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Joutnal of Neurochemistry
Raven Press, Ltd ., New York
1995 International Society for Neurochemistry

Local Influence of Endogenous Norepinephrine on
Extracellular Dopamine in Rat Medial Prefrontal Cortex
*Paul J . Gresch, *-~Alan F. Sved, *tMichael J. Zigroond, and *Janet M. Finlay
Departments of *Neuroscience and T Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, U.S.A .
Abstract : Noradrenergic and dopaminergic projections
converge in the medial prefrontal cortex and there is evidence of an interaction between dopamine (DA) and norepinephrine (NE) terminals in this region . We have examined the influence of drugs known to alter extracellular
NE on extracellular NE and DA in medial prefrontal cortex
using in vivo microdialysis . Local application of the NE
uptake inhibitor desipramine (1 .0 pM) delivered through
a microdialysis probe increased extracellular DA
(+149%) as well as NE (+201 %) in medial prefrontal
cortex . Furthermore, desipramine potentiated the tail
shock-induced increase in both extracellular DA (stress
alone, +64% ; stress + desipramine, +584°/x) and NE
(stress alone, +55% ; stress + desipramine, +443%) . In
contrast, local application of desipramine did not affect
extracellular DA in striatum, indicating that this drug does
not influence DA efflux directly . Local application of the
a2-adrenoceptor antagonist idazoxan (0 .1 or 5 .0 mM)
increased extracellular NE and DA in medial prefrontal
cortex . Conversely, the a2-adrenoceptor agonist clonidine (0 .2 mg/kg; i.p .) decreased extracellular NE and DA
in medial prefrontal cortex . These results support the hypothesis that NE terminals in medial prefrontal cortex regulate extracellular DA in this region . This regulation may
be achieved by mechanisms involving an action of NE on
receptors that regulate DA release (heteroreceptor regulation) and/or transport of DA into noradrenergic terminals (heterotransporter regulation) . Key Words: Microdialysis -Norepinephrine-Dopamine-Stress-a 2 Adrenoceptor-Norepinephrine transporter .
J. Neurochem. 65, 111-116 (1995) .

Dopamine (DA)- and norepinephrine (NE)-containing neurons share a common target in their projections to the prefrontal cortex (PFC) (Descarries et al .,
1987; van Eden et al ., 1987; Audet et al., 1988; Séguéla
et al ., 1990) . In addition, there is growing evidence
of an interaction between DA and NE terminals in
this brain region (for review, see Tassin, 1992) . For
example, it has been observed that a population of
cortical neurons are responsive to both DA and NE
(Bunney and Aghajanian, 1976) and that the evoked
activity of these cells may be differentially regulated

by the two neurotransmitters (Ferron et al ., 1984 ;
Mantz et al., 1988) . Furthermore, in addition to regulating the sensitivity of their own receptors, DA and
NE influence the sensitivity of each other's receptors
in this region (Tassin et al., 1986; Hervé et al 1990) .
Recently, it has also been suggested that interactions
between DA and NE at presynaptic sites may regulate
extracellular levels of these transmitters in the PFC
(Rossetti et al ., 1989 ; Carboni et al., 1990; Tanda et
al ., 1994) . For example, noradrenergic terminals may
contribute to the removal of DA from the extracellular
fluid, as the NE transporter has a similar affinity for
NE and DA (Raiteri et al., 1977) . In support of this
hypothesis, systemic administration of inhibitors of the
NE transporter increase extracellular fluid levels of DA
in PFC, as measured by in vivo microdialysis, and this
effect is eliminated by prior destruction of the NE
innervation of the PFC (Carboni et al., 1990; Tanda
et al., 1994) . However, due to the widespread effects
of systemically administered drugs, these data do not
preclude other interpretations . For example, NE may
increase the electrophysiological activity of midbrain
DA neurons (Grenhoff et al ., 1993) and thereby elicit
an increase in action potential-dependent DA release
in PFC. Thus, the present experiments were designed
to examine further the relationship between extracellular DA and NE in PFC by assessing the impact of
local application of drugs known to alter extracellular
NE on DA in this region .

