Vol. 285, Issue 1, 350-357, April 1998

Dopaminergic Regulation of Extracellular -Aminobutyric Acid Levels in the Prefrontal Cortex of the Rat¹

Departments of Pharmacology and Psychiatry, Yale University School of Medicine, New Haven, Connecticut and Psychiatry Service, Department of Veterans Affairs Medical Center, West Haven, Connecticut

	Abstract

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Dopaminergic axons in the prefrontal cortex synapse with interneurons as well as pyramidal cells. Electrophysiological data suggest that dopamine depolarizes certain -aminobutyric acid (GABA)-containing interneurons in the cortex. We investigated the dopaminergic regulation of extracellular GABA levels in the prefrontal cortex using in vivo microdialysis. Systemic administration of the mixed D₁/D₂ dopamine receptor agonist apomorphine increased extracellular GABA levels in the prefrontal cortex, but did not increase levels of glycine; the apomorphine-elicited increase in GABA levels was blocked by tetrodotoxin infusion into the prefrontal cortex. Local administration of the D₂ agonist quinpirole into the cortex via the dialysis probe resulted in a dose-dependent increase in extracellular GABA levels. In contrast, administration of the D₁ agonist SKF 38393 did not alter GABA levels. The ability of systemic apomorphine to increase extracellular GABA levels in the prefrontal cortex was blocked by local administration of the D₂-like antagonist sulpiride to the cortex, but was not attenuated significantly by local perfusion of the D₁ antagonist SCH 23390. Similarly, the ability of local infusion of the D₂ agonist quinpirole to enhance extracellular GABA levels was blocked by sulpiride but not by SCH 23390. These data suggest that dopamine agonists increase the release of GABA in the prefrontal cortex through a D₂-like receptor. In view of posited changes in prefrontal cortical dopamine and GABA systems in schizophrenia, it is possible that changes in GABAergic function in the cortex in schizophrenia are secondary to changes in cortical dopamine function.

	Introduction

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The medial PFC of the rat receives dopaminergic afferents from the mesencephalic ventral tegmental area (Fuxe et al., 1974; Swanson, 1982). Within the PFC, the major target of DA axons is the pyramidal cell (Goldman-Rakic et al., 1989; Seguela et al., 1988; van Eden et al., 1987). More recent studies indicate that DA axons also synapse onto GABA-containing interneurons in the PFC (Sesack et al., 1995; Smiley and Goldman-Rakic, 1993; Verney et al., 1990). Because a single GABA interneuron may synapse with hundreds of pyramidal cells (DeFelipe et al., 1985; Freund et al., 1983), local circuit neurons play a critical role in regulating pyramidal cell function and thus cortical output.

Electrophysiological studies have revealed that monoamines, including DA, excite interneurons in the PFC and other cortical regions (Gellman and Aghajanian, 1993; Penit-Soria et al., 1987; Sheldon and Aghajanian, 1990). Intracellular and whole-cell recordings from cortical interneurons indicate that monoamines depolarize these cells (Gellman and Aghajanian, 1994; Marek and Aghajanian, 1994; Yang et al., 1997; Zheng et al., 1997). Bath application of monoamines (including DA or DA agonists) to cortical slices induces bicuculline-sensitive inhibitory postsynaptic potentials in pyramidal cells in the PFC (Aghajanian, 1994; Penit-Soria et al., 1987) and pyriform cortex (Sheldon and Aghajanian, 1990), and recent in vitro data indicate that low concentrations of DA depolarize certain PFC interneurons (Yang et al., 1997; Zheng et al., 1997; Charles Yang, personal communication; Wei-Xing Shi, personal communication). Consistent with the suggestion that monoamines increase GABA release from interneurons is a recent report that norepinephrine increases extracellular GABA levels in the feline visual cortex (Shirokawa and Ogawa, 1994). There have been no corresponding studies of dopaminergic regulation of extracellular GABA levels in the PFC.

In vitro studies have demonstrated that DA agonists enhance basal [³H]GABA release from PFC slices (Retaux et al., 1991). Conversely, antipsychotic drugs that are D₂ receptor antagonists decrease extracellular GABA levels in the PFC in vivo (Bourdelais and Deutch, 1994), and lesions of the ventral tegmental area decrease expression of GAD₆₇ mRNA in the PFC (Retaux et al., 1994). Thus, available pharmacological data are consistent with the hypothesis that DA afferents to the PFC excite interneurons and thereby induce the release of GABA.

