Journal of Neurochernistry Raven Press, New York 0 1986 International Society for Neurochemistry

Dopamine Autoreceptors Modulate Dopamine Release from the Prefrontal Cortex

"Reiza K. Talmaciu, *Irene S. Hoffmann, and L. X. Cubeddu

Division of Clinical Pharmacology, Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, North Carolina, U.S.A.; and *School of Pharmacy, Department of Pharmacology, Central University of

Venezuela, Caracas, Venezuela

Abstract: Electrical stimulation (at 0.3, 1 , or 10 Hz, 120 pulses each) produced a calcium-dependent overflow of radioactivity from slices of the rabbit prefrontal cortex preloaded with [3H]3,4-dihydroxyphenylethylamine ([3H]DA, [3H]dopamine) in the presence of desipramine. Flat frequency-release curves were observed. Apomor- phine and LY-171555 inhibited in a concentration-depen- dent fashion the evoked overflow of DA, an effect antag- onized by haloperidol. Stimulation frequencies compa- rable to normal firing rates of mesocortical neurons (10 Hz) drastically reduced apomorphine-induced inhibition of DA overflow. Haloperidol produced greater facilita-

tion of DA overflow at 10 than at 1 Hz. Nomifensine, a neuronal uptake inhibitor, enhanced DA overflow. These results indicate that mesocortical DA neurons projecting to the prefrontal cortex have release modulatory autore- ceptors of the D2 subtype. Key Words: Dopamine autore- ceptors-Rabbit prefrontal cortex-Dopamine release -Desipramine - Apomorphine- LY- 17 1555 - Haloper- idol- Nomifensine- Electrical stimulation. Talmaciu R. K. et al. Dopamine autoreceptors modulate dopamine release from the prefrontal cortex. J . Neurochem. 47, 865-870 (1986).

The stimulation-evoked release of 3,4-dihydroxy- phenylethylamine (DA, dopamine) from striatal tissue slices of the rat, rabbit, and cat is modulated by autoreceptors (Farnebo and Hamberger, 1971 ; Starke et al., 1978; Kamal et al., 1981; Cubeddu and Hoffmann, 1982). These investigators have demonstrated that activation of striatal autore- ceptors by DA receptor agonists leads to inhibition of DA release whereas autoreceptor blockade by DA antagonists increases the evoked release of DA and prevents the inhibition of release produced by the agonists. The effects of DA receptor agonists and antagonists on transmitter release or nerve ter- minal excitability are highly dependent on the pa- rameters of stimulation employed or on the firing rates of the neurons, respectively (Zumstein et al., 1981; Cubeddu and Hoffmann, 1982, 1983; Hoff- mann and Cubeddu, 1982; Cubeddu et al., 1983; Tepper et al., 1984a,b, 1985; White and Wang, 1984). DA antagonists increase the evoked release of DA only at high stimulation frequencies, whereas DA agonists lose their inhibitory potency

and efficacy at high frequencies of stimulation. Fur- thermore, both agonists and antagonists lose their efficacy in inhibiting or facilitating transmitter re- lease when prolonged stimulations are applied (Cu- beddu and Hoffmann, 1982; Hoffmann and Cu- beddu, 1982).

Although the evidence for autoreceptor-mediated modulation of DA release from striatal tissues is well substantiated, there is much less available in- formation on whether DA release from mesolimbic and mesocortical DA neurons is susceptible to modulation via autoreceptors. It has been postu- lated that mesocortical dopaminergic neurons may lack both impulse-regulating and synthesis-modu- lating autoreceptors (Bannon et al., 1981a,b; 1982, 1983; Chiodo et al., 1984). Experimental evidence indicates that the mesocortical DA neurons are in- sensitive to the inhibition of firing and inhibition of DA synthesis normally produced by DA agonists. Mesocortical DA neurons exhibit faster sponta- neous firing rates and higher turnover rates than those of DA neurons projecting to the striaturn and

Received January 27, 1986; revised March 14, 1986; accepted March 17, 1986.

Address correspondence and reprint requests to Dr. L. X. Cubeddu at Division of Clinical Pharmacology, 906 Faculty Lab-

oratory Office Building 231H, University of North Carolina, Chapel Hill, NC 27514, U.S.A.

