A study of the contribution of hippocampal—accumbens—subpallidal projections to locomotor activity

BEHAVIORAL AND NEURAL BIOLOGY

42, 38-51 (1984)

A Study of the Contribution of HippocampaI-AccumbensSubpallidal Projections to LocomotorActivity GORDON J. MOGENSON AND MARK NIELSEN 1

Department of Physiology, University of Western Ontario, London, Ontario N6A 5C1, Canada Locomotor activity recorded in an automated open-field apparatus was increased substantially by unilateral injections of carbachol, a cholinergic agonist, into the dentate gyrus of the hippocampus. Hyperactivity elicited in this way was reduced significantly when glutamate antagonists were injected into the ipsilateral nucleus accumbens. Injecting y-aminobutyric acid into the ipsilateral subpallidal region also reduced the hyperactivity from injections of carbachol into the dentate gyrus. When these compounds were injected into the contralateral accumbens and subpallidal region, respectively, there was little or no reduction in the carbacholelicited locomotor activity. These observations suggest that neural pathways fore hippocampus to accumbens to subpallidal region may contribute to locomotor activity. © 1984 Academic Press, Inc.

Locomotor activity is a fundamental component of a number of adaptive behaviors and can be initiated in a variety of ways. Some of these initiators appear to involve neocortical integrative activities, whereas others, such as locomotion associated with mating behavior or tasteassociated food procurement, involve the hypothalamus and limbic system (Mogenson, 1977). The hippocampus, one of the prominent limbic structures, contributes to exploratory locomotion (Isaacson, 1982). It was recently reported that injecting the cholinergic agonist, carbachol, into the dentate gyrus of the hippocampus initiated locomotor activity in rats (Flicker & Geyer, 1982). This region of the hippocampus was selected for the carbachol injections because of its strong cholinergic innervation from the medial septum (Bland, Kostopoulos, & Phillis, 1974; Kuhar, 1975). The present study was undertaken to replicate this observation in order to develop an experimental preparation for investigating limbic-motor integrative mechanisms. We then undertook to block output i The authors thank Michael Wu and H. Y. Chow for assistance with the experiments presented in Fig. 5 and Becky Woodside and Vince Nicol for assistance in preparing the illustrations. Supported by the National Sciences and Engineering Research Council of Canada. Send requests for reprints to Dr. Mogenson. 38 0163-1047/84 $3.00 Copyright @ 1984 by Academic Press, Inc. All rights of reproduction in any form reserved

HIPPOCAMPAL-ACCUMBENS-SUBPALLIDAL PROJECTIONS

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pathways from the hippocampus which might mediate the carbacholelicited locomotion. The nucleus accumbens was selected as a target for administration of a blocker for a number of reasons. First, the accumbens has been implicated in the initiation of locomotion; locomotor activity occurs when dopamine or amphetamine is administered to this basal forebrain structure Jones & Mogenson, 1980a; Pijnenberg & Van Rossum, 1973). Second the accumbens receives strong neural connections from the hippocampus (Swanson & Cowan, 1977; Kelley & Domesick, 1982). Third, a major component of the hippocampal-accumbens projection is glutamatergic (Fonnum, Karlsen, Mathe-Sorenssen, & Skrede, 1979; Walaas, 1981). For the latter reason glutamate blockers [L-glutamic acid diethyl ester HCI (GDEE, Haldeman & McLennan, 1972; Spencer, 1976) or 2-amino-4-phosphobutyric acid (APB, Evans & Watkins, 1981)] were injected into the nucleus accumbens to see whether or not it would reduce the locomotor activity initiated by injecting carbachol into the dentate gyrus of the hippocampus. In a subsequent series of experiments, y-aminobutyric acid (GABA) was injected into the subpallidal region of rats in which locomotor activity was initiated by injecting carbachol into the dentate gyrus of the hippocampus. This compound was used because there is a GABAergic projection from the accumbens to the subpaUidal region (Jones & Mogenson, 1980b; Pycock & Horton, 1976; Walaas & Fonnum, 1979) and this GABAergic projection has been implicated in locomotor activity initiated by administering dopamine to the accumbens or picrotoxin to the subpallidal region (Jones & Mogenson, 1980a; Mogenson, Wu, & Jones, 1980). Based on these studies and the results of the earlier series of experiments in the present study it was predicted that GABA injected into the subpallidal region should attenuate locomotor activity initiated by injecting carbachol into the hippocampus. METHODS Male Wistar rats weighing 250-300 g at the time of surgery were anesthetized with pentobarbital sodium (Nembutal, 50 mg/kg ip) and placed in a stereotaxic instrument. Guide cannulas constructed from 23gauge hypodermic needle tubing were bilaterally inserted 1.25 mm above the target sites for drug injections and were secured with craneoplastic cement to jeweler's screws in the skull. The target sites were the dentate gyrus of the anterodorsal hippocampus (3.%4.1 mm anterior to the intraaural line, 2.2-2.3 mm lateral to the midline, and 3.5-3.6 mm ventral to the surface of the cortex), the nucleus accumbens (9.9-10.0 mm anterior, 1.3-1.5 mm lateral, and 6.0-6.6 mm ventral) and the subpallidal region (6.9-7.1 mm anterior, 2.0-2.5 mm lateral, and 7.3-7.8 mm ventral). Stainless-steel wire insert pins maintained the patency of the guide cannulas throughout the experimental tests. The animals were given a 1-week