However, there have been no pharmacological studies that characterize in vivo the dopaminergic regulation of cortical GABA neurons. In vitro studies have yielded important information concerning the regulatory mechanisms controlling PFC neurons, but do not directly address the role of afferent regulation over these neurons. Because the activity of cortical neurons is critically determined by afferent regulation as well as properties intrinsic to the cell, we undertook a series of studies examining the role of DA agonists on extracellular GABA levels in the PFC, using in vivo microdialysis in the freely-moving rat.

	Methods

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Surgical procedures. Adult male Sprague-Dawley rats (260-300 g; Camm, Wayne, NH) were group housed on a 12:12 light/dark cycle with lights on at 0600 h. Food and water were available ad libitum. Animals were deeply anesthetized with Equithesin (chloral hydrate/pentobarbital, 0.35 ml/100g b.wt.) and bilateral guide cannulae (20 g) implanted in the PFC (coordinates AP: +3.0, L: ± 2.1, DV: 2.3 from skull surface at bregma, implanted at a 17° angle from vertical). For animals scheduled to receive systemic drug administration, a catheter constructed from microbore Teflon tubing (Small Parts, Inc.; Miami Lakes, FL) was implanted subcutaneously in the intrascapular space. All animal experimentation was performed in accord with the "NIH Guide for the Care and Use of Laboratory Animals."

Microdialysis procedure. Concentric microdialysis probes were constructed as described by Bourdelais and Deutch (1994). Stainless steel tubing (26 g) was affixed to 3.5 mm of dialysis membrane (Spectrophor 240 µm OD cellulose fiber, 13 kdalton cutoff) obtained from Spectrum Medical Industries (Los Angeles, CA). The ventral 0.5 mm of the membrane was occluded, thus leaving an exchange length of 3.0 mm.

Five to seven days after surgery, the animals were removed from their home cage and placed in the dialysis chamber (30.5 × 30.5 cm floor surface). The microdialysis probes were inserted gently into the PFC through the guide cannulae and perfused with ACSF as described by Moghaddam and Bunney (1989), with the addition of 5 mM d-glucose (Fink and Gothert, 1993). ASCF flow through the probe was set at 0.12 µl/min overnight, and increased to 2.0 µl/min the next morning. After a 60-min equilibration period, samples were collected every 20 min. The first four or five samples were used to determine base-line values, after which drugs were administered. Dialysis solutions were switched from normal ACSF to drug-containing solutions manually, proximal to the swivel; ACSF delivery for vehicle (control)-treated animals also was switched to ensure comparability. Data presented are corrected for calculated delivery to the dialysis probe.

Drug treatments. The effects of both systemic and local administration of DA agonists on prefrontal cortical extracellular GABA levels were evaluated. To test the effects of a mixed D₁/D₂ agonist, APO (0.1 and 0.5 mg/kg) or vehicle was administered through the indwelling subcutaneous catheter.

We determined the degree to which DA agonist-evoked changes in extracellular GABA levels were impulse-dependent by perfusing locally the sodium channel blocker TTX through the microdialysis probe. After base-line samples were collected, 1.0 µM TTX was perfused through the dialysis probe for a total of 80 min; 20 min after the start of the TTX infusion, animals received a subcutaneous injection of APO (0.5 mg/kg).

To determine the anatomical and receptor specificity of DA regulation of GABA, subsequent studies examined the effects of specific DA agonists administered directly into the PFC through the dialysis probe. The D₂-like agonist quinpirole (1 × 10⁸ M, 1 × 10⁶ M or 1 × 10⁴ M) or the D₁ agonist SKF 38393 (2 × 10⁵ M or 2 × 10³ M) were dissolved in ACSF and perfused through the microdialysis probe for 20 min, and GABA levels were measured.

