Brain Research, 585 (1992) 1-6 © 1992 Elsevier Science Publishers B.V. All rights reserved 0006-8oq3/92/$05.00

BRES 17768

Research Reports

Ibotenic acid lesion of the ventral hippocampus differentially affects dopamine and its metabolites in the nucleus accumbens and prefrontal cortex in the rat B a r b a r a K. Lipska a, G e o r g e E. Jaskiw a, Stanislaw C h r a p u s t a b, F a r o u k K a r o u m b and Daniel R. W e i n b e r g e r a '~ Clinical Brain Disorders Branch and b Neuropsychiatry Branch, National Institute of Mental Health, Intramural Research Program, Neuroscience Center at St. Elizabeths, Washington, DC 20032 (USA) (Accepted 7 January 1992)

Key words: Hippocampus; Dopamine; lbotenic acid; Amphetamine; Locomotion; Nucleus accumbens; Prefrontal cortex

To determine the influence of neurons of the ventral hippocampus on dopamine (DA) turnover in other limbic areas, spontaneous and amphetamine-induced locomotion as well as DA and its metabolites were assayed in nucleus accumbens, medial prefrontal cortex and anteromedial striatum, 14 and 28 days after bilateral ibotenic acid (IA) or sham lesions of the ventral hippocampus in the rat. Spontaneous locomotion was increased 28 days postoperatively, while D-amphetamine induced locomotion was augmented both 14 and 28 days postoperatively in IA lesioned animals. DA levels in the nucleus accumbens were decreased on the 14th, but increased on the 28th day after the lesion. Dihydro~phenylacetic acid (DOPAC), homovanillic acid (HVA) and the DOPAC/DA ratio in the medial prefrontal cortex (MPFC) were reduced 28 days postoperatively. Moreover, there was a significant negative correlation between the DOPAC/DA ratio in the MPFC and DA levels in the nucleus accumbens at this time point. These data indicate that a lesion of the ventral hippocampus can produce differential changes in cortical and limbic DA activity. Implications for an animal model of schizophrenia are considered.

INTRODUCTION Certain terminal fields of the mesocorticolimbic dopamine (DA) system appear to be functionally interdependent 24,27,3°'33,34'41'4s.In agreement with the latter, we have previously demonstrated that an ibotenic acid (IA) lesion of the medial prefrontal cortex (MPFC) at least transiently increases amphetamine-induced locomotion and elevates biochemical indices of presynaptic DA turnover in the basal gangliat8. In contrast, we have found that IA lesion of the dorsal hippocampus (DH) does not affect such parameters 25. The latter was surprising, insofar as a variety of biochemical and behavioral changes following hippocampal lesions have been reported by others 23'42'56. Given the functional and anatomical heterogeneity of the hippocampai formation 1'45'5°, this apparent discrepancy may be attributable, in part, to differences in lesion size and location, e.g. ventral as compared with

dorsal, as well as in lesion technique 23. Even small ablative lesions are likely to interrupt a substantial number of projections to and from regions beyond the lesion site. Clarification of the functional relationship between the hippocampus and other mesocorticolimbic structures may be of particular importance in understanding psychotic illnesses, given increasing data implicating DA dysregulation as well as temporo-limbic and prefrontal cortical abnormalities in the pathophysiology of schizophrenia 44.s4'ss.The results of other studies 4°'s°'sxs7 led us to posit that the ventral hippocampus may make the predominant contribution to hippocampal regulation of mesolimbic DA system. Accordingly, the experiments reported here were undertaken to examine the effects of IA lesions of the ventral hippocampus (VHIP) on behavioral and biochemical indices of DAergic transmission in the MPFC, nucleus accumbens septi (NAS) and corpus striatum of the rat.

Correspondence: B.K. Lipska, Rm. 500, WAW Bldg., Neurosciences Center at St. Elizabeth's, Washington, DC 20032, USA. Fax: (1) (202) 373 6214.

