European Journal o f Pharmacology, 57 (1979) 35--42 © Elsevier/North-Holland Biomedical Press

35

GABA MODULATES THE RELEASE OF DOPAMINE AND ACETYLCHOLINE FROM RAT CAUDATE NUCLEUS SLICES J O H A N N E S C. STOOF, E G B E R T J.S. D E N B R E E J E N and A R I E H. M U L D E R

Departments of Pharmacology and Neurology, Free University Medical Faculty, Van der Boeehorststraat 7, 1081 B T Amsterdam, The Netherlands Received 7 September 1978, revised MS received 14 December 1978, accepted 27 March 1979

J.C. STOOF, E.J.S. DEN BREEJEN and A.H. MULDER, GABA modulates the release o f dopamine and acetylcholine from rat caudate nucleus slices, European J. Pharmacol. 57 (1979) 35--42. The effects of GABA on depolarization-induced (26 mM K +) release of radiolabeled dopamine (DA) and acetylcholine (ACh) from slices of rat caudate nucleus were examined with a superfusion method. GABA, in concentrations of 10-s--10 -3 M, dose-dependently enhanced the release of DA, either accumulated by high-affinity uptake or synthesized from 14-C-tyrosine. In contrast, the release of ACh was reduced by GABA. This reduction appeared to be caused by the increase in DA-release. These effects of GABA decreased from the caudal to rostral part within the caudate nucleus, an order which parallels the distribution of endogenous GABA and glutamic acid decarboxylase. However, GABA had little, if any, effect in the nucleus accumbens. Since it was difficult to antagonize the effects of GABA on DA and ACh release with bicuculline or picrotoxin, it remains uncertain whether these effects were mediated via GABA receptors. In view of the high endogenous GABA level in the caudate nucleus it is concluded that GABA may be one of the local factors involved in the control of the amount of transmitter that will be released from dopaminergic varicosities upon depolarization. Acetylcholine release Noradrenaline release

Dopamine release

Nucleus accumbens

1. Introduction Interactions between different neuronal systems are considered to play an important role in the regulation of brain functions. Thus far such interactions have been studied predominantly in the corpus striatum, a structure strategically positioned to mediate information transfer among the cerebral cortex, thalamus and substantia nigra. In accordance with its integrative function the striatum appears to consist of many anatomically distinct types of nerve cells and synaptic structures (Hassler, 1978). Some of the neurons occurring within the striatum or terminating in this region have been identified biochemically and contain dopamine (DA), acetylcholine (ACh), GABA, serotonin, gluta-

GABA

Caudate nucleus

mate, substance P or enkephalin as neurotransmitters (Fonnum, 1974; Brownstein et al., 1976; Barchas et al., 1978). A considerable part of striatal GABA seems to be localized in interneurons (McGeer and McGeer, 1975). Therefore, in a previous study we have examined the possible existence of a GABAergic/dopaminergic interaction in the striatum (Stoof and Mulder, 1977). In that study we found that when endogenous GABA was increased through the inhibition of GABA-aminotransferase, the depolarization-induced release of 3H-DA from striatal tissue slices was enhanced. Similar findings were reported by Starr (1978) and Giorguieff et al. (1978) indicating that GABA can stimulate the release of DA. In the present paper we report data on regional dif-

36 ferences in the effects of GABA on DA release and on the release of other neurotransmitters.

2. Materials and m e t h o d s

2.1. Preparation o f brain slices Male albino rats (140--160 g) of an inbred Wistar strain were used for all experiments. After the rats were decapitated the brain was quickly removed and placed in a special brain holder enabling successive frontal brain slices of 2 mm thickness to be made. When isolating the rostral, medial and caudal regions of the caudate nucleus, sections were taken at anterior planes A 11200--9200, A 9200-7200 and A 7200--5200 p respectively (KSnig and Klippel, 1970). The caudate nucleus regions were dissected from these frontal slices and small slices of 0.3 mm thickness were prepared with a McIlwain tissue chopper. Cortical tissue was dissected from the medial frontal slice (occipital cortex region).

