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Microinjection of a glutamate antagonist into the nucleus accumbens reduces psychostimulant locomotion in rats
Neuroscience Letters, 103 (1989) 213 218 Elsevier Scientific Publishers Ireland Ltd.
213
NSL 06260
Microinjection of a glutamate antagonist into the nucleus accumbens reduces psychostimulant locomotion in rats Luigi Pulvirenti*, Neal R. Swerdlow and George F. Koob Division of Preclinieal Neuroscience and Endocrinology, Research Institute of Scripps Clinic, La Jolla, CA 92037 (U.S.A.) Received 20 January 1989; Revised version received 22 April 1989; Accepted 25 April 1989) Key words:
L-Glutamic diethylester; Dopamine, Psychostimulant drug; Nucleus accumbens; Locomotion
In order to study a possible modulatory effect of glutamatergic afferents to the nucleus accumbens (NAC) on psychostimulant-induced locomotion, L-glutamic acid diethyl ester (GDEE), a glutamate antagonist, was injected in the NAC of rats acutely treated with cocaine, amphetamine or caffeine. GDEE at the doses of 5, 10, and 20/~g/side significantly reduced locomotion induced by cocaine (20 mg/kg, i.p.). Amphetamine-induced hyperactivity was also reduced by GDEE, whereas caffeine-induced hyperactivity was not significantly decreased by GDEE. This suggests that glutamatergic afferents to the NAC modulate the effects of psychostimulants and also dopamine function in the mesolimbic system.
The nucleus accumbens (NAC) of the ventral striatum has been shown to be a critical structure for locomotor activity in the rat [17]. The neuronal circuit involved in such behavior includes dopaminergic afferents from the ventral tegmental area (VTA) converging to GABAergic neurons within the NAC which then project to a ventral pallidal region [17]. Primary afferents to the NAC come also from a number of limbic structures, of which the amygdala and the hippocampus provide the densest input [7, 8]. The hippocampal afferents have been shown to be glutamatergic and behavioral studies suggest that this pathway contributes to the modulation of exploratory activity [13]. Psychostimulant drugs such as cocaine and amphetamine exert their behaviorally activating effects by facilitating dopaminergic transmission in the NAC [9, 10]. Lesions of this structure with 6-hydroxydopamine (6-OHDA) and local administration of dopamine antagonists into the NAC prevent cocaine and amphetamine locomotion but are not effective in c o n n t o r a c ' t i n o o~ffoino_ind,,oc~dc t l m l d n t i o n r171. *Visiting scientist from: 3rd Dept. of Neurology, University of Pavia, Italy. Correspondence: G.F. Koob, Division of Preclinical Neuroscience and Endocrinology, Research Institute of Scripps Clinic, 10666 No. Torrey Pines Rd, La Jolla, CA 92037, U.S.A. 0304-3940/89/$ 03.50 © 1989 Elsevier Scientific Publishers Ireland Ltd.
214 Glutamate receptors in the mammalian brain are classified as kainate, quisqualate and N-methyI-D-aspartate type according to their ligands [12]. The quisqualate antagonist e-glutamic acid diethyl ester (GDEE) [2], when injected in the NAC, has been shown to reduce both novelty-induced locomotion and the hyperactivity induced by injection of carbachol in the dentate gyrus of the hippocampus [14]. It is also noteworthy that the quisqualate receptor subtype plays an important role in locomotion induced by infusion of glutamate agonist into the NAC [3]. In the current study, we examined whether hyperlocomotion induced by psychostimulants was also modulated by glutamatergic afferents to the NAC. Our findings suggest that these N A C glutamatergic afferents are critical substrates for cocaine and amphetamine-stimulated locomotion, but are not critically involved in the locomotoractivating properties of caffeine. Male albino Wistar rats (240 260 g, Charles River) were housed in groups of 3, and exposed to a normal 12-h l i g h t , l a r k cycle, with free access to food and water. All rats were anesthetized with pentobarbital (50 mg/kg, i.p.) and secured in a K o p f stereotaxic instrument with the toothbar 5 m m above the interaural line. The animals