Abbreviation used: DA, 3,4-dihydroxyphenylethylamine (do- pamine).

865

866 R . K . TALMACIU ET AL.

mesolimbic regions (Lindvall et al., 1974, 1977; Brown et al., 1979; Bannon et al., 1981a, 1982; Chiodo et al., 1984). It has been postulated that the lack of autoregulatory mechanisms determines the faster spontaneous firing rates and higher turnover rates of the mesocortical DA neurons (Chiodo et al., 1984). However, it is also possible that the neg- ligible effects of DA agonists on mesocortical DA neurons are determined by the faster intrinsic rates of firing (10 Hz) of these neurons, since high firing rates greatly reduce the inhibitory effects of D,4 ag- onists on DA release from other DA neurons (see above). To investigate these possibilities we studied the effects of DA receptor agonists and antagonists on the release of DA from the prefrontal cortex, a source of mesocortical neurons. The effects of these drugs were studied both at high and at low stimulation frequencies. In addition, by using a se- lective D2 DA receptor agonist we investigated the pharmacological properties of the mesocortical DA autoreceptors. We propose that mesocortical DA neurons present in the prefrontal cortex h a w re- lease modulatory DA receptors (DA autoreceptors) that when activated by endogenous DA or exoge- nous DA agonists lead to inhibition of transmitter release.

MATERIALS AND METHODS

Albino rabbits of either sex weighing 1.7-2.5 kg were killed by decapitation. The two prefrontal cortices of a rabbit were rapidly dissected and 0.4-mm slices weighing 1.0-2 .0 mg were obtained with a McIlwain tissue chopper. Twenty-four to 28 slices were obtained anid in- cubated in 4 ml of medium containing 0.2 p M [3H]D.4 (sp act 26 Ciimmol; New England Nuclear, North Billerica, MA, U.S.A.) at 37°C for 30 rnin in the presence of desi- pramine (10 pM). The latter drug was used to prevent the uptake of DA into the norepinephrine-containing nerve terminals of the prefrontal cortex. After incubation the slices were transferred to superfusion chambers (two sliceskhamber) that contained two platinum electrodes. The superfusion rate was 1 mlimin. Sample collection started after 50 rnin of superfusion with drug-free me- dium. In general 5-min samples were collected. The slices were stimulated twice (S1 and S2) 40 rnin apart (at 60 and 100 rnin of superfusion). Trains of supramaximal, unipolar, rectangular pulses (20 mA, 2 ms) at either 0.3, 1 , or 10 Hz for a total of 120 pulses were applied. In con- trol experiments both S1 and S2 were carried out in the absence of drugs. The effects of drugs were evaluated only on S2, with S1 serving as an internal control. Super- fusion with drugs or drug combinations was initiated 20 rnin prior to S2 and maintained until the end of the exper- iment. At the end of the experiment the slices were :soh- bilized in 0.5 ml of Soluene 350. The radioactivity in the superfusate samples and in the tissue slices was deter- mined by liquid scintillation spectrometry. Appropriate corrections were made for counting efficiencies. The basal outflow of radioactivity was expressed as fractional rate of loss, using the medium/tissue ratio. The ;term overflow was used for the stimulation-evoked increase in

the outflow of radioactive products above prestimulation levels. In each experiment the ratio S2/S1 was calculated for control and drug-treated slices. Drug effects on S2IS1 ratios were generally reported as percent of control ratios.

Additional experiments were performed to determine whether any conversion of [3H]DA to [3H]norepinephrine occurred in the presence of 10 p M desipramine. Slices from the cortex were analyzed by column chromatog- raphy. Slices (postincubation with [3H]DA) were homog- enized in 1 ml of ice-cold 0.4 M HC104 containing Na2EDTA (0.5 mg) and sodium metabisulfite ( 1 mg). After centrifugation at 10,000 g for 10 min, the superna- tant were passed through a cation-exchange DOWEX 50 W-X4,6 x 0.4 crn column. After extensive washout, the catecholamines (norepinephrine and DA) were eluted with thirty I-ml aliquots of 1.5 M HCI. This procedure provided a complete separation of norepinephrine and DA. The recoveries for both catecholamines were 98 2 1%. In the prefrontal cortex only a very small fraction (7.8 t 1.5%) of the tissue tritium was found as [3H]nor- epinephrine under our experimental conditions (labeling in the presence of 10 k*.M desipramine); the rest was found as L3H1DA.