Received September 8, 1994 ; revised manuscript received December 20, 1994 ; accepted December 30, 1994.
Address correspondence and reprint requests to Dr . J . M . Finlay
at Department of Neuroscience, 446 Crawford Hall, University of
Pittsburgh, Pittsburgh, PA 15260, U .S .A .
The current address of Dr. P . J . Gresch is Department of Anatomy
and Cell Biology, Wayne State University, Detroit, Ml 48201,
U .S .A .
A preliminary communication of these results was presented at
the 23rd annual meeting of the Society for Neuroscience, November
7-12, 1993 .
Abbreviations used: DA, dopamine ; DMI, desipramine ; mPFC,
medial prefrontal cortex ; NE, norepinephrine : PFC, prefrontal cortex ; STR, striatum .

Male Sprague-Dawley rats (275-325 g ; Zivic-Miller
Laboratory, Allison Park, PA, U.S .A .) were housed two per
cage in wire mesh cages in a colony room (ambient temperature 22-23°C ; lights on from 8 :00 a.m . to 8:00 p.m .) . Food
and water were available ad libitum. Rats were housed for
at least 7 days before use in an experiment . All animal care
and use procedures were in strict compliance with the National Institutes of Health Guide fbr the Care and Use of
Laboratory Anhnals and were approved by the Animal Care
and Use Committee at the University of Pittsburgh .
Microdialysis probes of concentric design were constructed as described previously (Abercrombie and Finlay,
1991 ) . The active length of the dialysis membrane (MW
cutoff = 6,000; o.d . = 250 pm ; Spectrum Medical Industries) was restricted to 4 .0 trim . Rats were anesthetized with
Equithesin [258 mM chloral hydrate, 20°10 (vol/vol) Nembutal, 86 mM MgSO4, and 25% (vol/vol) propylene glycol ;
3.0 ml/kg, i.p .] and placed in a stereotaxic frame with the
skull flat. Microdialysis probes were implanted in the striatum (STR) or medial portion of the PFC (mPFC) . The
coordinates, relative to bregma and dura, were AP +0 .5, ML
2.5, and DV -7 .0 for STR and AP +3 .2, ML - 1 .2, and
DV -6 .0 for PFC (Paxinos and Watson, 1982) . One brain
region was examined per rat. Immediately following implantation, the microdialysis probe was perfused continuously
with an artificial CSF ( 145 mM NaCl, 2.7 mM KCI, 1 .0
mM MgCh, and 1 .2 niM CaCl,) at a rate of 1 .5 pl/min .
Experiments began 18-24 h after implantation of the microdialysis probe. Dialysate was collected at 30-min intervals, and then 20-pl fractions were assayed for either DA
(mPFC and STR) or NE (mPFC) by HPLC with electrochemical detection with minor modification of previously
described methods . The HPLC system consisted of an injector (Rheodyne ; Model 7126), a dual-piston pump (Waters;
Model 510), an external pulse dampener (Scientific Systems ; Model LP-21 ), and a Velosep C-18 column ( 100 X 3 .2
mm, 3-pin packing; Applied Biosystems, Brownlee Labs) .
Separation of DA was achieved using a mobile phase consisting of 100 mM sodium acetate, 100 pM EDTA, 1 .6 mM
sodium octyl sulfate, and 9% methanol (vol/vol ) ; the mobile
phase was filtered, degassed, and adjusted to pH 4.1 with
glacial acetic acid . DA was measured using an electrochemical detector (Waters; Model 460) equipped with a glassy
carbon working electrode that was set at a potential of +600
mV relative to a Ag/AgCI reference electrode. Separation
of NE was achieved using a mobile phase consisting of 60
mM sodium phosphate, 75 pM EDTA, 1 .36 mM sodium
octyl sulfate, and 3.5 070 methanol (vol/vol) ; the mobile
phase was filtered, degassed, and adjusted to pH 2.75 with
hydrochloric acid . NE content in dialysate was determined
using a coulometric detector (ESA ; Model 5100a) configured with three electrodes in series . A conditioning cell
(+260 mV ; ESA; Model 5021) was placed immediately
after the column, followed by an analytical cell (first electrode at -210 mV; second electrode at +210 mV ; ESA ;
Model 5011 ) . NE was quantified at the second electrode.
The limit of detection was approximately 0.5 pg/20 pl for
NE and DA . Neurochemical content of dialysate was represented as picograms per 20 pl . The present data were not

