Serotonin microinfusion into the ventral tegmental area increases accumbens dopamine release

Brain Research Euiletin, Vat. 23, pp. 541-547.

0361-9230/89

0 Pergamon Press plc, 1989. Printed in the U.S.A.

$3.00 i

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Serotonin Microinfusion Into the Ventral Tegmental Area Increases Accumbens Dopamine Release X.-M.

GUAN

AND W. J. MCBRIDE’

Departments of Psychiatry and Biochemistry, Institute of Psychiatric Research Indiana University School of Medicine, Indianapolis, IN 46202-4887

Received

19 December

1988

X.-M. AND W. J. MCBRIDE. Serotonin microinfusion into fhe ventral fegmental area increases accumbens dopnmine re6euse. BRAIN RES BULL 23(6) 541-547, 1989. -The effects of microinfusion of serotonin (5-HT) agents as well as glutamate and GUAN,

muscimol into the ventral tegmental area (VTA) on dopamine (DA) release in the ipsilateral nucleus accumbens (ACC) were investigated in freely moving rats, using a push-pull perfusion procedure. The baseline values for DA, 3,4~~hydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (S-HIAA) were approximately 0.24, 8.4, 2.1 and 2.7 pmoY15 min, respectively, in the push-pull perfusate of the ACC. When microinfused into the VTA, glutamate (0.74 pg) significantly @<0.05) increased the contents of DOPAC (110%) and HVA (90%) over baseline levels in the perfusate. On the other hand, 0.5 pg muscimol (a y-amino-n-butyric acid, GABA, agonist) significantly, QKO.05) decreased both DA (40%) and DOPAC (20%) levels relative to baseline values. Administration of 2 pg 5-HT into the VTA caused a significant QKO.05) elevation in the perfusate levels of DOPAC (80%) and HVA (70%) over baseline values. A similar effect was obtained with a nonselective 5-HT, agonist but not with a selective 5-HT,, agonist. The results suggest that 5-HT innervations in the VTA may have an excitatory action possibly via 5-HT,, rather than 5-HT,, receptors on the mesolimbic DA system projecting to the ACC and that this DA system may also be regulated by glutamatergic and GABAergic (via GABA, receptors) inputs. In vivo release of dopamine In vivo efflux of monoamine metaboiites Nucleus accumbens Glutamate Muscimol Ventral tegmental area Serotonin I-[3-(T~fluoromethyl)phenyl]-piperazine f rf: )-8-Hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT)

THE functional significance of the mesolimbic dopaminergic projections from the ventral tegmental area (VTA) to the nucleus accumbens (ACC) has received much attention. A large body of experimental evidence has indicated that this dopaminergic system plays an essential role in mediating brain reward functions (8, 32, 47) and is critically involved in the initiation and regulation of motor activities [for a review see (24)]. It is generally believed that the release of DA in the ACC is a key event in eliciting these behavioral changes. Therefore, the study of factors that regulate DA release in the ACC is an important step toward understanding the involvement of this pathway in mediating certain behaviors. Most studies have been directed toward examining presynaptic regulation of DA release under both in vitro (5, 20, 27, 37) and in vivo (38, 43, 44) conditions. However, relatively little is known about the transmitter systems that regulate the activity of the DA neurons in the VTA which project to the ACC. Alterations of DA-mediated behaviors as well as the tissue levels of DA metabolites in the ACC have been demonstrated after intra-VTA administration of neurotensin (16,17), a substance P analogue (6), and an enkephalin analogue (18). ‘Requests for reprints should be addressed to Dr. W. I. McBride, Drive, Indianapolis, IN 46202-4887.