2.2. Release experiments Slices (2 X 2 X 0.3 mm) were incubated for 15 min with 3H-DA, 3H-NA or 3H-choline at a final concentration of 10-7 M in Krebs-Ringer bicarbonate (KRB) medium in a 95% O2/5% CO2 atmosphere. Also some double label experiments were performed in which slices were incubated with 3H-DA (10 -7 M) in combination with 14C-tyrosine (10 -6 M) or 14Ccholine (10 -6 M). After rinsing the slices were transferred to each of 8 chambers (0.25 ml volume of a superfusion system, one slice, i.e. about I mg of tissue, per chamber) and superfused at 37°C with KRB m e d i u m at a constant rate of 0 . 2 5 m l / m i n . Following 4 0 m i n of superfusion 13 successive 5-min fractions were collected. Depolarization-induced transmitter release was accomplished by superfusion with medium containing 26 mM K ÷ for 5 min at t = 55 min (S~) and t = 8 5 m i n (S2). Drugs

J.C. STOOF ET AL. were present from t = 65 min. The ~'adio.activity remaining in the tissue was extracted by homogenization in 0.4 N HC104. In some experiments, in which slices labeled with 3H-DA or 14C-tyrosine were used, the effluent radioactivity was analyzed by ion-exchange chromatography on Dowex W-X4 columns, according to the m e t h o d of Kehr (1974).

2.3. Determination of radioactivity The radioactivity in superfusate samples and tissue extracts was determined by liquid scintillation counting. The necessary corrections were made for counting efficiency and, in the case of double label experiments, for the cross-over of 14C-radiation into the 3Hchannel.

2.4. Calculation of release data The release of radioactivity in excess of basal efflux, resulting from stimulation with 26 mM K * was calculated as the percentage of total radioactivity present at the onset of stimulation. The ratio of the percentage of radioactivity released during the first and second stimulation ($2/S~) was calculated for both control and drug-treated slices. All experiments were performed in quadruplicate. Statistical evaluation was carried out with the two-tailed Student's t-test.

2.5. Treatment of animals In some experiments animals were pretreated with one of the following drugs: biculline, 2 mg/kg b o d y weight, i.p., 1 h before decepitation, picrotoxin, 5 mg/kg, i.p. 1 h before decapitation, reserpine, 7.5 mg/kg, i.p. 1 6 h before decapitation, a-methyl-ptyrosine (a-MpT), 2 × 250 mg/kg, i.p., 16 and 3 h before decapitation.

2.6. Radiochemicals and drugs 3H-noradrenaline (28.3 Ci/mmol); 3H-dopamine (5 Ci/mmol); 3H-choline (13 Ci/mmol);

GABA MODULATES DOPAMINE AND ACETYLCHOLINE RELEASE

14C-choline (52 mCi/mmol) and 14C-tyrosine (513 mCi/mmol) were obtained from the Radiochemical Center (Amersham). G A B A and picrotoxin were purchased from Sigma, bicuculline methiodide from Pierce, reserpine (Serpasil) from Ciba-Geigy and s-methyl-ptyrosine from Labkemi. We are indebted to Dr. J. Korf and Dr. P. Krogsgaard-Larsen for generous gifts of muscimol and to Jansen Pharmaceutica (Beerse) for haloperidol.