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MOGENSON AND NIELSEN

recovery period following surgery and were then adapted to the test chamber for 4 days before the effects of intracranial drug injection on locomotor activity were investigated. Locomotor activity was recorded in an open-field test chamber (69 x 69 × 69 cm) by an electronic counter which detected interruptions of four independent light beams. Light beam sources were paced 23 cm apart and 5 cm above the floor on two adjoining walls. The rat was placed in this chamber for a 20-min pretest period which preceded the injection of a drug. Unilateral or bilateral injections were made by inserting a 30-gauge stainless-steel cannula, connected by PE-10 tubing to a Hamilton microliter syringe, to a depth of 1.25 mm beyond the guide cannula. Injections of 0.1, 0.2, 0.4, 0.5, and 1.0/~1 were carried out over 30-,40,60-,70-, and 120-s periods, respectively. Following an injection, the animal was returned to the box for 20 min and, in addition to the recording of the number of light beams broken each 5 min, its general behavior was observed. The first series of 10 rats received bilateral injections of three doses of the cholinergic agonist carbachol (0.2 /~g/0.2 /zl, 0.4 ~g/0.2 /xl, and 0.8/zg/0.4/zl) to the dentate gyrus of the hippocampus. A second series of 16 rats received unilateral injections of carbachol (0.1 /xg/0.1 /zl, 0.2 /zg/0.1 /xl, and 0.4/.,g/0.2/xl) to the dentate gyrus. Carbachol injections of both series were counterbalanced with injections of 0.9% NaC1 of equal volume. The schedule of injections of the third (n = 18), fourth (n = 7), and fifth (n = 8) series of rats was divided into two phases. First, the lowest dose of carbachol which resulted in at least a threefold increase in locomotor activity was determined for each rat. This was accomplished by administering in counterbalanced order a small number of injections of carbachol and saline unilaterally in the hippocampus. Second, an attempt was made to block any carbachol-elicited effects upon locomotion at the level of the nucleus accumbens and subpallidal region. Throughout this second phase, rats received unilateral injections into the hippocampus of the dose of carbachol determined in the first phase. In addition, these animals also received injections of blocking agents into either the nucleus accumbens or the subpallidal region. For the third series of rats, the blocking agent was GDEE (I0/zg/0.5/xl and 20/zg/1.0/.d) which was injected into the nucleus accumbens ipsilateral to the site of the carbachol injection into the dentate gyrus of the hippocampus. These injections were counterbalanced with injections of 0.9% NaC1 of equal volume to the nucleus accumbens, ipsilateral to the pretreated hippocampal injection sites. As a further control, these rats also received an injection of GDEE (20/zg/ 1.0/xl) to the accumbens contralateral to the site of the carbachol injection. Carbachol, GABA, and GDEE were obtained from Sigma Chemical Company (St. Louis, Mo.) and APB was from Calbiochem (La Jolla, Calif.).

