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Vol. 289, Issue 1, 14-23, April 1999
Department of Psychiatry, Case Western Reserve University, and Cleveland Veterans Affairs Medical Center, Brecksville, Ohio
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Abstract |
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 Top
 Abstract
 Introduction
Materials and Methods
Results
Discussion
References
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Research has shown that there are important neurochemical differences between the mesocortical and mesostriatal dopamine systems. The work reported in this paper has sought to compare the regulation of dopamine release in the medial prefrontal cortex and the anterior caudate-putamen. In vivo microdialysis was used to recover dialysate fluid for subsequent assay for dopamine concentrations. The responses to D2 antagonist (haloperidol) administration, which has been shown to increase impulse-dependent dopamine release, were compared. Results demonstrated a diminished effect of systemic haloperidol administration on dopamine efflux in the prefrontal cortex. The responses to systemic administration of a nonimpulse-dependent, transporter-mediated, dopamine releaser (d-amphetamine) were also contrasted. Results again demonstrated a diminished pharmacological effect in the cortex. The potential interaction of stimulation of these two types of dopamine release was examined by coadministration of these compounds. Haloperidol pretreatment dramatically potentiated the dopamine-releasing effect of amphetamine administration. This effect was observed in both the cortex and the striatum. Subsequent work demonstrated that this effect of haloperidol was mediated by D2-like receptors in the prefrontal cortex. These results are discussed in relation to other neurochemical and neuroanatomical studies demonstrating sparse densities of dopamine transporter sites and dopamine D2 receptors in the cortex compared with the striatum. They demonstrate a functional correlate to the recently reported, largely extrasynaptic localization of dopamine transporter sites in the prefrontal cortex. Furthermore, they demonstrate the existence of cortical D2-like autoreceptors that may normally be "silent" under basal conditions.
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Introduction |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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The
prefrontal cortex has been implicated in a number of important
functions, mental disorders, and behavioral states, including locomotion, working memory, schizophrenia, stress, and drug abuse. It
is believed that these are regulated, in part, by dopamine (DA) release
from the mesocortical dopaminergic pathway (Goeders and Smith, 1983
;
Weinberger, 1987; Abercrombie et al., 1989; Sawaguchi and
Goldman-Rakic, 1991). This tract originates in the ventral tegmental
area of the midbrain and projects to the medial prefrontal cortex
(mPFC) in the rat (Emson and Koob, 1978). Several studies have
shown that this pathway displays unique neurochemical characteristics relative to the other two major dopaminergic systems of the brain, the
nigrostriatal and mesolimbic pathways (Bannon and Roth, 1983). For
example, mesocortical neurons display faster rates of synthesis, turnover, and firing, exhibit more frequent and intense burst firing,
and are more resistant to inhibition by DA D2 receptor subtype agonists
(Cubeddu et al., 1990).
D2 receptor antagonists such as typical antipsychotic drugs increase DA
turnover and dialysate DA concentrations in the dorsal (caudate-putamen: CP) and ventral (nucleus accumbens) striatum (Wolf et
al., 1987; Moghaddam and Bunney, 1990). Studies have demonstrated that
these effects result from the blockade of inhibitory DA autoreceptors,
which, in turn, increase exocytotic, calcium-dependent, DA release. D2
antagonists produce relatively lesser effects on prefrontocortical DA
release, which may be related to the rather unique neurochemistry of
this brain region, including a relatively sparse density of DA D2
subtype receptors in the rat (Gaspar et al., 1995).
There are also differences between the mPFC and CP in the effects of
agents that increase nonimpulse-dependent, carrier mediated, DA
release. Few studies have been performed in the mPFC, but uptake blockers such as cocaine have been reported to produce relatively lesser increases in mesocortical versus mesostriatal dialysate DA
concentrations (Moghaddam and Bunney, 1989). In the striatum, when
drugs that block the DA transporter (DAT) are combined with D2
antagonists, a pronounced synergistic increase in DA turnover and
release is observed (Fuller et al., 1978; Waldmeier et al., 1985; Sharp
et al., 1986; Westerink et al., 1987; Watanabe et al., 1989; Gudelsky
et al., 1992; Tyler and Galloway, 1992). To our knowledge, this
experiment has not been performed in the mPFC.