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0,4 0,,2 0.10 0.0s

I-- I

0.06

3. Results 0,04

The K÷-induced release of radioactivity from striatal slices, previously labeled with 3H-DA or with 14C-tyrosine, was calciumdependent and was about 80% radiolabeled DA, as shown by chromatography (data not shown). Fig. 1 shows a typical experiment in which the effect of 3 × 10 -4 M GABA on the K+-induced release of 3H-DA was examined. In the presence of GABA, 3H-DA release was strongly enhanced; in addition, there was a small increase in the basal efflux of tritium. Similarly, the K÷-induced release of 14C-DA synthesized from ~4C-tyrosine was enhanced by GABA. The GABA-induced increase in 3H-DA release was dose-dependent (table 1) and was completely dependent on the presence of Ca 2÷ ions in the medium (data not shown). To get an impression of the specificity of the effect of GABA on DA release, we checked whether the amino acid would also modify the K+-induced release of radiolabeled noradrenaline (NA) or acetylcholine (ACh) in various brain regions (table 2). It has been demonstrated previously (Dismukes et al., 1977) that the K÷-induced release of radioactivity from brain slices labeled with 3H-NA was calcium-dependent and consisted mostly of radiolabeled NA. Others (Somogyi and Szerb, 1972; Hadh~zy and Szerb, 1977) have shown that the depolarization-induced release of radioactivity from brain slices previously incubated with radiolabeled

0.02

sl s=l 4b s'0 eb}70 ab ~ 150 ii0 GABA

Fig. 1. Typical experiment showing the effect of 3 × 10 -4 M GABA on K÷-induced release of 3H-DA from rat caudate nucleus slices. Slices previously labeled with 3H-DA were superfused and stimulated twice with 26 mM K ÷ ($1 and $2). A fractional rate of 0.01 corresponds to 250--300 d.p.m. ) control release (no drug). - . . . . . . . , GABA present in the medium from t - - 6 5 min. Ordinate: 3H-DA o v e r f l o w (fractional rate). Abscissa: superfusion time (rain).

TABLE 1 Effects of GABA on 26 mM K+-induced release of 3HDA and 14C-DA (synthesized from 14C-tyrosine) from rat caudate nucleus slices. GABA

3H.DA.Releas e I

14C.DA.Releas e 1

Control 3 × 10 -s M 10 -4 M 3 × 10 -4 M 10 -3 M

0.70-+ 0.03 0.99-+ 0.05 1.18 -+ 0.06 1.59 -+ 0.07 1.87 -+ 0.05

1.23 ~ 0.05

2 2 2 2

(8) (4) (4) (4) (4)

(4)

3.09 -+ 0.26 2 (4)

I Expressed as S2/SI ratio (see fig. 1); values represent means _+ S.E.M. for the number of determinations shown in parentheses. 2 p < 0.01 versus control (Student's t-test).

38

J.C. S T O O F ET AL.

TABLE 2 Effects o f 3 × 10 -4 M G A B A on 26 mM K+-induced release of 3H-DA, 3H-NA and 3H-ACh f r o m different brain regions. Brain region

Transmitter

T r a n s m i t t e r release 1 Control

Caudate nucleus Nucleus a c c u m b e n s Cortex Hypothalamus

3H-DA 3H-ACh 3H-DA 3H-ACh 3H-NA 3H-ACh 3HoNA

In presence o f G A B A

0.70 -+ 0.03 0.88 + 0.01 0.82 -+ 0.02 0.95-+ 0.04 0.65 + 0.02 0.78 -+ 0.04 0.64 -+ 0.02

(8) (8) (8) (4) (8) (4) (4)

1.59 -+ 0.07 0.67 -+ 0.02 0.90 + 0.05 0.93-+ 0.05 0.86 -+ 0.03 0.82 _+ 0.02 0.75 -+ 0.02

2 (4) 2 (8) (4) (4) 2 (8) (4) 2 (4)

1 Expressed as $2/$1 ratio (see fig. 1); values represent means + S.E.M. for the n u m b e r o f d e t e r m i n a t i o n s shown in parentheses. 2 p < 0.01 versus control ( S t u d e n t ' s t-test).