M A T E R I A L S AND M E T H O D S

Surgery and handling Adult male Sprague-Dawley rats (Zivic Miller Labs, 2q0-250 g) were housed 3 to a cage with free access to food and water in a tempera:ure-controlled environment. The 12:!2 h dark-light cycle was mmntained (lights on between 07.00 nd 19.00 h). After induction of anesthesia with Equithesin 3 ml/kg (i,p.), the animals were placed in a Kopf stereotaxic instrument with the tooth bar at 2.5 mm below the interaural line. lbotenic acid (Sigma Chemical Co.) (6/zg/0.6 p,! over 3 rain) or an equal volume of vehicle (0.1 M phosphate-buffered saline, pit 7.4) was administered by infusion pump (Harvard Apparatus) bilaterally (2 injections on each side) through stainless steel 26-gauge cannulae at the coordinates: AP -4.4 ram, ML _+5.0, VD - 8 . 0 and -6.0 ram, with respect to bregma. The cannulae remained in place for an additional 5 rain after the end of the infusion. Animals were tested between 09.00 and 13.00 h, 14 or 28 days after the surgery. Each animal was tested only once. Animals were brought to the testing area in their home cages and immediately placed in clear plexiglass photocell activity monitors (42 x 42 x 30 cm) (Omnitech model RXYZCM 16). Spontaneous locomotor activity was measured during a 60 rain habituation period. Each rat then received a saline injection (1 ml/kg, i.p.) and was replaced in the monitor for an additional 60 rain period. At that point 1.5 mg/kg of D-amphetamine (Sigma) was administered and locomotor activity was recorded for a final 90 min. Groups of testing naive rats with IA or sham lesion were sacririced on the 14th or 281h postoperative days. Animals were acclimatized to the dissection area for 24 h prior to decapitation. Brain regions (medial prefrontal cortex, anteromedial corpus striatum and NAS) were dissected over ice from 2 mm thick sections as reported previously m and frozen at -70°C until analysis by combined gas chromatography/mass fragmentography-'!. Sixteen rats with ibotenic acid and 4 with sham injections were randomly selected 14 and 28 days after the lesion and decapitated. The brains were quick-frozen on solid CO,. Cryostat sections were prepared and stained with Cresyl violet. The outermost area of neuronal cell loss as determined by light microscopy was used to d~fine the lesion boundaries, An average I~sion was reconstrticted that included the lesioned area within Ill rats,

Behavioral and biochemical results were analysed by ANOVA and MANOVA, respectively, followed by post,hoe Newman-Keuls test where appropriate, Spearman correlation coefficients were also calculated,

Fig. I, A low power photomierosraph of Cresyl violet-stained coronal section through the ventral hippoeampus of the rat. Note the cavitation of the lesioned ventral hippoeampus and sparin8 of pyramidal culls in the dorsal aspects of th~ hippocampus, Bar - I mm.

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RESULTS

Histology Cresyl violet sections t a k e n 14 a n d 28 days p o s t o p e r . atively r e v e a l e d n e u r o n a l loss, gliosis a n d c e n t r a l cavit a t i o n in the IA l e s i o n e d area, which i n c l u d e d large p a r t s o f the v e n t r a l h i p p o c a m p u s , d e n t a t e gyrus a n d s u b i c u l u m (Figs, 1 a n d 2). T h e lateral v e n t r i c l e s w e r e e n l a r g e d . D a m a g e to a d j a c e n t s t r u c t u r e s o r to t h e dorsal h i p p o c a m p u s was n o t s e e n in any a n i m a l ,

Behavior Total distances traveled over 3 consecutive time intervals (60 rain h a b i t u a t i o n , 60 m i n following s a l i n e injection, 90 rain following D - a m p h e t a m i n e i n j e c t i o n ) w e r e a n a l y z e d by an A N O V A w i t h time as a r e p e a t e d measure.

On

the

14th p o s t o p e r a t i v e d a y e f f e c t s o f

Fig, 2, Lesion boundaries defined as the area of neuronal absence and determined from Cresyl violet-stained coronal sections from 16 rats with IA lesions of the ventral hippocampus. Horizontal bars and the diagonal bars indicate the largest and smallest lesions, respectively, Stippling indicates the area encompassing the lesion boundaries in 10 rats,

Time ( F = 116.98, P--0.0001), Lesion (F--4.4, P 0.04) as well as Time x Lesion interaction (F = 3.67, P = 0.03) were significant. On the 28th day significant Time (F = 157.68, P ffi 0.0001) and Lesion effects persisted ( F = 6.42, P=0.01). Newman-Keuls' comparisons revealed that after D-amphetamine administration the distance traveled by IA lesioned rats was significantly greater than that of sham operates (P < 0.05) at both 14 and 28 days postoperatively (Fig. 3). In contrast, during the habituation period, VHIP lesioned rats traveled a greater distance than their sham counterparts, at 28 but not at 14 days after surgery. Biochemistry The concentration of DA in NAS was reduced on the 14th day (P < 0.04). On the 28th postoperative day, however, DA was increased (P < 0.05) in VHIP animals (Table I). No significant neurochemical changes were found in the MPFC on the 14th postoperative day. On day 28, however, NE levels were increased (P < 0.04), while dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels were decreased in the MPFC of the IA lesioned group (P < 0.02; P < 0.03, respectively). Furthermore, the MPFC D O P A C / D A ratio was reduced (P < 0.04). No significant neurochemical changes were found in the anteromedial corpus striatum at any time point. All the data were subjected to Spearman correlation analysis. There was a negative correlation (p = -0.46,

P = 0.03) between DOPAC/DA ratios in the MPFC (reduction) and DA levels in the NAS (increase) 28 days postoperatively.