The present study was designed to compare the effects of administration of the DA releaser/uptake blocker d-amphetamine (AMPH) on dialysate DA concentrations in the mPFC and the anterolateral CP and to compare the effects of DA autoreceptor blockade, produced by haloperidol (HAL) administration, on AMPH-stimulated DA release in these two structures. Additionally, whether these combined effects were the result of DA D2-like receptor blockade was tested in the prefrontal cortex.
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Materials and Methods |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Animal Preparation.
All animal use procedures were in strict
accordance with the NIH Guide for the Care and Use of Laboratory
Animals and were approved by the local animal care committee.
Experimentally naive, male Sprague-Dawley rats were used. Rats ranged
in weight from 200-400 g at the time of the surgery. Rats were
anesthetized with a mixture of ketamine (70 mg/kg) and xylazine (6 mg/kg) administered i.m. Subsequently, the animals were mounted
in a stereotaxic frame and dura was carefully removed. Stainless steel
guide cannulas (21 gauge) were implanted on the brain surface above the
prefrontal cortex (anterior-posterior 3.2, medial-lateral 0.8)
or anterior CP (anterior-posterior 1.2, medial-lateral 3.4) (
3.2 head
angle; Paxinos and Watson, 1982) 2 to 4 days before the experiments. On
the days of the experiments, dialysis probes were lowered through these
guide cannulas in awake animals, terminating in the structures of
interest. Rats were used once and, after each experiment, probe placements were verified. This was accomplished by perfusing the intact
microdialysis probes with cresyl violet dye. Brains were removed and
frozen. They were then dissected manually (sliced with a razor blade)
and drawn freehand on appropriate sections copied from a rat brain
atlas (Paxinos and Watson, 1982). Data from rats with probe placements
outside the brain regions of interest were not used.
Microdialysis.
The microdialysis probes used a concentric
flow design and were constructed as described previously (Yamamoto and
Pehek, 1990). The membranes were 5.5 and 4 mm long for probes
placed in the prefrontal cortex and striatum, respectively. Animals
were housed in cylindrical buckets and tethered to liquid swivels that
permitted free movement. Rats were relatively undisturbed during sample collections.
Drugs. All doses are expressed as the salts (except for HAL, where the free base was employed). Drugs were injected i.p. Three concentrations of AMPH (1.25, 2.5, and 5.0 mg/kg/ml; Sigma Chemical Co., St. Louis, MO) were employed. AMPH was dissolved in distilled water. Rats were pretreated with HAL (1.0 mg/kg/ml; Sigma) or vehicle. HAL was dissolved initially in a small amount of glacial acetic acid and then diluted with distilled water. The pH was adjusted to 6.0 with NaOH. Vehicle was made similarly. HAL was administered 30 min before injection of AMPH or vehicle. In some experiments, the DA agonists apomorphine (APO) or quinpirole (QUIN) (both hydrochloride salts from Research Biochemicals Inc., Natick, MA) were injected 30 or 60 min before treatment with HAL (i.e., 60-90 min before AMPH). APO (2.0 and 20 mg/kg/ml; both doses injected 30 min before HAL) was dissolved in ice-cold ascorbic acid (2.0 mg/10 ml) whereas QUIN (0.2, 1.0 and 10.0 mg/kg/ml) was dissolved in water (0.2 and 10.0 doses were 1 h before HAL, 1.0 dose was 30 min earlier).
