effects of selective dopamine depletion in medial prefrontal cortex on basal and evoked...

BRAIN RESEARCH

E L S E V I E R Brain Research 685 (1995) 117-128

R e s e a r c h r e p o r t

Effects of selective dopamine depletion in medial prefrontal cortex on basal and evoked extracellular dopamine in neostriatum

Deborah King, Janet M. Finlay *

Department of Neuroscience, University of Pittsburgh, 446 Crawford Hall, Pittsburgh, PA 15260, USA

Accepted 14 March 1995

Abstract

In this study, we demonstrate that 6-hydroxydopamine (6-OHDA) can be used to produce a lesion of dopamine (DA) terminals in medial prefrontal cortex (mPFC) while sparing the noradrenergic innervation in this region. Furthermore, we determined the impact of these lesions on both extracellular DA in neostriatum, using in vivo microdialysis, and locomotor activity. Our results demonstrate that, whereas higher doses of 6-OHDA ( > 4/~g) depleted both DA and norepinephrine (NE) in mPFC, 1 /xg 6-OHDA produced a depletion of DA ( - 79%) without significantly affecting NE content ( - 13%). Selective depletion of DA content in mPFC did not alter basal levels of extracellular DA in neostriatum determined 14 days after the lesion. The lesion also did not alter the ability of acute tail pressure (30 min) to increase extracellular DA in neostriatum or to stimulate locomotor activity. Depletion of DA in mPFC did not alter the ability of d-amphetamine (1.5 mg/kg, i.p.) to increase extracellular DA in neostriatum. In contrast, the maximum amphetamine-induced increase in locomotor activity was attenuated in lesioned rats as compared with control rats (670 and 280 locomotor counts/15 min, respectively). These data suggest that in the intact system, DA terminals in mPFC do not regulate extracellular DA in neostriatum. In addition, these data confirm that DA terminals in mPFC can influence stimulant-induced locomotion.

Keywords: d-Amphetamine; Dopamine; 6-Hydroxydopamine; Locomotor activity; Microdialysis; Neostriatum; Schizophrenia; Stress

1. Introduction

Dopaminergic terminals innervating medial prefrontal cortex (mPFC) arise primarily from cells in the ventral tegmental area (VTA) and synapse on dendrites of pyramidal neurons, the primary cortical efferents [23,61,74,76]. Pyramidal neurons of mPFC innervate both the origin of the nigrostriatal dopamine (DA) projection, the substantia nigra (SN), and the terminal region of these DA neurons, the neostriatum [6,12,47,62]. These efferent projections of the mPFC use an excitatory amino acid (EAA) neurotransmitter [12,37]. In the neostriatum, cortical terminals often synapse with the same postsynaptic target as do nigrostriatal DA terminals and, in some cases, form axoaxonic appositions with DA terminals [8]. Evidence suggests that mesocortical DA neurons inhibit the electrophysiological activity of pyramidal cells in the mPFC, including those

* Corresponding author. Fax: (1) (412) 624-9198. E-mail: [email protected].

0006-8993/95/$09.50 © 1995 Elsevier Science B.V. All fights reserved SSDI 0006-8993(95)00421 - 1

that project to neostriatum [19,22,50]. Furthermore, stimulation of the mPFC has been reported to increase the electrophysiological activity of DA neurons in SN [21] and extracellular levels of DA in neostriatum [68]. Taken together, these studies suggest that mesocortical DA neurons may inhibit excitatory projections arising in mPFC and thereby indirectly inhibit the activity of subcortical DA neurons. This proposed interaction is a key factor in hypotheses stating that alterations in the function of the DA innervation of prefrontal cortex and a related dysregu- lation of mesoaccumbens a n d / o r nigrostriatal DA systems may be involved in the etiology of schizophrenia [16,24,53,78] as well as Tourette syndrome [18].

Experiments that directly examine the interaction of cortical and subcortical DA systems have produced conflicting results. Consistent with the model, lesions of DA terminals in mPFC using 6-hydroxydopamine (6-OHDA) were originally reported to increase the activity of nigrostriatal DA neurons as determined by changes in postmortem tissue levels of DA, the DA metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC) and the DOPAC:DA

118 D. King, J.M. Finlay /Brain Research 685 (1995) 117-128

ratio [13,51,52]. However, in other studies 6-OHDA lesions of mPFC failed to alter indices of nigrostriatal DA neuronal activity [10,17,28,31,57,59,65].

