Brain Research 887 (2000) 259–265 www.elsevier.com / 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 ´ , Venezuela Laboratory of Behavioral Physiology, Department of Physiology, School of Medicine, Los Andes University, Merida 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. 2000 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 A coronal transection, separating the medial prefrontal cortex (MPFC) from the basal ganglia, enhances social interaction [5]. This result suggested that nerve impulses from the MPFC modulate social interaction. Several brain areas receive connections from the MPFC, and those areas might be involved in social interaction [15]. Specifically, it has been reported that there is an increase in dopaminergic transmission in the nucleus accumbens (NAC) septi during social interaction [14]. This nucleus receives glutamatergic projections from the MPFC [26] and these neurons, in turn, make synaptic contact with GABAergic neurons located in *Corresponding author. Address for correspondence: Departamento de ´ Apartado de correos 109, 5101-A Merida, ´ Fisiologıa, Venezuela. Tel.: 158-74-403111; fax: 158-74-638304. E-mail address:
[email protected] (S. Tucci).
the NAC [16]. In addition, the glutamatergic corticoaccumbens neurons and the GABAergic NAC neurons receive dopaminergic terminals that project from the ventral tegmental area (VTA) to the MPFC [1] and the NAC [24]. Therefore, MPFC, NAC and VTA are intimately connected and they might concert to modulate social interaction. Pharmacological evidence suggests that the dopaminergic, GABAergic and glutamatergic systems control social interaction. Systemic injections of amphetamine, a dopaminergic agonist, and PCP, a glutamatergic antagonist, decrease social interaction [21]. Injections of GABAergic agonists increase social interaction [3].Therefore, increases in social interaction due to MPFC transection might have, as their neurochemical basis, dopamine (DA), glutamate and GABA changes in the prefrontal cortex, NAC and VTA. In this report, we used brain microdialysis, micellar
0006-8993 / 00 / $ – see front matter 2000 Elsevier Science B.V. All rights reserved. PII: S0006-8993( 00 )02932-2
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electrokinetic chromatography (MEKC) with laser-induced fluorescence detection (CZE–LIFD) and high-performance liquid chromatography with electrochemical detection (HPLC–ED) to measure extracellular GABA, glutamate, and DA and its metabolites in the NAC of rats during electrical stimulation (ES) of the MPFC, after coronal transection caudal to the MPFC and after amphetamine administration in both normal and transected rats.
2. Material and methods
2.1. Subjects Male albino rats of the Wistar strain and weighing between 250 and 300 g were individually housed in wire cages with water and food ad libitum. The room temperature was 238C and the dark:light cycle was 12:12 h.
2.2. Surgery Under ketamine (Ketalar, 50 mg / kg i.p.; Parke Davis) and sodium thiopental (10 mg / kg i.p.; Abbot) anesthesia, a guide shaft made of a 10-mm long, 21 gauge stainless steel tubing was stereotaxically implanted above the accumbens shell (NAC-S) of 25 rats. With the level skull, the coordinates for NAC-S were 0.7 mm lateral (L), 4.0 mm ventral (V) and 1.2 mm anterior (A) with respect to the 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 cross-sectional area of the tip and connected to an Amphenol microconnector, was implanted in the ipsilateral prefrontal cortex at the coordinates 0.5 mm L, 4.0 mm V and 2.0 mm A. A stainless steel ground electrode was fixed to the skull. In eight rats bearing a NAC-S guide shaft, a medial frontal coronal transection was performed, introducing and retiring a 3-mm wide blade at the coordinates 2.5 mm A and 7.0 mm V. Eight rats bearing a guide shaft were sham-operated (craniotomy without performing the bilateral coronal frontal transection, but disrupting the dura and damaging the saggital sinus).
guide shaft. The inlet tube of the microdialysis probe was connected to a syringe that was loaded with artificial cerebrospinal fluid (136 mM NaCl, 3.7 mM KCl, 1.2 mM CaCl 2 , 1 mM MgCl 2 and 10 mM NaHCO 3 , at pH 7.4), which was delivered at a flow-rate of 1 ml / min. Sample collection started 14 h after insertion of the probe.