Chromatography. Dialysate samples (20 µl) were assayed for DA content by HPLC coupled with electrochemical detection. Samples were injected immediately after collection onto a Phenomenex Ultracarb (Belmont, CA) column (3-µm particle size, 2.0 × 100 mm). The column was maintained at 35°C. The mobile phase was pumped at a rate of 0.42 ml/min and consisted of 32 mM citric acid, 54.3 mM sodium acetate, 0.074 mM EDTA, 0.215 mM octylsulfonic acid, and 3% methanol (v/v), pH 4.2. The pH and concentrations of octylsulfonic acid and methanol were adjusted as needed to maintain separation of DA from its metabolites and 5-hydroxyindoleacetic acid. A BAS LC-4C electrochemical detector (Bioanalytical Systems, West Lafayette, IN) was used with a BAS glassy carbon electrode maintained at a potential of +0.60 V, relative to an Ag/AgCl reference electrode. The detection limit of the assay for DA was 0.1 pg/20 µl.
Data Analysis.
The data, absolute concentrations recovered
expressed as pg/20 µl, were analyzed by two-factor (time × drug
or time × brain area) repeated measure ANOVAs. Data were
uncorrected for probe recoveries because previous work has shown that
there is less than 10% variation in probe recoveries using this type
of microdialysis probe (Yamamoto and Cooperman, 1994). Significance
level was set at p < .05. For graphical depiction of
the data from studies comparing the magnitudes of responses to HAL and
AMPH, data were expressed as percentages of the three predrug baseline
levels. Because the basal levels of DA differed for the cortex and
striatum, this permitted more accurate comparisons of the relative
magnitude of effects between brain areas. Data were expressed
graphically as absolute concentrations (pg/20 µl) for the DA agonist studies.
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Results |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Concentrations of dialysate DA per HPLC injection (20 µl) were 0.39 ± 0.04 pg in the mPFC (equivalent to 0.13 fmol/µl; n = 80). Concentrations in the anterolateral CP were approximately ten times higher: 3.81 ± 0.10 pg/20 µl (1.25 fmol/µl; n = 49).
Effect of HAL Alone on DA Efflux in the CP and mPFC.
Injections of HAL + vehicleAMPH caused a moderate
increase in dialysate DA concentrations in the CP [F(7,35) = 9.09, p < .0001]. The maximal effect of HAL alone occurred
90 min after administration (Fig. 1). HAL
administration did not significantly affect dialysate DA concentrations
in the mPFC (these rats were part of an earlier study and did not
receive vehicleAMPH injections).
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Effect of AMPH on DA Efflux in CP and mPFC.
Administration of
AMPH dose dependently increased dialysate concentrations of DA in the
CP and mPFC. This effect was significantly greater in the CP at all
doses of AMPH (Fig. 2); significant
time × brain area interaction for all three doses: 1.25 mg/kg:
F(7,56) = 18.89, p < .001; 2.50 mg/kg: F(7,63) = 18.75, p < .001; 5.0 mg/kg: F(7,98) = 82.38, p < .00001 (all rats received
vehicleHAL injections 30 min before AMPH; in
addition, the 5.0 mg/kg AMPH rats received
vehicleAPO 60 min before AMPH). The time courses of action were also different for the two brain areas. In the CP, the
peak effect occurred at 30 min after AMPH administration (the 60-min
time point in Fig. 2). In contrast, the peak effect was delayed in the
mPFC, occurring 60 min after AMPH injection. The rate of decline in DA
concentrations was also greater in the CP relative to the mPFC (Fig.
2).
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Effect of HAL on AMPH-Stimulated DA Efflux in CP.
Pretreatment
with HAL potentiated AMPH-induced increases in striatal dialysate DA
concentrations (Fig. 3). This
potentiation depended on the dose of AMPH employed and was
statistically significant at the 5.0-mg/kg dose [significant time × treatment interaction for vehicle (VEH)/AMPH versus HAL/AMPH:
F(7,91) = 3.63, p < .002]. However, there was also a
trend toward statistical significance at the 2.5-mg/kg dose [F(7,56) = 1.99, p < .072 for the time × treatment
interaction].
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Effect of HAL on AMPH-Stimulated DA Efflux in mPFC.