Although the reasons for inconsistencies in the literature are not clear, there are some problems inherent to these previous studies that we have addressed in the present experiments. First, 6-OHDA infusion into mPFC can de- stroy norepinephrine (NE) as well as DA terminals in this region. This methodological constraint has made it difficult to exclusively examine the effects of cortical DA depletion on the activity of subcortical DA neurons. In the present study, we have produced a depletion of DA in the mPFC without significantly altering tissue NE content in this region. Second, previous studies examining the effects of DA depletion in mPFC used postmortem tissue to obtain biochemical indices of the activity of nigrostriatal DA neurons. Under some conditions, these measures may not reflect in vivo neurochemical activity [20]. Thus, we have used in vivo microdialysis to examine the impact of DA depletion of mPFC on extracellular DA and its metabolites, DOPAC and homovanillic acid (HVA), in neostriatum of freely moving rats. The neurochemical activity of nigrostriatal DA neurons was examined under basal conditions and in response to tail pressure and d-amphetamine. These treatments were used to evoke DA release since it is possible that the effects of the mPFC lesions on subcortical DA neurons are only apparent under conditions of increased dopaminergic transmission [17]. We have also examined locomotor activity as a behavioral correlate of the activity of subcortical DA neurons [36].

2. Materials and methods

2.1. Animals and materials

Male Sprague-Dawley rats (Zivic-Miller, Allison Park, PA) were housed singly in wire mesh cages in tempera- ture-controlled rooms (22-23 ° C). Lights were on from 08:00 to 20:00 and lab chow and water were available ad libitum. Upon arrival, rats were allowed at least 1 week to acclimate to the colony room before any treatment. All treatments were performed during the light phase of the

light-dark cycle. Procedures for treatment of rats were approved by the Institutional Animal Care and Use Com- mittee at the University of Pittsburgh using the criteria established by the Animal Welfare Act and the National Institutes of Health Guide for the Care and Use of Labora- tory Animals. All chemicals were obtained from Fisher Scientific (Pittsburgh, PA) except where otherwise noted.

2.2. 6-OHDA lesions of mPFC

A group of rats (200-250 g) was removed from the colony room and pretreated with desipramine hydrochlo- ride (DMI; Sigma Chemical, St Louis, MO) (25 mg/kg , free base, i.p.). After 30 min, these rats were anesthetized with Equithesin (3 ml /kg , i.p.; 258 mM chloral hydrate, 20% v / v Nembutal, 86 mM MgS04, 25% v / v propylene glycol). An infusion cannula (fused silica capillary tubing, o.d. = 100-150 /xM; Polymicro, Phoenix, AZ) was positioned in mPFC using the following stereotaxic coordinates: AP + 3.25 mm and ML _ 0.7 mm from bregma and DV - 3 . 2 mm from dura [48]. The cannula was left in position for 5 min and then 1, 4, 6 or 8 /xg 6-OHDA (Sigma) in 2 /xl of vehicle (0.9% NaC1 containing 0.03% ascorbic acid) was infused in each hemisphere over 5 min. The cannula was left in position for an additional 5 min to allow for dispersal of the toxin. After recovery from anesthesia, rats were returned to their cages in the colony room where they remained for 5 -14 days before sacrifice. In addition, as an assay control, two naive rats were treated with reserpine (5 m g / k g in 0.15% ascorbate vehicle, s.c.; Research Biochemicals, Natick, MA) and returned to their cages for 24 h. Rats were then sacrificed by decapitation and brains were rapidly removed and frozen on a micro- tome. A 1.4-mm coronal section was made at the level of the mPFC and the right and left mPFC were dissected from this section (Fig. 1). In some cases, 1.2-mm coronal sections were also taken for bilateral dissection of NAS and neostriatum. Tissues from mPFC, NAS and neostriatum were weighed, homogenized in 0.1 N perchloric acid with 0.2 mM sodium bisulfite (250, 400 and 500 /~1, respectively) and centrifuged (18,000 rpm for 15 min at - 4 ° C). The supernatants were partially purified by alu- mina extraction as previously described [67] and then

74OO ~'~'~,~..,...JA10050 ~ "~i~#,~.J/A8620 ~-~-------JA9820 ~600

Fig. 1. Schematic representation illustrating rostro-caudal extent of three coronal slices from which mPFC, NAS and neostriatum were dissected. In each case, tissue from entire area between shaded portions of rostral and caudal panels was dissected bilaterally.

D. King, J.M. Finlay /Brain Research 685 (1995) 117-128 119

analysed for DA, NE and DOPAC content using high-performance liquid chromatography (HPLC) with coulometric detection (see 2.4. Neurochemical analyses).

2.3. Microdialysis experiments

Treatment of rats used in microdialysis experiments was the same as described above except that all lesions were performed using 1 /xg 6-OHDA and lesioned rats remained in their home cages for 14 days before microdialysis experiments. Lesioned and naive, weight-matched control rats were then removed from their home cages and anesthetized with Equithesin. A vertical, concentric microdialysis probe [2] with a 4 mm active length (dialysis fiber: o.d. = 250 /xm, 6000 MW cutoff; Spectrum Medical, Los Angeles, CA) was implanted into right or left neostriatum of control and lesioned rats using the following stereotaxic coordinates: AP + 0.5 mm, ML ___ 2.5 mm from bregma and DV - 7 . 0 mm from dura [48]. The microdialysis probe was connected to an infusion pump via polyethylene tubing (covered by a metal spring tether) and a liquid swivel which was held above the rat by a counter-balanced rod, allowing rats to move freely at all times. Microdialysis probes were continuously perfused with artificial cere- brospinal fluid (145 mM NaC1, 2.7 mM KCI, 1.0 mM MgC12, 1.2 mM CaC12) at a rate of 1.5 /xl/min.