were then implanted with bilateral 23 gauge 10 m m steel cannulae aimed 3 mm above the NAC at coordinates AP + 3.2, L _+ 1.7, DV - 4.8 (skull surface), which were fastened to the skull with dental cement and sealed with a 10 m m stylet wire. Locomotor testing for all animals began one week after surgery using 16 wire cages as described previously [6]. Each cage measured 36 x 25 x 20 cm with twin photocell beams across the long axis 2 cm above the cage floor. One day before testing, all animals were familiarized with the photocell cages by placing them individually into the cages for 180 min. On a testing day, animals were placed in the photocell cages for 90 min. Subsequently all animals received an intra-accumbens injection (I Ill over 3 rain) of either saline or G D E E (Sigma, St Louis, MO) through 30 gauge injectors fashioned to extend 3 m m beyond the ventral tip of the cannula. In the first experiment, hyperactivity induced by cocaine (20 mg/kg IP) was examined after administration of G D E E at the doses of 5, 10 and 20/tg/side. In the second experiment, the most effective dose of G D E E (20/tg/side) was tested after cocaine, amphetamine and caffeine hyperactivity where the doses induced approximately the same amount of stimulation in 10 min (cocaine, 10 mg,;kg i.p., amphetamine 0.75 mg/kg s.c., or caffeine benzoate 20 mg/kg s.c.). Injection of one of these drugs or saline (in a volume of 1 ml/'kg) was performed immediately after intracranial injection in both experiments. All drugs were dissolved in saline vehicle. Immediately following the above treatments, animals were replaced in the photocell cages and locomotor activity was recorded for l0 min. This time was chosen due to the short duration of action of G D E E suggested by previous studies [14]. Following completion of behavioral testing, all animals were sacrificed by overdose of pentobarbital, and perfused through the heart with cold 10% formalin/saline. The brains were then removed and 30/lm frozen sections were cut in a frontal plane using a rotary microtome and stained with Cresyl violet. Cannulae sites were assessed without knowledge of behavioral results.
215 The site of injection as determined by histological examination is shown in Fig. I. Cannula, in general, fell within the NAC at locations 2.2 to 3.6 mm anterior to bregma. Fig. 2 shows the effect of G D E E on cocaine-induced locomotion. One-way ANOVA with repeated measures on dose of G D E E indicates that G D E E attenuated cocaine hyperactivity in a dose-dependent manner (F3,31=3.40; P<0.05). Post-hoc dose comparison revealed that this effect o f G D E E was statistically significant at the doses of 10 and 20 pg (P < 0.05, Newman-Keul's test). Figures in the columns represent number of animals in each group. Fig. 3 shows the effect of G D E E (20/tg/side) on cocaine-, amphetamine- and caffeine-induced locomotion. A two-way factorial ANOVA revealed that there was a main effect of G D E E (FI,19 = 11.71, P<0.001), the main effect of drug (cocaine vs amphetamine vs caffeine) was not significant (F2,19= 1.27, N.S.), with a significant interaction (F2,19=3.36, P=0.05). Comparison at the various levels revealed that G D E E after cocaine and amphetamine treatment was significant (F1,19=17.96, P<0.001 and F1,19=8.51, P < 0 . 0 5 , respectively), but not after caffeine treatment (F1,19=0.32, N.S.). Figures in the columns represent number of animals in each group.
Fig. 1. Histologicallocalizationofcannula placement. For coordinates see text.
216
5
0
Dose
10
2rl
of GDEE(yglside)
Fig. 2. Effect of G D E E , a glutamate antagonist, on cocaine-induced locomotion (20 mg/kg IP). Value,, represent mean +S.E.M. * P < 0.05 Neuman Keul's test vs control.
I loft
-2
200
Vehicb F I I
k
!I ,2
GEIEE 20Hglsidel
- ]
,ili
1
[
L V~!hi!:b!
c
[
GOEEt20~(],sldf,:
[_
bK:
11 Vehicle
GOEEl20pglside)
Fig. 3. Effec! of GDEE, a glutamate antagonist on cocaine- (lO mg/kg, J.p., A), amphetamine- (0.?5 rag,,' kg, s.c., B) and caffeine-induced (20 mg/kg, s.c., C) locomotion. Values represent mean _+S.E.M. *P < 0.05, ** P < 0.001 vs respective control.