choline and stimulated either electrically or with an elevated K÷-concentration, was a valid reflection of radiolabeled ACh release. GABA appeared to cause a small but statistically significant increase in the release of SH-NA from both cortical and hypothalamic tissue slices. On the other hand, the release of 3H-ACh from cortical slices remained unaffected but was significantly reduced in the caudate nucleus. This reduction was n o t observed in caudate nucleus slices obtained from rats pretreated with reserpine or with a-methyl-p-tyrosine (table 3). The release of both 3H-DA and 3H-ACh from the nucleus accumbens was nog significantly changed by GABA. In another a t t e m p t to establish the specificity of the effect of GABA on ACh and DA release, possible regional differences within the neo-striatum were studied. For these experiments, the caudate nucleus was divided into a caudal, a medial and a rostral part. As shown in table 4 the effects of GABA on 14C-ACh and on SH-DA release appeared to decrease from the caudal to the rostral part. In further experiments the effects of GABA-related drugs on DA release were investigated. While GABA produced strong effects in a concentration range of 3 × 1 0 -5 M--10 -3 M, muscimol, a p o t e n t GABA-recep-

tor agonist (Krogsgaard-Larsen, 1975), did not change 3H-DA release in a concentration range of 10 -7 M--10 -4 M (table 3). 7-Hydroxybutyric acid was also ineffective. In order to examine whether the effects of GABA could be antagonized, bicuculline methiodide and picrotoxin were used in a concentration of 10-4 M and added to the superTABLE 3 Effects o f 1 0 - 3 M G A B A on 26 mM K÷-induced release o f SH-ACh f r o m caudate nucleus slices obtained f r o m rats pretreated with reserpine or a-MpT. Treatment

Reserpine 2 ~-MpT 2 Nottreated

3H.ACh.releas e 1 Control

In presence o f GABA

0.87 -+ 0.02 (12) 0.90-+ 0.06 (8) 0.88+0.01 (8)

0.89 -+ 0.04 (12) 0.85 + 0.03 (8) 0 . 6 7 + 0 . 0 2 3 (8)

1 Expressed as $2/$1 ratio (see fig. 1); values represent means -+ S.E.M. for the n u m b e r o f determinations s h o w n in parentheses. 2 In these e x p e r i m e n t s animals were pretreated with 7.5 m g / k g reserpine (i.p.) 16 h b e f o r e decapitation or with 2 × 250 mg/kg 0l-MpT 16 and 3 h b e f o r e decapitation. In the latter case c~-MpT (10 -4 M) was continuously present during b o t h i n c u b a t i o n and superfusion. 3 p < 0.01 versus c o n t r o l ( S t u d e n t ' s t-test).

GABA MODULATES DOPAMINE AND ACETYLCHOLINE RELEASE

39

TABLE 4 Regional differences in effects of 10 -4 M GABA on 26 mM K+-induced release of 3H-DA and 14C-ACh in the caudate nucleus of the rat. 3H-DA release 1

Region

Caudal part of caudate nucleus Medial part of caudate nucleus Rostral part of caudate nucleus

14C-ACh release I

Control

In presence of GABA

Control

In presence of GABA

0.74 + 0.03 (8) -0.70 + 0.02 (8)

1.41 -+ 0.05 2 (8) 1.24-+ 0.06 (8) 1.06 + 0.06 2 (8)

0.89 + 0.03 (8)

0.75 + 0.02 2 (8) 0.77 + 0.03 (8) 0.95 _+0.03 (8)

0.95 + 0.04 (8)

i Expressed as $2/$1 ratio (see fig. 1); values represent means -+ S.EJYl. for the number of determinations shown in parentheses. 2 p < 0.01 versus control (Student's t-test).

fusion medium simultaneously with GABA. Picrotoxin alone had no effect, but bicucull i n e i n d u c e d a s m a l l i n c r e a s e i n 3H-DA r e l e a s e as s h o w n i n t a b l e 6. H o w e v e r , t h e e f f e c t o f G A B A was n o t i n f l u e n c e d b y these drugs. Only after pretreatment of the animals with ~ i c u c u l l i n e or p i c r o t o x i n , c o m b i n e d w i t h t h e continuous presence of the drugs both during incubation and superfusion of the tissue, were the effects of G A B A o n 3H-DA release partially blocked.