Approximately 18 h after implantation of the microdialysis probe, 3 - 4 dialysate samples (15-min sampling inter- val) were collected under basal conditions. Lesioned and control rats were then subjected to (1) 30 min of tail pressure (using a cuff positioned on the base of the tail) followed by an additional 90 min of sampling and (2) systemic d-amphetamine sulfate (1.5 mg/kg, i.p.) followed by 150 min of sampling. The order of the treatments was counter-balanced. At the completion of sampling for the first treatment, rats were left undisturbed for 1 h and then two basal dialysate samples were collected before initiation of the second treatment. Throughout the experiment, dialysate samples were analysed immediately after collection for DA, DOPAC and HVA content by HPLC with amperometric detection (see 2.4. Neurochemical analyses). In addition, horizontal locomotor activity was moni- tored using an activity monitor (Digiscan Model RXYZCM; Omnitech, Columbus, OH), consisting of a horizontal grid of photocell beams located 2.8 cm above the floor and spaced 5 cm apart along the perimeter of a Plexiglas cage (40 cm3). The total number of photocell interruptions during each 15 min dialysate sampling period was recorded. One to three days after the completion of the microdialysis experiment, the mPFC was dissected from a coronal brain slice as described above, and analysed for DA and NE content using HPLC with coulometric detection (see 2.4. Neurochemical analyses). Thin coronal sections (40 /xm) through neostriatum were then cut on a freezing micro- tome and mounted on glass slides. These sections were stained using Cresyl violet and the location of the micro-

dialysis probe in neostriatum was confirmed by visual inspection.

2.4. Neurochemical analyses

The concentrations of DA, NE and DOPAC in postmortem tissue and DA, DOPAC and HVA in neostriatal dialysate were determined by HPLC coupled to electrochemical detection. The HPLC consisted of a manual injector (Model 7126; Rheodyne, Cotati, CA) or an auto- matic injector (Model 712 WISP; Waters, Milford, MA), a pump (Model 510 at 0.7 ml /min or Model 501 at 1.0 ml/min; Waters) and a pulse dampener (Model LP-21; Scientific Systems, State College, PA). Peak separation was achieved using a reversed-phase C18 column (3.2 x 100 mm, 3 /.tm, Brownlee Velosep; Applied Biosystems, San Jose, CA) and a mobile phase composed of 50 mM sodium phosphate (tissues) or 0.1 M sodium acetate (dialysate), 0.08-0.1 mM EDTA, 7-8% v / v methanol and 0.7-1.4 mM octyl sodium sulfate. The mobile phase was vacuum filtered and adjusted to pH 2.7 with 10 N hydro- chloric acid (tissues) or to pH 4.1 with glacial acetic acid (dialysate). Electrochemical detection was performed using amperometric or coulometric detection. Amperometric detection (Model 460; Waters) was performed at a glassy carbon working electrode set at +0.6 V relative to a Ag/AgCI reference electrode. Coulometric detection (Coulochem Model 5100A; ESA, Bedford, MA) was performed using a conditioning cell (Model 5021; ESA) and a dual electrode analytical cell (Model 5011; ESA). The conditioning cell potential was set at + 0.45 V while the analytical cells 1 and 2 were working at 0.00 and + 0.37 V, respectively. Compounds were quantified at cell 2. The limit of detection was ~ 7 pg /50 /.d for tissue assays and 0.75 pg /20 /xl for dialysate. Acquisition of chromato- grams was performed by computer (Maxima 820 Chro- matography Workstation; Waters or Dynamax Macintegra- tor HPLC Method Manager; Rainin Instrument, Emeryville, CA). Concentrations of DA, NE, DOPAC and HVA in samples were determined by comparing the oxidation peaks produced by samples to those produced by standards of known concentration.

2.5. Retrograde tracing

In a separate group of control rats (n = 5), microdialysis probes were positioned in neostriatum as described above and infused with the retrograde tracer, Fluoro-Gold, using a modified version of the method described by Robertson and Fibiger [55]. Fluoro-Gold (0.004% in 0.9% saline; Fluorochrome, Englewood, CO) was perfused through the microdialysis probe for 1 or 2 h (1.5 /xl/min) and then rinsed with 0.9% NaC1 for at least 2 h. Six days later, these rats were anesthetized with Equithesin and transcardially perfused with heparinized NaC1 followed by 4% paraformaldehyde. Brains were postfixed in 4% para-


formaldehyde for 30 min and then sectioned (40 /zm) in 0.1 M sodium phosphate by vibratome. These sections were mounted on glass slides using a 0.01 M phosphate- buffered saline solution, dehydrated through a series of alcohols and coverslipped using Krystalon mounting medium (EM Diagnostic Systems, Gibbsville, N J). Sec- tions were examined for extent of Fluoro-Gold diffusion at the infusion site in neostriatum and for the distribution of retrograde transport in frontal cortex. Microscopic (Nikon Optiphot) analysis of the sections was completed using epifluorescence (100-W mercury lamp) with an excitation wavelength of 365-375 nm (Nikon UV-1A filter cube) and a fluorescence objective (Nikon Fluor 10). By visual inspection, areas containing retrogradely labeled cells were categorized as having either a light and sparse or a dense distribution of labeled cells (see Fig. 7 legend).