217
The present results suggest that the stimulatory activity of amphetamine and cocaine, but not caffeine, are modulated by glutamate activity within the NAC. Several studies have suggested an interaction between glutamate and dopamine in the NAC. Biochemical studies have shown that dopamine release is stimulated in vitro by infusion of glutamic acid [16]. Further, the increase in locomotor activity following microinjections of glutamate agonists in the NAC is blocked by either systemic or intraNAC injection of dopaminergic antagonists [3]. This glutamate effect may also modulate postsynaptic NAC dopamine activity since intraNAC injection of glutamate antagonists suppress locomotion induced by direct local administration of dopamine [5]. Cocaine and amphetamine are psychostimulant drugs known to stimulate locomotion by inhibiting dopamine reuptake [11] and promoting dopamine release from presynaptic terminals [4] within the NAC [9, 10]. NAC glutamatergic afferents originate from limbic structures including the hippocampus and the amygdala [7, 8]. The fact that cocaine and amphetamine hyperactivity is reduced by GDEE injections suggests that NAC glutamatergic input is of importance in the confluence of afferent information eliciting motor activation induced by psychostimulants. Caffeine-induced hyperlocomotion is apparently independent of this NAC glutamate activity. Caffeine is an antagonist at central adenosine receptors [1] and its site of action seems to rely mainly on sites outside the mesolimbic system [17]. The present data provide further support to this hypothesis, in that the glutamatergic activity in the NAC is not critical for the hyperlocomotion induced by caffeine. Anatomical studies have provided a considerable amount of information regarding glutamate innervation of the NAC, showing the amygdala and the hippocampus the major inputs [7, 8]. Behavioral and electrophysiological studies, however, have suggested that a predominant role is played by the hippocampus [15, 18]. The hippocampus-accumbens pathway was proposed as a link modulating dopamine-dependent behavior [15]. The hippocampus may play a key role in limbic motor integration, as a functional gating mechanism translating motivation to motion (for instance goaldirected locomotor responses). Our data further support this hypothesis, showing that pharmacological activation of the mesolimbic system is modulated by glutamic acid. The NAC has been implicated in the pathophysiology of schizophrenia, depression and drug-seeking behavior: whether limbic glutamate inputs play a role in these conditions is a matter for future investigation. This work was supported in part by NIDA Grant DA 04398 (G.F.K.) and a Sandoz Fellowship (L.P.) (Sandoz Ltd, Basel, CH).
1 Daly, J.W., Burns, R.E. and Snyder, S.H., Adenosine receptors in the central nervous system: relation to central action of methylxanthines, Life Sci., 28 (1981) 2083 2097. 2 Davies, J. and Watkins, J.C., Selective antagonism of amino acid-induced and synaptic excitation in the cat spinal cord, J. Physiol. (Lond.), 297 (1979) 631 635. 3 Donzanti, B.A. and Uretsky, N.J., Effects of excitatory amino acids on locomotor activity after bilateral microinjections into the rat nucleus accumbens: possible dependence on dopaminergic mechanisms, Neuropharmacology, 22 (1983) 971 981.
218 4 Farnebo, L.O., Effect of d-amphetamine on spontaneous and stimulation-induced release ofcatecholamines, Acta Physiol. Scand., 371 ( 197 l) 45 52. 5 Hamilton, M.tt., deBelleroche, J.S., Gardiner, J.M. and Herberg, L.J., Stimulatory effect of N-methyl aspartate on locomotor activity and transmitter release from rat nucleus accumbens, Pharmacol. Biochem. Behav., 25 (1986) 943 948. 6 ,Ioyce, A.M. and Koob, G.F., Amphetamine-, scopolamine- and caffeine-induced locomotor activity tollowing 6-OHDA lesions of the mesolimbic dopamine system, Psychopharmacology, 73 (1981) 311 313. 7 Kelley, A.E. and Domesick. V.B.. The distribution of projection from the hippocampal li~rmation to the nucleus accumbens in the rat: an anterograde and retrograde horseradish peroxidase study, Neuroscience, 7 (1982) 2321 2335. Kelley, A.E., Domesick, V.13, and Nauta, W.J.H., The amygdaloslriatal projections in lhe rat an anatomical study by anterograde and retrograde tracing methods, Neuroscience, 7 (1982) 615 630. 