HIPPOCAMPAL-ACCUMBENS-SUBPALLIDAL PROJECTIONS

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For the fourth series of rats the procedures were the same as for the third series except that APB (7.5 /xg/0.5 txl and 12.5 txg/0.5 txl) was injected into the nucleus accumbens ipsilateral (and, as a control, contralateral) to the unilateral injection of carbachol into the dentate gyms of the hippocampus. For the fifth series of animals, the blocking agent was GABA (2.5 ixg/0.5 pJ, 5.0/xg/0.5/xl, and 5.0 txg/1.0 txl), which was injected into the subpallidal region ipsilateral to the pretreated hippocampal sites. These injections were counterbalanced with injections of 0.9% NaC1 of equal volume to the subpallidal region, ipsilateral to the sites of the carbachol injections. As a further control these rats also received injections of GABA (5.0/xg/1.0/zl) to the subpallidal region contralateral to the carbachol injections. When the behavioral tests were completed the animals were given an overdoese of urethane and perfused with 50 ml of 0.9% NaC1 followed by 50 ml of buffered Formalin. Their brains were then removed from the skull and fixed in Formalin. They were then sectioned with a freezing microtome at 80/xm and stained with thionin for histological determination of cannulae sites. Locomotor activity was expressed as the 2-min mean of the total number of photobeams broken during the 20-rain test period. The effects of bilateral and unilateral injections of carbachol to the dentate gyms were analyzed using a repeated-measures design analysis of variance (Winer, 1962). Possible dose-dependent responses were tested for significance using simple linear regression analysis (Zar, 1974). All pairwise analysis was completed using the t test for paired comparisons (Zar, 1974). RESULTS Injecting carbachol (0. l, 0.2, 0.4/xg) bilaterally into the dentate gyrus of the hippocampus in the first series of animals significantly increased locomotor activity as compared to control injections of isotonic saline IF(3, 27) = 3.63, p < .05]. Locomotor activity increased as the dose of carbachol was increased [F(1, 38) = 3.52, p < 0.10]. The cannulae were in the dentate gyrus or dorsal and medial to the dentate gyms. Since the pairs of hippocampal cannulae were frequently not symmetrically placed it was difficult to decide whether or not certain cannulae placements were less effective than others. This is one of the reasons that unilateral injections of carbachol were used in subsequent experiments. The other reason is that with unilateral injections of carbachol into the dentate gyms it was possible to use contralateral injections of the blockers (GDEE or APB into the accumbens and GABA into the subpallidal region) as further control for unilateral injections of the blockers. Unilateral injections of carbachol into 21 sites within the dentate gyrus of the hippocampus in the second series of animals significantly increased

42

MOGENSON AND NIELSEN

locomotor activity as compared to control injections of 0.9% NaC1 of equal volume. As shown in Fig. 1, locomotor activity increased as the dose and volume of carbachol injections were increased [F(1, 82) = 67.19, p < .01]. Unilateral injections of carbachol to sites outside of the dentate had no significant effect upon locomotion. For 19 of the 21 cannulae sites in the dentate gyrus the carbachol injections increased locomotor activity sufficiently to satisfy the threefold criterion employed (see Fig. 2). By comparison, locomotion following carbachol injections to only 1 of the 10 cannulae sites dorsal and medial to the dentate reached this criterion. The third series of animals were prepared with cannulae in accumbens and hippocampus to investigate the possible blocking effects of GDEE injected into the accumbens on carbachol-elicited locomotion. The cannulae sites are shown in Fig. 3. In order to obtain at least a threefold increase in locomotor activity 0.2 tzg of carbachol in 0.1 ~1 was injected into 11 of the hippocampal cannulae and 0.4 /xg of carbachol in 0.2 /xl was injected into 21 of the hippocampal cannulae. These injections increased locomotor activity from 3.98 --- 0.74 to 17.50 + 1.87 as shown in Fig. 4. Injecting GDEE into the accumbens ipsilateral to the carbachol injections into the hippocampus produced a dose-dependent decrease in locomotor activity which was statistically significant [F(1, 94) = 34.28, p < .01]. Injecting isotonic saline into the ipsilateral accumbens had no effect on the carbachol-elicited locomotor activity. When the largest dose of GDEE

