2. (A) Basal levels of dopamine are higher in the prefrontal groups, i.e., the medial prefrontal transected group (F9,275 transected group (open squares) than in sham-operated rats (black circles). After the systemic amphetamine injection, there was an increase in extracellular dopamine concentrations that was significantly higher in medial prefrontal transected rats. (B) There is no difference in basal levels of DOPAC between the prefrontal transected group (open squares) and the sham-operated group (black circles). After amphetamine administration, there was a decrease in extracellular DOPAC in both groups, although, in the prefrontal transected group, this decrease was greater than in the sham-operated group, *P,0.05, **P,0.01, ***P,0.005, t-test. 2.24; NS) and the sham-operated group (F9, ; NS), and there was no difference between them (Fig. 3B). 4. Discussion Electrical stimulation of the MPFC increased glutamate and dopamine levels in the nucleus accumbens. The

5 S. Tucci et al. / Brain Research 887 (2000) well known that extracellular glutamate is tightly regulated, to prevent glutamate excitotoxicity [11]. An increase in dopamine levels in the nucleus accumbens caused by electrical stimulation of the prefrontal cortex has also been reported [17,22]. An explanation might be that neurons from the MPFC project to the ventral tegmental area and excite dopaminergic neurons that, in turn, project into the nucleus accumbens. However, in the present set of experiments, another time discrepancy occurred. The duration of dopamine increase (almost 2 h) was longer than the stimulation time (2 min). This can only happen if excitation of the dopaminergic neurons is maintained for 2hbyapolysynaptic reverberating pathway. The coronal transection of the MPFC did not affect basal levels of glutamate. This makes sense because most of the basal level of glutamate is of glial origin [9]. However, the same transection increased basal levels of dopamine, suggesting an inhibitory action of the prefrontal cortex on dopaminergic neurons projecting from the VTA to the nucleus accumbens. Alternatively, the lesion might injure dopaminergic neurons and cause sprouting that enhances the dopamine levels in the nucleus accumbens [13]. Systemic administration of amphetamine had no effect on extracellular levels of glutamate. Other laboratories have reported an increase in glutamate levels after amphet- Fig. 3. (A) After the systemic administration of amphetamine in prefronamine injections [12,20]. There are technical differences tal transected rats (open squares), extracellular levels of GABA showed a decrease, while in sham-operated rats (black circles), GABA levels between those reports and the present one. Specifically, increased, ***P,0.005, t-test. (B) There was no significant variation in amphetamine was administered locally in the experiments extracellular levels of glutamate after the systemic administration of done by others. In the present experiment, amphetamine amphetamine in both groups, i.e., prefrontal transected rats (open squares) was administered systemically. In addition, the analytical and sham-operated rats (black circles). technique and the sample collection times were different. When HPLC is used, long sample collection times are increase in glutamate levels might be due to stimulation of required and, in the present report, micellar electrokinetic glutamatergic neurons projecting from the MPFC to the chromatography allowed shorter sample collection times. nucleus accumbens. This result confirms similar findings However, these disparate results deserve further explorafrom other laboratories [26]. However, the increase in tion. glutamate levels reported here and elsewhere differ in Amphetamine injection decreased GABA levels in several aspects. We used 2 min of stimulation compared to dialysates of lesioned rats and increased GABA levels in the 40 min used in other experiments [26]. We found that sham-operated rats. In lesioned rats, it might be that the the duration of the glutamate increase was shorter (30 s) MPFC maintains an excitatory tone on the GABAergic than the duration of the stimulation (2 min). In other neurons of the nucleus accumbens, and this excitatory tone reports, the increase in glutamate levels lasted for as long disappears after the lesion. It has been shown that the as the stimulation. The disparate techniques might help to majority of the cortical projections to the nucleus accumexplain the differences. In the present set of experiments, bens come from glutamatergic neurons that synapse we used capillary zone electrophoresis, which enhances the GABAergic medium spiny neurons and interneurons time resolution of microdialysis whereas, others used [2,25]. The medium spiny neurons send recurrent collater- HPLC with fluorescence detection. HPLC requires long als ending in the nucleus accumbens itself, and the collection times (40 min). That may lead to short-lasting GABAergic interneurons terminate in the nucleus accumtransient glutamate increase being pooled together into a bens also. Dopamine terminals inhibit the medium spiny single point. However, this difference does not explain neurons and the interneurons. Therefore, dopamine release why the glutamate increase lasted for less than the induced by amphetamine can decrease extracellular levels stimulation time One possible explanation is that reuptake of GABA. This explanation is feasible because amphetmechanisms removed the glutamate overflow and masked amine-induced dopamine overflow is enhanced by MPFC the glutamate increase in the last 60 s of stimulation. It is transection (see below). The amphetamine-induced GABA

6 264 S. Tucci et al. / Brain Research 887 (2000) increase in accumbens dialysates in sham-operated rats is [3] R. Corbett, S. Fielding, M. Cornfeldt, R.W. Dunn, GABAmimetic harder to explain. Recent evidence has shown that amphetelevated plus maze procedures, Psychopharmacology 104 (1991) agents display anxiolytic-like effects in the social interaction and amine increases extracellular levels of GABA in a cal cium-dependent way and through a high-affinity GABA- [4] A. Del Arco, J.L. Gonzalez-Mora, V.R. Armas, F. Mora, Amphettransporter mechanism [4]. One explanation could be that amine increases the extracellular concentration of glutamate in the increase in GABA levels is caused by amphetamine striatum of the awake rat: involvement of high affinity transporter inhibition of the GABA reuptake mechanism. mechanisms, Neuropharmacology 38 (1999) [5] L. Gonzalez, M. Rujano, S. Tucci, D. Paredes, L. 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