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Effect of ibotenic acid lesions of the medial prefrontal cortex on amphetamine-induced locomotion and regional brain catecholamine concentrations in the rat
263
Brain Research, 534 (1990) 263-272 Elsevier BRES 16092
Effect of ibotenic acid lesions of the medial prefrontal cortex on amphetamine-induced locomotion and regional brain catecholamine concentrations in the rat George E. Jaskiw 1, Farouk Karoum 2, William J. Freed 2, Ingrid Phillips 1, Joel E. Kleinman 1 and Daniel R. Weinberger 1 1Clinical Brain Disorders Branch and 2Neuropsychiatry Branch, National Institutes of Mental Health, Intramural Research Program, St. Elizabeths Hospital, Washington, DC 20032 (U.S.A.) (Accepted 12 June 1990) Key words: Prefrontal cortex; Dopamine; Ibotenic acid; Amphetamine; Locomotor response; Corpus striatum
To determine the influence of intrinsic medial prefrontal cortex (MPFC) neurons on regional brain catecholamine turnover, dopamine (DA) and its metabolites were assayed in several brain areas 14 and 28 days after bilateral ibotenic acid (IA) lesions of the MPFC in the rat. The locomotor response to o-amphetamine was also assessed. On the 14th postoperative day levels of DA, homovanillic acid concentrations and 3,4-dihydroxyphenylacetic acid were elevated in the anterior striatum of IA-lesioned animals. Spontaneous and amphetamine-induced locomotion were also increased. These changes disappeared by the 28th postoperative day. It is concluded that destruction of the efferents of the MPFC induces transient increases in DA turnover within the medial striatum and transiently increases spontaneous and amphetamine-induced locomotion. INTRODUCTION Several lines of evidence suggest that the medial prefrontal cortex (MPFC) can influence subcortical dopamine ( D A ) systems. Depletion of D A in the M P F C is associated with increases in several measures of D A activity in the nucleus accumbens 52,58,7° and corpus striatum 5s'7°, as well as with behavioral changes consistent with augmented mesolimbic or nigrostriatal D A activity 29'52'67'7°'a5. Changes in M P F C D A turnover under certain conditions are opposite to those in the nucleus accumbens and corpus striatum 6,s4,82. Though some contradictory results have emerged 19,62,63,75,84, in general the D A innervation of the M P F C has been implicated in the inhibitory regulation of several other D A terminal fields. The role of intrinsic M P F C neurons in mediating these effects has been less extensively studied. Electrolytic destruction of the M P F C enhances amphetamine-induced stereotypy ~, and increases D 1 receptor density 7~ in the nucleus accumbens. Electrolytic lesion techniques, however, destroy intrinsic neurons as well as fibers of passage. Since even small surgical lesions in the vicinity of the M P F C can deprive distant cortical areas of noradrenergic innervation 64 and disrupt other corticocortical pathways, the effects of intrinsic MFPC cell loss
cannot be definitively determined from these experiments. Excitotoxins such as kainic acid, ibotenic acid (IA) and N-methyl-D-aspartate ( N M D A ) produce relatively selective lesions, destroying predominantly intrinsic neurons 2°. Changes in D A and metabolites have been observed in one study following N M D A lesion of the MPFC. However, because these changes were transient and were not reflected in alterations in D A turnover assessed after D A depletion, they were judged to be functionally insignificant 16. In the latter study, however, relatively large regions of the nucleus accumbens and corpus striatum were assayed 16, whereas M P F C projections to these structures are not homogeneously distributed 5'14'33'6°'79. Moreover, behavioral changes might assist in clarifying the functional significance of neurochemical alterations following such lesions. Accordingly, we have determined whether subcortical catecholamine concentrations as well as spontaneous and amphetamine induced locomotor activity are altered following I A lesions of the MPFC. MATERIALS AND METHODS Surgery and handling Male Sprague-Dawley rats (Zivic-Miller Labs) weighing 220-250 g were housed 4 to a cage in a room with a 12-h light/12-h dark cycle
Correspondence: G.E. Jaskiw, WAW Bldg., Rm. 500, Neurosciences Center, St. Elizabeths Hospital, Washington, DC 20032, U.S.A. 0006-8993/90/$03.50 © 1990 Elsevier Science Publishers B.V. (Biomedical Division)
264 and with unlimited access to food and water. After anesthesia with ketamine (70 mg/kg) and xylazine (6 mg/kg) i.m., rats were immobilized in a stereotaxic frame (Kopf Instruments, model 900), with the incisor set at 2.5 mm below the interaural line. Ibotenic acid (Sigma Chemical Co.) (5 ~g/0.5 ~1 over 2.5 rain) or an equal volume of vehicle (0.1 M phosphate buffered saline, pH 7.4) was stereotaxically administered bilaterally through 26-gauge stainless steel cannulae with an infusion pump at the coordinates68: AP +3.5 ram, ME +_0.7 mm from the bregma and VD -3.5 mm relative to dura. The cannulae remained in place for 5 rain after the end of the infusion. Behavioral testing was conducted between 09.00 and 13.00 h on different groups of rats 14 and 28 days after surgery. Animals were moved in their home cages to the testing area and immediately placed in clear plexiglass activity monitors (42 × 42 × 30 cm) (Omnitech model RXYZCMI6) TM. After 5 min of habituation, spontaneous activity was assessed for 60 min. Vehicle (VEH) (normal saline 1 ml/kg i.p.) was then administered and activity measured for the following 60 rain. Finally activity was monitored for 90 min following D-amphetamine sulfate (AMP) (Sigma) (0.75 mg/kg i.p.). Thus the total duration of data collection testing was 210 min.
