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Vol. 285, Issue 1, 143-154, April 1998
Department of Medicinal Chemistry (B.H.C.W., J.F., J.B.D.) University Center for Pharmacy, University of Groningen, Groningen, The Netherlands and Institute of Pharmacology (P.E.), University of Sassari, Sassari, Italy
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Abstract |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Receptor-specific compounds were applied by retrograde microdialysis to
the ventral tegmental area (VTA) of the rat brain. The effects of
intrategmental infusions on extracellular dopamine in the ipsilateral
prefrontal cortex (PFC) were recorded with a second microdialysis
probe. Intrategmental infusion of tetradotoxin (1 µM), muscimol (20 µM) or baclofen (50 µM) decreased extracellular dopamine in the
PFC. Infusion of N-methyl-D-aspartate (NMDA) (300 µM; 1 mM, 15 min) or kainate (50 µM, 15 min) increased extracellular dopamine in the PFC. The effects of the excitatory amino acids were
suppressed by co-infusion with
(±)-3(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (300 µM),
with (±)-2-amin-5-phosphonopentanoic acid (500 µM), with dizocilpine
maleate (500 µM) (partly) or with
6-cyano-7-nitroquinoxaline-2,3-dione (500 µM) (partly).
Intrategmental infusion of carbachol (50 µM) increased extracellular
dopamine in the PFC. These results provide evidence for the
localization of GABAA, GABAB, NMDA, non-NMDA and cholinergic receptors on mesocortical neurons in the VTA. Intrategmental infusion of AP-5, (±)-2-amino-5-phosphonopentanoic acid
(500 µM), of (±)-3(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid
(300 µM), of (+)-3-amino-1-hydroxy-2-pyrrolidone (1 mM) and of
6-cyano-7-nitroquinoxaline-2,3-dione (500 µM) decreased extracellular dopamine in the PFC. Infusion of mecamylamine, of atropine, and of
3-[[(3,4)-dichlorophenyl)methyl]propyl](diethoxymethyl) phosphonic acid into the VTA did not modify extracellular dopamine in the PFC.
Infusion of bicuculline (50 µM) and that of (
)-sulpiride (50 µM)
were followed by an increase in extracellular dopamine in the PFC.
These data suggest that mesocortical dopamine neurons, at the level of
the VTA, are tonicly excitated by glutamatergic neurons by acting on
NMDA and non-NMDA receptors and are tonicly inhibited by GABA and
dopamine by acting on GABAA and D2 receptors, respectively. No tonic stimulation by cholinergic neurons was detected.
The effects on mesocortical neurons and earlier published data on
mesolimbic and nigrostriatal dopamine neurons are compared and
discussed.
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Introduction |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Mesocortical
dopamine (A10) neurons originate in the VTA of the brain stem and
innervate the PFC. Various authors have emphasized that mesocortical
dopamine neurons play an important role in the mediation of cognitive
and affective functions (Fibiger and Phillips, 1986
; Sachs and Meisel,
1988; Le Moal and Simon, 1991; Blackburn et al., 1992). Both
rewarding and stressful conditions stimulate dopamine release in the
PFC, which suggests that mesocortical dopamine neurons are involved in
emotional arousal, irrespective of its aversive or nonaversive nature
(Imperato et al., 1991).
The antipsychotic effects of dopamine blockers are believed to exert their effects on prefrontal cortical dopamine release. It is very important, in the development of new antipsychotic drugs, whether these compounds exert a selective action on the release of dopamine in the PFC. For this purpose a comparison with other dopaminergic forebrain structures, such as nucleus accumbens and striatum, is crucial.
Because less than 10% of the VTA dopamine neurons project to the PFC,
these neurons are difficult to discern by electrophysiologic means from
A10 neurons that project to the nucleus accumbens. Therefore, compared
with what we know about the mesolimbic and striatal dopamine neurons,
our knowledge of the pharmacology of mesocortical dopamine neurons is
still limited. An alternative way to study the mesocortical A10 neurons
is to use dual-probe microdialysis (Karreman et al., 1996;
Santiago and Westerink, 1991, 1992; Wang et al., 1994;
Westerink et al., 1992, 1996). In the present study, we
applied dual-probe microdialysis to the mesocortical dopamine neurons.