DISCUSSION

As previously reported 26, our IA lesion was confined to the ventral hippocampal formation including the dentate gyrus and subiculum. The extensive hippocampal atrophy is consistent with studies employing similar IA doses 2°. Though axon-sparing properties of IA in the hippocampus have been demonstrated 9,2°,22.29, in view of the atrophy and cavitation some damage to axons of passage cannot be precluded. The principal neurochemicai finding was a differential effect on DAergic indices in the NAS and in the MPFC. A reduction in DOPAC/DA, DOPAC, HVA in the MPFC and ,he increase in DA in the NAS were evident only 28 days postoperatively. These changes were modestly but negatively correlated (DOPAC/DA in MPFC vs. DA in NAS). NE levels in the MPFC were increased 28 days postoperatively, but their significance without corresponding NE metabolite levels is difficult to assess. The NE system is in general thought to modulate DA transmission 3°. Striatal levels of NE, DA or metabolites were not affected. Overall, earlier studies have yielded less than consistent results. A decrease in NAS DA utilization and in

TABLE I

Concentrations of NE, DA and its metabolite~ after IA le~ion of the central hippocanlpus All values are expressed as p M / m 8 proteln:t:S.D. ( , - - 1 2 animals per group). Abbreciations: NAS, nucleus accumbens; MCS, medial corpus striatum; MPFC, medial prefrontal cortex; DA, dopamine; NE, norepinephrine; DOPAC, dihydrox~'phenylacetic acid; HVA, homovanillic acid; IBO, ibotenic acid (IA) lesioned group; Sham, control group.

28 days postoperaticely

14 days postoperatively Sham

IBO

56.23 49.91 977.28 4- 139,84 142.39 4- 18,94 48.56 4-1067 0.14840,026

59.93 4873.90 4130.96 441.81 5: 0.150-1-

48.91 + 865.27 486.58 438.83 40.1004-

13.71 77.51 11.97 9.32 0.012

52.57 4- 14,90 942,92 -I-120,54 87.47 4- 12,90 41,39 5: 9.36 0.0934- 0.010

16.72 + 7.36 + 3.06 + 3.76 + 0.425 +

1,82 1,54 0.61 1.06 0.09

16,28 + 3,29 7,66 + 1,93 2.85 + 0,28 3,57 4- 0,62 0.389 4- 0.09

Sham

IBO

NAS NE DA DOPAC HVA DOPAC/DA

10.34 73.78 * 18.09 6.61 0,016

48.74 5:10.04 922.00 4-162.00 144.74 4- 25.81 52.09 5: 10.07 0.158::1: 0.016

50.07 4- 6.00 1024.56 + 64.50 * 147.93 + 14.80 53.35 + 10.11 0,146-1- 0.019

54,89 4- 13,29 1014,49 -I-120,36 109,07 4- 19,48 50.18 :t: 13,42 0,1045: 0.014

64.24 5:11.27 984.03 + 63.09 104.05 5:16,66 48.35 :t: 9.52 0.106+ 0.015

MCS NE DA DOPAC HVA DOPAC/DA

MPFC NE DA DOPAC HVA DOPAC/DA

* P < 0.05 - IA lesioned significantly different from Sham.

14,33 + 6.60 + 3.13 5: 4.04 + 0.542 +

1,33 2,26 0.45 1,23 0,183

15.99 + 7.09 + 2.60 + 3.15 40.402 +

2,23 * 1.87 0.59 * 0,48 * 0,127 *

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20000

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5000 . 0 HAB (60 MIN) SAL (60 MIN) D-AMP (90 MIN) Fig. 3. Total distances traveled by rats in a novel photocell apparatus

(means~:S.D., n ~ 12/group), Differentsham or ihotenic acid (IA) lesioned groupswere tgsted 14 (A) and 28 (B) days postoporativcly. After overnightacclimatizationto the testingarea, rats were placed in the apparatus for a 60 rain habituation poriod (HAB), After 60 rain saline (I ml/ku, i,p,)was administered and activity recorded for a further 60 rain, Rals then r¢,:eived ( + )-amphetamine (1,5 mg/kg, i.p,) and had their activity recorded for a further ~0 rain, (a) different from (b), and (c) different from (d), P < 0,05.