Sixteen rats with IA and 4 with sham injections were randomly selected 5-7 days after the lesion, anesthetized with chloral hydrate 300 mg/kg i.p., and perfused with a 4% buffered formalin solution. After immersion in a 30% sucrose solution for 72 h, cryostat sections were prepared and stained with Cresyl violet. The outermost area of neuronal cell loss as determined by light microscopy was used to define the lesion boundaries. The area which would encompass the lesion boundaries from 10 rats was determined. Groups of untested, unmedicated animals were decapitated by guillotine on the 14th or 28th postoperative day. The order of euthanasia was counterbalanced so that in a given hour both IA and sham-treated rats were used. Brain regions were dissected on wet ice from 2 mm thick sections as shown (Fig. 1). Mean regional wet weights were determined on 8 unoperated rats not used for assay. Samples were frozen and stored at -40 °C until homogenization in 0.25 ml 1 N HC1 containing known amounts of deuterated noradrenaline (NA) and DA and centrifuged at 12,000 g. The clear supernatant obtained was stored at -16 °C until analyzed. For the assays of NA and DA, a portion of the supernatant (75 ml) was evaporated to dryness under nitrogen and the amines derivatized to their pentafluoropropionate derivative. The remainder of the supernatant was extracted under ethyl acetate. The ethyl acetate was
ClN
Fig. 1. Dissection of brain regions. MPFC, medial prefrontal cortex; FC', frontal cortex; CIN, cingulate cortex; NAS, nucleus accumbens septi; MCS, medial corpus stratum; LCS, lateral corpus striatum. Coordinates refer to distances anterior to bregma (Paxinos and Watson68).
265 dried under N 2 and the DA metabolites in the residue derivatized to their ethyl esters/pentafluoropropionate derivatives46. A Finnigan gas chromatograph quadrupole mass spectrometer model 5500 was used for mass fragmentography. Results were expressed as pmol/mg protein.
Statistics Data are expressed as mean + S.E.M. and were analyzed by a computer-based Statistical Analysis System (SAS Institute Inc.). Behavioral and biochemical measures were analyzed by ANOVA and MANOVA, respectively, followed by Newman-Keuls tests for
post-hoc comparisons. Pearson correlation coefficients were also used where appropriate.
RESULTS
Histology Small areas of central cavitation, surrounded by a larger area of gliosis with concomitant cell loss was seen at the lesion site (Fig. 2a,b). The lesion extended from the genu of the corpus callosum to just caudal to the rostral tip of the frontal pole (Fig. 3). Virtually all of the MPFC was affected, that is cingulate cortex area 3 (Cg3) 68. In addition, parts of infralimbic cortex (IL), medial and ventral orbital cortices ( M O N O ) , frontal cortex area 2 and C g l and Cg2 were involved68. Corpus striatum, nucleus accumbens, and the dissected parts of cingulate cortex and frontal cortex (Fig. 3) were not involved.
Behavior The activity monitoring system used provides a number of indices of locomotor behavior. Results were similar for several indices of locomotor activity (hori-
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Fig. 2. Photomicrographs of Cresyl violet-stained sections taken 6 days after induction of IA lesion in the MPFC. a: low power; calibration bar = 1 mm. b: high power; calibration bar = 50 ~m.
Fig. 3. 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 MPFC. Horizontal bars and the blackened area indicate the largest and smallest lesions, respectively. Stippling indicates the area encompassing the lesion boundaries in 10 rats. CPu, caudate-putamen; FMI, forceps minor; NAS, nucleus accumbens septi. Coordinates refer to distance in mm anterior to bregma (Paxinos and Watson68).
266
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TIME ( M I N I Fig. 4. Time course of distance traveled by rats in a novel photocell apparatus. Different sham or IA-lesioned groups were tested 14 or 28 days postoperatively. After overnight acclimatization to the testing area, rats were placed in the apparatus for a 5-rain habituation period. Activity was then recorded at 15-min intervals. After 60 min, saline (1 ml/kg i.p.) was administered and activity recorded for a further 60 rain. Rats then received D-amphetamine (0.75 mg/kg i.p.) and had their activity recorded for a further 90 min.
zontal, vertical, distance traveled) and only data for distance traveled will be presented. Total distances traveled for the 3 consecutive intervals (60 min of habituation, 60 min following saline, 90 min following D-amphetamine) were analyzed by an A N O V A with time as a repeated factor. A significant overall times x lesion effect (F2.2~ = 3.37, P < 0.05) was evident on the 14th postoperative day (Figs. 4 and 5a). N e u m a n - K e u l s ' indicated that IA-lesioned rats were 40% more active during habituation, 70% more active after saline, and 80% more active after o-amphetamine (0.75 mg/kg i.p.) administration, relative to controls (Fig. 5a). The percentage increases in activity of the IA-lesioned animals after saline as compared to amphetamine administration were not significantly different (t-test for matched pairs: t - 0 . 5 2 , P > 0.6). In contrast there was no overall times x lesion effect 28 days postoperatively (F2,19 = 0.9, P > 0.4) (Fig. 5b). It is interesting to note, however, that if the distances travelled during the period following saline injection were subjected to post-hoc tests, the IAlesioned animals were significantly more active than sham-lesioned ones.