l . Neuroc'hem_ Vol . 65, Nu . / . 1995

corrected for recovery ; however, the in vitro recoveries of
the 4-mm microdialysis probes have been determined previously to be approximately 18% (Finlay et al ., 1995) . In
all experiments, dialysate was sampled for I h prior to any
treatment to establish baseline concentrations of neurotransmitter .
In separate groups of rats with microdialysis probes located in either STR (n = 3) or mPFC (n - 5), desipramine
hydrochloride (DMI, Sigma) dissolved in artificial CSF was
delivered through the microdialysis probe at a dose ( 1 .0 PM)
that we had determined to be submaximal for increasing
extracellular NE and DA . In additional rats with microdialysis probes located in the niPFC, idazoxan (0 .1 or 5.0 in M,
n = 2 al each concentration; Research Biochemicals Inc.)
was delivered via the dialysis probe for 120 min or clonidine
(0 .2 mg/kg, n = 3 ; Sigma Chemicals) was administered
intrapcritoneally. Both of these treatments have been shown
previously to produce large changes in cortical NE efflux
(L'Heureux et al ., 1986 ; Dennis et al ., 1987 ; van Veldhuizen
et a1 ., 1994) . During local drug application, the perfusion
rate of the microdialysis probe continued to be maintained
at 1 .5 pl/min .
Rats treated with DMI were also exposed to tail-shock
stress for 30 min beginning 90 min after the onset of drug
infusion . Tail shocks were administered via a cuff containing
two stainless steel electrodes placed on the base of the tail .
Intermittent tail shocks were comprised of constant current
pulses of 1 .0-mA intensity delivered for I s every 10 s for
a duration of 45 s; this series was repeated every 5 min for
30 min resulting in the delivery of a total of 30 shocks . In
control rats, artificial CSF was perfused through the probe
prior to and during tail shock; data from these rats were
published previously (Gresch et al ., 1994) and are included
here for comparison .
Histological analysis
At the termination of each experiment, the rat was given
an overdose of Equithesin (8 .0 nil/kg) and perfused intracardially with 10 070 formalin in saline. The brain was removed,
sectioned, and stained with Luxol fast blue and Safranin-O .
The tip of the probe tract was then located in the coronal
sections . Because the active membrane area of the probe
began 0.5 mm from the tip, we could determine whether the
4-min active area of the membrane was within the mPFC
based on the atlas of Paxinos and Watson (1982) . If any
portion of the active membrane was determined to be outside
the target location, data from that animal were excluded .
Data analysis
The effect of DMI and/or tail shock on extracellular NE
and DA levels was determined by a one-way ANOVA with
repeated measures . The contribution of individual means to
a significant F ratio then was determined by Tukey's HSD
test . The impact of tail shock on extracellular NE and DA
in DMI-treated and control rats was calculated by subtracting
the concentration of NE and DA present in the sample collected immediately prior to stress (during perfusion of artificial CSF with or without DMI) from that obtained during
acute tail shock. The effect of DMI on the stress-induced
net change in extracellular NE and DA was then determined
by independent t tests. The relationship between extracellular
NE and DA under basal conditions and during idazoxan and


in the mPFC (Fig . 3 ; maximum response to idazoxan
in individual rats) . The idazoxan-induced increase in
NE and DA reached a plateau within the first 30-min
dialysate sample and remained elevated for the duration of the drug application (120 min ; time-response
curve not shown) . Conversely, systemic administration of the "2 -adrenoceptor agonist clonidine (0 .2 mg/
kg, i .p.) decreased both extracellular NE and DA in
mPFC (Fig . 3 ; maximum response to clonidine in indiFIG. 1 . Effects of local application of DMI (1 .0 N,M ; indicated by
horizontal black bar), delivered via a microdialysis probe, on
extracellular concentrations of NE and DA in mPFC, and DA in
STIR . DMI produced a significant increase in extracellular NE
and DA in mPFC [F(4,16) = 19 .70 and 12 .63, respectively] . In
contrast, local application of DMI in STIR did not affect extracellular DA levels [F(7,14) = 0 .66] . Baseline levels of NE and DA in
dialysate of mPFC were 4 .6 ± 0 .7 and 1 .2 - 0 .3 pg/20 N,l,
respectively; DA in dialysate of STIR was 5 .3 ± 2 .9 pg/20 pl .
`Significantly different from within-group sample 2 value (Tukey's HSD; p < 0 .05) .