Pretreatment with HAL potentiated AMPH-induced increases in cortical
dialysate DA concentrations (Fig. 4).
This potentiation depended on the dose of AMPH employed and was
observed at doses of 2.5 and 5.0, but not 1.25 mg/kg [significant
time × treatment interaction for VEH/AMPH versus HAL/AMPH at 2.5 mg/kg AMPH: F(7,84) = 3.66, p < .002 and at 5.0 mg/kg
AMPH: F(7,119) = 11.43, p < .0001]. Injections of HAL
without AMPH caused no significant increase in dialysate DA in the mPFC
(see Fig. 1).
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Effect of APO on HAL Potentiation of AMPH-Stimulated DA Efflux in
CP and mPFC.
In the CP, pretreatment with 20 mg/kg APO reversed
the effect of HAL on AMPH-induced DA release [significant drug × time interaction for VEH/HAL/AMPH group versus APO 20/HAL/AMPH group:
F(7,91) = 2.81, p < .01, Fig.
5]. In the mPFC, 2.0 mg/kg attenuated
this potentiation [significant drug x time interaction for
VEH/HAL/AMPH group versus APO/HAL/AMPH group: F(7,119) = 5.82, p < .0001; Fig. 6]. A
dose of 20 mg/kg APO did not reverse the effect of HAL + AMPH in the
mPFC.
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Effect of QUIN on HAL Potentiation of AMPH-Stimulated DA Efflux in
the mPFC.
QUIN administration dose dependently attenuated the
potentiation by HAL administration of AMPH-stimulated cortical DA
release (Fig. 7). This attenuation was
significant at the 10.0 mg/kg quinpirole dose [significant drug × time interaction for the VEH/HAL/AMPH versus QUIN 10.0/HAL/AMPH
groups: F(7,70) = 2.46, p < .026].
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Discussion |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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The results of the present study demonstrate that, administered
individually, both the DA D2 antagonist HAL and the DA uptake blocker/releaser AMPH increase dialysate DA concentrations to a greater
degree in the anterolateral CP than the mPFC. When these agents were
combined, a potentiation was observed in both structures. This
potentiation was dependent on the dose of AMPH that was employed. In
both structures, this effect was attenuated by earlier administration of the nonspecific DA agonist APO. This effect was characterized in the
mPFC to be D2-like as the D2, D3, and D4 agonist QUIN dose dependently
attenuated it. These results are in agreement with previous findings
that the mesocortical DA system possesses D2-like inhibitory
release-regulating autoreceptors (Wolf and Roth, 1987). However, the
present work indicates that these mesocortical DA receptors may
normally be "silent" under basal conditions, and thus their
presence may not be revealed experimentally until DA release is stimulated.
Comparison of AMPH Effects in CP and mPFC
The primary
mechanism of inactivation of synaptic DA is the process of uptake back
into the presynaptic terminal through the DAT. Previous research has
shown that d-AMPH acts on the DAT protein to reverse its
direction so that DA is released instead of being taken up through this
site into the synapse (Liang and Rutledge, 1982). Uptake
blockers like cocaine may also increase dialysate DA concentrations,
but to a lesser degree than AMPH (Moghaddam and Bunney, 1989). The
majority of this work has been done in the striatum. However, several
in vitro and in vivo studies of the mPFC have demonstrated diminished
effects of uptake inhibitors on DA uptake and release in the prefrontal
cortex (Hadfield and Nugent, 1983; Izenwasser et al., 1990; Elsworth et
al., 1993; Wheeler et al., 1993; Cass and Gerhardt, 1995). One study
that compared the ventral striatum (nucleus accumbens) with the mPFC demonstrated that cocaine administration produced less of an increase in dialysate DA in the mPFC (Moghaddam and Bunney, 1989). These structures did not differ in the magnitude of response to AMPH. However, this latter finding does not conflict with the present results, because the dorsal striatum (CP) was studied here. Other work
has shown that DA efflux is more sensitive to AMPH administration in
the dorsal, relative to the ventral, striatum (Pehek et al., 1990). The
present study, employing three doses of AMPH in the unanesthetized rat,
clearly demonstrates that, over the dose range employed, anterolateral
dorsal striatal dialysate DA concentrations are more sensitive to AMPH
administration than prefrontocortical DA.