Biochemistry Mean tissue weights in mg were as follows: M P F C 14.14 + 0.64, cingulate cortex 9.65 + 0.41 mg, nucleus accumbens 10.2 + 0.73, medial corpus striatum 13.65 + 0.47 mg, lateral corpus striatum 11.08 + 0.55 mg. Fourteen days postoperatively there were no significant lesion effects on the M P F C (F4,1o = 1.59, P < 0.2), frontal cortex (F4,1o = 0.9, P < 0.5), N A S (F4,16 = 0.98, P < 0.4) or lateral corpus striatum (/73,17 = 1.47, P < 0.3) (Table I). Lesion effects were evident within the cingulate cortex (F4,10 = 47.57, P < 0,0001) and the medial corpus striatum (F3,17 = 6.76, P < 0.003). Post-hoc tests showed that in the MPFC-lesioned group, N A within ei.ngnlate cortex was reduced (P < 0.01) while homovanilli¢ acid (HVA) levels were nearly doubled (P < 0.00t). There were no significant correlations within cingulate cortex between concentrations of N A and those of either D O P A C or H V A . Significant increases were detected within the medial corpus striatum in concentrations of D A (P < 0.05), D O P A C (P < 0.001) and H V A (P < 0.001), and there was a high degree of correlation between D A and D O P A C concentrations (r -- 0.84, P <
267
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Fig. 5. a: total distances traveled 14 days postoperatively. ANOVA with lesion status as one factor and time as a repeated factor showed a significant time x lesion interaction (F2,21 = 3.37, P < 0.05). Newman-Keuls tests were used for post-hoe comparisons (*P < 0.05). b: total distances traveled 28 days postoperatively. Time x lesion interaction was not significant (F2,t9 = 0.9, P = 0.4).
0.005) in the IA-lesioned rats. By the 28th postoperative day there was no lesion effect on any of the assayed areas (data not shown) (MPFC: F4A3 = 1.68, P > 0.2; frontal cortex: F4,13 = 2.32, P > 0.1; cingulate cortex: F4,~3 = 0.77, P > 0.6; NAS: F4,13 = 0.54, P > 0.7; medial corpus striatum: F3,14 = 1.97, P > 0.2; lateral corpus striatum: F3,~4 = 0.31, P
> o.3).
DISCUSSION I A destroyed intrinsic n e u r o n s in an extensive area of the M P F C k n o w n to receive dopaminergic afferents 86. The induction of some central cavitation is in agreement with reports of others 42 and suggests that I A can induce non-specific damage. While the absence of changes in M P F C levels of N A or D A suggest that most terminals
268 TABLE I Neurochemical changes after IA lesion of the MPFC 14 days postoperatively
All values are expressed as pmol/mg protein + S.E.M. Post-hoc Neuman-Keuls tests *P < 0.05, **P < 0.01, ***P < 0.001 applied if the overall MANOVA for the brain region was significant. Numbers in parentheses denote the number of animals used in the assay for a given brain area. MPFC, medial prefrontal cortex; FC', frontal cortex excluding MPFC; CIN, cingulate cortex; NAS, nucleus aceumbens; MCS, medial corpus striatum; LCS, lateral corpus striatum. Sham
IA lesion
MPFC
DA DOPAC HVA NA
4.16 + 0.39 (7) 1.06 + 0.11 1.67 + 0.18 19.3 + 0.54
4.26 _+0.71 (8) 1.25 _+0.23 2.72 + 0.40 17.4 _+ 1.6
FC"
DA DOPAC HVA NA
2.96 + 0.15 (7) 0.989 + 0.09 1.39 + 0.22 15.24 +_0.57
3.34 _+0.55 (8) 0.82 _+0.19 1.66 _+0.35 15.5 _+0.60
CIN
DA DOPAC HVA NA
4.20+0.46(7) 2.04 + 0.25 1.10+0.13 27.43 + 2.5
3.18+__0.44(8) 2.24 + 0.40 2.18+_0.24"** 18.9 _+ 1.5**
NAS
DA DOPAC HVA NA
422 + 94.2 + 35.6 + 20.9 +
29 (9) 6.3 2.4 1.1
MCS
DA DOPAC HVA
603 + 28 (9) 69.8 + 2.4 23.8 + 0.86
LCS
DA DOPAC HVA
719 + 22 (9) 59 + 2.8 38.04 + 1.3
478 _+26 (12) 95.1 + 4.6 39.5 _+2.3 20.6 _+1.0 692 + 25* (12) 85.8 + 4.3** 45.31"** 729 + 14.9 (12) 66.6 + 3.3 42.9 + 2.6
were spared, the possibility that I A had some effect on catecholaminergic terminals cannot be precluded. M P F C deafferentation induced a transient but nonspecific increase in l o c o m o t o r behavior, evident during the p e r i o d of normal exploration as well as after saline and D-amphetamine administration. The effect of excitotoxic M P F C lesions on such behaviors has not, to our knowledge, been previously evaluated. Increases in spontaneous 3,9,28,3°,34,48,56,57,72'91 activity, as well as amp h e t a m i n e - i n d u c e d locomotion or stereotypy 1'26'27'37-39' ~5,57 have been observed after ablative frontocortical lesions, most of which either exceeded the boundaries of the M P F C 3'9'26'27'30'37'72"91 or spared it considerably while affecting adjacent areas 1'38"39'56'57. Ablations confined to the M P F C 28"34'35"48 damage fibers of passage 64 to regions also involved in l o c o m o t o r activity 61. A s has been noted by others 36, conclusions drawn from such studies about the role of the M P F C in modulating locomotor and