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HIPPOCAMPUS INJECTION (.ug/~ul) FIG. 1. Unilateral injections o f carbachol into the dentate gyrus of the h i p p o c a m p u s increased l o c o m o t o r activity as a function of both dose and volume (n = 21 sites). A s a control, rats received unilateral injections of 0.9% NaC1 (saline) of equal volume. R e s u l t s are e x p r e s s e d as the m e a n -- S E M (vertical bars).

H I P P O C A M P A L - A C C U M B E N S - S U B P A L L I D A L PROJECTIONS

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FIG. 2. Sites of 31 unilateral injections of carbachol in the region of the dentate gyrus of the anterodorsal region of the hippocampus in 16 rats. The sites in the hippocampus at which at least a threefold increase in locomotor activity, as compared to locomotion following injections of 0.9 NaCI, occurred with the following doses: • 0.1 txg/0.1 /xl; A 0.2/xg/0.1 b~l; /x 0.4 ~g/0.2 gl. ©, Sites for which a significant increase was not observed, nine dorsal and medial to the dentate gyrus and two in the ventral dentate gyrus. Brain drawings are adapted from Konig and Klippel (1963). Abbreviahons: AC, anterior commissure: Acc, nucleus accumbens: C, caudate putamen: CC, corpus callosum; DG, dentate gyrus: FH, fimbria of the hippocampus; HI, hippocampus; SE, septum; T, thalamus.

was injected into the contralateral accumbens there was a small decrease in the carbachol-elicited locomotion but it was not statistically significant (see fight column of Fig. 4). The results for the fourth series of animals, in which APB was the blocker, as shown in Fig. 5. Locomotor activity was increased more than threefold by injecting carbachol (0.2/.~g/0.1 pA) unilaterally into the dentate gyrus of the hippocampus. Injecting APB into the ipsilateral nucleus accumbens reduced significantly the carbachol-elicited locomotor activity [F(1, 40) = 7.12, p < .05]. APB injected to the contralateral nucleus accumbens did not reduce the carbachol-elicited locomotor activity. Histological verification of the cannulae placements indicated that injection sites in the dentate gyrus and in the accumbens were similar to those for series 3 shown in Fig. 3.

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MOGENSON AND NIELSEN

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FIG. 3. Sites of unilateral injections of carbachol in the region of the dentate gyrus of the anterodorsal region of the hippocampus (A to C) and of unilateral injections of Lglutamic acid diethyl ester HC1 (GDEE) in the dorsomedial region of the nucleus accumbens (D to F) in 18 rats. Carbachol injections of either 0.2 ~g/0.2/xl (n = 11 sites) or 0.4 p.g/ 0.2 /zl (n = 21 sites) into the hippocampal sites shown by black dots elicited at least a threefold increase in locomotor activity. Four sites of carbachol injections that did not increase locomotor activity are shown by open circles on the right of B and C. Black dots in D, E, and F indicate injection sites for GDEE into the nucleus accumbens which reduced locomotor activity by 50% or more. O, Sites at which GDEE injections did not reduce carbachol-elicited locomotor activity. GDEE tests were not made for the 4 carbachol injections sites in B and C that did not result in increased locomotor activity and, accordingly, only 14 cannulae sites are shown on right side of brain sections D, E, and F. Brain drawings are adapted from K6nig and Klippel (1963). Abbreviations: AC, anterior commissure; Acc, nucleus accumbens; C. caudate putamen; CC, corpus callosum; DG, dentate gyrus; FH, fimbria of the hippcampus; HI, hippocampus; S, subiculum; SE, septum; T, thalamus.