Microinfusion (TFMPP)

Studies of the afferent pathways to the VTA have indicated that this region receives serotonergic innervations from the dorsal and median raphe nuclei (25, 29, 33); as many as 50% of the serotonergic terminals in the VTA make direct synaptic contacts on both dopamine (DA) and non-DA cells (10). Moreover, the VTA has been shown to have high levels of serotonin (38) and possess high affinity serotonin (5-HT) uptake sites (2). In addition, a Ca++ -dependent, K+-stimulated [3H]5-HT release has also been demonstrated in slices of the VTA (2). It has been reported that catecholamine-mediated behavioral hy~ractivity can be generated by lesioning or i~ibitin~ the serotonergic neurons in the raphe nuclei, presumably disinhibiting the mesencephalic catecholamine neurons that coordinate locomotor activities (40,48). in support of these behavioral studies, Herve et al. (11,12) found that electrolytic lesion of both dorsal and median raphe nuclei significantly increased the metabolism of DA in the ACC and concluded that the DA neurons projecting to the ACC were under a tonic inhibitory control by pathways from the lesioned raphe nuclei. On the other hand, Redgrave and Horrell (35) reported that localized perfusion of 5-HT in the ventral

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mesencephalon potentiated medial forebrain bundle electrical self-stimulation, suggesting that 5-HT may be increasing the excitability of DA cell bodies in the VTA region. In a more recent study, Beart and McDonald (2) showed that S-HT enhanced both spontaneous and K+-evoked efflux of 13H]DA in slices of the VTA. Overall, the data suggest that there is a 5-HT input into the VTA which can influence DA neuronal activity. However, the effect of the 5-HT innervation on the activity of DA neurons which project from the VTA to the ACC is not known. The VTA also receives excitatory amino acid transmitter projections via corticofugal pathways (3) and ~-amino-~-buty~c acid (GABA) inputs from the ACC (45). Activity of DA neurons in the VTA can be increased or decreased by iontophoretic administration of glutamate or GABA, respectively (46). Furthermore, locomotor activities of the rat, which are presumably mediated through the mesolimbic DA system, are altered following administration of GABAergic and excitatory amino acid agents into the VTA (4. 23, 34). Microinfusion experiments are becoming more widely used in various psychopharmacological studies. However, there have been few attempts to determine directly the effects that microinfusion of psychoactive compounds may have on the activity of neuronal circuits. The present study was designed to provide neurochemical evidence that DA release in the ACC can be regulated by activation of 5-HT and amino acid receptors in the VTA. This was achieved by monitoring the release of DA in the ACC (using a push-pull cannula) while microinfusion S-HT agents, glutamate and muscimol (a GABA, agonist) into the VTA of freely moving rats. In addition, the major metabolites of DA and 5-HT were also measured in the ACC perfusate since, under certain conditions, changes in their levels can be used to monitor alterations in DA and 5-HT neuronal activity and turnover (36,41). METHOD

Male Wistar rats (250-350 g; Harlan Industries, Indianapolis). were housed in a temperature (2l”Cj and humidity (50%) controlled environment with a 12-hour light-dark cycle (lights on at 0600 hr). Animals had free access to water and standard laboratory rat chow. Rats were anesthetized with sodium pentob~bital (40 mgikg, 1P) and placed in a Kopf stereotaxic apparatus. After the skull was exposed, two burr holes were drilled and a push-pull guide cannula and a microinjection guide cannula (Plastic Products Company, Roanoke, VA) were implanted at 5 mm above the left ACC and 2 mm above the left VTA, respectively, using standard procedures. The coordinates were AP: 1.7 anterior to bregma, L: 1.1, DV: 7.0 mm from the surface of the skull for the ACC; and AP: 5.3 posterior to bregma, L: 0.8, DV: 8.4 mm for the VTA, according to the atlas by Paxinos and Watson (30). Before beginning the release measurements, rats were allowed to recover for at least two days at which time they appeared to be behaving normahy. On the day of the experiment, the rat was removed from its home cage and placed in a cylindrical container (21 cm diameter) for at least one hour prior to insertion of the push-pull cannula through the guide into the ACC. The basic procedure for push-pull perfusion was essentially the same as previously described (9). Briefly, a physiological medium containing (in mM) 120 NaCl, 4.75 KCl, 1.2 KH,PO,, 1.2 MgSO,, 25 NaHCO,, 2.5 CaCl, and 10 D-glucose was equilibrated with 95% 02/5% CO, (final pH 7.3) and circulated through the push-pull perfusion system at a flow rate of 20 pl/min using a peristaltic pump. After an initial washout period of at least 30 minutes, samples were collected sequentially for 15 minutes each into test tubes containing 75 pl 0.1 N HCI. Following collection of 4 fractions for baseline values, a microinjector (Plastic Product Company) back-