exploratory behaviors r e m a i n e d to be confirmed. O u r results are consistent with earlier inferences. Although probably not unique in this regard (see refs. 1, 38, 39, 56, 57, 83), under certain testing conditions intrinsic M P F C neurons contribute to inhibition of l o c o m o t o r exploratory activity. The time course of behavioral changes following I A lesion of the M P F C paralleled several neurochemical changes. F o u r t e e n days postoperatively H V A and N A levels were elevated in the cingulate cortex. It may be that the I A lesion affected some N A e r g i c fibers which pass through the forebrain before innervating the cingulate cortex 64. The increase in H V A m a y thus represent a c o m p e n s a t o r y increase in N A synthesis in a subset of unimpaired N A neurons. Alternatively, the H V A change may reflect an increase in local D A turnover unrelated to the N A system. D A , D O P A C and H V A were transiently increased within the anterior striatum. With one exception 65, most authors have not found such changes in striatal D A or its metabolites after ablative frontocortical lesions 38'69'8°. Available descriptions suggest that in those studies the dissection techniques were considerably different from ours, and that the lesions either exceeded M P F C boundaries 65 or primarily affected areas (e.g. area 10 of Krieg) 5~ o t h e r than the the M P F C 38'69"8°. Christie et al. 16 induced selective M P F C lesions using N M D A and assayed several brain regions at 2, 6 and 12 days. By day 12 nucleus accumbens N A was increased but no significant changes in D A , D O P A C or the D O P A C / D A utilization ratio could b e d e t e c t e d in the M P F C , nucleus accumbens, c a u d a t e - p u t a m e n or ventral t e g m e n t a l areas. H o w e v e r , the dissection technique used yielded mean weights of 19.6 + 0.2 mg and 61.7 + 2.9 mg for nucleus accumbens and corpus striatum, respectively, in earlier experiments 4. These are several times greater than ours, and may be an important variable given the t o p o g r a p h y of M P F C corticostriatal projections. The M P F C projects most densely to the a n t e r o m e d i a l striatum 5"32'6°'79, the area in which we detected elevations of D A and its metabolites. Given that c o m p a r a b l e changes were not found in the lateral striatum it is likely that subtle regional elevations would not have been d e t e c t e d had a less specific striatal dissection been e m p l o y e d . There are several routes by which an M P F C lesion could influence the striatal D A system. The M P F C projects directly to the substantia nigra 1° and the ventral tegmental area 15, the nuclei of origin of striatal D A 23. These mesencephalic nuclei are anatomically linked 21 and topographically project to forebrain structures 23. While it is of interest that changes in D A indices following M P F C lesion were confined to that part of the striatum where the projection fields of the M P F C and ventral tegmental
269 area overlap 53, the ineractions of the MPFC with mesencephalic nuclei are poorly understood. The corticostriatal system has been more extensively studied. Corticostriatal neurons form synapses at the heads, whereas nigrostriatal DA terminals synapse at the necks of dendritic spines of spiny striatal projection neurons 7'25. While there is no evidence for axo-axonic synapses between corticostriatal and nigrostriatal terminals, glutamate, the putative neurotransmitter of the corticostriatal system 59'9° appears to influence striatal DA release 13. If as some studies suggest, glutamate simply facilitates striatal DA release 73, alterations in presynaptic striatal DAergic activity might be expected to parallel changes in impulse dependent corticostriatal glutamate release. The latter is consistent with the augmentation of striatal transmission observed following DA depletion of the MPFC 58'7°, given that DA is inhibitory to most cells of the MPFC 8'87. However, we find that a non-specific deefferentation of the MPFC which destroys glutamatergic projections to the striatum, not only does not reduce but appears to increase striatal DA release, albeit transiently. Striatal glutamate-DA interactions are complex and a simple facilitatory role for glutamate on DA release is unlikely. Depending on the concentrations used, glutamate may stimulate or inhibit nigrostriatal DA release 13. Studies of the glutamate receptor subtype responsible for affecting DA release have also yielded conflicting results 12'77. Moreover, mechanisms of glutamate-DA interactions have been largely inferred from acute manipulations of these systems. Following a chronic disturbance of glutamatergic innervation, as would be induced by a cortical lesion, compensatory processes occur. Accordingly, the mechanism by which our MPFC lesion transiently increased presynaptic striatal DA indices remains to be clarified. No changes were detected in mesolimbic DA or its