RESULTS Rabbit prefrontal cortex slices were incubated in

vitro with [3H]DA and then superfused with amine- free medium at a rate of 1 ml/min. After 45 rnin of washout a constant rate of efflux of 3H products was obtained in which 1.46 ? 0.08% of the 3H present in the slices was released every 5 rnin into the superfusate. The slices were stimulated after 60 and again after 100 min of superfusion. Electrical stimulation produced an increase in the outflow of radioactive products above prestimulation levels. As previously described for the striatum, flat fre- quency-release curves were observed in the pre- frontal cortex. In fact, a comparable fraction of tissue tritium was released by stimulation at 0.3, 1, and 10 Hz (120 pulses each) (Fig. IB). In addition, approximately a similar percentage of tissue radio- activity was released by S1 and S2, at 1 or 10 Hz since the ratio S2IS1 averaged 0.94 and 0.99, re- spectively (Table 2). The stimulation-evoked over- flow of [3H]DA from prefrontal cortex slices was calcium-dependent. Reduction of the calcium con- centration of the perfusion fluid from 1.3 to 0.13 mM inhibited by 95% or more the stimulation- evoked overflow of 3H at the three frequencies of stimulation employed (Fig. 1B). Reduction of cal- cium had no effect on the basal efflux of 3H. A greater proportion of tissue 3H was released from the prefrontal cortex than from the striatum in slices obtained from the same rabbit. The [3H]DA content of striatal slices was six times greater than that of the prefrontal cortex slices (Table I ) . This is in agreement with existing differences in endoge- nous DA content in both tissues (Brown et al., 1979).

The DA agonist apomorphine decreased in a

J . Neurochrm., Vol. 47, No. 3 , 1986

DOPAMINE AUTORECEPTORS IN PREFRONTAL CORTEX

at 0.3 Hz, 120 pulses: 1 Hz, 120 pulses; or at 10

ferent concentrations of apomorphine. Results are expressed as percent inhibition of DA release (total 3H) produced by apomorphine. *'Signifi- cantly different from 0.3 Hz and 1 Hz at p < 0.01. B: Slices were stimulated as described above while perfused with normal Krebs-Ringer bicar- bonate solution (1.3 mM Ca2+) or with a Krebs- Ringer bicarbonate solution containing 0.13 mM Ca2+. Results are expressed as percent of tissue

~

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Hz, 120 pulses in the absence or presence of dif- y

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0 3 I 3 10 Hz STIMULATION FREQUENCY

concentration-dependent manner the stimulation- evoked release of DA (Figs. 1A and 2). The drug had no effects on spontaneous efflux of radioac- tivity. Maximum inhibition (Emax) of stimulation- evoked DA overflow at 1 Hz was 85 & 3% and the EC,, averaged 64 -+ 8 nM. Although apomorphine inhibited DA overflow both at low and high fre- quencies of stimulation, the magnitude of the inhib- itory effect was reduced at high rates of stimulation (Fig. 1A; Table 2). Apomorphine (100 nM) inhibited DA release by 34 & 4% at 10 Hz and by 64 k 3% at 1 Hz (Table 2). Haloperidol antagonized competi- tively the inhibitory effect of apomorphine on the evoked overflow of DA (Fig. 2; Table 2). Similarly to apomorphine, LY171555, a D2-DA receptor ago- nist, inhibited the stimulation-evoked overflow of 3H by 70%, an effect blocked by haloperidol (Table 2). In contrast to the effects of apomorphine and LY 171555, haloperidol (30- 100 nM) produced sig- nificant increases in the stimulation-evoked over- flow of tritium (Table 2). Greater facilitation of re- lease by haloperidol was observed at 10 Hz (71 ? 9%) than at 1 Hz (31 2 10%). Nomifensine (10 p M ) , a neuronal uptake inhibitor, produced a 2.0-2.5-fold increase in the stimulation-evoked overflow of total 3H from the prefrontal cortex (Table 2).