).
The dopaminergic innervation of the rat cortex is less dense than that
of the striatum. This diminished density of cortical DA axon terminals
is correlated with reductions in intracellular and dialysate DA
concentrations relative to the striatum (Hemby et al., 1992; Garris et
al., 1993). Corresponding to this, receptor autoradiographic studies
have demonstrated fewer DAT sites (Javitch et al., 1985; Mennicken et
al., 1992). Thus, the present reduced responsivity of the mPFC to AMPH
may, in part, simply reflect this diminished dopaminergic innervation.
However, recent work by Sesack and colleagues suggests that this
reduced responsivity to a DAT ligand may also reflect reduced numbers
of DAT sites per neuron in the mPFC (Sesack et al., 1998). This latter
study examined the cellular distribution of DAT antibodies in the rat and monkey. They determined that prefrontocortical DAT sites were largely extrasynaptic, both in absolute terms and relative to the
anterior cingulate cortex and the striatum. Quantitatively, there were
less DAT sites/neuron in the mPFC. Thus, the low DA innervation density
of the mPFC, in combination with sparse and mostly extrasynaptic DAT
sites, may result in a diminished capacity of this structure to respond
to drugs like AMPH, which act on these sites. Corresponding to this,
the peak effect of AMPH in the present study was delayed in the mPFC
relative to the CP (Fig. 2). Additionally, the decline in DA
concentrations post-AMPH was more gradual in the mPFC, perhaps
reflecting reduced clearance (see below).
The present diminished sensitivity of the mPFC to AMPH demonstrates a
functional in vivo correlate to the previous neurochemical and
neuroanatomical studies. It also agrees with other functional studies.
A reduced clearance of prefrontal DA has been demonstrated in an in
vivo electrochemical study measuring the disappearance of exogenously
applied DA (Cass and Gerhardt, 1995). These authors also found a
relatively small increase in DA concentrations after administration of
the DA uptake blocker nomifensine or GBR-12909. In contrast to
carrier-mediated release, other in vivo studies have shown that
K+-stimulated release may be augmented in the
mPFC relative to the CP (Moghaddam et al., 1990). This finding may also
result from decreased clearance of exocytotically-released DA from the
synapse secondary to a sparse, extrasynaptic localization of DAT sites. Other previous physiological and neurochemical findings such as increased rates of DA synthesis, DA turnover, and capacity to release
DA (Bannon and Roth, 1983; Garris et al., 1993) could also be related,
at least in part, to diminished DA uptake in the mPFC.
Comparison of HAL Effects in CP and mPFC.
In contrast to AMPH,
D2 antagonists like HAL are known to increase impulse-dependent DA
release in the striatum (Wolf et al., 1987). In the striatum, this has
been shown to result from the blockade of inhibitory D2-like nerve
terminal release-regulating and somatodendritic impulse-modulating DA
autoreceptors. HAL also antagonizes striatal inhibitory D2-like nerve
terminal synthesis-modulating autoreceptors, resulting in increased
synthesis of DA (Wolf et al., 1987). Mesocortical DA autoreceptors are
thought to be lacking, or less sensitive to, DA agonists (Bannon and
Roth, 1983). Specifically, it has been proposed that the mesocortical
system only possesses nerve terminal D2-like release regulating
autoreceptors. This autoreceptor subsensitivity, coupled with the
relative paucity of prefrontocortical D2 receptors (Gaspar et al.,
1995), may explain the present finding that basal DA is not augmented
significantly in the mPFC after systemic HAL administration. Thus,
under basal conditions, these cortical autoreceptors may be
"silent".
;
Yamamoto et al., 1994).