2.4. Experiments 2.4.1. Experiment 1: microdialysis during electrical stimulation ( ES) For glutamate and GABA analysis, samples were collected every 30 s (500 nl) into hematocrit tubes and stored in a humid chamber to minimize evaporation [19]. After the first five samples, five animals received electrical stimulation for 2 min and eight additional samples were collected, four during the stimulation and four after stimulation. A Grass S11 stimulator provided square pulses of 0.35 ms duration, 145 Hz frequency and 45 V for electrical stimulation. The pulses were passed through a stimulus isolation unit and were delivered through an electrical swivel joint. For analysis of DA and its metabolites, samples were collected every 20 min. When the chemicals in four consecutive samples showed less than 10% variation, four animals received electrical stimulation and then four more samples were collected. 2.4.2. Experiment 2: bilateral frontal coronal transection experiment For glutamate and GABA analysis, the samples were collected every 5 min (5 ml). In all groups (four rats were operated upon and four rats received a sham operation) four baseline samples were taken. Then, an i.p. injection of amphetamine (2 mg / kg) was administered and six additional samples were collected. For analysis of DA and its metabolites, four samples were collected every 20 min (20 ml). Then, all rats (four rats were operated upon and four received a sham operation) received an i.p. injection of amphetamine (2 mg / kg) and five additional samples were collected.
2.3. Microdialysis The microdialysis probe was made of a concentric fused-silica polyimide covered capillary tubing (150 mm OD375 mm ID) in 26 gauge stainless-steel tubing. A cellulose hollow fiber was plugged with epoxy at one end and attached inside the 26 gauge tube with 3 mm of cellulose exposed. This cellulose tube had a 13,000 molecular-weight cut-off, and its permeability data have been reported elsewhere [6]. One week after surgery, the animals were placed in a 32-cm high, 30 cm diameter cylindrical Plexiglass cage and a probe was inserted. The microdialysis probe protruded 5 mm from the tip of the
2.5. Glutamate and GABA analysis 2.5.1. Derivatization procedure Each sample was mixed in a 5:1:1 ratio with 20 mM carbonate buffer, pH 9.4, and 2.57 mM fluorescein isothiocyanate isomer I (FITC) in acetone. A blank solution (ACSF) and 5310 26 M glutamate and GABA standard solutions were derivatized using the same protocol. The mixtures were placed in a water-saturated chamber for 24 h in the dark. Then, the mixtures were diluted fivefold with water and injected into the CZE–LIFD instrument.
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2.5.2. Capillary zone electrophoresis instrument The CZE system is a colinear instrument, model R2D2 (Meridialysis , Merida, Venezuela), which has been described elsewhere [7,8]. Briefly, a 3 mW Argon ion laser beam was tuned to 488 nm and reflected by a dichroic mirror centered at 510 nm. The laser beam was focused by 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 was filled with buffer. Fluorescence was measured by the objective, and stray radiation was attenuated by a high pass filter, centered at 520 nm and a notch filter, centered at 488 nm. The fluorescence was focused on a R1477 multialkali photomultiplier (PMT). The current of the PMT was converted to voltage by a voltage follower and fed to a computer. The electropherograms were acquired and analyzed by means of a pentium II computer and ONICE software (Dialdemo , Merida, Venezuela) 2.5.3. Micellar electrokinetic chromatography ( MEKC) Micellar electrokinetic chromatography analysis consisted of injecting each of the three solutions, blank, standard and sample by the hydrodynamic method. A suction of 210 p.s.i. (1 p.s.i.56894.76 Pa) was applied for 1 s at the cathodic end of the capillary, while the anodic end 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.
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compared by a t-test. To compare neurotransmitter levels between transected and sham rats, data were subjected to a mixed two-way ANOVA, with time and treatment as the repeated measures and independent factors, respectively. Concentrations at specific time points were compared by t-tests.