filled with normal saline with or without the transmitter agent was inserted into the VTA through the guide with minimal disturbance to the rats. By the time the microinjector was inserted, the rats were usually inactive or asleep. In order to reduce the physical damage to the tissue, the original 28 gauge injector was miniaturized by inserting a piece of 33 gauge stainless steel tube into the tip of the injector and fixing it with solder so that the tip of the 33 gauge tube protruded 2 mm beyond the tip of the 28 gauge tube. A volume of 0.5 ~1 was injected over a IO-min period using a microinfusion pump (SAGE, Cambridge, MA). The injector remained in place for an additional minute before it was withdrawn. Only one microinjection (control or t~atment) was made in each rat and only one experiment was carried out per day. Control experiments were conducted separately among the treatment experiments. ACC per&sate samples were collected before, during and after VTA microinfusion. At the end of each experiment, the K’ concentration of the push-pull perfusion medium was increased to 35 mM to stimulate DA release in the ACC and verify the viability of the DA nerve terminals (9). Data was not used from the rare experiment in which K + -stimulated DA release was not observed. Aliquots (200 p.1) of the ACC perfusate were immediately injected into the HPLC (Bio-Analytical Systems, West Lafayette, IN) with electrochemical detection for measurement of DA. 3,4-dibydroxyphenyiacetic acid (DOPAC), homovan&c acid (HVA) and 5-hydroxyindoieacetic acid (5HIAA) as previously described (26). All the compounds injected into the VTA were dissolved in sterile saline immediately before injection and adjusted to pH 7.3-7.4 with diluted HCl and NaOH. The amount of compounds injected (in salt weight) were 0.74 p,g L-glutamate (Sigma. St. Louis, MO); 0.5 p,g muscimol (Sigma), 2 p.g S-HT creatinine sulfate (Sigma), l-2 p.g (1)-8-hydroxy-2-(di-N-propylamino) tetralin hydrobromide (8-OH-DPAT; BRl, Natick, MA) and l-2 pg I-[3-(trifluoromethyl) phenyll-piperazine (TFMPP; BRI). Microinjection of saline alone produced no noticeable changes in the behavior of the animal whereas microinjection of glutamate. 8OH-DPAT and TFMPP appeared to produce various degrees of arousal. In agreement with published data (14), muscimol consistently produced a strong contralateral circling behavior in the rats. No attempt was made to quantitate the behavioral effects of the microinfused agents. After each experiment, the rat was decapitated and the brain was removed. Coronal sections of 40 pm were cut on a cryostat microtome and stained with cresyl violet. The placements of the push-pull cannula and injector tip were verified histologically under a microscope. The results were considered valid only when both the perfusion cannula and the microinjector were positioned within the designated brain sites. No extensive tissue damage was observed at the push-pull perfusion site except for the narrow cannula track. The data are expressed as percentage of the premicroinfusion baseline values (i.e., the fractions immediateiy preceding the treatment). Statistical analysis was performed on the normalized data using two-way ANOVA (~eatment x time) with repeated measures on one factor; the post hoc Dunnett f-test f2-tailed) was used to determine statistical significance between treatment and control (saline-infused) values. RESULTS

Within the ACC. perfusates HVA and 8.41t0.50,

90 minutes after insertion of the push-pull cannula into the levels of DA, DOPAC, HVA and 5-HIAA in the had stabilized. The baseline values for DA, DOPAC, 5-HIAA were (means + SEM, N = 32-33) 0.24 20.02, 2.05rtO.14 and 2.66?0.10 pmolilfj min. respec-

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Dunnett r-test.