T h e fifth s e r i e s o f r a t s w e r e p r e p a r e d w i t h c a n n u l a e in t h e h i p p o c a m p u s a n d s u b p a l l i d a l r e g i o n to i n v e s t i g a t e t h e p o s s i b l e b l o c k i n g e f f e c t s o f G A B A injected into the subpallidal region on carbachol-elicited l o c o m o t i o n . T h e c a n n u l a e s i t e s a r e s h o w n in Fig. 6. I n o r d e r to o b t a i n a t h r e e f o l d i n c r e a s e in l o c o m o t o r a c t i v i t y 0 . 2 / x g o f c a r b a c h o l in 0 . 1 / x l w a s i n j e c t e d into 2 o f t h e h i p p o c a m p a l c a n n u l a e a n d 0.4 /xg o f c a r b a c h o l in 0.2 /zl w a s i n j e c t e d into 14 o f the h i p p o c a m p a l cannulae. T h e s e injections i n c r e a s e d l o c o m o t o r a c t i v i t y f r o m 3.80 __ 0.66 to 17.65 -+ 2.32 as s h o w n in Fig. 7. I n j e c t i n g G A B A i n t o t h e s u b p a l l i d a l r e g i o n i p s i l a t e r a l to t h e c a r b a c h o l i n j e c t i o n s i n t o t h e h i p p o c a m p u s r e d u c e d l o c o m o t o r a c t i v i t y as a f u n c t i o n o f d o s e a n d v o l u m e [F(1, 50) = 23.9, p < .01]. I n j e c t i n g i s o t o n i c s a l i n e

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F ~ . 4. Locomotor activity elicited by injections of carbachol into the dentate gyrus of the hippocampus was attenuated when L-glutamic acid diethyl ester HCL (GDEE) was injected into the lpsilateral nucleus accumbens (n = 32 sites). Injections of carbachol alone into the dentate gyrus resulted in at least a threefold increase in locomotion (stipled column) when compared to injections of isotonic saline (open column). Unilateral injections of GDEE ipsilateral to the carbachol injections reduced locomotor activity as a function of dose and volume in comparison to ipsilateral injections of saline (columns designated I). Contralateral injections of GDEE (column designated C) did not reduce carbachol-elicited locomotor activity significantly. Results are expressed as the mean ~ SEM (vertical bars).

into the ipsilateral accumbens had no effect on the carbachol-elicited locomotor activity. When the largest dose of GABA was injected into the contralateal subpallidal region there was a small decrease in carbacholelicited locomotion but it was significantly less than that following the ipsilateral injection It(12) = 6.95, p < .01] (see right column of Fig. 6.).

DISCUSSION Unilateral injections of carbachol, a cholinergic agonist, into the dentate gyrus of the hippocampus increased locomotor activity of rats in an openfield apparatus. This carbachol-elicited locomotor activity was reduced significantly when G D E E or APB, glutamate blockers, were administered to the ipsilateral nucleus accumbens and when GABA was administered to the ipsilateral subpallidal region. These hyperkinetic effects of carbachol injections into the hippocampus are similar to those reported recently by Flicker and Geyer (1982). With injections into the dentate gyrus locomotor activity increased as the dose and volume of carbachol were increased. Carbachol injections into sites dorsal and medial to the dentate gyrus had little or no effect on locomotor

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F1G. 5. Locomotor activity elicited by injections of carbachol into the dentate gyrus of the hippocampus was attenuated when 2-amino-4-phosphobutyric acid (APB) was injected into the ipsilateral nucleus accumbens (n = 14 sites in seven rats). Unilateral injections of carbachol alone into the dentate gyrus resulted in at least a threefold increase in locomotion (stipled column) when compared to injections of isotonic saline (open column). Unilateral injections of APB ipsilateral to the carbachol injections reduced locomotor activity in comparison to ipsilateral injections of isotonic saline (columns designated I). Contralateral injections of APB (columns designated C) did not reduce carbachol-elicited locomotion. Results are expressed as the mean _* SEM (vertical bars).