3.2. Effects of DA depletions of mPFC on tissue DA and DOPAC levels in NAS and neostriatum

In corroboration with the results described above, infusion of either 1 or 8 /zg 6-OHDA into mPFC significantly depleted tissue DA content in this area (Fig. 3A; F2,t4 = 9.55). In addition, although 8 /xg 6-OHDA depleted 50 10% of mPFC tissue NE content, 1 /zg 6-OHDA depleted only 18 _ 3% of the NE content (F2,14 = 19.28). In this case, the small NE loss after the low dose of 6-OHDA was statistically significant. Furthermore, these lesions did not alter tissue levels of DA or DOPAC in NAS (Fig. 3B; /72, n = 0.81 and 0.30, respectively) or neostriatum (Fig. 3C; F2,17 = 2.96 and 2.84, respectively). These lesions also did not affect the DOPAC:DA ratio in NAS or neostriatum (F2,17 = 0.28 and 0.22, respectively).

2.6. Data analysis 3.3. Effects of DA depletions of mPFC on extracellular DA and metabolites in neostriatum

Neurochemical data from postmortem tissues were analysed using Student's t test or A N O V A followed by pairwise comparisons (Tukey's HSD). Tissue concentrations of DA, NE and DOPAC were analysed either as n g / m g tissue wet weight or as a percent of control in cases where data from several experiments were combined. Neuro- chemical data from microdialysis experiments and locomotor activity were analysed using A N O V A with repeated measures followed by pairwise comparisons (Tukey's HSD or t tests with Bonferroni correction, respectively). Dialysate levels of DA, DOPAC and HVA were analysed as p g / 2 0 /zl. The level of significance for all tests was P < 0.05.

As in the results described above, bilateral infusions of 1 /zg 6-OHDA into mPFC significantly reduced tissue DA content in this region ( - 6 8 + 4%) without significantly depleting NE content ( - 1 5 + 6%) ( t 1 9 = 4.73 and 1.64, respectively). These selective lesions of mPFC DA terminals did not alter basal extracellular levels of DA, DOPAC or HVA in neostriatum as compared with control values (Table 1; t18 = 0.24, t t 9 = 0.33 and 0.76, respectively).

Treatment with tail pressure (30 min) increased extracellular DA, DOPAC and HVA in neostriatum by 15-20% (Fig. 4 A - C ; F9,162 = 8.95, F9,171 = 11.32 and 27.34, respectively). The extracellular levels of these neurochemi- cals remained significantly elevated for at least 75 min

3. Results

3.1. Lesions of DA terminals in mPFC

In an effort to produce a selective loss of DA in mPFC, we examined the content of DA and NE in this region after local treatment with several doses of 6-OHDA. Infusion of 4, 6 or 8 /xg 6-OHDA into mPFC of DMI-pretreated rats significantly depleted both DA and NE in the mPFC (Fig. 2; F5,40 = 21.00 and 22.91, respectively). In contrast, infusion of 1 /xg 6-OHDA produced a large depletion of DA ( - 79 _ 9%) without significant loss of NE ( - 13 _+ 5%). In comparison, the monoamine depleting agent, reserpine (5 m g / k g , i.p., 24 h before sacrifice) almost completely depleted tissue DA and NE content in the mPFC ( - 9 9 _ 1.8 and - 93 _ 1%, respectively). The absence of DA and NE in mPFC tissue samples from rats treated with reserpine confirms that the remaining electroactive species in mPFC tissue after infusion of 6-OHDA into mPFC were DA and NE.

• DA [ ] NE

!.o Control I l~J 4 Izg 6 IJg 8 ~ j Reserpine

6-OHDA

Fig. 2. Tissue concentration of DA and NE in mPFC after local infusion of 6-OHDA in DMI-pretreated rats (n = 5-8/group) or after administration of systemic reserpine (5 mg/kg, n = 2). Control levels of DA and NE in mPFC tissue (n= 16) were 0.11+0.01 and 0.22+0.01 ng/mg tissue wet weight, respectively. Data are presented as a percent of control (group mean _+ S.E.M.). * Significantly different from control value (Tukey's HSD, P < 0.05).