DISCUSSION

Electrical stimulation (at 0.3, 1, or 10 Hz, 120

pulses each) produced a calcium-dependent over- flow of radioactivity from slices of the rabbit pre- frontal cortex that had been preloaded with [3H]DA in the presence of desipramine. Under these experi- mental conditions only 7% of the tissue 3H was found as [3H]norepinephrine; the rest was present as [3H]DA. Comparable stimulation-evoked over- flows of 3H were produced by both periods of stim- ulation (S1 and S2), suggesting that the preparation was stable; such stability allowed testing of drug ef- fects on S2 while S1 served as an internal control (no drugs). Contrary to the stimulation-evoked overflow, the basal efflux of 3H products was not affected by reductions in the concentration of cal- cium in the perfusion medium. These results are comparable to those observed when monitoring DA release from slices of the corpus striatum preloaded with [3H]DA (see introductory section). It thus ap- pears that slices from the prefrontal cortex of the rabbit preloaded with [3H]DA are useful to study the functional characteristics of DA release from mesocortical DA terminals.

Contrary to what has been previously described in the literature (Bannon et al., 1981a,b, 1982; Chiodo et al., 1984), in the present study we dem- onstrated that the stimulation-evoked release of DA from prefrontal cortical slices could be drastically modified by drugs that act on DA receptors. Fur- thermore, the following observations indicate that the stimulation-evoked release of DA from the pre- frontal cortex may be modulated by DA autore-

TABLE 1. Stimulation-evoked overflow of t3H]DA from rabbit prefrontal cortex and corpus striatum

S1 3H Tissue

S2IS1 content (nCi) n

Prefrontal cortex control 3.51 ? 0.14 0.94 t 0.02 64.3 2 4 8 Striatum control 1.36 t 0.09 1.14 t 0.04 485.2 ? 25.7 8

Slices of the prefrontal cortex and of the corpus striaturn from the same rabbits were labeled with [3H]DA and superfused. Slices were stimulated twice (Sl and S2) at 1 Hz and 120 pulses. Stimulation- evoked overflow of 3H was calculated as the percent of tissue 3H present at the moment of stimula- tion. The amount of tissue radioactivity in nanocuries present at the end of the experiment was quan- tified. Shown are mean values & SEM of n rabbits.

J . Neurochem., Vol. 47, No . 3, 1986

868 R. K . TALMACIU ET AL.

TABLE 2. Stimulation-evoked overflow of DA j?om rabbit prefrontal cortex: Effects of apomorphine, LY-171555, nomijensine, and haloperidol

~ -~

s1 s 2 SlIS2 n

A. Low frequency of stimulation ( I Hz, 120 pulses) Control Haloperidol (30 nM) Haloperidol (100 nM) Apomorphine (100 nM) Apomorphine (100 nM) + haloperidol (100 nM) LY 171555 (300 nM) LY171555 (300 nM) + haloperidol (100 nM) Nomifensine (10 pM)

Control Haloperidol (100 nM) Apomorphine (100 nM) Nomifensine (10 pM)

6. High frequency of stimulation (10 Hz, 120 pulses)

3.51 t 0.14 1.77 -c 0.11

3.26 t 0.20 2.95 t 0.63 3.47 2 0.52 3.84 t 0.20 3.65 ? 0.24

3.16 t 0.20

4.95 i- 0.47 3.28 c 0.47 4.98 i- 0.78 5.00 t 0.16

3.29 i- 0.15 2.04 t 0.25 4.01 k 0.25 1.44 ? 0.15 2.80 f 0.63 1.12 t 0.20 4.20 f 0.18 8.00 f 0.37

4.87 t 0.45

3.10 2 0.63 5.21 2 0.79

10.6 2 0.90

0.94 t 0.02 1.15 0.050 1.27 f 0.04b 0.42 2 0.03" 0.95 f 0.05'' 0.32 ? 0.0Ib 1.10 F 0.10b 2.25 ? 0.09b

0.99 f 0.05 1.58 i 0.08b 0.61 i 0.04b 2.24 i- 0.25"

17 8 7

15 3 4 3 9

~ ~~~~

Slices of the prefrontal cortex were labeled with [ 3 H ] D P ~ and superfused. Slices were stimulated twice (S1 and S2) either at 1 Hz, 120 pulses or at 10 Hz, 120 pulses. Drugs were added 20 min before S2. Results are expressed as the percent of tissue 3H released by stimulation at S1 and S2. S2/S1 ratios were calculated. Shown are means f SEM of n rabbits.