The hypothesis that DA regulates GABA release via a D₂ receptor mechanism also was tested by examining the ability of specific DA receptor antagonists (SCH 23390 as the D₁ antagonist and sulpiride as the D₂ antagonist) to block agonist-induced changes in extracellular GABA levels. The antagonists were administered locally to the PFC through the microdialysis probe before systemic administration of APO or local administration of quinpirole. ()Sulpiride (2 × 10⁵ M) or SCH 23390 (1 × 10⁷ M) was delivered through the microdialysis probe for 80 min, beginning 20 min before the systemic administration of APO (0.5 mg/kg) or vehicle. Similarly, sulpiride was infused into the PFC for 20 min before the local administration of quinpirole, and continued for the 20-min duration of the quinpirole infusion and for the next 40 min.

Chromatography and data analysis. All dialysis samples were stored at 75°C until assayed for amino acid content. Liquid chromatographic analysis of the samples was performed after precolumn derivitization with o-phthaldialdehyde, as described in Bourdelais and Deutch (1994).

Raw data (femtomoles of GABA per microliter, not corrected for recovery) were analyzed for overall significance by two-way analyses of variance with repeated measures on the time factor. Sheffe's post hoc test was used to analyze the data further when indicated.

Anatomical studies. On completion of dialysis the animals were anesthetized deeply with chloral hydrate. India ink was perfused through the implanted subcutaneous catheter to verify patency. The brain was then removed and postfixed in 4% paraformaldehyde in phosphate buffer for a week or more. Coronal sections (70 µm) were then cut through the frontal cortices, mounted on gelatin-coated slides, stained with cresyl violet and viewed under a microscope to verify probe placement by a rater who was not aware of the treatment condition of the animal. An acceptable probe placement had the exchanging portion of the probe in the deep layers of the prelimbic/infralimbic regions of the PFC and did not cross the midline.

To confirm that the microdialysis probe was placed within the PFC areas that receive a dopaminergic input from the midbrain, a retrograde tracer evaluation was performed in ten representative animals (see Robertson et al., 1991). At the completion of a dialysis experiment, the microdialysis probe was filled with 4% FG in 0.1 M cacodylic acid; the FG-filled probe remained in situ overnight. One to two weeks later the rats were anesthetized deeply with chloral hydrate and perfused transcardially with phosphate-buffered saline followed by cold 4% paraformaldehyde in 0.1 M phosphate buffer. The brain was removed and cryoprotected, and 40-µm coronal sections cut through the frontal cortices and midbrain. One set of sections was viewed under UV illumination to reveal retrogradely labeled cells. A second set of sections was immunohistochemically processed to reveal retrogradely labeled DA neurons. Free-floating sections were incubated for 18 to 24 h in a monoclonal antibody directed against tyrosine hydroxylase (1:1500). Sections were washed extensively in Tris-buffered saline and then incubated in a rhodamine-conjugated anti-mouse IgG (1:80). Sections were then washed, mounted and viewed under epifluorescent illumination.

Chemicals and reagents. FG was obtained from Fluorochrome, Inc. (Englewood, CO) and the tyrosine hydroxylase antibody from Incstar, Inc. (Stillwater, MN); secondary antibodies were from Antibodies Inc. (Davis, CA). Apomorphine HCl, SKF 38393 HCl, SCH 23390 HCl, quinpirole HCl and ()sulpiride were obtained from Research Biochemicals, Inc. (Natick, MA). All other chemicals and reagents were obtained from Sigma Chemical Co. (St. Louis, MO).

	Results

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Dopamine agonists increased extracellular GABA levels in the PFC. Both systemic administration and direct infusion of DA agonists into the PFC increased extracellular GABA levels. The increase in extracellular GABA levels elicited by DA agonists appeared to be due to stimulation of a D₂-like DA receptor.

Systemic administration of APO. Basal extracellular GABA levels in the PFC were 46.1 ± 3.5 (mean ± S.E.M.) fmol/µl; basal glycine levels were 17.1 ± 1.7 fmol/µl. Systemic administration of the mixed D₁/D₂ DA agonist APO increased extracellular GABA levels in the PFC in a dose-dependent fashion (see fig. 1). Although APO increased extracellular levels of GABA, levels of glycine, a "control" amino acid, remained unchanged after administration of 0.5 mg/kg APO (fig. 1). The ability of systemic APO to elicit an increase in GABA levels, although significant, was somewhat variable: an increase in GABA levels in response to systemic APO challenge, as defined by an increase of 50% over the base-line mean, was not seen in every animal. Nine of the 13 animals displayed increases of greater than 50% in extracellular GABA levels at the peak response; in contrast, no animal injected with vehicle exhibited an increase in GABA levels of 50%.