HAL + AMPH in CP.
In the striatum, there are a number of
studies demonstrating D2 antagonist potentiation of the effects of DA
uptake blockers on DA neurochemistry. Studies of tissue content have
shown that HAL administration increases DA metabolism
(dihydroxyphenylacetic acid concentrations) in both the striatum
and frontal cortex (McMillen, 1981). This effect was potentiated by
administration of the DA uptake blocker amfonelic acid.
). In this study, the additional presence of the D2
blocker eticlopride further potentiated DA synthesis in the striatum.
Thus, augmentation of DA synthesis may at least partially explain the
present potentiation of DA release by the coadministration of HAL and
AMPH in the CP.
In vivo microdialysis studies in the striatum have also demonstrated a
potentiation of dialysate DA levels by combined administration of a D2
antagonist and a DA uptake blocker. These studies include systemic
coadministration of sulpiride with AMPH (Sharp et al., 1986), HAL with
amfonelic acid (Gudelsky et al., 1992), and HAL with amfonelic acid or
GBR-12909 (Westerink et al., 1987). The results of the present study
are similar to those of Westerink and colleagues, who reported "a
strong synergistic rise of DA release". Tetrodotoxin
administration blocked this synergism, indicating a role for
impulse-dependent DA release (Westerink et al., 1987).
Intrastriatal administration of methamphetamine was also potentiated by
local application of sulpiride (Watanabe et al., 1989). The present
results demonstrate that this potentiation is also observed with the
combination of HAL and AMPH. Furthermore, DA receptor blockade was
implicated, as pretreatment with the nonspecific DA agonist APO
reversed the potentiation.
HAL + AMPH in mPFC.
Despite the present lack of effect of HAL
on basal mPFC DA, pretreatment before AMPH administration dramatically
potentiated the AMPH-induced release of cortical DA. This result was
similar to those previously reported in the striatum. Previous
electrophysiological reports have indicated that the mesocortical
system lacks both cell body impulse-regulating and nerve terminal
synthesis-regulating autoreceptors (Bannon and Roth, 1983). Thus, it is
unlikely that the HAL-induced potentiation in the mPFC resulted from
actions at the cell body level or on synthesis-regulating autoreceptors per se. Rather, research has indicated the presence of nerve terminal release-regulating autoreceptors in the mesocortical system (Cubeddu et
al., 1990; Gobert et al., 1996). Thus, it is likely that the present
results with HAL and AMPH resulted from actions on D2-like release-regulating autoreceptors. However, the present work considered alone cannot differentiate between these autoreceptor subtypes.
suggested that, because the mPFC lacks
synthesis-regulating autoreceptors, regulation of synthesis might be
achieved solely by end-product inhibition of tyrosine hydroxylase.
Thus, intracellular DA stores may normally act to decrease cortical DA
synthesis. However, blockade of D2-like release regulating inhibitory
autoreceptors would produce an increase in release and subsequent
decrease in intracellular stores of DA. This, in turn, may decrease
end-product inhibition and thereby increase the synthesis of DA, which
would provide additional substrate for AMPH to act upon. Thus, the
present HAL + AMPH potentiation in the mPFC may have resulted from
effects of release-regulating autoreceptors on AMPH-stimulated, but not
basal, cortical DA efflux. It is possible that these autoreceptors only
play an active role in the regulation of mesocortical DA release under
conditions of activation. Alternatively, these autoreceptors may
function tonically, but may fail to affect basal DA efflux as measured by microdialysis. Because the density of cortical D2 receptors is low,
blockade by HAL may slightly increase basal release, but below the
detection limits for microdialysis sampling.