TABLE 5 Effects of GABA and related drugs on 26 mM K÷-induced release of 3H-DA from rat caudate nucleus slices. Drug Muscimol

9'-Hydroxybutyric acid GABA Control

3H-DA release 2 10 -4 10 -s 10 -6 10 -7 3 ×

M M M M 10-4 M

3 × 10 -4 M

0.72-+ 0.70-+ 0.73-+ 0.78 + 0.66-+

0.03 0.05 0.09 0.04 0.02

(4) (4) (4) (4) (4)

1.59 -+ 0.07 2 (4) 0.70-+ 0.03 (8)

I Expressed as $2/S1 ratio (see fig. 1); values represent means -+ S.E~/I. for the number of determinations shown in parentheses. 2 p < 0.01 versus control (Student's t-test).

TABLE 6 Effects of bicuculline and picrotoxin on 3H-DA release and on the GABA-induced increase of 3H-DA release from rat caudate nucleus slices. Drug

Control GABA Picrotoxin Bieuculline GABA + picrotoxin GABA + bicuculline GABA GABA + picrotoxin GABA + bicueulline

3H-DA release 1

(10 -4 (10-4 (10 -4 (10 -4 (10 -4 (10 -4 (10-4

M) M) M) M) M) M) M) ( 5 × 10 -$ M) (5 X 10 -s M) (10 -4 M) 4 (5 × 10 -s M) (10 -4 M) 4

0.70 1.24 0.67 0.98 1.19

+ 0.03 -+ 0.04 2 -+ 0.03 -+ 0.04 2 -+ 0.03

1.27 + 0.06 1.06 + 0.03 0.95 + 0.02 3 0.81 + 0.04 3

1 Expressed as $2/$1 ratio (see fig. 1); values represent means + S.E.M. for the number of determinations shown in parentheses. 2 p < 0.01 versus control (Student's t-test). 3 p < 0.01 versus 5 × 10 -s M GABA (Student's t-test). 4 In these experiments animals were pretreated with 5 mg/kg picrotoxin or 2 mg/kg bicuculline (i.p.) 1 h before decapitation. Picrotoxin or bicuculline were also continuously present during both incubation and super fusion.

40

4. Discussion We had found that increasing endogenous GABA levels by using inhibitors of GABA aminotransferase enhanced the depolarizationinduced release of 3H-DA from neostriatal tissue slices, while the addition of exogenous GABA appeared to be ineffective in this respect (Stoof and Mulder, 1977). However, in contrast to our findings, Starr (1978) and Giorguieff et al. (1978) demonstrated that exogenous GABA could also increase DA release. An obvious difference between our experimental procedure and the methods used by the other investigators was that in our previous experiments the tissue was exposed to GABA for a considerable length of time (more than 1 h). In the present study, using conditions similar to those reported by Starr, i.e. reducing the time of exposure of the tissue to GABA to 20 min, we also observed a stimulation of DA release by exogenous GABA. Apparently, exposure to GABA for an extended period of time renders the tissue refractory to the action of the amino acid. It is unlikely that GABA enhanced the K ÷induced release of radiolabeled DA by inhibiting its reuptake, since Giorguieff et al. (1978) have demonstrated that GABA did not inhibit the uptake of DA into synaptosomes. In order to examine the specificity of the effect of GABA on DA release, we also studied its effect on the release of radiolabeled ACh and NA. Surprisingly, instead of causing an increase, GABA appeared to decrease ACh release from neostriatal tissue where ACh is thought to be mainly present in interneurons (Hattori et al., 1976). In contrast, ACh release from cortical slices was not affected b y GABA. However, since ACh release may be inhibited by dopaminergic agonists (Bartholini et al., 1974; Trabucchi et al., 1975) GABA might act indirectly by enhancing the release of endogenous DA. This possibility was examined bY pretreating rats with either reserpine or a-methyl-p-tyrosine; both treatments resulted in a depletion of endogenous DA. Indeed, we found that after