metabolites. This is puzzling for several reasons. The nucleus accumbens receives excitatory amino acid input from the MPFC 14'17 as well as DA innervation from the mesencephalic nuclei 23 and has other similarities to the medial striatum 22,32. The recent observation that tetrodotoxin blockade of transmission from the ventral MPFC acutely elevates DOPAC levels in the nucleus accumbens, has suggested that cortico-accumbal projections tonically inhibit mesolimbic DA release 54. We, as well as others 71 have not, however, detected any changes in basal presynaptic DA indices within the nucleus accumbens following chronic interruption of innervation from the MPFC. It is possible that tolerance develops to the partial destruction of glutamatergic input more rapidly or effectively in the nucleus accumbens than in the striatum. Loss of MPFC projections can perhaps be compensated
for by excitatory input to the nucleus accumbens from other structures17'74'88. The absence of mesolimbic neurochemical changes is also odd in light of the behavioral changes observed. Although DA release in the corpus striatum has been linked to locomotor activity24, D A transmission in the nucleus accumbens is believed to be of primary importance in determining locomotion 19'47. Yet, the time course of augmented locomotor activity paralleled increases in striatal DA and its metabolites. That mesolimbic DA systems were also involved cannot, however, be definitively precluded. Given that MPFC DA terminals are highly stress-sensitive 76, and that the behavioral effects of ablative MPFC lesions vary with testing conditions 34'35, it may be relevant that the rats we used for neurochemical analysis were well acclimatized before euthanasia, whereas animals undergoing behavioral assessment were exposed to mild stresses (novel open field, i.p. injections). In other experiments, MPFC lesions have been found to alter behavioral and biochemical responses to stressful stimuli T M . Accordingly, it is possible that neurochemical changes not present in acclimatized rats, but evoked by the mildly stressful conditions of testing, may be associated with the increased locomotor activity evident 14 days postoperatively. Similar considerations may also account for some of the inconsistent findings following DA depletion of the MPFC 29'44'52'58'67'70'75. Although amphetamine-induced locomotion as well as levels of DA and its metabolites normalized by 1 month, postoperatively, it would be premature to conclude that IA lesions of the MPFC have no enduring effects on subcortical DA systems. Animals were tested following a single dose of D-amphetamine, an agent which amplifies release of serotonin and NA, as well as of DA 2. Postsynaptic indices of DA transmission in the nucleus accumbens or corpus striatum were not assessed. Experiments were completed by the 28th postoperative day. Other striatal denervation paradigms suggest that lesioninduced changes in DA transmission may continue beyond the fourth postoperative week 31,32. Moreover, the response of an apparently 'compensated' system to an activation demand or pharmacological challenge remains to be determined. Some enduring effects of MPFC deefferentation might only become evident under conditions that normally require activation of the MPFC DA system and/or participation of MPFC terminal projection fields. For instance, abnormal locomotor and biochemical responses to stressful stimuli can be elicited several months after MPFC lesion 4°,41. In summary, increases in spontaneous and amphetamine-induced locomotor activity as well as in DA and its metabolites within the medial corpus striatum are evident 14 days after bilateral destruction of intrinsic MPFC
270 n e u r o n s . T h e s e changes a t t e n u a t e by the f o u r t h w e e k .
useful in c h a r a c t e r i z i n g the p a t h o p h y s i o l o g y of a com-
T h e d a t a are consistent with earlier studies implicating
p r o m i s e d brain u n d e r c o n d i t i o n s w h i c h n o r m a l l y elicit a
M P F C n e u r o n s in the m o d u l a t i o n of c a t e c h o l a m i n e t u r n o v e r in o t h e r brain areas 54'7°. T h e n a t u r e of this
c o o r d i n a t e d r e s p o n s e of c e r e b r a l D A systems.
m o d u l a t i o n and t h e c o n d i t i o n s u n d e r which it b e c o m e s
Acknowledgements. The authors wish to thank Mrs. E. Krauthamer for preparing the histological specimens, Mr. J. Aarons for his drawings, Mr. R. Alexander for helping with biochemical analyses and Dr, M. Casanova for his assistance in producing the photomicrographs. Parts of this work were presented at the 141st Annual Meeting of the American Psychiatric Association, Montreal, 1988 and at the 17th Annual Meeting of the Society for Neuroscience, New Orleans, 1987.