View larger version (17K): [in this window] [in a new window]   Fig. 1.   Effects of systemic APO administration on extracellular GABA (top panel) and glycine (bottom panel) levels in the PFC. Data are presented as the mean percent (± S.E.M.) change from base line. Systemic administration (arrow) of the high dose of APO significantly increased extracellular GABA levels, but did not alter extracellular levels of glycine. *P < .05 relative to vehicle (VEH) at the respective time point.

Changes in extracellular GABA levels in response to APO challenge were impulse-dependent: local perfusion of TTX through the dialysis probe almost completely blocked the APO-elicited increase in PFC GABA levels (see fig. 2). Of the eight animals that received TTX pretreatment before APO administration, one animal displayed an increase in GABA levels reaching the 50% criterion.

View larger version (14K): [in this window] [in a new window]   Fig. 2.   The effects of TTX treatment on the APO-elicited increase in extracellular GABA levels in the PFC. Cessation of impulse flow by TTX almost completely blocked the ability of apomorphine to elicit an increase in extracellular GABA levels. *P < .01 relative to APO alone group at the respective time point.

PFC administration of DA agonists. To determine whether the increase in extracellular GABA levels elicited by systemic APO administration was caused by local PFC actions of the DA agonist, we examined the effects of DA agonists infused into the PFC through the microdialysis probe.

Local administration of the specific D₂ agonist quinpirole dose-dependently increased extracellular GABA levels in the PFC (see fig. 3), with significant increases seen in response to both 1 × 10⁶ and 1 × 10⁴ M quinpirole administration. In contrast, local administration of the D₁ agonist SKF 38393 failed to alter extracellular GABA levels (fig. 4). The effects of intra-PFC infusion of DA agonists through the dialysis probe yielded much more consistent effects than observed after systemic administration. Every rat receiving 1 × 10⁶ M quinpirole responded by an increase of at least 50% in extracellular GABA levels, whereas at the 1 × 10⁴ M concentration of quinpirole 5/6 rats responded at the criterion level. None of the animals that received the D₁ agonist SKF 38393 responded to the agonist at the 50% criterion level.

View larger version (21K): [in this window] [in a new window]   Fig. 3.   Effects of intra-PFC administration of the D2 DA receptor agonist quinpirole (QUIN) on extracellular GABA levels in the PFC. There is a dose-dependent increase in extracellular GABA levels after local administration (bar) of quinpirole. *P  .05 relative to vehicle (VEH) at the time points indicated.

View larger version (18K): [in this window] [in a new window]   Fig. 4.   Extracellular GABA levels in the PFC do not change in response to local infusion (bar) of the D1 agonist SKF 38393 (SKF). VEH, vehicle.

Antagonism of DA agonist-induced changes in GABA levels. D₂ and D₁ antagonists were infused into the PFC to block the increase in GABA levels elicited by systemic administration of APO or local PFC administration of quinpirole. The D₂ antagonist ()sulpiride was delivered at a concentration of 2 × 10⁵ M; this concentration was selected on the basis of pilot experiments that revealed no significant effect of sulpiride alone on PFC GABA levels.

Sulpiride prevented the APO-induced increase in extracellular GABA levels (see fig. 5), with none of the seven animals tested displaying an increase to APO at any time. In contrast, the D₁ antagonist SCH 23390 did not significantly attenuate the APO-elicited increase in GABA levels.

View larger version (16K): [in this window] [in a new window]   Fig. 5.   Effects of local infusion of DA receptor antagonists (bar) on the ability of systemic APO (injected at the 0 time point marked by an arrow) to increase GABA levels in the PFC. The D2 agonist sulpiride (SUL) completely blocked the effects of APO, whereas the D1 antagonist SCH 23390 (SCH) was without effect. *P  .05 relative to animals receiving APO that were pretreated with sulpiride at the respective time points. VEH, vehicle.

The increase in extracellular GABA levels elicited by local infusion of quinpirole was blocked completely by the D₂ antagonist sulpiride but not significantly attenuated by SCH 23390 (see fig. 6).