Earlier administration of 2.0 mg/kg of the nonspecific DA agonist APO
reversed the present HAL-induced potentiation in the mPFC. This
suggests that the augmentation of DA release is mediated by DA
receptors, but does not indicate what type. Surprisingly, a higher dose
(20 mg/kg) did not reverse the effect of HAL in the mPFC (but did in
the CP). DA D1 receptors are more abundant than the D2 subtype in the
mPFC. This situation is reversed in the CP. Perhaps differential
effects of 20 mg/kg APO on contrasting D1/D2 receptor ratios explains
the contrasting effects of this dose in the two brain areas. However,
the present finding that pretreatment with QUIN attenuated the
HAL-induced potentiation in the mPFC implies that functional D2-like
autoreceptors are present in this structure and mediate the effects of
HAL pretreatment on AMPH-induced DA release. This is consistent with
earlier studies (Wolf et al., 1987).
Gobert and colleagues (Gobert et al., 1995; Gobert et al., 1996) have
provided neurochemical evidence that the mesocortical system contains
inhibitory D3 autoreceptors that are normally "silent" but are
activated under conditions of stimulated DA release. However, recent
findings with D3-knockout mice indicate that, while D3 receptors
modulate mesolimbic DA release, they do not serve as autoreceptors in
this DA system (Koeltzow et al., 1998). Rather, they may be part of a
short-loop feedback system. Whether or not the mesocortical system is
regulated in a similar manner remains to be determined. Because both
HAL and QUIN have appreciable affinities for D2, D3, and D4 receptors
(Seeman and Van Tol, 1994), the present findings can only suggest that
D2-like receptors modulate mPFC DA release.
Summary and Conclusions.
The present paper demonstrates a
diminished functional neurochemical effect of the DA releaser
d-AMPH on in vivo DA release in the rat mPFC relative to the
CP. This may be related to previous reports demonstrating decreased DA
innervation and numbers of DAT sites as well as a predominant
extrasynaptic localization of these sites. Confirming previous reports,
there was also a diminished neurochemical effect of the D2 antagonist
HAL on dialysate DA concentrations. This may be related to the
relatively low D2-receptor density in the mPFC. However, the present
results support the existence of D2-like autoreceptors that may
normally be "silent" under basal conditions. Based on previous work
by others, it is likely that these autoreceptors regulate release of
mesocortical DA (Cubeddu et al., 1990, Gobert et al., 1996, Wolf et
al., 1987). When DA release was stimulated by AMPH, earlier blockade of
these autoreceptors by HAL administration resulted in a dramatic
potentiation of AMPH-stimulated DA release in the mPFC and CP. In both
structures, blockade of release-inhibition may decrease the
intracellular pool of DA and thus decrease end-product inhibition of DA
synthesis. DA synthesis may then be augmented, resulting in increases
in newly synthesized DA, which have been shown to be released
preferentially by AMPH (Chiveh and Moore, 1975). This
augmentation of intracellular DA, the substrate for AMPH, may explain
the greater than additive effects of a D2 antagonist and a drug acting
on DAT sites. As suggested by Cass and Gerhardt (1995), synaptic
concentrations of prefrontocortical DA may be regulated more by
modulation of release than uptake.
). Collectively, these findings may have important functional implications in the mPFC, where dopaminergic activity is thought to regulate emotion, cognition, and responses to stress and psychostimulants.
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Acknowledgments |
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I thank Melanie Schaldach for her excellent technical assistance.
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Footnotes |
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Accepted for publication October 20, 1998.
Received for publication June 29, 1998.
1 This work was supported by grants from the Pharmaceutical Manufacturers Association Foundation and the National Institutes of Mental Health (MH52220) to E.A.P. and by the Medical Research Service at the Cleveland Veterans Affairs Medical Center.
Send reprint requests to: Elizabeth A. Pehek, Ph.D., Psychiatry Service 116A(B), Veterans' Affairs Medical Center, 10000 Brecksville Rd., Brecksville, OH 44141. E-mail: eap6{at}po.cwru.edu
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Abbreviations |
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AMPH, amphetamine; APO, apomorphine; CP, caudate-putamen; DA, dopamine; DAT, dopamine transporter; haloperidol, HAL; mPFC, medial prefrontal cortex; QUIN, quinpirole.
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References |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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