Significantly different from its respective control at "p << 0.05; bp < 0.01.

ceptors: (1) Apomorphine and LY-171555 inhibited the stimulation-evoked release of DA and this inhi- bition was antagonized by haloperidol. (2) The de- gree of inhibition of DA release produced by apo- morphine was much greater at low than at high stimulation frequencies. (3) Haloperidol-induced fa- cilitation of the stimulation-evoked release of DA was frequency-dependent. Greater facilitation of release was obtained at higher than at lower stimu- lation frequencies.

Recently, release modulatory DA receptors have been demonstrated in mesocortical DA neurons projecting to the rat entorhinal cortex (Plantje et al., 1985). These investigators demonstrated that LY-171555, a DA D-2 receptor agonist, inhibits [3H]DA release from the entorhinal cortex, an ef-

G 3'0 100 300 1000

APOMORPHINE (nM)

FIG. 2. Apomorphine-induced inhibition of DA release from rabbit prefrontal cortical slices: antagonism by haloperidol. Stimulation-evoked (1 Hz, 120 Dukes) release of 3H was

fect antagonized by ( -)-sulpiride. These observa- tions on the entorhinal cortex as well as ours in the prefrontal cortex suggest that mesocortical DA neurons of the rat and rabbit projecting to the en- torhinal and prefrontal cortex, respectively, appear to have release modulatory autoreceptors, most likely of the D2 subtype.

Bannon and co-workers (1981a,h, 1982, 1983) and Chiodo et al. (1984) reported that mesocortical DA neurons have more rapid turnover and firing rates than mesolimbic or nigrostriatal DA neurons. In addition, these authors failed to observe autore- ceptor-mediated modulation of DA synthesis or firing rates in the mesocortical DA neurons. On the other hand, the results of Plantje et al. (1985) and our results suggest that DA release from rat and rabbit mesocortical DA neurons could be modu- lated by DA autoreceptors, These discrepancies could be explained as follows: mesocortical DA neurons may have nerve terminal release modula- tory DA receptors, but may lack synthesis and/or impulse modulatory DA receptors. However, Anden et al. (1983) demonstrated turnover rate mod- ulatory DA autoreceptors in mesocortical neurons innervating the rostra1 cortex. It might also be pos- sible that because of the rapid intrinsic firing rates of mesocortical DA neurons, the effects of DA ago- nists on autoreceptor-mediated events would be drastically reduced despite the presence of autore- ceptors in these neurons. In fact, autoreceptor-me- diated inhibition of DA release by apomorphine was greatly decreased when the prefrontal cortex slices were stimulated at frequencies (10 Hz) com-

measured from slicesof the rabbit prefrontal cortex. The ef- fects of different concentrations of apornorphine on DA re- lease were studied in the absence (0) and in the presence (0) of 30 nM haloperidol. Shown are mean values t SEM of at least four rabbits per group. Significantly different at *p < 0.05; "p < 0.01,

parable to the firing rates reported for these neu- rons in viva (present study). favor with this hy- POthesis are the observations Of Shepard and German (1984) and of Loughlin and Fallon (1984). These investigators suggested the existence of two

J . Neurochem.. Vo l . 47, N o . 3, 1986

DOPAMINE AUTORECEPTORS IN PREFRONTAL CORTEX 869

subpopulations of mesocortical DA neurons: a me- dial fast-firing group with a low sensitivity to apo- morphine and a lateral slow-firing group with a high sensitivity to apomorphine. The medial group projects exclusively to cortical regions and the lat- eral group to the cortical, limbic, and striatal re- gions. Against this second possibility is the obser- vation that haloperidol is less effective in enhancing the turnover rates of mesocortical DA neurons than of other DA neurons (Bannon et al., 1982, 1983; Chiodo et al., 1984). However, it is possible that nearly maximal turnover rates are already present in these neurons prior to neuroleptic treatment. Furthermore, the facilitatory effect of DA antago- nists on DA release at high stimulation frequencies is reduced if prolonged periods of rapid stimulation rates are applied (Hoffmann and Cubeddu, 1982).