View larger version (18K): [in this window] [in a new window]   Fig. 6.   Prefrontal cortical extracellular GABA levels in response to local quinpirole (QUIN) administration in animals pretreated with the D2-like antagonist ()sulpiride (SUL) or the D1 antagonist SCH 23390 (SCH). Pretreatment with the D2 antagonist completely blocked the effects of ability of quinpirole to elicit an increase in extracellular GABA levels, whereas the D1 antagonist SCH 23390 was without effect. *P  .05 relative to rats pretreated with SCH 23390 and then injected with quinpirole.

Retrograde tracer studies. The infusion of FG was predominantly into the infralimbic and prelimbic cortices. Analysis of labeling in the contralateral PFC revealed retrogradely labeled cells in the homotypic infralimbic and prelimbic parts of the PFC (see fig. 7); the density of labeling dropped off rapidly dorsal to the prelimbic cortex.

View larger version (102K): [in this window] [in a new window]   Fig. 7.   Photomicrographs illustrating retrograde transport of FG administered into the PFC through the dialysis probe. Panel A shows retrogradely labeled cells in the contralateral (homotypic) cortex, which indicates that the tracer was deposited primarily into the infralimbic (il) and prelimbic (pl) cortices, with substantially less involvement of the more dorsal "shoulder" cortex. Panel B shows retrogradely labeled neurons in the ventral tegmental area (fr, fasciculus retroflexus). In panel C, two adjacent neurons (arrows) in the A10dc region of the VTA are shown that are retrogradely labeled (bottom) and express tyrosine hydroxylase immunoreactivity (top).

Both dopaminergic and nondopaminergic cells in the ventral midbrain were labeled retrogradely from the PFC. The distribution of these cells is consistent with the reports of previous studies (Swanson, 1982). We observed retrogradely labeled DA neurons primarily in the VTA, including its caudal and dorsal part (the A10dc region of Hökfelt et al., 1984), with a smaller cluster of retrogradely labeled cells in the extreme substantia nigra (see fig. 7).

Dialysis probes located more dorsally or in the superficial layers, outside of the most dense target area in the PFC (see above). resulted in a much sparser retrograde labeling in the VTA, but with more labeling seen laterally in the medial substantia nigra.

	Discussion

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The present data suggest that DA, acting through a D₂-like DA receptor, increases GABA release from interneurons in the PFC. This dopaminergic modulation of GABA function is probably the result of direct actions of DA in the PFC, because local as well as systemic administration of DA agonists increased extracellular GABA levels.

Technical considerations. Early GABA microdialysis studies in anesthetized animals suggested that extracellular GABA levels are derived primarily from the metabolic pool of GABA (Drew et al., 1989; Westerink and DeVries, 1989). However, subsequent studies in nonanesthetized rats revealed that both neuronal and metabolic pools contribute to basal GABA levels and suggested that the neuronal pool is the primary source of evoked GABA release (Anderson and DiMicco, 1992; Bourdelais and Kalivas, 1992; Campbell et al., 1993; Osborne et al., 1991; Shirokawa and Ogawa, 1995; Timmerman et al., 1992; Welsch-Kunzle et al., 1993). In the nonanesthetized animal, extracellular GABA levels in the PFC are impulse- and calcium-dependent and are increased by both veratradine and elevated potassium concentrations (Bourdelais and Deutch, 1994). Moreover, we observed that TTX pretreatment blocked the APO-elicited increase in cortical GABA levels, which suggests that DA agonist-evoked release is derived from the neuronal pool of GABA. Finally, we noted that levels of glycine, which like GABA is both an inhibitory neurotransmitter and an intermediary metabolic product, did not increase after APO administration. This observation suggests that the DA agonist-evoked increase in extracellular GABA levels is not caused by nonspecific changes in the metabolism of neurons. In summary, the present data indicate that the DA agonist-induced increase in GABA levels predominantly reflects release of GABA from the transmitter pool of the amino acid.

Under certain circumstances an increase in extracellular GABA levels can be the result of GABA extrusion by reversal of the GABA transporter (Bernath and Zigmond, 1989, 1990). This does not appear to be the mechanism through which DA agonists elicit increased GABA levels; our TTX data, coupled with the observation that DA depolarizes interneurons in the pyriform and prefrontal cortices (Gellman and Aghajanian, 1993; Yang et al., 1997; Zheng et al., 1997), suggest that the DA agonist-induced increase in extracellular GABA levels is due to increased release of the transmitter GABA.