NE levels 7 days after hippocampal aspiration have been reported; these normalized by day 28 42. in another study, forebrain DA and NE were similarly elevated 90 days after hippocampal or after 'control' aspiration lesions of the overlying cortex 56. Hippocampal and 'control' lesions were also reported to similarly increase NAS membrane phosphorylation3, Behaviorally. Lanier and lsaacson 23 found that ventral or combined dorsal-ventral hippocampal aspiration lesions permanently increase spontaneous locomotion, while dorsal hippocampal lesions do so transiently. Our earlier 2"s, and current data are consistent with the latter. Our findings suggest, insofar as mesolimbic DA transmission has been linked to spontaneous and Damphetamine

induced

31 32 37 , that locomotion 8.....

aug-

mentation of D-amphetamine induced DA release occurs early and is enduring after VHIPP lesion. DAmphetamine, however, affects several monoamine systems 2. Spontaneous locomotion may offer a more physiologically important index of mesolimbic DA transmission. The data could suggest then the delayed emergence of an augmented mesolimbic DA 'releasability' in response to environmentally relevant stimuli. At 28 but not 14 days after VHIP lesion DOPAC as well as the DOPAC/DA ratio in the MPFC were reduced, strongly suggesting a reduction in DA turnover/release. In the NAS only DA was significantly (20%) increased. Such a delayed increase could result from heterotypic sprouting, a phenomenon described in other neurotransmitter systems 2s'3s. Alternatively, mechanisms affecting tyrosine hydroxylase could increase the intraneuronal storage of DA (for review see ref. 7). Whatever the mechanism, the functional significance of alterations in postmortem DA cannot be deduced from the magnitude of such changes per se. In the current experiment, two additional data are available. Firstly, the delayed neurochemical changes were accompanied by the similarly delayed emergence of increased spontaneous locomotor exploration in a parallel cohort of rats exposed to a novel environment. Secondly, the magnitude of the mesolimbic DA increase was modestly (21%) correlated with the reduction in MPFC DA utilization/release. Thus the change in mesolimbic DA can be linked to two other significant indices, Although many explanations are possible, one is particularly appealing. Novelty is a stressor which normally increases MPFC but not NAS DA activity in intact animals4,4~. Depletion of MPFC DA, however, reduces the threshold for stress-induced activation of NAS DA turnover tz. it is possible that when basal MPFC DA turnover/release is depressed 28 days after VHIP lesion, exposure to the mild stress of novelty can augment mesolimbic DA release, which is functionally expressed as increased spontaneous locomotion. Accordingly, the increase in DA levels in NAS of acclimatized animals may represent an increase in available neuronal DA which may be released under appropriate conditions. It is noteworthy that DA depletion of the amygdala, located adjacent to the ventral hippocampus, increases mesolimbic DA turnover but a reduces DA turnover in the MPFC 4t. Opposite changes in DA turnover in MPFC and NAS have also been demonstrated after amygdaloid kindling34. Such data suggest that the ventral hippocampus/amygdaloid area may be unique in its ability to induce reciprocal changes in MPFC and mesolimbic DA transmission.

Several mechanisms must be considered. Direct, presumably glutamatergic 5m2.Ss ventral hippocampal efferents innervate NAS neurons that receive DA input from the ventral tegmental area (VTA) 4°. These glutamatergic projections are believed to modulate terminal DA release, although the nature of this interaction remains controversial "s'~''t4"3a.Reduced cortical DA activity after VHIP lesions may represent a compensatory effort to inhibit mesolimbic DA transmission. Alternatively, interruption of VHIP efferents to the MPFC t3aS'4¢' or to the V T A 16 which in turn provides DA innervation of MPFC and NAS 47 could be involved. The delayed appearance of changes in basal ganglia DAergic transmission is a puzzling though frequently reported phenomenon ~7'36'43. In summary, IA lesions of the ventral hippocampus are followed by enduring augmentation of Damphetam~r~e-induced hyperactivity, and by the delayed appearance of increased spontaneous locomotion accompanied by an increase in NAS DA and reduced DA turnover in the MPFC. The parallel evolution of and correlation between these neurochemicals suggests that the reduction in MPFC DA activity is related to increased DA levels in NAS. It is noteworthy that recent studies in schizophrenia have implicated (i) structural changes in the ventral hippocampal formation44; (ii) a profile of prefrontocortical dysfunction suggestive of reduced cortical DAergic activity ~0.55;and (iii) a general dysregulation of DA systems in the striato-limbic system t~''~q (for review see ref. 19). Accordingly, the IA VHIP lesioned rat may provide an interesting model of cortically driven subcortical DA dysregulation, isomorphic with several neurobiological features of schizophrenia. Acknowledgements. 3'he authors thank Miss lngrid Phillips and Miss Tracy Matthews for their skilled technical assistance.

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