J.C. S T O O F ET AL.

these pretreatments, GABA (10 -3 M) had no effect on the release of radiolabeled ACh from striatal tissue slices. Therefore, the inhibition of ACh release of GABA is presumably mediated by its facilitation of DA release. GABA caused a small, but statistically significant increase in the release of NA from cortex slices, which confirms the data reported by ArbiUa and Langer (1978). The fact that GABA enhanced DA but not ACh release suggests that the amino acid is not acting in an unspecific way. This hypothesis is strengthened by the regional differences which were detected in the caudate nucleus. The effect of GABA on DA release thus decreased from the caudal to the rostral part, which parallels the distribution of endogenous GABA and glutamic acid decarboxylase. (Fonnum et al., 1978). Our data do not permit to answer the question whether the effect of GABA on DA release is receptor-mediated. Thus, in contrast to GABA, muscimol, considered to be a rather specific GABA-receptor stimulating drug (Krogsgaard-Larsen et al., 1975) did not enhance the K÷-induced DA-release. Furthermore, the GABA-induced facilitation of DA release was not antagonized by the GABA receptor antagonists picrotoxin and bicuculline, although pretreatment of the animals with these drugs resulted in a partial inhibition of the GABA effect. These findings appear to be at variance with the data of Giorguieff et al., (1978), who found an increase in DA release after muscimol and a partial antagonism of the GABAinduced DA released by picrotoxin. Although it is difficult to explain these discrepancies the differences in experimental parameters must be pointed out, e.g. Giorguieff et al. examined the spontaneous efflux of newly synthesized radiolabeled DA. In our experiments, bicuculline did not antagonize the effect of GABA which agrees with the findings of Start (1978). Surprisingly, bicuculline itself caused an increase in K ÷induced DA release. This might suggest that

GABA MODULATES DOPAMINE AND ACETYLCHOLINERELEASE bicuculline acts as a partial agonist. On the other hand, bicuculline may n o t be a suitable drug in view of its possible instability at a physiological pH (Olsen et al., 1975). Since the number of pharmacological agents t h o u g h t to act more or less specifically on GABA receptors is very limited, it is difficult to ascertain whether the effect of GABA on DA release is receptor-mediated or not. Nevertheless, our present data do n o t provide strong support for this possibility unless there are GABA receptors which are not effectively activated or blocked by the drugs used in this study. Although the mechanism of action of GABA in modulating neostriatal DA and ACh release remains unclear, the possible physiological relevance of our findings should be emphasized, since the endogenous concentration of GABA in neostriatal regions may be as high as 10 -3 M, while an in vitro concentration of 3 × 10 -s M suffices to induce significant effects. Obviously, it is impossible to prove that such concentrations are actually achieved in vivo in the neighbourhood of the dopaminergic nerve terminals which are affected in vitro by exogenous GABA. Transmitter release from dopaminergic nerve terminals appears to be liable to modulation by m a n y drugs which interact primarily with receptors for transmitters other than DA (Giorguieff et al., 1977; Chdramy et al., 1977; Giorguieff et al., 1976). Taking into consideration the extensive axonal arborizations of a dopaminergic neuron with a large number of varicosities, it is hard to believe that transmitter release from all these varicosities is under the sole c o m m a n d of the cell body. It seems more likely that local factors or mechanisms are also involved in the regulation of transmitter release and ultimately control the a m o u n t of DA that will be released from particular varicosities upon depolarization. GABA m a y be one of these local factors.

41

Acknowledgement The authors thank Mrs. Ria Mouwen-de Boer for typing the manuscript.

References

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GABA modulates the release of dopamine and acetylcholine from rat caudate nucleus slices.

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