i m p o r t a n t r e m a i n to be d e t e r m i n e d . It has b e e n postulated that s o m e psychiatric s y m p t o m s m a y result w h e n the i n t e g r a t e d f u n c t i o n of several D A cannot
be
maintained
in the
t e r m i n a l fields
face of an
activation
d e m a n d s9. T h u s the animal m o d e l d e s c r i b e d m a y p r o v e
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Brain Research, 534 (1990) 263-272 Elsevier BRES 16092
Effect of ibotenic acid lesions of the medial prefrontal cortex on amphetamine-induced locomotion and regional brain catecholamine concentrations in the rat George E. Jaskiw 1, Farouk Karoum 2, William J. Freed 2, Ingrid Phillips 1, Joel E. Kleinman 1 and Daniel R. Weinberger 1 1Clinical Brain Disorders Branch and 2Neuropsychiatry Branch, National Institutes of Mental Health, Intramural Research Program, St. Elizabeths Hospital, Washington, DC 20032 (U.S.A.) (Accepted 12 June 1990) Key words: Prefrontal cortex; Dopamine; Ibotenic acid; Amphetamine; Locomotor response; Corpus striatum
To determine the influence of intrinsic medial prefrontal cortex (MPFC) neurons on regional brain catecholamine turnover, dopamine (DA) and its metabolites were assayed in several brain areas 14 and 28 days after bilateral ibotenic acid (IA) lesions of the MPFC in the rat. The locomotor response to o-amphetamine was also assessed. On the 14th postoperative day levels of DA, homovanillic acid concentrations and 3,4-dihydroxyphenylacetic acid were elevated in the anterior striatum of IA-lesioned animals. Spontaneous and amphetamine-induced locomotion were also increased. These changes disappeared by the 28th postoperative day. It is concluded that destruction of the efferents of the MPFC induces transient increases in DA turnover within the medial striatum and transiently increases spontaneous and amphetamine-induced locomotion. INTRODUCTION Several lines of evidence suggest that the medial prefrontal cortex (MPFC) can influence subcortical dopamine ( D A ) systems. Depletion of D A in the M P F C is associated with increases in several measures of D A activity in the nucleus accumbens 52,58,7° and corpus striatum 5s'7°, as well as with behavioral changes consistent with augmented mesolimbic or nigrostriatal D A activity 29'52'67'7°'a5. Changes in M P F C D A turnover under certain conditions are opposite to those in the nucleus accumbens and corpus striatum 6,s4,82. Though some contradictory results have emerged 19,62,63,75,84, in general the D A innervation of the M P F C has been implicated in the inhibitory regulation of several other D A terminal fields. The role of intrinsic M P F C neurons in mediating these effects has been less extensively studied. Electrolytic destruction of the M P F C enhances amphetamine-induced stereotypy ~, and increases D 1 receptor density 7~ in the nucleus accumbens. Electrolytic lesion techniques, however, destroy intrinsic neurons as well as fibers of passage. Since even small surgical lesions in the vicinity of the M P F C can deprive distant cortical areas of noradrenergic innervation 64 and disrupt other corticocortical pathways, the effects of intrinsic MFPC cell loss
cannot be definitively determined from these experiments. Excitotoxins such as kainic acid, ibotenic acid (IA) and N-methyl-D-aspartate ( N M D A ) produce relatively selective lesions, destroying predominantly intrinsic neurons 2°. Changes in D A and metabolites have been observed in one study following N M D A lesion of the MPFC. However, because these changes were transient and were not reflected in alterations in D A turnover assessed after D A depletion, they were judged to be functionally insignificant 16. In the latter study, however, relatively large regions of the nucleus accumbens and corpus striatum were assayed 16, whereas M P F C projections to these structures are not homogeneously distributed 5'14'33'6°'79. Moreover, behavioral changes might assist in clarifying the functional significance of neurochemical alterations following such lesions. Accordingly, we have determined whether subcortical catecholamine concentrations as well as spontaneous and amphetamine induced locomotor activity are altered following I A lesions of the MPFC. MATERIALS AND METHODS Surgery and handling Male Sprague-Dawley rats (Zivic-Miller Labs) weighing 220-250 g were housed 4 to a cage in a room with a 12-h light/12-h dark cycle
Correspondence: G.E. Jaskiw, WAW Bldg., Rm. 500, Neurosciences Center, St. Elizabeths Hospital, Washington, DC 20032, U.S.A. 0006-8993/90/$03.50 © 1990 Elsevier Science Publishers B.V. (Biomedical Division)
264 and with unlimited access to food and water. After anesthesia with ketamine (70 mg/kg) and xylazine (6 mg/kg) i.m., rats were immobilized in a stereotaxic frame (Kopf Instruments, model 900), with the incisor set at 2.5 mm below the interaural line. Ibotenic acid (Sigma Chemical Co.) (5 ~g/0.5 ~1 over 2.5 rain) or an equal volume of vehicle (0.1 M phosphate buffered saline, pH 7.4) was stereotaxically administered bilaterally through 26-gauge stainless steel cannulae with an infusion pump at the coordinates68: AP +3.5 ram, ME +_0.7 mm from the bregma and VD -3.5 mm relative to dura. The cannulae remained in place for 5 rain after the end of the infusion. Behavioral testing was conducted between 09.00 and 13.00 h on different groups of rats 14 and 28 days after surgery. Animals were moved in their home cages to the testing area and immediately placed in clear plexiglass activity monitors (42 × 42 × 30 cm) (Omnitech model RXYZCMI6) TM. After 5 min of habituation, spontaneous activity was assessed for 60 min. Vehicle (VEH) (normal saline 1 ml/kg i.p.) was then administered and activity measured for the following 60 rain. Finally activity was monitored for 90 min following D-amphetamine sulfate (AMP) (Sigma) (0.75 mg/kg i.p.). Thus the total duration of data collection testing was 210 min.