One probe was implanted in the VTA, and a second probe was placed in
the ipsilateral PFC. Receptor-specific compounds were infused into the
VTA, whereas extracellular dopamine was recorded in the ipsilateral
PFC.
Three issues were investigated:
| 1. | Identification of receptors that modify the activity of mesocortical dopamine neurons at the somatodentritic level. |
| 2. | The participation of afferents in the tonic regulation of the mesocortical dopamine neurons. |
| 3. | A comparison among the mesocortical, mesolimbic and nigrostriatal dopaminergic systems. |
On the basis of earlier studies (for review see Kalivas, 1993), we
investigated three different neuronal pathways that are well known to
send efferents to the VTA. These pathways consists of GABAergic,
glutamatergic and cholinergic neurons. Six different types of receptor
interactions were studied: GABAA, GABAB, NMDA, non-NMDA, D2 and cholinergic.
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Materials and Methods |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Animals, drug treatment and doses. Male albino rats of a Wistar-derived strain (275-320 g) (Harlan, Zeist, The Netherlands) were used for the experiments. The rats were housed at most eight to a cage (40 × 25 × 55 cm) with light from 7 A.M. until 7 P.M. and food and water ad libitum.
The following drugs and chemicals were kindly provided by or obtained from the sources indicated: atropine, AP-5, (±)-baclofen, ()-bicuculline methchloride, carbachol, CPP, (+)-HA966, kainate, CNQX, mecamylamine, HCl, NMDA, (+)-MK-801, muscimol (Research Biochemicals International, Natick, MA), TTX (Sigma, St. Louis, MO) and
()-sulpiride (Ravizzi, Milano, Italy) and CGP 52432 (Ciba Geigy,
Basel, Switzerland). All drugs were dissolved in the perfusion fluid
and infused via retrograde microdialysis into the VTA.
Infused doses were based on earlier studies on related experiments
(Santiago and Westerink, 1991, 1992; Westerink et al., 1992,
1996).
The experiments were approved by the Animal Care Committee of the
Faculty of Mathematics and Natural Science of the University of
Groningen.
Surgery and brain dialysis.
Microdialysis was performed with
two I-shaped cannulas. Polyacrylonitrile/sodium methalyl sulfonate
copolymer (I.D. 0.22 mm, O.D. 0.31 mm; AN 69, Hospal, Bologna, Italy)
was used as the dialysis membrane. One probe (exposed length 1 mm) was
implanted into the VTA, and the second probe (exposed length 4 mm) was
implanted into the ipsilateral PFC. Drugs were infused into the brain
via the VTA probe, and the PFC probe was used to record
extracellular dopamine. Coordinates of the implantation were A/P 3.0, L/M 1.2, and V/D 5.0 (for the PFC) and A/P 5.3, L/M 0.9 and V/D
8.0 (for the VTA) from bregma point and dura. The probes were
implanted during general chloralhydrate anesthesia (400 mg/kg i.p.) and local lidocaine (10%) anesthesia. Rats were placed in individual perspex cages (25 × 25 × 25 cm) in which they had free
access to food and water.
.
Chemical assays.
Dopamine was quantified by HPLC with
electrochemical detection. A Shimadzu (LC-10AD) pump was used in
conjunction with an electrochemical detector (ESA Coulochem II) with a
Coulochem 5011 detector cell, potential first electrode +200 mV,
potential second electrode 250 mV). A reverse-phase column (Supelco
LC18; 150 × 4.7 mm) was used. The mobile phase consisted of a
mixture of 0.1 mol/l sodium acetate adjusted to pH 4.1 with acetic
acid, 1.8 mmol/l octanesulfonic acid, 0.3 mmol/l Na2EDTA
and 120 ml methanol/l H2O at a flow of 1.0 ml/min. The
detection limit of the assay was about 1 fmol per sample (on-column).