The mechanism(s) by which some mesocortical DA neurons have faster firing rates than meso- limbic or mesostriatal DA neurons is unknown. It has been proposed that the lack of impulse-modula- tory DA autoreceptors in mesocortical neurons is responsible for the rapid firing rates (Bannon et al., 1981a,b, 1982, 1983; Chiodo et al., 1984). However, a greater ratio of excitatory to inhibitory inputs to mesocortical DA neurons compared to other DA neurons may determine the faster firing rates of the mesocortical neurons.

In summary, our findings in the prefrontal cortex are quite similar to those reported in the striatum, and suggest that activation of DA autoreceptors by exogenously added agonists or by endogenous DA may modulate DA release. There are, however, other aspects that are worth considering. First, the EC5, for apomorphine in inhibiting DA release from the prefrontal cortex is two to three times greater than that reported in the striatum in our laboratory (Hoffmann and Cubeddu, 1984) and by others (Hertting et al., 1980). Second, a greater percentage of tissue 3H is released from the rabbit prefrontal cortex than from the rabbit striatum under identical stimulation conditions (present study). Third, no- mifensine produced a greater increase in the stimu- lation-evoked overflow of DA from the prefrontal cortex than from the striatum (Cubeddu et al., 1983). These experimental observations suggest that although release modulatory autoreceptors are present in the mesocortical DA neurons these re- ceptors may be less sensitive to inhibition by en- dogenous DA or DA agonists than those present in the striatal DA neurons. This reduced sensitivity might be the consequence of an intense activation of the autoreceptors by synaptic DA as a conse- quence of the rapid firing rates (receptor desensiti- zation). Differences in receptor reserve may also account for these results.

Acknowledgment: This work was supported by grants from CONICIT S1-1425 to I . S . Hoffmann, CDCH

F-02.3Bl to R . K. Talmaciu, and NIH Grant I-RO1- NS21645-01A1 to L. X. Cubeddu. The technical assis- tance of Mr. Rafael Clavo and Adelaida Matos is highly appreciated.

REFERENCES And& N. E., Grabowska-Anden M., and Liljenberg B. (1983)

On the presence of autoreceptors on dopamine neurons in different brain regions. J . Neural Transm. 57, 129-137.

Bannon M. J., Bunney E. B., and Roth R. H. (1981~) Mesocor- tical dopamine neurons: rapid transmitter turnover com- pared to other brain catecholamine systems. Bruin Res. 218,

Bannon M. J., Michaud R. L., and Roth R. H. (1981b) Meso- cortical dopamine neurons: lack of autoreceptors modu- lating dopamine synthesis. Mol. Pharmacol. 19, 270-275.

Bannon M. J., Reinhard J. F., Jr., Bunney E. B., and Roth R. H. (1982) Unique response to antipsychotic drugs is due to absence of terminal autoreceptors in mesocortical dopa- mine neurons. Nature 296, 444-446.

Bannon M. J . , Wok M. E., and Roth R. H. (1983) Pharmacology of dopamine neurons innervating the prefrontal, cingulate and piriform cortices. Eur. J . Phurmacol. 91, 119-125.

Brown R. M., Crane A. M., and Goldman P. S . (1979) Regional distribution of monoamines in the cerebral cortex and me- socortical striatus of the rhesus monkey: concentrations and in vivo synthesis rates. Bruin Res. 168, 133-150.

Chiodo L . A , , Bannon M. J., Grace A. A , , Roth R. H. , and Bunney B. S. (1984) Evidence for the absence of impulse- regulating somatodendrite and s ynthesis-modulating nerve terminal autoreceptors on subpopulation of mesocortical dopamine neurons. Neuroscience 12, 1 - 16.

Cubeddu L . X. and Hoffmann I. S. (1982) Operational charac- teristics of the inhibitory feedback mechanism for regulation of dopamine release via presynaptic receptors. J . Phur- macol. Exp. Ther. 223, 497-501.