Dialysis studies in the nonanesthetized animal dictate that stress effects be controlled. Mild stressors potently increase release of DA in the PFC (see Deutch and Roth, 1990; Kalivas, 1993), and handling stress has been reported to increase potassium-evoked (although not basal) GABA release in the frontal cortex (File et al., 1990). Recent data indicate that mild stress increases extracellular GABA levels in the PFC (Neff and Finlay, 1997); we have found that the stress-elicited increase in extracellular GABA levels in the PFC lasts longer than that observed in response to DA agonists (A. C. Grobin and A. Y. Deutch, unpublished observations). We took two steps to minimize stress of the rats in our studies. The interval between surgical implantation of the guide cannulae and the microdialysis procedure (6 days) is generally sufficient to allow for recovery from surgical stress. In addition, all drug injections were accomplished without handling of the animal: DA agonist challenges were performed remotely through an indwelling subcutaneous catheter (systemic drug administration) or guide cannula (probe delivery of drugs). While we tried to minimize the contribution of stress, it is difficult to completely control the stress-induced release of DA in the PFC, given the high degree of sensitivity that this cortical DA system has for various stressors (see Deutch and Roth, 1990).

Microdialysis probe placement appears to be an important variable for studies of the effects of DA on cortical GABA neurons. Although interneurons are distributed widely in the PFC, the density of the DA innervation and the functional effects of DA in the PFC are quite heterogeneous (Deutch, 1992; van Eden et al., 1987). We observed that animals implanted with probes into the superficial layers of the cortex (which were also more dorsal in the PFC because of the angled approach for probe implantation) showed a much weaker or no GABA response to APO challenge. The DA innervation of the PFC is more dense in the deep layers and the more ventral aspects (e.g., infralimbic and prelimbic areas) of the cortex (van Eden et al., 1987), and the cells expressing the D₂ receptor transcript are found predominantly in layer V of the infralimbic and prelimbic parts of the PFC (Mansour and Watson, 1995; Deutch et al., 1996). The localization of the D₂ receptor to the deep layers of the PFC is consistent with our observation that D₂ DA agonists increase extracellular GABA levels in the deep layers of the PFC, and with the observation of Retaux et al. (1994) that lesions of the source of the DA innervation of the PFC increase GAD₆₇ mRNA levels in interneurons of the deep but not superficial layers of the PFC. These observations suggest that relatively small differences in probe placement may contribute to the variable GABA responsiveness to DA agonist challenges that we observed.

Finally, we used manual changing of the dialysis solutions for infusion of drugs through the microdialysis probe. This approach leads to uncertainties concerning the exact delivery times of drugs to the brain (as based on in vitro modeling) and therefore contributes to variability in the temporal characteristics of changes in extracellular GABA levels.

Receptor mechanisms. Several observations are consistent with the suggestion that DA agonists increase extracellular GABA via a D₂-like receptor. APO administration increased extracellular GABA levels. Although APO is a mixed D₁/D₂ agonist, it has a much higher affinity in vivo for the D₂ receptor (Anderson and Jansen, 1990). More importantly, we observed that the D₂-like agonist quinpirole increased extracellular GABA levels. Finally, the ability of systemic administration of APO or local PFC infusion of quinpirole to increase extracellular GABA levels was blocked by local perfusion of the D₂ antagonist ()sulpiride, but not the D₁ antagonist SCH 23390.

Our data are not consistent with D₁ receptor-mediated events playing a key role in DA stimulation of GABA release. Attempts to block APO-induced increases in GABA levels with the D₁ antagonist SCH 23390 failed. Moreover, PFC administration of high concentrations of the D₁ agonist SKF 38393 had no effect on extracellular GABA levels. Although SKF is a partial agonist at the D₁ receptor, the inability of SCH 23390 to block the APO effect also suggests that the D₁ receptor does not play a major role in subserving DA-stimulated GABA release in the PFC. Finally, the apparent lack of D₁ receptor-mediated changes in GABA is consistent with the cellular localization of this receptor as revealed by immunohistochemical studies, which indicate that D₁ and D₅ (D_1b) receptors are localized predominantly to pyramidal cells in the prefrontal cortex of the primate (Bergson et al., 1995). Future studies will be required to define more conclusively the role that D₁ receptors may play in the regulation of cortical GABA release.