Expression of results and statistics. All values given are expressed as percentages of controls. The average concentration of three stable base-line samples (less than 10% variation) was considered as the control and was defined as 100%. Data were analyzed by nonparametric repeated measurement one-way ANOVA on ranks (Friedman's test), followed by the Dunnett's multiple comparisons test when appropriate. Individual time-points of two time-effect curves were compared with Mann-Whitney ranked sum test. The level of significance was set at P < .05.
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Results |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Basal values. The average basal values of dopamine in dialysates of the PFC for the different experiments did not differ significantly. Therefore, they are grouped together. Basal values (± S.D.) were 0.71 ± 0.42 fmol/min.
Effect of infusion of TTX into the VTA on the dialysate content of
dopamine in the ipsilateral PFC.
TTX infused in a concentration of
1 µmol/l into the VTA decreased extracellular dopamine in the
ipsilateral PFC to about 20% of controls (fig.
1). This decrease was statistically
significant (
211 = 32.8; P < .0001;
n = 5). This effect can be used as a functional test of
proper implantation of the probe. The TTX effect demonstrates that the
two probes are properly implanted with respect to the mesocortical
dopaminergic pathway. Occasionally some turning behavior was noticed
during TTX infusion.
|
Effect of infusion of muscimol and bicuculline into the VTA on the
dialysate content of dopamine in the ipsilateral PFC.
The
GABAA agonist muscimol was infused via the
microdialysis probe into the VTA in concentrations of 20 µmol/l. The
infusions caused a decrease in extracellular dopamine in the PFC to
about 60% of controls (fig. 2). This
decrease was statistically significant (27 = 39.3; P < .0001; n = 6). The decrease in
extracellular dopamine reached statistical significance 30 min after
the start of the infusion.
|
28 = 35.3; P < .0001;
n = 5). The rise in extracellular dopamine reached
statistical significance 30 min after the start of the infusion.
Bicuculline infusion occasionally caused some behavioral activation.
|
Effect of infusion of baclofen and CGP 52432 into the VTA on the
dialysate content of dopamine in the ipsilateral PFC.
The
GABAB agonist D,L-baclofen was infused into the
VTA in a concentration of 50 µmol/l. The GABAB agonist
caused an decrease of extracellular dopamine in the ipsilateral PFC to
about 60% of controls (fig. 4). This
decrease was statistically significant (27 = 107.9; P < .0001; n = 20) and was used as
functional test for proper implantation of the probes. The decrease was
statistically significant 30 min after the start of the infusion.
|
),
did not modify extracellular dopamine in the PFC (results not shown).
Effect of infusion of NMDA, CPP, AP-5, MK-801 and (+)-HA-966 into
the VTA on the dialysate content of dopamine in the ipsilateral
PFC.
NMDA was infused into the VTA in a concentration of 1 mmol/l.
Because NMDA caused strong behavioral activation, the infusion period
was restricted to 15 min. The extracellular dopamine in the ipsilateral
PFC increased to about 210% of controls (fig. 5). This increase was statistically
significant (28 = 50.9; P < .0001;
n = 8). The rise in dopamine reached statistical significance 15 min after the start of the infusion.
|
213 = 32.6; P = .002;
n = 4). During infusion of CPP, the effects of NMDA on
extracellular dopamine in the PFC, as well as its effects on behavior,
were fully blocked.
|
213 = 36.5; P = .0005;
n = 4). During infusion of AP-5, the effects of NMDA on
extracellular dopamine in the PFC, as well as its effects on behavior,
were fully blocked.
|
26 = 21.9; P = .057; n = 4). The NMDA-induced increase seen after t = 90 min was statistically significant
(27 = 25.5; P = .001, n = 4). Co-infusion of 1 mmol/l (+)-MK-801 and NMDA (300 µmol/l) partly
blocked the increase in extracellular dopamine in the PFC. During
infusion of (+)-MK-801, the effects of NMDA on behavior were not
blocked.
|
26 = 13.6; P = .035;
n = 4). Infusion of NMDA (300 µmol/l) in the presence
of 1 mmol/l (+)-HA-966 increased extracellular dopamine in the PFC to
157% of controls. However, when this effect was corrected for the
decrease in basal values (to 79% of controls), the suppression by
(+)-HA-966 of the stimulation by NMDA did not reach statistical
significance. (+)-HA-966 also did not modify the behavioral effects of
NMDA infusion. We conclude that although intrategmentally infused
(+)-HA-966 decreased basal values of extracellular dopamine in the PFC,
the compound was unable to block the NMDA-induced stimulation of
dopamine.
|
Effect of intrategemental infusion of NMDA during halothane
anesthesia on extracellular dopamine in the ipsilateral PFC.