Cubeddu L . X. and Hoffmann I. S. (1983) Frequency-dependent release of acetylcholine and dopamine from rabbit striatum: its modulation by dopaminergic receptors. J . Neurochem. 41, 94-101.

Cubeddu L. X . , Hoffmann I. S. , and James M. K. (1983) Fre- quency-dependent effects of neuronal uptake inhibitors on the autoreceptor-mediated modulation of dopamine and acetylcholine release from the rabbit striatum. J . Phar- m a d . Exp. Ther. 226, 89-94.

Farnebo L. 0. and Hamberger B. (1971) Drug-induced changes in the release of 3H-monoamines from field-stimulated rat brain slices. Acta Physiol. Scand. 84, 35-44.

Hertting G., Zumstein A., Jackisch R., Hoffman I., and Starke K. (1980) Modulation by endogenous dopamine of the re- lease of acetylcholine in the caudate nucleus of the rabbit. Naunyn Schmiedebergs Arch. Pharmacol. 315, 1 1 1 - 1 17.

Hoffmann I. S. and Cubeddu L . X. (1982) Rate and duration of stimulation determine presynaptic effects of haloperidol on dopaminergic neurons. J . Neurochem. 39, 585-588.

Hoffmann I . S. and Cubeddu L. X. (1984) Differential effects of bromocriptine on dopamine and acetylcholine release mo- dulatory receptors. J . Neurochem. 42, 278-282.

Kamal L. A, , Arbilla S. , and Langer S. Z. (1981) Presynaptic modulation of the release of dopamine from the rabbit cau- date nucleus: differences between electrical stimulation, amphetamine and tyramine. J . Pharmacol. Exp. Ther. 216,

Lindvall O., Bjorklund A., Moore R. Y., and Stenevi U. (1974) Mesencephalic dopamine neurons projecting to neocortex. Brain Res. 81, 325-331.

Lindvall O., Bjorklund A., and Divac I. (1977) Subcortical af- ferents to the prefrontal cortex: organization of mesen- cephalic dopaminergic and mediodorsal thalamic projec- tions. Acta Physiol. Scand. Suppl. 452, 35-38.

Loughlin S. E. and Fallon J. H. (1984) Substantia nigra and ven-

376-382.

592 - 598.

J . Neurorhem., Vol. 47, No. 3 , 1986

870 R. K . TALMACIU ET AL.

tral tegmental area projections to cortex: topography and collateralization. Neuroscience 2, 425-435.

Plantje J. F., Dijcks F. A,, Verheij den F. H. M., and Stoof J. C. (1985) Stimulation of D-2 doparnine receptors in rat meso- cortical areas inhibits the release of 3H-dopamine. Eur. J . Pharmacol. 114, 401 -402.

Shepard P. D. and German D. C. (1984) A subpopulation of mesocortical dopamine neurons possesses autoreceptors. Eur. J . Pharmcicol. 98, 455-456.

Starke K.. Reirnann W., Zumstein A,, and Hertting G. (1978) Effect of dopamine receptor agonists and antagonists on re- lease of dopamine from rabbit caudate nucleus in vitro. Naunvn Schmiedebergs Arch. Pharmacol. 305, 27-316.

Tepper J . M., Nakamura S., Young S. J.. and Groves P. M . (19844 Autoreceptor-mediated changes in dopaminergic

terminal excitability: effects of striatal drug infusions. Brain Res. 309, 317-333.

Tepper J. M., Young S. J. , and Groves P. M. (19846) Autore- ceptor-mediated changes in dopaminergic terminal excit- ability: effects of increases in impulse flow. Brain Res. 309,

Tepper J. M., Groves P. M., and Young S. J. (1985) The neuro- pharmacology of the autoinhibition of rnonoamine release. Trends Pharrnacol. Sci. 6, 251 -256.

White J. W. and Wang R. Y. (1984) A10 dopamine neurons: role of autoreceptors in determining firing rate and sensitivity to dopamine agonists. Life Sci. 34, 1161-1 170.

Zumstein A,, Karduck W., and Starke K. (1981) Pathways of dopamine metabolism in the rabbit caudate nucleus in vitro. Naunyn Schmiedebergs Arch. Pharmacol. 316, 205-217.

309-3 16.

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