The present data suggest that a D₂-like receptor subserves DA-elicited GABA release in the PFC, but it is unclear which (if any) of the known D₂-like receptors is involved. APO exhibits low nanomolar affinities for the D₂, D₃ and D₄ receptors (Levesque et al., 1992; Sokoloff et al., 1992; van Tol et al., 1991). Quinpirole also has significant affinities for all three D₂ family receptors, with higher affinities for the D₃ and D₄ sites (Levesque et al., 1992; Sokoloff et al., 1992; van Tol et al., 1991). The high affinities of APO and quinpirole for all three D₂-like receptors raise the possibility that DA agonist-elicited increases in GABA levels may be caused by interaction with D₃ or D₄ receptors. The involvement of D₄ receptors is particularly appealing in light of recent data indicating that this DA receptor is expressed preferentially in GABAergic neurons of the cortex in primate brain (Mrzljak et al., 1996). A report recently suggested a wide distribution of D₄-like immunoreactive neurons in the rat brain, with both pyramidal and nonpyramidal cortical neurons being labeled (Defagot et al., 1997); however, this study used antisera that recognized at least four protein bands. Neither D₃ nor D₄ receptor mRNAs are present in detectable levels by in situ hybridization in the rat PFC (Mansour and Watson, 1995; Damask et al., 1996). Thus, the degree to which D₃ and D₄ receptors are present in PFC neurons and contribute to regulation of interneurons remain unclear.

There is a broad consensus that D₂ receptors are present in the rat cortex. D₂ binding sites (Al-Tikriti et al., 1992; Nisoli et al., 1988) and D₂ transcripts (Deutch et al., 1996; Mansour and Watson, 1995) are present in the rodent PFC. Neurons expressing the D₂ receptor transcript are found predominantly in layer V of the rat PFC, and D₂ mRNA-expressing cells include both small (presumptive interneurons) and larger cells (Deutch et al., 1996).

The precise cellular location of the D₂-like receptor that subserves PFC DA regulation of GABA is not known. The most parsimonious explanation for our findings would place the D₂ receptor on GABA interneurons. This suggestion is consistent with recent data that indicate that D₂-like binding sites are present on both small nonpyramidal cells and pyramidal cells (Vincent et al., 1993) and that show localization of D₂ transcripts to both interneurons marked by GAD₆₇ mRNA and pyramidal cells in the PFC (Deutch et al., 1996). However, it is possible that the actions of DA are indirect, involving depolarization of pyramidal cells and the subsequent activation of the interneuron, or even operating through a long-loop feedback to the VTA. The latter possibility seems remote, because DA depolarizes interneurons in PFC slices (Yang et al., 1997; Zheng et al., 1997).

Although the exact anatomical arrangement remains to be determined, it seems clear that DA increases extracellular GABA levels in the PFC.

Correlation with electrophysiological data. DA and other monoamines depolarize interneurons in the pyriform and prefrontal cortices (Gellman and Aghajanian, 1993; Marek and Aghajanian, 1994; Yang et al., 1997; Zheng et al., 1997) and thereby generate inhibitory postsynaptic potentials in pyramidal cells. However, these effects of DA and other monoamines are seen in a subset of interneurons, with a substantial population of interneurons showing no response to monoamine application (Gellman and Aghajanian, 1993).

Different populations of interneurons can be distinguished on the basis of electrophysiological characteristics (Kawaguchi, 1995; Kawaguchi and Kubota, 1993). Similarly, cortical interneurons can be divided into several different populations on the basis of morphology (Fairen et al., 1984) and peptide and calcium-binding protein expression (see DeFelipe, 1993). It is possible that the different physiological characteristics exhibited by interneurons reflect in part differential responses to DA and other modulatory inputs. For example, the antipsychotic drug clozapine, which is a potent DA and serotonin receptor antagonist, increases immediate-early gene expression in a distinct subset of PFC interneurons (Deutch and Duman, 1996); similarly, systemic administration of APO increases Fos expression in subsets of interneurons as well as pyramidal cells (A. C. Grobin and A. Y. Deutch, unpublished observations). Recent electrophysiological studies suggest that even among those PFC interneurons that exhibit a response to DA application in vitro, there are several subtypes of interneurons distinguished by response characteristics (C. Yang, personal communication; W.-X. Shi, personal communication).