Because NMDA infusion caused strong behavioral activation, we
investigated whether indirect stress effects were implicated in the
stimulation of dopamine release in the PFC. When NMDA (1 mmol) was
infused into the VTA during halothane anesthesia, extracellular dopamine in the PFC increased to about 210% of controls (fig. 10). This effect was statistically
significant (28 = 24.8; P = .0017;
n = 4) and comparable to the effects seen in
nonanesthetised animals. Halothane itself did not affect extracellular dopamine (results not shown).
|
Effect of infusion of kainate and CNQX into the VTA on
extracellular levels of dopamine in the ipsilateral PFC.
Kainate
was infused into the VTA in a concentration of 30 µmol/l. Because
kainate caused behavioral activation, the infusion period was
restricted to 15 min. The extracellular dopamine in the ipsilateral PFC
increased to about 195% of controls (fig. 11). This increase was statistically
significant (28 = 64.3; P < .0001;
n = 10). The rise in dopamine reached statistical significance 15 min after the start of the infusion.
|
26 = 19.3; P = .037; n = 4). When kainate was co-infused with CNQX, the rise in extracellular
dopamine in the PFC was suppressed. The suppression was statistically
evaluated after the dopamine values at 90 min were reset as 100%. The
suppression by kainate reached statistical significance at
t = 120 min. We conclude that the effects of kainate on
extracellular dopamine in the PFC are partly blocked by CNQX.
|
Effect of intrategmental infusion of kainate during halothane
anesthesia on extracellular dopamine in the ipsilateral PFC.
Because intrategmental infusion of kainate caused a behavoral
activation, we investigated whether indirect stress effects were
implicated in the stimulation of dopamine release in the PFC. When
kainate (30 µmol) was infused into the VTA during halothane anesthesia, extracellular dopamine in the PFC increased to about 200%
of controls (fig. 13). This increase
was statistically significant (28 = 26.3;
P < .001; n = 4) and comparable to the effect of
kainate infusion seen in control rats. Halothane itself did not modify extracellular dopamine in the PFC (data not shown).
|
Effect of infusion of carbachol, atropine and mecamylamine into the
VTA on the dialysate content of dopamine in the ipsilateral PFC.
The cholinomimetic compound carbachol was continuously infused into the
VTA in a concentration of 50 µmol/l. Carbachol caused an increase of
extracellular dopamine in the ipsilateral PFC to about 150% of
controls (fig. 14)
(28 = 23.6; P = .003; n = 4). The increase in dopamine reached statistical significance 45 min
after start of the infusion of carbachol. The muscarinic antagonist
atropine and the nicotinic antagonist mecamylamine, both infused in a
relatively high concentration of 100 µmol/l, were without effect on
the ipsilateral concentration of dopamine in the PFC (data not shown).
|
Effect of infusion of ()-sulpiride into the VTA on the dialysate
content of dopamine in the ipsilateral PFC.
The specific
D2 antagonist ()-sulpiride, infused into the VTA in a
concentration of 50 µmol/l, induced an increase in extracellular dopamine in the ipsilateral PFC to about 160% of controls. This increase was statistically significant (27 = 32.1; P < .0001; n = 5). The increase in
extracellular dopamine reached statistical significance 30 min after
the start of the sulpiride infusion (fig.
15).
|
Comparison of mesocortical, mesolimbic and nigrostriatal
neurons.
For comparison of the present data with those generated
in other studies, we have indicated the results from mesolimbic and nigrostriatal experiments in the various figures. Data were taken from
earlier dual-probe microdialysis studies (Santiago and Westerink, 1991,
1992; Westerink et al., 1992, 1996).