clonidine treatments was determined by linear regression .
For each subject, linear regression analysis was performed
on the maximum drug-induced change in catecholamine
level . In all cases, the significance level was p < 0.05 .
Local application of the NE uptake inhibitor DMI

(1 .0 I-tM) increased extracellular NE in mPFC by 201

± 51% (from 4.6 {- 0.7 to 12 .4 - 1 .3 pg/20 M1 ; Fig . 1) .
The increase in NE was accompanied by an increase in
extracellular DA of 149 ± 32%
1 .2 -+_(from 0 .3 to
2 .7 ± 0.4 pg/20 pl ; Fig . 1) . In contrast, local application of this same concentration of DMI into the STR
had no effect on DA efflux (Fig . 1) .
Using identical methods, we observed that 30 min
of intermittent tail shock increased NE in the dialysate
by 55 } I I % (from 2.6 -!- 0 .3 to 4 .1 ± 0 .4 pg/20 p1 ;
Fig . 2A) and DA by 64 ± 18% (from 2.2 -!- 0.3 to
3 .5 ± 0 .4 pg/20 p1 ; Fig. 213) (Gresch et al ., 1994) .
In the present experiment, DMI ( 1 .0 aM) was found
to potentiate the stress-induced increase in catecholamines . In the presence of DMI, tail shock increased
NE by 443 ± 39% from baseline (from 4 .6 -- 0.7 to
24.5 -!- 3 .4 pg/20 p1 ; Fig . 2A) . This potentiation was
also evident as a greater net increase in NE efflux
above the newly established baseline produced by
DMI . Furthermore, tail shock now increased DA by
584 ± 108% from baseline (from 1 .2 - 0.3 to 7 .9
1 .9 pg/20 pl ; Fig . 2B) . Again, this potentiated increase was evident even when the new drug-induced
baseline was taken into account .
Local application of the a2 -adrenoceptor antagonist
idazoxan (0 .1 or 5 .0 in M) infused through the microdialysis probe increased both extracellular NE and DA

FIG . 2 . Effects of local application of DMI (1 .0 pM ; indicated by
horizontal black bar) on the stress-induced increase in extracellular NE (A) and DA (B) levels in mPFC expressed as a percentage of pretreatment baseline levels . Thirty minutes of intermittent
tail shock (indicated by horizontal open bar) produced a significant increase in extracellular NE and DA under control conditions
[artificial CSF (aCSF)] and during local application of DMI (aCSF
+ DMI) [NE : F(4,36) = 23 .92 and F(7,28) = 23 .37, respectively ;
DA : F(4,36) = 11 .48 and F(7,28) = 7 .80, respectively] . Stress
produced a greater net increase in extracellular NE and DA (indicated by vertical dashed lines) in DMI-treated rats than in control
rats, and this was evident even when the DMI-induced increase
in basal catecholamine levels was taken into account [NE : 12 .9
± 1 .2 versus 1 .4 ± 0 .3 pg/20 NI, respectively ; t(13) = 2 .95 ; DA :
5.2 ± 1 .8 versus 1 .2 ± 0 .1 pg/201J1, respectively ; t(13) = 4 .97] .
'Significantly different from pretreatment baseline (sample 2 for
aCSF + DMI group or sample 5 for aCSF group) (Tukey's HSD ;
p < 0 .05) . tSignificantly different from aCSF group (Student's
t test ; p < 0 .05) .