A. mPFC A. 130.1 BB Control 0.4- • DA | I [ ] Lesion 0.3- [ ] NE 120J . * 1" r* ,* *[

L B. NAS

12] • DA [ ] DOPAC

8

4

0 Control 1 i~j 8 Ixg

i C. Neostnatum • DA

121"l n DOPAC Tail Pressure

8

0 Contrd 1 ~g 8 t~g

Fig. 3. Effects of mPFC 6-OHDA infusions on tissue concentration of DA and NE in (A) mPFC and DA and DOPAC in (B) NAS and (C) neostriatum. Data are presented as group mean+S.E.M. ( n = 5 - 8/group). * Significantly different from control value (Tukey's HSD, P < 0.05).

after te rminat ion o f the stressor. Les ions o f m P F C D A

terminals did not alter the ta i l -pressure- induced increase in

D A or H V A (F9,171 = 1.20 and F9,162 = 0.47, respect ively) . H o w e v e r , there was a non-s igni f icant t rend for potent ia t ion

Table 1 Basal extracellular levels of DA, DOPAC and HVA in neostriatum of control and mPFC 6-OHDA lesioned rats a

DA DOPAC HVA (pg/20/zl) (ng/20/.tl) (ng/20/zl)

Control 13.5 + 0.9 4.3 5:0.6 3.6 5:0.4 Lesion 13.1 5:1.3 4.5 5:0.4 4.1 5:0.6

a ~ 18 h after implantation of microdialysis probe, dialysate was collected at 15-min intervals (1.5 /zl/min) and immediately analysed for baseline neurochemical content. Data are presented as group mean Jr S.E.M. (n = 10-11/group).

C. 130q . ,

i1,o a

Tail Pressure

Fig. 4. Effects of mPFC DA depletion on tail pressure-induced increases in extracellular (A) DA, (B) DOPAC and (C) HVA in neostriatum. Data are presented as a percent of baseline (group mean-i-S.E.M., n = 9- ll/group). * Significantly different from baseline; data from control and lesioned groups were combined for pairwise comparisons (Tukey's HSD, P < 0.05).

o f the ta i l -pressure- induced increase o f D O P A C in le-

s ioned rats (F9,16 e = 1.54; P = 0.14). Moreover , the aver- age m a x i m u m increase in D O P A C induced by tail pressure

in les ioned rats was 23 + 4% above basel ine in contrast to an increase o f 14 ___ 2% above basel ine in control rats

(/19 = 1.69; P = 0.07). Trea tment wi th d -amphe tamine (1,5 m g / k g , i.p.) in-

creased extracel lular D A ( + 500%) and decreased extracel-

122 D. King, J.M. Finlay / Brain Research 685 (1995) 117-128

lular D O P A C and H V A ( - 6 0 % ) (Fig. 5 A - C ; F l l , 1 9 s =

89.5, 107.96 and 54.13, respect ively) . Les ions o f m P F C

D A terminals did not alter the effects of d -amphe tamine

on extracel lular DA, D O P A C or H V A in neostr ia tum ( F 11'198 = 0.09, 0.90 and 0.64, respect ively) .

Note that in these microdia lys i s exper iments , all rats

A. 800 / ~ • • Control

| t *. I~j Lesion

0 I I I I I I I I I I I I

15 30 45 60 75 90 105 120 135 150 165 180 4k time (rain)

d-amphetamine

"°t1 -*- • *

. o •

8

I I I | I I l I I I I I

d - a n ~ t a m i n e

C. 100

80 * . *

=o . ,

X~ 60 * *

I i I I I I i I i | I I

d-amp ~l~etamine Fig. 5. Effects of mPFC DA depletion on systemic d-amphetamine-induced (1.5 mg/kg, i.p.) alterations in extracellular (A) DA, (B) DOPAC and (C) HVA in neostriatum. Data are presented as a percent of baseline (group mean -t- S.E.M., n = 9-11/group). * Significantly different from baseline; data from control and lesion groups were combined for pairwise comparisons (Tukey's HSD, P < 0.05).

A. 10004 W

(~ 750- >.,

<

250-

. J

0

-il-- Control

time (rain) Tall Pressure

B . 8 0 0 - 1o "E

8 600-

400- .<

~ - 0 0 0

. J

0

=o 1" - - I ! - Control

- 0 - Lesion

15 30 45 60 75 90 105 120 135 150 165 180

d-.amph~tamine time (mini

Fig. 6. Effects of mPFC DA depletions on locomotor response to (A) tail pressure (30 min) and (B) systemic d-amphetamine (1.5 mg/kg, i.p.). Data are presented as group mean + S.E.M. (control n = 4, lesion n = 9- 10/group). Pairwise comparisons were performed on data collected at 15-90 min using t tests with Bonferroni correction. A: data from control and lesion group were combined for pairwise comparisons; * significantly different from baseline (4 comparisons, P < 0.01). B: data from control and lesion group were analysed separately; tsignificantly different from respective baseline or oosignificantly different from control (12 comparisons, P < 0.0004).

were treated wi th tail pressure and d -amphe tamine in a

counterba lanced order. In general , statistical analysis of

t reatment order effects revea led that prior exposure to

stress or d -amphe tamine did not affect the impact of the

alternate s t imulus on extracel lular DA, D O P A C or H V A .