3. Results
3.1. Experiment 1: electrical stimulation of the medial prefrontal cortex Electrical stimulation of the MPFC increased glutamate and DA in the accumbens shell dialysates. Fig. 1A shows the variations in glutamate and GABA concentrations in the extracellular space of the NAC-S during and after electrical stimulation of the prefrontal cortex. Electrical stimulation elicited an immediate significant increase on glutamate that lasted one sample and then returned to basal levels (F12,48 53.07; P,0.05). GABA variations were not statistically significant (F12,48 51.74; NS). Fig. 1B shows the variations in dopamine concentrations in the extracellular space of the NAC-S after electrical stimulation of the prefrontal cortex. Electrical stimulation elicited a signifi-
2.6. 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.
2.7. Statistical analysis In both experiments, data were subjected to one-way ANOVA for repeated measures followed by NewmanKeuls 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.
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cant increase of dopamine that lasted for 1 h and then decreased in the last sample (F7,24 52.51; P,0.05). DOPAC and HVA showed a slight increase after the electrical stimulation that was not statistically significant (data not shown). In summary, electrical stimulation of the MPFC increased extracellular concentrations of glutamate and DA. GABA, DOPAC and HVA did not change significantly.
3.2. Experiment 2 3.2.1. Medial prefrontal cortex coronal transection Medial prefrontal transection increased NAC-S basal levels of dopamine. Frontal transected rats had 4.36 pg / 20 ml60.3 and sham operated rats had 2.22 pg / 20 ml60.18. This difference was statistically significant (t 6 517.15; P, 0.0001, Fig. 2A). Basal levels of DOPAC, HVA, glutamate and GABA were not different when the MPFC transected rats were compared to sham-operated rats.
Fig. 2. (A) Basal levels of dopamine are higher in the prefrontal 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.
3.2.2. Systemic amphetamine administration Administration of amphetamine to the sham-operated group increased DA release in the accumbens shell. Amphetamine elicited a 250% increase in DA levels that lasted for four samples (80 min) and then returned to basal levels (F8,24 54.82; P,0.0001). In the medial prefrontal transected group, amphetamine administration elicited a 650% increase in DA levels that lasted for 100 min (F8,24 518.00; P,0.0001). The difference between the sham-operated and the medial prefrontal transected group was statistically significant (time3treatment, F8,48 512.49; P,0.0001; treatment factor F1,6 5128; P,0.0001). Fig. 2A shows the variations in extracellular DA concentrations after the administration of amphetamine. Amphetamine administration to the sham-operated group elicited an immediate 30% decrease in DOPAC levels that also lasted for 100 min (F8,24 574.79; P, 0.0001). Amphetamine administration to the prefrontal transected group elicited an immediate 50% decrease in DOPAC levels that lasted for all samples collected (100 min) (F8,24 536.15; P,0.0001).The difference between the sham-operated and transected groups was statistically significant (time3treatment, F8,48 53.88; P,0.001; treatment factor F1,6 510.98; 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 (F9,27 53.72; 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 (F9,27 52.29; P,0.05). The difference between the sham and transected groups was statistically significant (time3treatment, F9,54 53.38; P,0.005; treatment factor F1,6 528.80; P,0.005). Glutamate concentrations in the extracellular space showed no statistically significant variation after the administration of amphetamine in both groups, i.e., the medial prefrontal transected group (F9,27 5 2.24; NS) and the sham-operated group (F9,27 51.44; 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
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Fig. 3. (A) After the systemic administration of amphetamine in prefrontal transected rats (open squares), extracellular levels of GABA showed a decrease, while in sham-operated rats (black circles), GABA levels increased, ***P,0.005, t-test. (B) There was no significant variation in extracellular levels of glutamate after the systemic administration of amphetamine in both groups, i.e., prefrontal transected rats (open squares) and sham-operated rats (black circles).