tively. Microinfusion of vehicle into the VTA did not change the amounts of DA and 5-HIAA in the perfusates from the ipsilateral ACC, but it did elevate the amount of DOPAC and HVA by approximately 30% (Figs. l-5). Intra-VTA infusion of 0.74 pg L-glutamate and 0.5 +g muscimol significantly altered the amounts in the ACC perfusates of (a) DA, F(2,9)=7.39, pcO.05, for treatment; F(4,36)=2.83, p
at 45 to 60 minutes for DOPAC and HVA (Fig. 2). Intra-VTA microinfusion of 1 p,g 8-OH-DPAT did not alter the amounts of DA, DOPAC and HVA (Fig. 3) whereas intra-VTA infusion of 1 pg TFMPP significantly increased the contents of DOPAC and HVA in the perfusates of the ACC (Fig. 4). The maximal increase in the levels of DOPAC (100%) and HVA (110%) occurred at 45 and 105 minutes, respectively, after drug administration (Fig. 4). Infusion of 2 kg 8-OH-DPAT into the VTA resulted in an increased amount of HVA (70%) in the ACC perfusate after 60 minutes (Fig. 3). The 2 p,g dose of TFMPP, when infused into the VTA, did not produce any marked further increase in the amount of DOPAC and HVA than was observed with the 1 pg dose (Fig. 4). The levels of 5-HIAA in the perfusate of the ACC were not altered by microinfusion of 5-HT, TFMPP or 8-OH DPAT into the VTA (Fig. 5). DISCUSSION

The present study provides neurochemical evidence that serotonergic innervations in the VTA may exert an excitatory influence on the DA projections from this region to the ACC (Fig. 2) and this effect may be mediated via a 5-HT,, and/or 5-HT, (Fig. 4) rather than a 5-HT,, receptor (Fig. 3). In addition, the present results suggest that excitation and suppression of neuronal activity of DA projections from the VTA to the ACC can be mediated via glutamate and GABA, receptors, respectively (Fig. 1). However, it is not possible to draw any definitive conclusions until a more comprehensive study can be undertaken when specific agonists and antagonists become available. Also, it is not clear from the present data whether the effects on DA neuronal activity by any of the agents are direct or indirect. The present findings that 5-HT in the VTA may have an excitatory control on the mesolimbic DA system are in general agreement with previous studies by Redgrave and Horrell (35), who demonstrated that medial forebrain bundle electrical self-

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FIG. 2. Effect of intra-VTA infusion of 5-HT on the amount of DA. DOPAC and HVA in the perfusate of the ipsilateral ACC. Data are expressed as percentage of the preinfusion baseline values and plotted as means t SEM (N = 4 for 5-HT; N = 5 for control), The intra-VTA infusion is indicated by the arrows. *p
was potentiated by perfusion of S-HT in the ventral mesencephalon and Beart and McDonald (2), who reported that X-IT enhanced the dendritic efflux of 13H]DA in slices of VTA. On the other hand, the present data do not appear to be in agreement with the findings by Herve et al. (I 1.12). which suggested that DA neurons were under tonic inhibitor control by pathways from the dorsal and median raphe nuclei. However, in these latter studies, lesions of the dorsal and median raphe nuclei were used to produce the observed enhanced metabolism of DA. With this experimental approach, both 5-HT and non-5-HT neurons in the raphe nuclei are destroyed and widespread effects are produced which could indirectly influence the observed increased utilization of DA. The existence of subtypes of serotonergic receptors in the brain has been well documented (15,31). The possibility that the 5-HT effects observed in the present study were mediated by a specific subtype of 5-NT receptor was assessed preliminarily by using &OH-DPAT. a selective 5-HT,, a g onist (13,22), and TFMPP, a serotonergic agonist with certain selectivity for the 5-HT,, receptor (1,42). While I p,g TFMPP, like 5-HT. signi~cantly stimustimulation