The only except ion was that prior d -amphe tamine treat-

ment at tenuated the effects o f tail pressure on H V A in both

control and les ioned rats ( - 9 . 0 + 1.0%, F9,81 = 2.24; and

- 13.5 + 2.0%, F9,72 = 2.29, respect ively) . Because the responses of control and les ioned rats to tail pressure or

d -amphe tamine were not different ial ly affected by treat-

ment order, groups rece iv ing both t reatment schedules were combined .

3.4. Behavioral effects o f DA depletions o f mPFC

Basal l ocomoto r act ivi ty was not s ignif icant ly different

in rats wi th D A deplet ions of the m P F C as compared with

controls (120 __+ 43 and 1 7 _ 9 c o u n t s / 1 5 min, respec-

t ively; t12 = 2.14). Both tail pressure and d -amphe tamine

s ignif icant ly increased locomoto r act ivi ty (F9,108 = 6.23


and Fl1 ,121 = 7.06, respectively). Lesions of mPFC DA terminals did not significantly alter the locomotor response to tail pressure (Fig. 6A; F9,t08 = 1.55). In contrast, lesioned rats were significantly less responsive to the locomotor stimulant effect of d-amphetamine than were con- trois (Fig. 6B; F l l , 1 2 1 = 2.45).

+ 4 . 7 m m

3.5. Retrograde transport of Fluoro-Gold to mPFC after administration through microdialysis probe

Fluoro-Gold infusions delivered through microdialysis probes implanted unilaterally in neostriatum of naive rats resulted in the appearance of labeled cells throughout the rostrocaudal extent of frontal cortex (Fig. 7). According to the nomenclature used by Krettek and Price [38], areas of PFC that were densely labeled included medial precentral, anterior cingulate and prelimbic subregions of mPFC as well as agranular insular, ventrolateral orbital and lateral orbital regions. In two cases, there also were highly scat- tered but darkly labeled cells forming an arc in the deep layers extending from the dorsal mPFC to the agranular insular area. In all areas of frontal cortex, retrogradely labeled cells were observed bilaterally although more dense labeling was found ipsilateral to the infusion.

+ 3.7 mm

+ 2.7 mm

~n=1-2 ~n=3-4 ~n=5

Fig. 7. Schematic representation of retrograde transport of Fluoro-Gold in frontal cortex (+4.7, +3.7 and +2.7 mm anterior to bregma) after infusion of tracer (0.004% for 1 or 2 h @ 1.5 /xl/min) through a microdialysis probe located in neostriatum. The right hemisphere of each coronal section in the schematic represents the mPFC hemisphere ipsilateral to the neostriatal infusion. Only densely labeled regions are repre- sented in the schematic. The darkest shading represents areas showing retrograde label in all five subjects, medium shading represents areas in which 3-4 rats showed retrograde transport and light shading represents areas in which only 1-2 rats had labeled cells.

4. Discussion

4.1. Lesions of DA terminals in mPFC

In the present study, infusion of 1 /xg 6-OHDA into the mPFC of DMI-pretreated rats depleted DA in that region without significantly reducing NE content although higher doses (> 4 ~g) reduced both DA and NE content. Previ- ous studies using high doses of 6-OHDA (8-12 /xg) have also reported a depletion of both catecholamines [13,17,27,28,33,44,51,52]. However, there are two reports in which local infusion of high doses of 6-OHDA (4 or 12 /xg) did not significantly deplete NE content in mPFC [39,45]. It is unclear why lesion selectivity was observed with the high doses of 6-OHDA used in the latter studies although it is possible that the specific lesion site and area of dissection were contributing variables.

The ability to deplete DA in the mPFC without loss of NE content may be crucial to studying the function of DA in this region, because interactions between DA and NE terminals are suggested by several studies [70]. The interactions between DA and NE neurons include heterologous regulation of extracellular neurotransmitter levels [11,25,58] and receptor sensitivity within mPFC [29,73]. Of particular relevance to the present study is the observa- tion that NE terminals in mPFC can influence the effects of electrolytic lesions of the VTA on behavioral correlates of subcortical DA neurotransmission [69,75].

In the present study, DA loss in mPFC was incomplete after local infusion of either 1 /xg 6-OHDA ( - 7 9 % ) or 8 /xg 6-OHDA ( - 8 9 % ) . The portion of DA remaining in tissue after 6-OHDA may be present either in remaining DA terminals or in intact NE terminals where it serves as a precursor to NE. The latter possibility would indicate that although tissue levels of DA in mPFC after local infusion of 6-OHDA are not fully depleted, the loss of DA terminals may be nearly complete.


4.2. Postmortem tissue levels of DA and DOPAC in NAS and neostriatum after DA depletions of mPFC

In the present study, neither lesions of DA terminals made with 1 /zg 6-OHDA (minimal NE depletion) nor those made with 8 /xg 6-OHDA (large NE depletion) altered basal levels of DA or DOPAC in tissue of NAS or neostriatum. In contrast, Pycock et al. as well as others have reported an increase in the DOPAC:DA ratio in NAS and/or neostriatum after 6-OHDA infusion into mPFC [13,27,44,51,52]. However, the present data are consistent with the majority of studies that report an absence of this effect [10,15,17,28,39,57,59,65]. Furthermore, the present data demonstrate that differences in the extent of depletion of NE in mPFC do not appear to contribute to the conflicting results noted above.