activity. A number of earlier studies implicated the hippocampus in locomotor activity. These include lesion, electrophysiological recording, and neurochemical experiments (Dudar, Whishaw, & Szerb, 1979; Jarrard, 1968; Ranck, 1975; Suess & Berlyne, 1978; Vanderwolf, Kramis, Giilespie, & Bland, 1975). Of particular interest to the present study is the report of increased acetylcholine release when rats were running in a treadmill (Dudar et al., 1979). The latter observation, together with the results shown in Figs. 1, 4, and 5, implicate the hippocampal cholinergic system in locomotor activity. It is likely, as suggested by Flicker and Geyer (1982), that carbachol acted on cholinergic synapses in the hippocampus (Wheal & Miller, 1980), possibly on muscarinic receptors (Zheng, Berman, & Geyer, 1983). However, this is a pharmacological effect and cannot be easily related to hippocampal mechanisms having to do with attention and habituation to environmental stimuli, spatial organization of the external environment, behavioral response alteration, or behavioral response perseveration (Isaacson, 1982). In any case, we merely used dentate carbachol injections to initiate locomotor activity so that we could investigate the

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FIG. 6. Sites of unilateral injections of carbachol in the region of the dentate gyms of the anterodorsal region of the hlppocampus and of unilateral injections of GABA in the sublenticular substantla innominata and the ventral globus pallidus in a series of eight rats. Carbachol injections of either 0.2 p~g/0.2/xl (n = 2) or 0.4 p~g/0.2/xl (n = 14) which elicited at least a threefold increase in locomotor activity are shown by black dots in A, B, and C. GABA injections which reduced carbachol-elicited locomotor activity are shown by black dots in D, E, and F. The black dot with asterisk in dorsal GP, which appears in D, is an injection site at which only the largest dose of GABA (5 /xg in 1.0 /xl) reduced carbachol-elicited locomotor activity. O, Two sites (one in dorsal GP in D and one in IC in E) at which injections the three doses of GABA had no effect upon carbachol-elicited locomotion. Brain drawings are adapted from Konig and Klippel (1963) and Mogenson, Swanson, and Wu (in press). Abbrevations: AAA, anterior amygdaloid area; BST. bed nucleus of the stria terminalis; CP, caudate putamen: DG, dentate gyrus; FH, fimbria of the hippocampus; GP, globus paltidus; HI, hippocampus; IC, internal capsule; LPO, lateral preoptic area: MPO, medial preoptic area; OT, optic tract; S, subiculum; SI, sublentlcular substantia innominata; SO, supraoptic nucleus.

possible functional significance of hippocampal-accumbens-subpallidal projections. The major finding from the present study is that injecting GDEE or APB into the ipsilateral nucleus accumbens attenuated the locomotor activity initiated by carbachol injections into the dentate gyrus of the hippocampus. This finding suggests that the output from the hippocampus for carbachol-elicited locomotion is to the accumbens and, according to earlier studies, it may involve a glutamatergic hippocampal-accumbens projection (Fonnum et al., 1979; Walaas, 1981). There is evidence from acute electrophysiological recording experiments supporting this suggestion. Accumbens neurons are activated orthodromically by electrical stimulation of the ventral subiculum, the site of hippocampal output neurons to the accumbens (DeFrance, Kitai, & Shimono, 1973; Yang & Mogenson,

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FI~. 7. L o c o m o t o r activity elicited by injections of carbachol into the dentate gyrus of the h i p p o c a m p u s was attenuated in a dose-dependent m a n n e r w h e n G A B A as injected into the subpallidal region (n = 13 sites in eight rats). Injections of carbachol alone into the dentate resulted in at least a threefold increase in locomotion (stipled column) w h e n