Sixteen rats with IA and 4 with sham injections were randomly selected 5-7 days after the lesion, anesthetized with chloral hydrate 300 mg/kg i.p., and perfused with a 4% buffered formalin solution. After immersion in a 30% sucrose solution for 72 h, cryostat sections were prepared and stained with Cresyl violet. The outermost area of neuronal cell loss as determined by light microscopy was used to define the lesion boundaries. The area which would encompass the lesion boundaries from 10 rats was determined. Groups of untested, unmedicated animals were decapitated by guillotine on the 14th or 28th postoperative day. The order of euthanasia was counterbalanced so that in a given hour both IA and sham-treated rats were used. Brain regions were dissected on wet ice from 2 mm thick sections as shown (Fig. 1). Mean regional wet weights were determined on 8 unoperated rats not used for assay. Samples were frozen and stored at -40 °C until homogenization in 0.25 ml 1 N HC1 containing known amounts of deuterated noradrenaline (NA) and DA and centrifuged at 12,000 g. The clear supernatant obtained was stored at -16 °C until analyzed. For the assays of NA and DA, a portion of the supernatant (75 ml) was evaporated to dryness under nitrogen and the amines derivatized to their pentafluoropropionate derivative. The remainder of the supernatant was extracted under ethyl acetate. The ethyl acetate was
ClN
Fig. 1. Dissection of brain regions. MPFC, medial prefrontal cortex; FC', frontal cortex; CIN, cingulate cortex; NAS, nucleus accumbens septi; MCS, medial corpus stratum; LCS, lateral corpus striatum. Coordinates refer to distances anterior to bregma (Paxinos and Watson68).
265 dried under N 2 and the DA metabolites in the residue derivatized to their ethyl esters/pentafluoropropionate derivatives46. A Finnigan gas chromatograph quadrupole mass spectrometer model 5500 was used for mass fragmentography. Results were expressed as pmol/mg protein.
Statistics Data are expressed as mean + S.E.M. and were analyzed by a computer-based Statistical Analysis System (SAS Institute Inc.). Behavioral and biochemical measures were analyzed by ANOVA and MANOVA, respectively, followed by Newman-Keuls tests for
post-hoc comparisons. Pearson correlation coefficients were also used where appropriate.
RESULTS
Histology Small areas of central cavitation, surrounded by a larger area of gliosis with concomitant cell loss was seen at the lesion site (Fig. 2a,b). The lesion extended from the genu of the corpus callosum to just caudal to the rostral tip of the frontal pole (Fig. 3). Virtually all of the MPFC was affected, that is cingulate cortex area 3 (Cg3) 68. In addition, parts of infralimbic cortex (IL), medial and ventral orbital cortices ( M O N O ) , frontal cortex area 2 and C g l and Cg2 were involved68. Corpus striatum, nucleus accumbens, and the dissected parts of cingulate cortex and frontal cortex (Fig. 3) were not involved.
Behavior The activity monitoring system used provides a number of indices of locomotor behavior. Results were similar for several indices of locomotor activity (hori-
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Fig. 2. Photomicrographs of Cresyl violet-stained sections taken 6 days after induction of IA lesion in the MPFC. a: low power; calibration bar = 1 mm. b: high power; calibration bar = 50 ~m.
Fig. 3. 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 MPFC. Horizontal bars and the blackened area indicate the largest and smallest lesions, respectively. Stippling indicates the area encompassing the lesion boundaries in 10 rats. CPu, caudate-putamen; FMI, forceps minor; NAS, nucleus accumbens septi. Coordinates refer to distance in mm anterior to bregma (Paxinos and Watson68).
266
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TIME ( M I N I Fig. 4. Time course of distance traveled by rats in a novel photocell apparatus. Different sham or IA-lesioned groups were tested 14 or 28 days postoperatively. After overnight acclimatization to the testing area, rats were placed in the apparatus for a 5-rain habituation period. Activity was then recorded at 15-min intervals. After 60 min, saline (1 ml/kg i.p.) was administered and activity recorded for a further 60 rain. Rats then received D-amphetamine (0.75 mg/kg i.p.) and had their activity recorded for a further 90 min.
zontal, vertical, distance traveled) and only data for distance traveled will be presented. Total distances traveled for the 3 consecutive intervals (60 min of habituation, 60 min following saline, 90 min following D-amphetamine) were analyzed by an A N O V A with time as a repeated factor. A significant overall times x lesion effect (F2.2~ = 3.37, P < 0.05) was evident on the 14th postoperative day (Figs. 4 and 5a). N e u m a n - K e u l s ' indicated that IA-lesioned rats were 40% more active during habituation, 70% more active after saline, and 80% more active after o-amphetamine (0.75 mg/kg i.p.) administration, relative to controls (Fig. 5a). The percentage increases in activity of the IA-lesioned animals after saline as compared to amphetamine administration were not significantly different (t-test for matched pairs: t - 0 . 5 2 , P > 0.6). In contrast there was no overall times x lesion effect 28 days postoperatively (F2,19 = 0.9, P > 0.4) (Fig. 5b). It is interesting to note, however, that if the distances travelled during the period following saline injection were subjected to post-hoc tests, the IAlesioned animals were significantly more active than sham-lesioned ones.