9 Kelly, P.I|. and lversen, S.D., Selective 6-OHDA-induced destruction of mesolimbic dopamine neurons: abolition of psychostimulanl induced locomotor activity in rats, Eur. J. Pharmacol., 40 (1976) 45 56, 10 Kelly, P.H.. Seviour, P. and lversen, S.D., Amphetamine and apomorphine responses in the rat following 6 - O H D A lesions of the nucleus accumbens septi and corpus striatum, Brain Res.. 94 (1975) 5O7 522. II Komiskey, H.I... Miller, D.D., LaPidus, J. and Patil, P.N., The isomers of cocaine and lropocaine: effect on ~lt-catecholamine uptake by rat brain synaptosomes, Life Sci., 21 (1977) 1 I17 1121. 12 McLennan, H.. Hicks, T.P. and Hall, I--l.J., Receptors for the excitatory amino acids. In: F.V. DeFeudis and P. Mandel (Eds.), Advances in Biochemical Psychopharmacology. Amino Acid Neurotransmitters, Vol. 29, Raven, New York, 1981, pp. 213 221. 13 Mogenson, G.J. and Nielsen, M., Neuropharmacological evidence that the nucleus acculnbens and subpallidal region contribulc to exploratory locomotion, Behav. Neural Biol., 42 {1984) 52 60. 14 Mogenson, G J . and Nielsen, M., A study of the contribution of hippocampal-accumbens-subpallidal projections to locomotor activity, Behav. Neural Biol., 42 (1984) 38 51. 15 Mogenson, G.J., Limbic-motor integration. In Progress in Psychobiology and Physiological Psychology, Vol 12, Academic Press, New York, 1987, pp. 117 170. 16 Roberts, P.J. and Anderson. S.D., Stimulatory effect of L-glutamate and related amino acids on pH]dopamme release from the rut striatum in an in vitro model for glutamate action, J. Ncurochem., 32(1979) 1539 1545. 17 Sx~erdlow, N.R.. Vaccarmo, F'..I., Amalric, M. and Koob, G.E., The neural substrates li)r the motoractivating properties of psychostimulants: a review of recent findings, Pharmacol. Biochem. Behav., 25 (1986) 233 248. IS Yang, C . R and Mogenson, G.J., Elcctrophysiological responses of neurones in the nucleus accumbens to hippocampal stinlulation and the attenuation of excitatory responses by the mesolimbic dopaminergic system, Brain Res., 324 (1984) 69 84.
213
NSL 06260
Microinjection of a glutamate antagonist into the nucleus accumbens reduces psychostimulant locomotion in rats Luigi Pulvirenti*, Neal R. Swerdlow and George F. Koob Division of Preclinieal Neuroscience and Endocrinology, Research Institute of Scripps Clinic, La Jolla, CA 92037 (U.S.A.) Received 20 January 1989; Revised version received 22 April 1989; Accepted 25 April 1989) Key words:
L-Glutamic diethylester; Dopamine, Psychostimulant drug; Nucleus accumbens; Locomotion
In order to study a possible modulatory effect of glutamatergic afferents to the nucleus accumbens (NAC) on psychostimulant-induced locomotion, L-glutamic acid diethyl ester (GDEE), a glutamate antagonist, was injected in the NAC of rats acutely treated with cocaine, amphetamine or caffeine. GDEE at the doses of 5, 10, and 20/~g/side significantly reduced locomotion induced by cocaine (20 mg/kg, i.p.). Amphetamine-induced hyperactivity was also reduced by GDEE, whereas caffeine-induced hyperactivity was not significantly decreased by GDEE. This suggests that glutamatergic afferents to the NAC modulate the effects of psychostimulants and also dopamine function in the mesolimbic system.
The nucleus accumbens (NAC) of the ventral striatum has been shown to be a critical structure for locomotor activity in the rat [17]. The neuronal circuit involved in such behavior includes dopaminergic afferents from the ventral tegmental area (VTA) converging to GABAergic neurons within the NAC which then project to a ventral pallidal region [17]. Primary afferents to the NAC come also from a number of limbic structures, of which the amygdala and the hippocampus provide the densest input [7, 8]. The hippocampal afferents have been shown to be glutamatergic and behavioral studies suggest that this pathway contributes to the modulation of exploratory activity [13]. Psychostimulant drugs such as cocaine and amphetamine exert their behaviorally activating effects by facilitating dopaminergic transmission in the NAC [9, 10]. Lesions of this structure with 6-hydroxydopamine (6-OHDA) and local administration of dopamine antagonists into the NAC prevent cocaine and amphetamine locomotion but are not effective in c o n n t o r a c ' t i n o o~ffoino_ind,,oc~dc t l m l d n t i o n r171. *Visiting scientist from: 3rd Dept. of Neurology, University of Pavia, Italy. Correspondence: G.F. Koob, Division of Preclinical Neuroscience and Endocrinology, Research Institute of Scripps Clinic, 10666 No. Torrey Pines Rd, La Jolla, CA 92037, U.S.A. 0304-3940/89/$ 03.50 © 1989 Elsevier Scientific Publishers Ireland Ltd.