)-sulpiride into the substantia nigra or VTA induced a
rise in extracellular dopamine in the PFC that was somewhat more
pronounced than the increases seen in the mesolimbic and nigrostriatal
dopamine neurons. This difference reached statistical significant
difference 75 min after the start of the infusion (indicated in fig.
15).
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Discussion |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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GABA, glutamate and ACh receptors in the VTA.
Infusion of the
GABAA agonist muscimol and the GABAB agonist
baclofen into the VTA clearly decreased extracellular dopamine in the
ipsilateral PFC. These findings indicate the presence of GABAA as well as GABAB receptors on
somatodendritic sites of mesocortical dopamine neurons. The
localization of both types of GABA receptors on dopamine cell bodies in
the VTA is supported by anatomical data (Bayer and Pickel, 1991) and by
electrophysiologic studies based on brain slices (Johnson and North,
1992; Jiang et al., 1993; Seutin et al., 1994).
; 1992; Westerink et al., 1992;
1996), a significant difference emerges with respect to the
participation of GABAA receptors. Although the stimulatory effect of bicuculline was very similar for the three dopamine systems
studied, muscimol stimulated the A9 neurons but inhibited the A10
neurons. Although there are some differences in methodology in terms of
probe length and perfusion time when VTA and substantia nigra probes
are compared, it is unlikely that they could contribute to the observed
qualitative differences between the A9 and A10 neurons. Stimulation of
nigrostriatal neurons after intranigral administration of GABA receptor
agonists has been described by various authors, and some speculate that
a second inhibitory interneuron located in the A9 participates in the
GABAergic striatonigral pathway (Leviel et al., 1979; Grace
and Bunney, 1979). Apparently it is not necessary to postulate such an
interneuron in the GABAergic regulation of both types of A10 dopamine
neurons. The finding that muscimol interacts in opposite ways with the
two dopamine systems is of theoretical interest, because it opens the
possibility of discriminating pharmacologically between
mesolimbic-mesocortical and striatal dopamine neurons. Mesocortical
neurons seem to be somewhat less sensitive to GABAB
stimulation than are mesolimbic and nigrostriatal neurons.
Infusion of the glutamate receptor agonists NMDA and kainate into the
VTA induced a pronounced increase in extracellular dopamine in the PFC.
The stimulation by NMDA was fully suppressed during co-infusion of the
competitive antagonist CPP or AP-5. However, the noncompetitive
antagonist MK-801 was less effective, and (+)-HA-966, a potent
inhibitor of the glycine site of the NMDA receptor, even infused in
high concentrations (1 mmol/l) did not inhibit the effect of NMDA
stimulation. The finding that MK-801 did not affect the NMDA-induced
behavior could be explained if the compound by itself induced
behavioral activation. The enhancement of extracellular dopamine in the
PFC after kainate infusion in the VTA was partly blocked by CNQX. This
could be explained by the limited potency of CNQX as a non-NMDA
receptor antagonist. Interestingly all glutamate receptor antagonists,
including CNQX, decreased basal values of extracellular dopamine in the
PFC. A similar tendency, but much less pronounced, was observed during
dual-probe experiments on mesolimbic dopamine neurons (Karreman
et al., 1996; Westerink et al., 1996). The
finding that MK-801 and HA-966, at the high doses used, either did not
block or hardly blocked the effect of NMDA infusion was unexpected. The
fact that the two antagonists clearly modified the basal values in the
PFC argues against a poor penetration efficiency of the drugs from the
dialysis probe. Apparently it is easier to antagonize the basal
activity of the tonic glutamatergic excitation than to block the
pharmacologically enhanced activity (with the competitive antagonists
an exception).
During intrategmental infusion of NMDA and kainate, we noted behavioral
activation such as grooming and turning. Numerous studies have shown
that stress stimulates dopamine release in the PFC. The reported
stress-induced increase in extracellular dopamine in the PFC is in the
same range as seen after intrategmental NMDA or kainate infusion
(Abercrombie et al., 1989). We therefore investigated
whether induction of stress during infusion of the glutamate agonists
might have indirectly induced an increase in extracellular dopamine in
the PFC. We did this by repeating the NMDA and kainate infusions in
anesthetised animals. Because the anesthetised animals showed similar
responses to the conscious rats, we concluded that stress effects
probably did not contribute to the observed effects.