increase in glutamate levels might be due to stimulation of glutamatergic neurons projecting from the MPFC to the nucleus accumbens. This result confirms similar findings from other laboratories [26]. However, the increase in glutamate levels reported here and elsewhere differ in several aspects. We used 2 min of stimulation compared to the 40 min used in other experiments [26]. We found that the duration of the glutamate increase was shorter (30 s) than the duration of the stimulation (2 min). In other reports, the increase in glutamate levels lasted for as long as the stimulation. The disparate techniques might help to explain the differences. In the present set of experiments, we used capillary zone electrophoresis, which enhances the time resolution of microdialysis whereas, others used HPLC with fluorescence detection. HPLC requires long collection times (40 min). That may lead to short-lasting transient glutamate increase being pooled together into a single point. However, this difference does not explain why the glutamate increase lasted for less than the stimulation time One possible explanation is that reuptake mechanisms removed the glutamate overflow and masked the glutamate increase in the last 60 s of stimulation. It is
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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 2 h by a polysynaptic 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 amphetamine injections [12,20]. There are technical differences between those reports and the present one. Specifically, amphetamine was administered locally in the experiments done by others. In the present experiment, amphetamine was administered systemically. In addition, the analytical technique and the sample collection times were different. When HPLC is used, long sample collection times are required and, in the present report, micellar electrokinetic chromatography allowed shorter sample collection times. However, these disparate results deserve further exploration. Amphetamine injection decreased GABA levels in dialysates of lesioned rats and increased GABA levels in sham-operated rats. In lesioned rats, it might be that the MPFC maintains an excitatory tone on the GABAergic neurons of the nucleus accumbens, and this excitatory tone disappears after the lesion. It has been shown that the majority of the cortical projections to the nucleus accumbens come from glutamatergic neurons that synapse GABAergic medium spiny neurons and interneurons [2,25]. The medium spiny neurons send recurrent collaterals ending in the nucleus accumbens itself, and the GABAergic interneurons terminate in the nucleus accumbens also. Dopamine terminals inhibit the medium spiny neurons and the interneurons. Therefore, dopamine release induced by amphetamine can decrease extracellular levels of GABA. This explanation is feasible because amphetamine-induced dopamine overflow is enhanced by MPFC transection (see below). The amphetamine-induced GABA
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increase in accumbens dialysates in sham-operated rats is harder to explain. Recent evidence has shown that amphetamine increases extracellular levels of GABA in a calcium-dependent way and through a high-affinity GABAtransporter mechanism [4]. One explanation could be that the increase in GABA levels is caused by amphetamine inhibition of the GABA reuptake mechanism. Amphetamine was more effective in enhancing extracellular dopamine levels in lesioned rather than normal rats. In lesioned rats, both the increase in dopamine levels as well as the decrease in DOPAC levels were significantly greater than those found in intact rats. The decrease in GABA levels in lesioned rats might in turn increase dopamine levels. Recent evidence suggests that dopamine release in the nucleus accumbens is under GABAergic control [10]. The administration of bicuculline, through reverse microdialysis in freely moving rats, increased levels of extracellular dopamine in nucleus accumbens dialysates [23]. If the GABA level in turn affects dopamine release, then, in the normal rat, the increase in GABA levels attenuates the amphetamine-induced dopamine release. In the lesioned rat, the decrease in GABA levels might remove an inhibition of the dopamine terminals, and amphetamine would release more dopamine under these circumstances. The neurochemical changes induced by MPFC transection in the nucleus accumbens might be relevant to social interaction. The enhancement of dopaminergic activity that occurs during social interaction in normal rats might be exaggerated in lesioned animals because the dopaminergic system is already overactive. This activity of the dopaminergic system might enhance sensory perception and locomotor performance in lesioned rats and this might contribute to augmented social interaction. However, other brain areas, such as the amygdala, which are connected to the MPFC, might also contribute to the modulation of social interaction. In summary, coronal transection of the MPFC reverses the effect of amphetamine on GABA in the nucleus accumbens and enhances the release of extracellular dopamine induced by amphetamine.
Acknowledgements This work was supported by grants CDCHT M-6539903-A and CONICIT G-97000820.
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