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FIG. 3. Effect of intra-VTA infusion of X-OH-DPAT on the amount of DA, DOPAC and HVA in the perfusate of the ipsilateral ACC. Data are expressed as percentage of the preinfusion baseline values and plotted as means + SEM (N = 4 for 1 pg 8-OH-DPAT: N = 5 for 2 pg 8-OH-DPAT and control). The intra-VTA infusion is indicated by the arrows. *p
lated the efflux of DOPAC and HVA in the ACC (Fig. 4). a similar dose of X-OH-DPAT (1 pg) had very little effect (Fig. 3). Furthermore. even at the 2 p.g dose, S-OH-DPAT produced only a moderate increase of DOPAC and HVA in the ACC perfusates. Therefore, the action of S-HT on DA neurons in the VTA projecting to the ACC appears to be mediated more likely by 5-HT,, than by S-HT,, receptors. However, the possible involvement of other receptor subtypes cannot be ruied out since TFMPP also has high affinity for 5-HT,o and S-HT, binding sites (I 5). The lack of a consistent finding of elevated DA in the ACC perfusate following glutamate and TFMPP treatment when a consistent and sustained enhanced level of DOPAC was observed (Figs. 1 and 4) is likely due to a combination of reasons. For one, the dopaminergic projections from the VTA are not uniformly distributed within the ACC (28). Secondly, the clearance of the released DA occurs rapidly and effectively due to the active uptake systems, preventing DA from diffusing away from its site of release (7). Consequently, the alteration of DA in the perfusate only represents the changes in the near vicinity of the perfusion site whereas DOPAC and HVA in the perfusate come from both local and more distal areas within the ACC. Therefore, when the placement of push-pull cannuia does not coincide well with the

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FIG. 4. Effect of intra-VTA infusion of TFMPP on the amount of DA, DOPAC and HVA in the perfusate of the ipsilateral ACC. Data are expressed as percentage of the preinfusion baseline values and plotted as means z!zSEM (N =4 for 1 and 2 pg TFMPP; N = S for control). The intra-VTA infusion is indicated by the arrows. *p
VTA projections being affected, any increase in the concentration of DA occurring at a site away from the tip of the push-pull cannula might not be fully detected, while the resulting elevation of DOPAC and HVA levels are readily observed. The inhibition of dopaminergic transmission in the ACC following the in&a-VTA injection of muscimol (Fig. 1) is consistent with electrophysiological results (46), supporting the notion that the DA cells (AlO) are under the inhibitory influence of GABAergic neurons. In addition, the observation that the DA terminals in the ACC were activated after the intra-VTA infusion of glutamate is also in line with the electrophysiological and behavioral studies (34,46). The fact that an elevation and a decrement in the levels of DA or its major metabolites in the pet&sate of the ACC can be detected after intra-VTA microinfusion of a stimulatory (i.e., glutamate) and an inhibitor agent (i.e., muscimol), respectively (Fig. 1). strongly indicates the utility of local perfusion in conjunction with microinfusion techniques in studying the regula-

FIG. 5. Effect of intra-VTA infusion of S-HT, S-OH-DPAT and TFMPP on the levels of S-HIAA in the perfusate of the ipsilateral ACC. Data are expressed as Percentage of the preinfusion baseline values and plotted as means t SEM (N =4-S for each treatment as indicated in Figs. 2-4). The intra-VTA infusion is indicated by the arrows.

tion of neuronal systems in vivo. This applicability was also demonstrated by a recent study (19), in which intra-VTA infusions of haloperidol and DA produced an increase and a transient decrease, respectively, of DOPAC levels in the ACC of anesthetized rats as monitored by in vivo voltammetry. Moreover, it is also evident from the present data that, for the most part, there was a good correlation in the direction of changes between DA and its metabolites in the ACC upon the different treatments in the VTA (Figs. l-4). Because of this correlative relationship and considering the dif~culties for the accurate qu~ti~cation of released DA due to its rapid clearance, the levels of DOPAC and HVA in the perfusate may be a useful index for measuring changes in DA release in vivo under certain experimental conditions. However, it is important to point out that, although the alteration of DOPAC levels in the perfusate may reflect the stimulation or inhibition of DA release under certain circumstances, the time course of detecting such changes is different. The small increase in DA release occurred sooner and lasted for a much shorter period than that for DOPAC and HVA (Figs. 14). This temporal relationship is in good agreement with a previous report showing that a l-minute period of stimulated DA release results in a slow, but prolonged elevation of extracellular levels of DOPAC in the striatum (21). The small increase of DOPAC and HVA in the ACC perfusate