Taken together, the present data clearly indicate that NMDA as well as
non-NMDA receptors are present on somatodendritic sites of mesocortical
dopamine neurons. This conclusion is consistent with electrophysiologic
studies that have provided evidence for the presence of NMDA and
non-NMDA on dopamine cell bodies in the VTA (Seutin et al.,
1990; Johnson and North, 1992; Johnson et al., 1992; Wang
and French 1993; Zhang et al., 1994). It should be noted
that the latter studies could not discriminate between mesolimbic and
mesocortical A10 neurons.
On the basis of local injection and post-mortem tissue analysis, it has
been speculated that the NMDA receptor subtype modulates mesocortical
dopamine neurons, whereas the non-NMDA subtype regulates mesolimbic
neurons (Kalivas et al., 1989). The latter conclusion is not
supported by the present data, because NMDA infusions and kainate
infusions induced comparable increases in extracellular dopamine in the
PFC; moreover, NMDA antagonists and the non-NMDA antagonist decreased
extracellular dopamine in the PFC to a similar degree (80%-75% of
controls). However, the present data clearly indicate that A10 dopamine
neurons are more responsive than A9 neurons to NMDA as well as non-NMDA
receptor stimulation.
The marked increase in extracellular dopamine in the PFC during
infusion of carbachol into the VTA illustrates the ability of
cholinergic afferents to stimulate mesocortical dopamine cells at the
level of the VTA. This result is consistent with a recent electrophysiological study showing that dopamine neurons in the VTA
were excited by carbachol (Seutin et al., 1990).
Electrophysiologic studies on brain slices indicated the presence of
muscarinic as well as nicotinic receptors on dopamine cell bodies in
the VTA (Calabresi et al., 1989; Lacey et al.,
1990). Because carbachol is a nonspecific agonist, additional
experiments are needed to interpret this effect in terms of muscarinic
or nicotinic receptors.
Although the various experiments clearly indicated the presence of
GABAergic, glutamatergic, cholinergic and dopamine receptors on
mesocortical neurons in the VTA, we cannot, by the present methodology,
rule out the possibility that certain indirect effects participated in
the observed changes in extracellular dopamine in the PFC.
Tonic regulation of the activity of mesocortical dopamine
neurons.
Regarding the tonic regulation of mesocortical dopamine
neurons, the results of the infusion of a series of receptor-specific antagonists are meaningful. Indeed, both NMDA antagonists and non-NMDA
antagonists decreased the extracellular dopamine in the ipsilateral PFC
to about 80% to 75% of controls. These results indicate that
glutamatergic projections to the VTA play a significant role in the
tonic excitation of mesocortical dopamine neurons. It has been
suggested that glutamatergic pathways projecting to the midbrain
dopamine neurons induce burst firing in A10 neurons. However, results
of studies on the administration of competitive glutamate antagonists
are controversial. Some authors report an inhibition of the burst
firing of A10 neurons by glutamate antagonists (Charlety et
al., 1991; Overton and Clark, 1992; Chergui et al., 1993), but French et al. (1993) found no effect of the
systemic administration of competitive glutamate antagonists on the
firing rate or firing pattern of the A10 neurons. The present data
indicate that mesocortical neurons display a greater sensitivity than
mesolimbic neurons to glutamate antagonists (Karreman et
al., 1996; Westerink et al., 1996); this finding could
account, in part, for the discrepant reports on this matter.
). The
present data suggest that any such mechanism is restricted to
GABAA receptors.
Intrategmental infusion of high concentrations of the muscarinic
agonist atropine and that of the nicotinic antagonist mecamylamine were
without effect on extracellular dopamine in the PFC. These findings
support the notion that the mesolimbic dopamine system is phasically
rather than tonicly regulated by cholinergic receptor activation within
the VTA. Infusions of carbachol revealed that the three types of
dopamine neurons all receive a cholinergic input. Mesocortical dopamine
neurons displayed a higher sensitivity for ACh receptor stimulation
than did mesolimbic and nigrostriatal neurons.