J. Nerrochenv_ Vol. 65, No . 1, 1995


FIG. 3. Relationship between extracellular levels of NE and DA
in the mPFC of individual rats under basal conditions (open symbols) and following idazoxan or clonidine administration (closed
symbols) . Local application of the a2adrenergic receptor antagonist idazoxan (n = 2 at each concentration) delivered via the
microdialysis probe increased extracellular NE and DA levels in
mPFC . Systemic administration of the " 2 -adrenergic receptor
agonist clonidine (n = 3) decreased extracellular concentrations
of NE and DA in mPFC . Across all conditions, the relationship
between extracellular concentrations of NE and DA was highly
correlated (r = 0.90) .

vidual rats) . In all cases, the maximum clonidine-induced decrease in catecholamines occurred in the dialysate samples collected between 30 and 60 or 60 and
90 min after clonidine administration (time-response
curve not shown) . There was a highly significant positive correlation between extracellular NE and DA in
rnPFC of individual rats under basal conditions and
following idazoxan or clonidine administration .
Our data indicate that treatments known to alter extracellular NE also influence extracellular DA in
mPFC . Most notably, local application of DMI, a drug
that is highly selective for blocking the NE uptake
carrier (Maxwell and White, 1978; Harms, 1983), increased extracellular DA as well as NE in rnPFC. Similarly, the selective a2-adrenergic receptor antagonist
idazoxan (Doxey et al ., 1983 ; Freedman and Aghajanian, 1984) increased the efflux of both NE and DA
in mPFC . These observations support the hypothesis
that in the mPFC there is an influence of NE terminals
on extracellular DA .
Previously, it was reported that systemically administered DMI increased both extracellular NE and DA
in the PFC (Carboni et al ., 1990; Pozzi et al., 1994;
Tanda et al., 1994) . However, due to the systemic
route of drug administration, it is unclear whether this
effect is mediated by a local action of this drug in the
PFC or by the drug acting elsewhere . For example,
stimulation of the locus ceruleus NE neurons has been
shown to increase the electrophysiological activity of
DA neurons in the ventral tegmental area (Grenhoff

J. Ne wrochern., Vol. 65, No. 1, /995

et al ., 1993), providing a pathway by which systemic
DMI administration could influence rnPFC DA efflux .
Our observation that 1 .0 pM DMI applied directly to
rnPFC also increases both NE and DA extends the
recent observation that 10-fold higher doses of DMI
also produce this effect (Pozzi et al ., 1994) and provides additional support for the existence of a local
interaction between NE and DA terminals in rnPFC.
Similar observations also have been made in the hippocampus (Xu et al., 1993), suggesting that local influences of NE on DA terminals may exist in other areas
in which these innervations converge.
Low micromolar concentrations of DMI appear to
be specific for blocking the NE uptake site (Maxwell
and White, 1978; Harms, 1983) . Furthermore, if DMI
acts on the DA transporter or DA receptors then it
would be expected to effect DA efflux in the STR and
nucleus accumbens where the concentration of DA is
much greater than that of NE (Versteeg et al ., 1976) ;
this does not occur (present data ; Carboni et al ., 1990 ;
Pozzi et al ., 1994) . Of course, these observations cannot exclude the possibility that DMI acts on a unique
population of DA receptors or transporters located on
DA terminals in mPFC . Indeed, there is marked heterogeneity of DA receptors (Schwartz et al., 1992; Sunahara et al ., 1993), and recently it has been suggested
that the DA transporter may be heterogeneous in its
molecular structure and regional functioning (Amara
and Kuhar, 1993 ; Garris and Wightman, 1994) . Furthermore, it is possible that DMI, even at concentrations in the low micromolar range, may have actions
unrelated to blocking NE uptake (Cat and McCaslin,
1992) . Nonetheless, at present our observations are
most readily explained by an impact of DMI on extracellular NE which, in turn, influences extracellular DA
concentrations .
The possibility that NE terminals in the PFC may
exert a local influence on DA efflux is further supported by our observation that other treatments that
increase NE efflux in the rnPFC elicit parallel changes
in DA efflux . Thus, the a,-adrenergic receptor antagonist idazoxan, which increases extracellular NE, also
produced an increase in extracellular DA . Conversely,
the a2 -adrenergic receptor agonist, clonidine, which
decreases NE efflux, produced a correlated decrease
in extracellular DA in mPFC. Furthermore, a nonpharmacological stimulus, acute tail shock, increased both
extracellular NE and DA in the mPFC, and the stressevoked efflux of both amines was potentiated in rats
previously exposed to chronic stress (Gresch et al .,
1994) . Together, these results suggest that under both
pharmacological and physiological conditions the levels of NE and DA in extracellular fluid of mPFC are
correlated .
The available data do not preclude the possibility
that extracellular DA concentrations are regulated by
NE terminals in mPFC via a polysynaptic pathway
rather than local interactions between catecholaminer-