4.3. Basal and evoked extracellular DA in neostriatum after DA depletions of mPFC

Analysis of postmortem tissue has yielded conflicting results regarding the impact of DA depletions of the mPFC on the activity of subcortical DA neurons. Furthermore, under some circumstances, postmortem tissue measures may not accurately reflect in vivo neurochemical activity [20]. Therefore, we determined the impact of DA depletions of the mPFC on the concentration of DA and its metabolites in the extracellular fluid of neostriatum in freely moving rats as an alternative index of DA release and synthesis. In our study, destruction of the dopaminergic innervation of mPFC did not alter extracellular DA or its metabolites in neostriatum under basal conditions. This suggests that DA terminals in the mPFC do not influence extracellular DA in neostriatum under basal conditions. However, the lack of effect of these lesions may be a result of compensatory mechanisms that allow any remaining DA terminals in the mPFC to maintain prelesion levels of extracellular DA in this region under basal conditions as previously demonstrated for nigrostriatal DA neurons [1,56,82]. Alternatively, compensations could occur within the intact nigrostriatal DA neurons allowing these neurons to maintain homeostasis despite altered afferent input.

In the presence of partial injury or altered afferent input, DA neurons may be capable of maintaining normal function under basal conditions, however, compensatory mechanisms may 'fail with additional challenge to the animal [66]. Therefore, we examined the effect of DA depletions of the mPFC on nigrostriatal DA neurons when these systems were activated by stress or d-amphetamine. The effects of these stimuli are also relevant to the study of the neurobiological bases of schizophrenia and Tourette syndrome since both stimuli can precipitate symptoms of these disorders [4,9,30,40].

Stress imposed by tail pressure significantly increased extracellular DA and its metabolites in neostriatum as reported previously [3,26,34,35,49]. Lesions of DA termi-

nals in the mPFC did not alter the stress-evoked increase in extracellular DA in neostriatum. However, there was a trend for potentiation of the stress-induced increase in extracellular DOPAC within neostriatum of lesioned rats. It has been suggested that extracellular DOPAC derives largely from newly synthesized DA and, therefore, provides a measure of DA synthesis [64,81]. Thus, our data suggest that depletion of DA in mPFC enhances DA synthesis in neostriatum during stress. This could occur if the loss of DA terminals in mPFC disinhibits EAA-containing projections from mPFC that stimulate DA synthesis in neostriatum during stress. In support of this hypothesis, EAA antagonists administered into neostriatum blocked the tail-shock-induced increase in extracellular 3,4-dihy- droxyphenylalanine (DOPA), measured in the presence of a decarboxylase inhibitor, although they had no effect on basal extracellular DOPA [14]. Together, these studies suggest that in vivo the dopaminergic innervation of the mPFC may influence DA synthesis in neostriatum under stimulated but not basal conditions.

d-Amphetamine (1.5 mg/kg , i.p.) increased extracellular DA and decreased its metabolites in neostriatum as previously reported [63,80,81]. These effects were not altered by lesions of DA terminals in mPFC. As discussed above, we hypothesized that depletion of DA in the mPFC disinhibits DA synthesis in neostriatum and that this is expressed as a change in the level of extracellular DOPAC occurring under conditions of evoked activity (i.e., stress). However, the effect of d-amphetamine on extracellular DOPAC in neostriatum was the same in control and lesioned rats. Differential effects of the lesions on the response to stress and d-amphetamine may reflect the unique mechanism by which each stimulus alters the neurochemical activity of the DA neurons themselves or the afferent projections regulating these neurons. For example, whereas stress increases extracellular DOPAC, d- amphetamine decreases this metabolite by inhibiting the degradative enzyme, monoamine oxidase [42]. It is possible that the ability of d-amphetamine to inhibit monoamine oxidase may have obscured any change in extracellular DOPAC in neostriatum produced by lesions of the mPFC. In addition, stress and d-amphetamine differentially affect the activity of neurons in the mPFC that may regulate nigrostriatal DA neurons. Specifically, tail pinch has been reported to activate a subpopulation of pyramidal neurons in the mPFC [43] whereas systemic d-amphetamine in- hibits spontaneously active neurons in this region [46].

Our data indicate that depletion of DA in the mPFC does not affect either basal or evoked extracellular DA in neostriatum. However, in a recent report 6-OHDA lesions of the dorsolateral, medial and orbital areas of PFC increased potassium-induced DA efflux in caudate of mar- mosets [54]. There are many differences between the latter study and the present experiments that make comparisons difficult, including differences in the species examined, the subareas of PFC that were lesioned and the degree of


tissue NE loss [54]. In addition, the microdialysis probes in the previous study were implanted acutely and the monkeys were anesthetized throughout the experiments whereas in the present study microdialysis probes were implanted the day before the experiment and the rats were moving freely [54]. Nevertheless, a crucial difference between these studies may be the route of administration of the challenge stimulus. We administered d-amphetamine systemically whereas Roberts et al. [54] infused potassium directly into neostriatum. The effect of systemically administered drugs, as well as stressors, may be dependent upon the completeness of the DA lesion in mPFC since these stimuli would release DA from any remaining terminals in the mPFC as well as the subcortical DA regions. Hence, depending upon the extent of the DA depletion in mPFC as well as the degree of compensation in this region, alterations in neostriatal DA efflux evoked by systemic treatments may be obscured by the countereffect produced by also promoting DA efflux from residual DA terminals in mPFC.