214 Glutamate receptors in the mammalian brain are classified as kainate, quisqualate and N-methyI-D-aspartate type according to their ligands [12]. The quisqualate antagonist e-glutamic acid diethyl ester (GDEE) [2], when injected in the NAC, has been shown to reduce both novelty-induced locomotion and the hyperactivity induced by injection of carbachol in the dentate gyrus of the hippocampus [14]. It is also noteworthy that the quisqualate receptor subtype plays an important role in locomotion induced by infusion of glutamate agonist into the NAC [3]. In the current study, we examined whether hyperlocomotion induced by psychostimulants was also modulated by glutamatergic afferents to the NAC. Our findings suggest that these N A C glutamatergic afferents are critical substrates for cocaine and amphetamine-stimulated locomotion, but are not critically involved in the locomotoractivating properties of caffeine. Male albino Wistar rats (240 260 g, Charles River) were housed in groups of 3, and exposed to a normal 12-h l i g h t , l a r k cycle, with free access to food and water. All rats were anesthetized with pentobarbital (50 mg/kg, i.p.) and secured in a K o p f stereotaxic instrument with the toothbar 5 m m above the interaural line. The animals were then implanted with bilateral 23 gauge 10 m m steel cannulae aimed 3 mm above the NAC at coordinates AP + 3.2, L _+ 1.7, DV - 4.8 (skull surface), which were fastened to the skull with dental cement and sealed with a 10 m m stylet wire. Locomotor testing for all animals began one week after surgery using 16 wire cages as described previously [6]. Each cage measured 36 x 25 x 20 cm with twin photocell beams across the long axis 2 cm above the cage floor. One day before testing, all animals were familiarized with the photocell cages by placing them individually into the cages for 180 min. On a testing day, animals were placed in the photocell cages for 90 min. Subsequently all animals received an intra-accumbens injection (I Ill over 3 rain) of either saline or G D E E (Sigma, St Louis, MO) through 30 gauge injectors fashioned to extend 3 m m beyond the ventral tip of the cannula. In the first experiment, hyperactivity induced by cocaine (20 mg/kg IP) was examined after administration of G D E E at the doses of 5, 10 and 20/tg/side. In the second experiment, the most effective dose of G D E E (20/tg/side) was tested after cocaine, amphetamine and caffeine hyperactivity where the doses induced approximately the same amount of stimulation in 10 min (cocaine, 10 mg,;kg i.p., amphetamine 0.75 mg/kg s.c., or caffeine benzoate 20 mg/kg s.c.). Injection of one of these drugs or saline (in a volume of 1 ml/'kg) was performed immediately after intracranial injection in both experiments. All drugs were dissolved in saline vehicle. Immediately following the above treatments, animals were replaced in the photocell cages and locomotor activity was recorded for l0 min. This time was chosen due to the short duration of action of G D E E suggested by previous studies [14]. Following completion of behavioral testing, all animals were sacrificed by overdose of pentobarbital, and perfused through the heart with cold 10% formalin/saline. The brains were then removed and 30/lm frozen sections were cut in a frontal plane using a rotary microtome and stained with Cresyl violet. Cannulae sites were assessed without knowledge of behavioral results.