Finally, we infused ()-sulpiride in a dose that is effective in
maximally blocking D2 receptors (Santiago and Westerink, 1991). From the observed increase in extracellular dopamine in the
ipsilateral PFC, we conclude that D2 autoreceptors at
somatodendritic sites of mesocortical neurons participate in tonic
autoinhibition under control conditions. Infusions of sulpiride
revealed that the three types of dopamine neurons all contain
D2 autoreceptors. Mesocortical dopamine neurons displayed a
higher sensitivity for D2 receptor stimulation than did
mesolimbic and nigrostriatal neurons.
In conclusion. The results of the present study support the following conclusions:
| 1. | The dual-probe microdialysis approach is a sensitive and unique method of studying the pharmacology of mesocortical dopamine neurons. |
| 2. | GABAA, GABAB, NMDA, non-NMDA, cholinergic receptors and D2 autoreceptors are functionally present at somatodentritic sites of mesocortical dopamine neurons. |
| 3. | Mesocortical dopamine neurons are tonicly excitated by glutamatergic neurons via NMDA receptors as well as non-NMDA receptors. |
| 4. | Mesocortical dopamine neurons are tonicly inhibited by GABAergic neurons acting via GABAA receptors and D2 autoreceptors. |
| 5. | No tonic stimulation by cholinergic neurons or inhibition by GABAeric neurons acting via GABAB receptors could be demonstrated on the mesocortical neurons. |
| 6. | Mesocortical neurons are less sensitive to GABAB stimulation than are mesolimbic or nigrostriatal dopamine neurons. |
| 7. | Compared with nigrostriatal and mesolimbic dopamine neurons, mesocortical neurons are more responsive to stimulation of cholinergic receptors and inhibition of D2 autoreceptors. |
| |
Footnotes |
|---|
Accepted for publication December 29, 1997.
Received for publication May 27, 1997.
Send reprint requests to: Dr. B.H.C. Westerink, University Centre for Pharmacy, University of Groningen, Deusinglaan 1, 9713 AV Groningen, The Netherlands.
| |
Abbreviations |
|---|
VTA, ventral tegmental area; PFC, prefrontal cortex; TTX, tetradotoxin; (+)-HA966, (+)-3-amino-1-hydroxy-2-pyrrolidone; AP-5, (±)-2-amino-5-phosphonopentanoic acid; CPP, (±)-3(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid; (+)-HA966, (+)-3-amino-1-hydroxy-2-pyrrolidone; CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione; NMDA, N-methyl-D-aspartate; (+)-MK-801, dizocilpine maleate; CGP 52432, 3-[[(3, dichlorophenyl)methyl]propyl](diethoxymethyl) phosphonic acid.
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References |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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R. Ventura, A. Alcaro, and S. Puglisi-Allegra Prefrontal Cortical Norepinephrine Release Is Critical for Morphine-induced Reward, Reinstatement and Dopamine Release in the Nucleus Accumbens Cereb Cortex, December 1, 2005; 15(12): 1877 - 1886. [Abstract] [Full Text] [PDF]
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F. Georges and G. Aston-Jones Activation of Ventral Tegmental Area Cells by the Bed Nucleus of the Stria Terminalis: A Novel Excitatory Amino Acid Input to Midbrain Dopamine Neurons J. Neurosci., June 15, 2002; 22(12): 5173 - 5187. [Abstract] [Full Text] [PDF]
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H. E. Melikian and K. M. Buckley Membrane Trafficking Regulates the Activity of the Human Dopamine Transporter J. Neurosci., September 15, 1999; 19(18): 7699 - 7710. [Abstract] [Full Text] [PDF]
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). Data on a similar experiment carried out in the mesolimbic
pathway (Westerink et al., 1996
)
(expressed as percent of basal values ± S.E.M.). The control NMDA
infusion is shown with closed circles. * P < .05 vs.
t = 90 min; # P < .05 vs. t = 30 min.