gic terminals. For example, within the mPFC, afferent
noradrenergic terminals may synapse on efferent projections that influence the electrophysiological activity
of mesocortical DA neurons. However, such a mechanism seems unlikely as an explanation of the present
results because even large increases in the firing rate
of DA neurons do not elicit changes in extracellular
DA as large as some of those observed in the present
study (Bean and Roth, 1991) . The present experiments
also do not preclude the possibility that extracellular
DA within the mPFC derives in part from release from
noradrenergic terminals where it resides as a precursor
to NE . However, it may be estimated that less than
10% of tissue DA content resides in NE terminals .
This value is based on the tissue content of DA and
NE in the spinal cord (Sved, 1990), which receives a
prominent noradrenergic innervation but little dopaminergic innervation . It is unlikely that this relatively
small pool of DA could account for the large changes
in extracellular DA observed in the present experiment.
A local interaction between NE and DA terminals
within the mPFC could involve an action of NE on
adrenoceptors located on DA nerve terminals or interneurons (heteroreceptor regulation), and/or a role of
the NE transporter in the clearance of DA from extracellular fluid (heterotransporter regulation) . In support
of heteroreceptor regulation, a2 -adrenergic binding
sites and gene expression have been localized to the
mPFC (Unnerstall et al ., 1984 ; Boyajian et al ., 1987 ;
Scheinin et al ., 1994) . Moreover, presynaptic a 2-adrenergic heteroreceptors have been suggested to regulate DA release in the retina and hypothalamus (Ueda
et al ., 1983 ; Dubocovich, 1984) . Thus, treatments that
influence extracellular NE concentrations may, in turn,
alter DA release through a receptor-mediated action of
NE . Alternatively, as suggested previously (Carboni
et al ., 1990 ; Xu et al ., 1993 ; Pozzi et al ., 1994 ; Tanda et
al ., 1994), DA may be removed from the extracellular
space by transport into NE terminals. This possibility
is consistent with the observation that the NE transporter has a high affinity for DA (Raiteri et al ., 1977)
and that the accumulation of [ 3 H] DA in PFC is largely
blocked by inhibitors of the NE transporter (Izenwasser et al ., 1990) . If extracellular DA is cleared, in
part, by the NE transporter, then inhibiting the NE
transporter (as with DMI) or changing the extracellular
concentrations of NE (by treatment with an a2-adrenergic receptor agonist or antagonist) would affect the
extracellular concentrations of DA by virtue of a competitive interaction for the same transporter. This
mechanism implies that DA released in the mPFC has
access to the NE transporter, which is localized exclusively to noradrenergic neurons (Lorang et al ., 1994) .
Whatever the mechanism, our observation that
changes in mPFC extracellular NE are correlated with
changes in extracellular DA may be of clinical significance. Numerous tricyclie antidepressant drugs such
as DMI block the reuptake of NE, and many theories

of the therapeutic actions of tricyclie antidepressant
drugs focus on the changes produced in central noradrenergic systems (Heninger and Charney, 1987) .
However, the interaction between noradrenergic transmission and DA release in the mPFC may play a role
in the mechanism of the therapeutic actions of antidepressants. Indeed, hypotheses implicating a role of DA
in clinical depression have been described (Winner,
1983 ; Kapur and Mann, 1992) .
In conclusion, the present study indicates that local
alterations in extracellular NE in the mPFC induce
changes in extracellular DA . Although the exact mechanism of action in unclear, it is becoming evident that
catecholamine systems interact in the cortex and influence each other's extracellular concentrations . Furthermore, these findings may have an important implication for the mechanism of action of some antidepressant drug treatments .
Acknowledgment: We would like to thank J.-S . Yen for
the histological preparations . This work was supported by
the U.S . Public Health Service (MH 43947 and MH 45156),
the Tourette Syndrome Association, and the Scottish Rite
Schizophrenia Research Program.
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