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after vehicle injection in the control experiment (Figs. 1-I) may be due to the mechanical stimulation resulting from the insertion of the injector into the VTA since a similar increase of DOPAC and HVA was seen in other experiments where the injector was lowered into the VTA and no infusion occurred (data not shown). These small elevations in metabolite levels are not likely due to

enhanced arousal since the rats generally remain asleep or at rest during insertion of the microinjector. ACK~O~l.EDGEME~T

Supported in part by AA 03243 and The Association ment of Mental Health Research and Education, Inc.

for the Advance-

REFERENCES I. Asarch, K. B.: Ranson, R. W.; Shih, J. 5-HT-IA and 5-HT-IB selectivity of two phenylpiperazine derivatives: evidence for 5-HT- I B heterogeneity. Life Sci. 361265-1273; 1985. 2. Beart, P. M.; McDonald, D. 5.Hy~oxyt~ptamine and S-hydroxytryptaminergic-dopaminergic interactions in the ventral tegmental area of rat brain. J. Pharm. Pharmacol. 34:591-593: 1982. 3. Christie, M. J.; Bridge, S.; James, L. B.; Beart, P. M. Excitotoxin lesions suggest an aspartatergic projection from rat medial prefrontal cortex to ventral tegmental area. Brain Res. 333:169-172; 1985. 4. Dawbam, D.; Pycock, C. J. Motor effects following application of putative excitatory amino acid antagonists to the region of the mesencephalic dopamine cell bodies in the rat. Naunyn Schmiedebergs Arch. Pharmacol. 318:100-104; 1981. 5. de Beileroche, J. S.; Gardiner, I. M. Cholinergic action in the nucleus accumbens: modulation of dopamine and acetylcholine release. Br. J. Pharmacol. 75:359-365: 1982. 6. Elliott, P. J.: Alpert, J. E.; Bannon, M. J.; Iversen, S. D. Selective activation of mesolimbic and mesocortical dopamine metabolism in rat brain by infusion of a stable substance P analogue into the ventral tegmental area. Brain Res. 363:145-147; 1986. 7. Ewing, A. G.; Wightman, R. M. Monitoring the stimulated release of dopamine with in vivo voltammetry. II: clearance of released dopamine from extracellular fluid. J. Neurochem. 43570-577; 1984. 8. Fibiger. H. C.: Phillips, A. G. Reward. motivation. cognition: psychobiology of mesotelencephalic dopamine systems. In: Bloom. F. E., ed., Handbook of physiology, section 1:The nervous system, vol. IV. Baltimore, MD: American Physiological Society; 1986:647-675. 9. Guan, X.-M.; McBride. W. J. Effects of K~‘-stimulation and precursor loading on the in vivo release of dopamine, serotonin and their metabolites in the nucleus accumbens of the rat. Life Sci. 40: 2579-2586; 1987. IO. Herve, D.; Pickel, V. M.: Hoh, T. H.: Beaudet, A. Serotonin axon terminals in the ventral tegmental area of the rat: fine structure and synaptic input to dop~inergic neurons. Brain Res. 435:71-83: 1987. I I. Herve, D.; Simon, H.: Blanc, G.; LeMoal, M.; Glowinski, J.; Tassin. J. P. Opposite changes in dopamine utilization in the nucleus accumbens and the frontal cortex after electrolytic lesion of the median raphe in the rat. Brain Res. 216:422-428: 1981. 12. Herve, D.: Simon, H.; Blanc, G.; Kisoprawski, A.; LeMoal. M.: Glowinski, J.; Tassin, J. P. Increased utilization of dopamine in the nucleus accumbens but not in the cerebral cortex after dorsal raphe lesion in the rat. Neurosci. Lett. 15:127-133; 1979. 13. Hjorth, S.; Carisson, A.; Lindberg, P.; Sanchez, D.; Wikstrom. I.: Arvidsson, L. E.; Hacksell, U.; Nilsson, J. L. G. 8-Hydroxy2-(di-n-propylamino) tetralin, I-OH-DPAT, a potent and selective simplified ergot congener with central 5-HT-receptor stimulating activity. J. Neural Transm. 55:169-188; 1982. 14. Holmes, L. J.; Wise, R. A. Contralateral circling induced by tegmental mo~hine: anatomical localization, ph~acological specificity, and phenomenology. Brain Res. 326:19-Z; 1985. 15. Hoyer, D. Functional correlates of serotonin 5-HT, recognition sites. J. Recept. Res. 8:59-81; 1988. 16. Kalivas, P. W.; Burgess, S. K.; Nemeroff, C. B.; Prange. A. J. Behavioral and neu~chemical effects of neurotensin microinjections into the ventral tegmental area of the rat. Neuroscience 8:495-505; 1983. 17. Kalivas, P. W.; Nemeroff, C. B.; Prange, A. J. Increase in spontaneous motor activity following infusion of neurotensin into the ventral tegmental area. Brain Res. 229:525-529; 1981. 18. Kdivas, P. W.; Winderlov, E.; Stanley, D.; Breese, G.: Prange, A. J. Enkephalin action on the mesolimbic system: a dopamine-dependent and dopamine-independent increase in locomotor activity. J. Pharmacol. Exp. Ther. 227229-237: 1983.