215 The site of injection as determined by histological examination is shown in Fig. I. Cannula, in general, fell within the NAC at locations 2.2 to 3.6 mm anterior to bregma. Fig. 2 shows the effect of G D E E on cocaine-induced locomotion. One-way ANOVA with repeated measures on dose of G D E E indicates that G D E E attenuated cocaine hyperactivity in a dose-dependent manner (F3,31=3.40; P<0.05). Post-hoc dose comparison revealed that this effect o f G D E E was statistically significant at the doses of 10 and 20 pg (P < 0.05, Newman-Keul's test). Figures in the columns represent number of animals in each group. Fig. 3 shows the effect of G D E E (20/tg/side) on cocaine-, amphetamine- and caffeine-induced locomotion. A two-way factorial ANOVA revealed that there was a main effect of G D E E (FI,19 = 11.71, P<0.001), the main effect of drug (cocaine vs amphetamine vs caffeine) was not significant (F2,19= 1.27, N.S.), with a significant interaction (F2,19=3.36, P=0.05). Comparison at the various levels revealed that G D E E after cocaine and amphetamine treatment was significant (F1,19=17.96, P<0.001 and F1,19=8.51, P < 0 . 0 5 , respectively), but not after caffeine treatment (F1,19=0.32, N.S.). Figures in the columns represent number of animals in each group.
Fig. 1. Histologicallocalizationofcannula placement. For coordinates see text.
216
5
0
Dose
10
2rl
of GDEE(yglside)
Fig. 2. Effect of G D E E , a glutamate antagonist, on cocaine-induced locomotion (20 mg/kg IP). Value,, represent mean +S.E.M. * P < 0.05 Neuman Keul's test vs control.
I loft
-2
200
Vehicb F I I
k
!I ,2
GEIEE 20Hglsidel
- ]
,ili
1
[
L V~!hi!:b!
c
[
GOEEt20~(],sldf,:
[_
bK:
11 Vehicle
GOEEl20pglside)
Fig. 3. Effec! of GDEE, a glutamate antagonist on cocaine- (lO mg/kg, J.p., A), amphetamine- (0.?5 rag,,' kg, s.c., B) and caffeine-induced (20 mg/kg, s.c., C) locomotion. Values represent mean _+S.E.M. *P < 0.05, ** P < 0.001 vs respective control.
217
The present results suggest that the stimulatory activity of amphetamine and cocaine, but not caffeine, are modulated by glutamate activity within the NAC. Several studies have suggested an interaction between glutamate and dopamine in the NAC. Biochemical studies have shown that dopamine release is stimulated in vitro by infusion of glutamic acid [16]. Further, the increase in locomotor activity following microinjections of glutamate agonists in the NAC is blocked by either systemic or intraNAC injection of dopaminergic antagonists [3]. This glutamate effect may also modulate postsynaptic NAC dopamine activity since intraNAC injection of glutamate antagonists suppress locomotion induced by direct local administration of dopamine [5]. Cocaine and amphetamine are psychostimulant drugs known to stimulate locomotion by inhibiting dopamine reuptake [11] and promoting dopamine release from presynaptic terminals [4] within the NAC [9, 10]. NAC glutamatergic afferents originate from limbic structures including the hippocampus and the amygdala [7, 8]. The fact that cocaine and amphetamine hyperactivity is reduced by GDEE injections suggests that NAC glutamatergic input is of importance in the confluence of afferent information eliciting motor activation induced by psychostimulants. Caffeine-induced hyperlocomotion is apparently independent of this NAC glutamate activity. Caffeine is an antagonist at central adenosine receptors [1] and its site of action seems to rely mainly on sites outside the mesolimbic system [17]. The present data provide further support to this hypothesis, in that the glutamatergic activity in the NAC is not critical for the hyperlocomotion induced by caffeine. Anatomical studies have provided a considerable amount of information regarding glutamate innervation of the NAC, showing the amygdala and the hippocampus the major inputs [7, 8]. Behavioral and electrophysiological studies, however, have suggested that a predominant role is played by the hippocampus [15, 18]. The hippocampus-accumbens pathway was proposed as a link modulating dopamine-dependent behavior [15]. The hippocampus may play a key role in limbic motor integration, as a functional gating mechanism translating motivation to motion (for instance goaldirected locomotor responses). Our data further support this hypothesis, showing that pharmacological activation of the mesolimbic system is modulated by glutamic acid. The NAC has been implicated in the pathophysiology of schizophrenia, depression and drug-seeking behavior: whether limbic glutamate inputs play a role in these conditions is a matter for future investigation. This work was supported in part by NIDA Grant DA 04398 (G.F.K.) and a Sandoz Fellowship (L.P.) (Sandoz Ltd, Basel, CH).