4.4. Localization of microdialysis probe within neostriatum

Given the hypothesis that nigrostriatal DA neurons are regulated by direct corticostriatal projections, we evaluated whether our microdialysis probes were placed within the terminal field of neurons projecting from mPFC to neostriatum. After infusion of the tracer, Fluoro-Gold, through microdialysis probes in neostriatum, we observed retrogradely labeled cells in mPFC suggesting that mPFC efferents terminate in the vicinity of our microdialysis probes. However, we cannot evaluate the degree to which the diffusion of Fluoro-Gold from the microdialysis probe matches the diffusion of DA to the probe. As a result, the specific degree to which the retrogradely labeled cells in mPFC represent those that may regulate the extracellular DA that is sampled by the microdialysis probe in neostriatum is unknown.

Although there are efferent terminals from mPFC near the microdialysis probes, these probes were not directly centered in the neostriatal area that receives the densest input from mPFC, the medial neostriatum [7,62]. There- fore, it must be considered that our results might have been different with a more medial placement of the microdialysis probe. However, others did not find enhanced synthesis of DA in medial neostriatum after 6-OHDA lesions of mPFC although they did observe such an effect in the NAS [57]. Additionally, it is notable that our microdialysis probe was within the region of neostriatum previously reported to exhibit increased DA turnover after 6-OHDA lesions of mPFC [51] and yet we did not observe such effects in vivo. Of course, mPFC efferents may influence nigrostriatal DA neurons at the soma and/or indirectly through polysynaptic pathways, neither of which were examined in the present experiment.

4.5. Behavioral effects of mPFC DA lesions

Dopaminergic neurons projecting to the NAS and neostriatum are necessary for stimulant-induced locomotor activity and stereotypy [5,36]. Additionally, the dopaminergic innervation of mPFC may play a role in regulating locomotion [71,77]. Hence, we examined the impact of DA depletions of mPFC on locomotor activity. We observed that lesions of the DA terminals in mPFC attenuated the locomotor stimulant effects of d-amphetamine measured 14 days postlesion. This finding is consistent with a re- cently published study [65]. It has been suggested that non-stereotyped locomotion and stereotyped behaviors compete for expression [32,79] and, therefore, the decrease in amphetamine-induced locomotor activity may be due to an increase in stereotypy. In fact, previous studies have reported an increase in amphetamine-induced stereotypy 10-14 days after 6-OHDA lesions of mPFC [13,65]. The latter behavioral findings together with our neurochemical data suggest that DA depletions of the mPFC may alter the behavioral response to d-amphetamine without producing a correlated change in DA effiux in neostriatum. A dissoci- ation between amphetamine-induced behavior and extracellular levels of DA in neostriatum has been previously reported [60]. We are currently examining whether the attenuation of d-amphetamine-induced locomotion after DA depletions of the mPFC is associated with an increase in stereotyped responses and/or alterations in amphetamine-evoked DA release in the NAS.

Alternative hypotheses could account for the observa- tion that depletion of DA in the mPFC attenuated d- amphetamine-induced locomotion. For example, DA depletion of mPFC may induce increases in the sensitivity of DA receptors in this region as has been described after electrolytic VTA lesions [72,73]. Systemic d-amphetamine may evoke a substantial increase in DA effiux from any remaining DA terminals in mPFC which would then act on supersensitive postsynaptic receptors to potentiate the inhibitory effect of DA in mPFC on locomotor activity. Given this hypothesis, the fact that stress-evoked locomotion was not also significantly decreased after lesions may be explained by the small magnitude of DA efflux in mPFC induced by tail-shock stress ( + 90%) [3] as compared with systemic d-amphetamine ( + 1000%) [41].

These data suggest that in the intact system DA terminals in mPFC do not regulate the effiux of DA in neostria- rum but may have the capacity to regulate DA synthesis in neostriatum during stress. In addition, these data confirm that mesocortical DA neurons modulate stimulant-induced locomotor activity.

Acknowledgements

We gratefully acknowledge M.J. Zigmond for many discussions regarding this research. We thank S.R. Sesack

126 D. King, J.M. Finlay / Brain Research 685 (1995) 117-128

for training and supervision of the retrograde tracing. We also acknowledge J-S. Yen for preparation of histology. This work was supported by awards from Tourette Syn- drome Association, Scottish Rite Schizophrenia Research Program, National Alliance for Research on Schizophrenia and Depression and USPHS Grants MH45156 and MH29670.

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