The observation that there are distinct subsets of DA neurons may help explain the paradoxical finding of Retaux et al. (1991), who noted that DA enhanced basal [³H]GABA efflux from PFC slices, but dampened electrically evoked GABA release. We observed that APO and quinpirole elicited an increase in extracellular GABA levels, consistent with the data of Retuax et al. (1991) concerning basal release; this effect is probably caused by the direct actions of DA agonists on GABA interneurons seen in electrophysiological studies (Yang et al., 1997; Zheng et al., 1997). In contrast, electrical stimulation presumably depolarizes all cells in the slice, including pyramidal cells, and thus indirectly may drive interneurons through the release of glutamate from pyramidal cells. Because DA inhibits the activity of pyramidal neurons, it is plausible that DA would decrease evoked GABA release in the PFC by dampening the activation of pyramidal cells.

Clinical implications. Electrophysiological studies indicate that DA inhibits the firing of PFC pyramidal cells in vivo (Sesack and Bunney, 1989; Thierry et al., 1990). Recent anatomical data suggest that DA and GABA may terminate on the same pyramidal cell (Cowan et al., 1994; Sesack et al., 1995), which suggests that DA can inhibit pyramidal cell activity both indirectly (by enhancing GABA release) and directly through synapses with pyramidal cells. The DA hypothesis of schizophrenia, in its broadest form, posits dopaminergic hyperactivity as the central pathophysiological feature in schizophrenia (see Goldstein and Deutch, 1992). Paradoxically, current hypotheses hold that decreased cortical DA tone may be present in schizophrenia. This relative hypodopaminergic state has been suggested to contribute to the genesis of negative symptoms (being cortically based), but at the same time transynaptically increase dopaminergic tone in the striatal complex, and thus contribute to positive symptoms (Berman and Weinberger, 1990; Davis et al., 1992; Deutch, 1992).

Recent postmortem studies of the schizophrenic brain have suggested decreased numbers of certain types of interneurons and decreases in GABA function in the PFC (Akbarian et al., 1993, 1995; Benes et al., 1991, 1992; see Lewis, 1995). However, it is not clear if changes in cortical GABA systems in schizophrenia are primary changes, or alternatively reflect an impaired function of the cortical DA system, or both. It is likely that there is a complex interplay between DA and GABA in maintaining effective inhibitory tone over the pyramidal cell. Our data suggest that a defect in the cortical DA innervation may result in impaired GABAergic inhibition over cortical projection neurons. Our observations further suggest that novel treatment strategies aimed at selectively increasing GABAergic tone in the PFC may be a useful treatment or adjunct to conventional neuroleptic treatment of schizophrenia.

	Acknowledgments

We gratefully acknowledge the technical assistance of Dorothy Cameron. We have benefited greatly from frequent discussions with Dr. George K. Aghajanian. We also appreciate the helpful comments of Drs. Walid Abi-Saab, Reinhard Jahn, J. Murdoch Ritchie, Robert H. Roth and Michael Zigmond.

	Footnotes

Accepted for publication December 29, 1997.

Received for publication September 12, 1997.

¹ This work was supported in part by MH-45124, MH-57999, the National Centers for Schizophrenia Research and Post-Traumatic Disorder Research at the VA Medical Center, West Haven, CT, and the National Parkinson Foundation Center of Excellence at Yale University.

² Current address: Center for Alcohol Studies, CB #7178, Thurston-Bowles 3021, University of North Carolina, Chapel Hill, NC 27599.

³ Current address: Departments of Psychiatry and Pharmacology and Center for Molecular Neuroscience, Vanderbilt University School of Medicine, Nashville, TN 37212.

Send reprint requests to: Ariel Y. Deutch, Psychiatric Hospital at Vanderbilt, Suite 313, 1601 23rd Ave South, Nashville, TN 37212.

	Abbreviations

ACSF, artifical cerebrospinal fluid; APO, apomorphine; DA, dopamine; FG, Fluoro-gold; GABA, -aminobutyric acid; PFC, prefrontal cortex; TTX, tetrodotoxin; VTA, ventral tegmental area.

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