19. Maidment, N. T.; Marsden. C. A. In viva voltammetric and behavioural evidence for somatodendritic autoreceptor control of mesolimbit dopamine neurones. Brain Res. 338:317-325: 1985. 20. Marien. M.; Brien. J.; Jhamandas. K. Regional release of [‘HI dopamine from rat brain in vitro: effects of opioids on release induced by potassium, nicotine and L-glutamic acid. Can. J. Physiol. Pharmacol. 61:43-60: 1983. 21. Michael. A. C.: Justice. J. 5.. Jr.: Neitl, D. B. In vivo voltammetric determination of the kinetics of dopamine metabolism in the rat, Neurosci. Lett. 56:365-369; 1985. 22. Middlemiss. D. N.; Fozard. J. R. 8-hydroxy-2-(di-n-propylamino) tetralin discriminates between subtype\ of the 5-HT, recognition sites. Eur. J. Pharmacoi. 90:151-153: 1983. 23. Mogenson. G. J.: Wu. M.: Manchanda, S. K. Locomotor activity initiated by microinfusions of picrotoxin into the ventral tegmental area. Brain Res. 161:31 l-319: 1979. 24. Mogenson, G. J.: Jones. D. L.: Yim, C. Y, From motivation to action: functional interface between the limhic system and the motor system. Prog. Neurobioi. 1469-97; 1980. 25. Moore, R. Y.; Halaris. A. E.: Jones, B. E. Serotonin neurons ofthe midbrain raphe: ascending projections. J. Camp. Neurol. I X0:41 7437; 1978. 26. Murphy, J. M.; McBride, W. J.; Lumrng, L.; Li. T.-K. Regional brain levels of monoamines in alcohol-prefe~ing and nonprefe~ing lines of rats. Pharmacol. Biochem. Behav. l&145-149: 1982. 27. Nurse. 5.; Russell. V. A.: Taljaard. J. J. F. a-2 and P-adrenoceptor agonists modulate [‘Hldopamine release from rat nucleus accumbens slices. Neurochem. Res. 9:1231-1238; 1984. 28. Oades, R. D.: Halliday. G. M. Ventral tegmental (A101 system: neurobiology: 1. Anatomy and connectivity. Brain Res. Rev. 12: 117-165: 1987. 29. Parent, A.; Descarries. L.: Beaudet. A. Organization of ascending serotonin systems in the adult rat brain. A radioautographic study after lntraventricular administration of [‘HI 5.hydroxytrypt~ine. Neuroscience 6115-138: 1981. 30. Paxinos, G.; Watson. C. The rat brain in stereotaxic coordinates. 2nd ed. New York: Academic Press; 1986. 31. Peroutka. S. J. Serotonin receptor subtypes. IS1 Atlas Sci. Phannacol. 2: 13: 1988. 32. Phillips. A. G. Brain reward circuitry: A case for separate systems. Brain Res. Bull. 12:195-201: 1984. 33. Phillipson. 0. T. Afferent projections to the ventral tegmental area of Tsai and interfascicular nucleus: a horseradish peroxidase study in the rat. J. Comp. Neurol. 187:I 17-144: 1979. 34. Pycock, C. J.; Dawbam. D. Acute motor effects of N-methylD-aspartic acid and kainic acid applied focally to mesencephalic dopamine cell body regions in the rat. Neurosci. Lett. 18:85-90: 1980. 35. Redgrave, P.; Horrell, R. I. P(~tentiation of central reward by localized perfusion of acetylcholine and 5-hydroxytryptamine. Nature 262:305-307; 1976. 36. Roth, R. H.; Murrin, L. C.; Walters, J. R. Central dopaminergic neurons: effects of alterations in impulse flow on the accumulation of dihydroxyphenylacetic acid. Eur. J. Pharmacol. 36: 163-l 7 1; 1976. 37. Rowell, P. P.; Carr. L. A.: Gamer, A. C. Stimulation of [‘H] dopamine release by mcotine in rat nucleus accumbens. J. Neurothem. 49:1449-1454; 1987. 38. Ruggeri, M.: Ungerstedt, U.: Agnati, L.; Mutt, V.; Harfstrand, A.; Fuxe. K. Effects of choiecystokinin peptides and neurotensin on dopamine release and metabolism in the rostra1 and caudai part of the nucleus accumbens using intracerebral dialysis in the anaesthetized rat. Neurochem. Int. 10:509-520: 1987. 39. Saavedra. .I. M.: Brownstein. M.: Palkovits, M. Serotonin distribu-