compared to injections of 0.9% NaC1 alone (open column). Unilateral injections of GABA into the subpallidal region ipsilateral to the carbachol injections reduced locomotor activity as a function of dose and volume in comparison to ipsilatetal injections of saline (columns designated I). Contralateral injections of the largest dose of GABA (column designated C) resulted in a decrease in locomotion that was less than the decrease observed following ipsilateral injections of this dose of GABA. Results are expressed as the mean _+ SEM (vertical bars). 1984) and ventral subiculum neurons are activated antidromically by stimulation of the nucleus accumbens (Yang & Mogenson, in press). Furthermore, the iontophoretic application of G D E E significantly reduced this activation in 5 of a series of l0 accumbens neurons investigated (Yang & Mogenson, in press). However, G D E E and APB are not selective antagonists of excitatory amino acid receptors (Evans & Watkins, 1981). Further experiments are needed to determine the type of receptors which mediate the excitatory influence of the ventral subiculum of the hippocampus on nucleus accumbens neurons. One of the components of the accumbens projection to the subpallidal region is GABAergic (Jones & Mogenson, 1980a; Pycock & Horton, 1976; Walaas & Fonnum, 1979). Since injecting GABA into the subpallidal region was previously shown to reduce locomotor activity initiated by dopamine injections into the accumbens (Jones & Mogenson, 1980a, 1980b), it was expected that injecting GABA into the subpallidal region would also reduce l o c o m o t o r activity initiated by carbachol injections into the dentate gyrus o f the hippocampus. As can be seen in Fig. 7,

HIPPOCAMPAL-ACCUMBENS-SUBPALLIDAL PROJECTIONS

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this prediction was confirmed. It appears that signals for the carbacholinitiated locomotion utilize a glutamatergic projection from the hippocampus to the nucleus accumbens and a GABAergic projection from the accumbens to the subpallidal region. As indicated in the introduction, this study is part of a series of experiments concerned with investigating limbic-motor integrative mechanisms. A major focus of these experiments has been the nucleus accumbens, which is positioned strategically between the hippocampus, and other limbic forebrain structures, and the subpallidal region (Mogenson, Jones, & Yim, 1980; Nauta & Domesick, 1978) and which may modulate signals that contribute to behavioral response initiation (Yim & Mogenson, 1983). Of particular interest are observations from axonal tracer and electrophysiological recording experiments demonstrating neural projections from the subpallidal area to the pedunculopontine nucleus, a major component of the mesencephalic locomotor region (Swanson, Mogenson, Gerfen, & Robinson, 1984). The possible functional significance of these descending projections was investigated by injecting the neuronal blocker procaine unilaterally into the pedunculopontine nucleus or into the subpallidal-pedunculopontine projection at the level of the zona incerta which significantly reduced locomotor activity elicited by injecting amphetamine into the ipsilateral nucleus accumbens or picrotoxin into the ipsilateral subpallidal area (Mogenson, Brudznski, & Nielsen, 1983; Mogenson, Swanson, & Wu, in press). The present study is the first step to investigate the possible functional relevance of the hippocampal-accumbens-subpallidal projections. The results are sufficiently encouraging to warrant continuing to the next step, which is to see whether or not these projections contribute to adaptive behavioral responses, such as exploratory locomotion in response to novel stimuli and food procurement.

REFERENCES Bland, B. H., Kostopoulos, C. K., & Phillis, J. W. (1974). Acetychohne sensitivity of hippocampal formation neurons. Canadian Journal of Physiology and Pharmacology, 52, 966, 971. DeFrance, J. F., Kitai, S. T., & Shimono, T. (1973). Electrophysiological analysis of hippocampal-septal projections: 1. Response and topographical characteristics. Experimental Brain Research, 17, 447-462. Dudar. J. D., Whishaw, I. Q., & Szerb, J. C. (1979). Release of acetylcholine from the hippocampus of freely moving rats during sensory stimulation and running. Neuropharmacology, 18, 673-678. Evans, R. H., & Watkins, J. C. (1981). Pharmacological antagonists of excitant amino acid action. Life Sciences, 28, 1303-1308. Flicker, C., & Geyer, M. A. (1982). Behavior during hippocarnpal microinfusion. II. Muscarinic locomotor activation. Brain Research Reviews, 4, 105-127. Fonnum, F., Karlsen, R. L., Mathe-Sorenssen, P., & Skrede. K. K. (1979). Localization of neurotransmitters, particularly glutamate in hippocampus, septum, nucleus accumbens and superior colliculus. Progress in Brain Research, 51, 169-191.

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