1 Daly, J.W., Burns, R.E. and Snyder, S.H., Adenosine receptors in the central nervous system: relation to central action of methylxanthines, Life Sci., 28 (1981) 2083 2097. 2 Davies, J. and Watkins, J.C., Selective antagonism of amino acid-induced and synaptic excitation in the cat spinal cord, J. Physiol. (Lond.), 297 (1979) 631 635. 3 Donzanti, B.A. and Uretsky, N.J., Effects of excitatory amino acids on locomotor activity after bilateral microinjections into the rat nucleus accumbens: possible dependence on dopaminergic mechanisms, Neuropharmacology, 22 (1983) 971 981.
218 4 Farnebo, L.O., Effect of d-amphetamine on spontaneous and stimulation-induced release ofcatecholamines, Acta Physiol. Scand., 371 ( 197 l) 45 52. 5 Hamilton, M.tt., deBelleroche, J.S., Gardiner, J.M. and Herberg, L.J., Stimulatory effect of N-methyl aspartate on locomotor activity and transmitter release from rat nucleus accumbens, Pharmacol. Biochem. Behav., 25 (1986) 943 948. 6 ,Ioyce, A.M. and Koob, G.F., Amphetamine-, scopolamine- and caffeine-induced locomotor activity tollowing 6-OHDA lesions of the mesolimbic dopamine system, Psychopharmacology, 73 (1981) 311 313. 7 Kelley, A.E. and Domesick. V.B.. The distribution of projection from the hippocampal li~rmation to the nucleus accumbens in the rat: an anterograde and retrograde horseradish peroxidase study, Neuroscience, 7 (1982) 2321 2335. Kelley, A.E., Domesick, V.13, and Nauta, W.J.H., The amygdaloslriatal projections in lhe rat an anatomical study by anterograde and retrograde tracing methods, Neuroscience, 7 (1982) 615 630. 9 Kelly, P.I|. and lversen, S.D., Selective 6-OHDA-induced destruction of mesolimbic dopamine neurons: abolition of psychostimulanl induced locomotor activity in rats, Eur. J. Pharmacol., 40 (1976) 45 56, 10 Kelly, P.H.. Seviour, P. and lversen, S.D., Amphetamine and apomorphine responses in the rat following 6 - O H D A lesions of the nucleus accumbens septi and corpus striatum, Brain Res.. 94 (1975) 5O7 522. II Komiskey, H.I... Miller, D.D., LaPidus, J. and Patil, P.N., The isomers of cocaine and lropocaine: effect on ~lt-catecholamine uptake by rat brain synaptosomes, Life Sci., 21 (1977) 1 I17 1121. 12 McLennan, H.. Hicks, T.P. and Hall, I--l.J., Receptors for the excitatory amino acids. In: F.V. DeFeudis and P. Mandel (Eds.), Advances in Biochemical Psychopharmacology. Amino Acid Neurotransmitters, Vol. 29, Raven, New York, 1981, pp. 213 221. 13 Mogenson, G.J. and Nielsen, M., Neuropharmacological evidence that the nucleus acculnbens and subpallidal region contribulc to exploratory locomotion, Behav. Neural Biol., 42 {1984) 52 60. 14 Mogenson, G J . and Nielsen, M., A study of the contribution of hippocampal-accumbens-subpallidal projections to locomotor activity, Behav. Neural Biol., 42 (1984) 38 51. 15 Mogenson, G.J., Limbic-motor integration. In Progress in Psychobiology and Physiological Psychology, Vol 12, Academic Press, New York, 1987, pp. 117 170. 16 Roberts, P.J. and Anderson. S.D., Stimulatory effect of L-glutamate and related amino acids on pH]dopamme release from the rut striatum in an in vitro model for glutamate action, J. Ncurochem., 32(1979) 1539 1545. 17 Sx~erdlow, N.R.. Vaccarmo, F'..I., Amalric, M. and Koob, G.E., The neural substrates li)r the motoractivating properties of psychostimulants: a review of recent findings, Pharmacol. Biochem. Behav., 25 (1986) 233 248. IS Yang, C . R and Mogenson, G.J., Elcctrophysiological responses of neurones in the nucleus accumbens to hippocampal stinlulation and the attenuation of excitatory responses by the mesolimbic dopaminergic system, Brain Res., 324 (1984) 69 84.