RE~ULA~ON

547

OF DOPAMINE RELEASE

tion in the iimbic system of the rat. Brain Res. 79:437-441; 1974. 40. Sainati, S. M.; Lorens, S. A. Intra-raphe muscimol induced hyperactivity depends on ascending serotonin projections. Pharmacol. Biochem. Behav. 17:973-986; 1982. 41. Shannon, N. J.; Gunnet, J. W.; Moore, K. E. A comparison of biochemical indices of %hydroxytryptaminergic neuronal activity following electrical stimulation of the dorsal raphe nucleus. J. Neurochem. 47:958-965; 1986. 42. Sills, M. A.; Wolfe, B. B.; Fraer, A. Determination of selective and nonselective compounds for the 5-HT,, and 5-HT,, receptor subtypes in rat frontal cortex. J. Pharmacol. Exp. Ther. 231:480-487; 1984. 43. Voigt, M. M.; Wang, R. Y. In vivo release of dopamine in the nucleus accumbens of the rat: m~ulation of cholecystokinin. Brain Res. 296: 189-193; 1984. 44. Voigt, M. M.; Wang, R. Y.; Westfall, T. C. The effects of

45.

46.

47.

48.

cholecystokinin on the in vivo release of newly synthesized [sH] dopamine from the nucleus accumbens of the rat. J. Neurosci. 527442749; 1985. Walaas, I.; Fonnum, F. Biochemical evidence for y-aminobutyratecontaining fibres from the nucleus accumbens to the substantia nigra and ventral tegmental area in the rat. Neuroscience 5:63-72; 1980. White, F. J.; Wang, R. Y. A10 dopamine neurons: role of autoreceptors in determining firing rate and the sensitivity to dopamine agonists. Life Sci. 34:1161-1170; 1984. Wise, R. A.; Bozarth, M. A. Brain reward circuitry: Four circuit elements “wired” in apparent series. Brain Res. Bull. 12:203-208; 1984. Yamamoto, T.; Utki, S. Effects of drugs on hyperactivity and aggression induced by raphe lesions in rats. Pharmacol. Biochem. Behav. 9:821-826; 1978.