Biochemistry Mean tissue weights in mg were as follows: M P F C 14.14 + 0.64, cingulate cortex 9.65 + 0.41 mg, nucleus accumbens 10.2 + 0.73, medial corpus striatum 13.65 + 0.47 mg, lateral corpus striatum 11.08 + 0.55 mg. Fourteen days postoperatively there were no significant lesion effects on the M P F C (F4,1o = 1.59, P < 0.2), frontal cortex (F4,1o = 0.9, P < 0.5), N A S (F4,16 = 0.98, P < 0.4) or lateral corpus striatum (/73,17 = 1.47, P < 0.3) (Table I). Lesion effects were evident within the cingulate cortex (F4,10 = 47.57, P < 0,0001) and the medial corpus striatum (F3,17 = 6.76, P < 0.003). Post-hoc tests showed that in the MPFC-lesioned group, N A within ei.ngnlate cortex was reduced (P < 0.01) while homovanilli¢ acid (HVA) levels were nearly doubled (P < 0.00t). There were no significant correlations within cingulate cortex between concentrations of N A and those of either D O P A C or H V A . Significant increases were detected within the medial corpus striatum in concentrations of D A (P < 0.05), D O P A C (P < 0.001) and H V A (P < 0.001), and there was a high degree of correlation between D A and D O P A C concentrations (r -- 0.84, P <
267
a
SHAM 8000-
l
Z
G.I
IA 6000.
=.d
4000 I.=.
2000
z m o
HABITHATION 60 M I N
D-AMP
SALINE 60 M I N
0 . 7 5 MG/KG 90 M I N
b
w
II
SHAM
II
IA
10000
-l-
7500
a:
5000 z
2500 m lID
0
0
HABITUATION 60 M I N
SALINE 60 M I N
D-AMP 0 . 7 5 MG/KG 90 M I N
Fig. 5. a: total distances traveled 14 days postoperatively. ANOVA with lesion status as one factor and time as a repeated factor showed a significant time x lesion interaction (F2,21 = 3.37, P < 0.05). Newman-Keuls tests were used for post-hoe comparisons (*P < 0.05). b: total distances traveled 28 days postoperatively. Time x lesion interaction was not significant (F2,t9 = 0.9, P = 0.4).
0.005) in the IA-lesioned rats. By the 28th postoperative day there was no lesion effect on any of the assayed areas (data not shown) (MPFC: F4A3 = 1.68, P > 0.2; frontal cortex: F4,13 = 2.32, P > 0.1; cingulate cortex: F4,~3 = 0.77, P > 0.6; NAS: F4,13 = 0.54, P > 0.7; medial corpus striatum: F3,14 = 1.97, P > 0.2; lateral corpus striatum: F3,~4 = 0.31, P
> o.3).
DISCUSSION I A destroyed intrinsic n e u r o n s in an extensive area of the M P F C k n o w n to receive dopaminergic afferents 86. The induction of some central cavitation is in agreement with reports of others 42 and suggests that I A can induce non-specific damage. While the absence of changes in M P F C levels of N A or D A suggest that most terminals
268 TABLE I Neurochemical changes after IA lesion of the MPFC 14 days postoperatively
All values are expressed as pmol/mg protein + S.E.M. Post-hoc Neuman-Keuls tests *P < 0.05, **P < 0.01, ***P < 0.001 applied if the overall MANOVA for the brain region was significant. Numbers in parentheses denote the number of animals used in the assay for a given brain area. MPFC, medial prefrontal cortex; FC', frontal cortex excluding MPFC; CIN, cingulate cortex; NAS, nucleus aceumbens; MCS, medial corpus striatum; LCS, lateral corpus striatum. Sham
IA lesion
MPFC
DA DOPAC HVA NA
4.16 + 0.39 (7) 1.06 + 0.11 1.67 + 0.18 19.3 + 0.54
4.26 _+0.71 (8) 1.25 _+0.23 2.72 + 0.40 17.4 _+ 1.6
FC"
DA DOPAC HVA NA
2.96 + 0.15 (7) 0.989 + 0.09 1.39 + 0.22 15.24 +_0.57
3.34 _+0.55 (8) 0.82 _+0.19 1.66 _+0.35 15.5 _+0.60
CIN
DA DOPAC HVA NA
4.20+0.46(7) 2.04 + 0.25 1.10+0.13 27.43 + 2.5
3.18+__0.44(8) 2.24 + 0.40 2.18+_0.24"** 18.9 _+ 1.5**
NAS
DA DOPAC HVA NA
422 + 94.2 + 35.6 + 20.9 +
29 (9) 6.3 2.4 1.1
MCS
DA DOPAC HVA
603 + 28 (9) 69.8 + 2.4 23.8 + 0.86
LCS
DA DOPAC HVA
719 + 22 (9) 59 + 2.8 38.04 + 1.3
478 _+26 (12) 95.1 + 4.6 39.5 _+2.3 20.6 _+1.0 692 + 25* (12) 85.8 + 4.3** 45.31"** 729 + 14.9 (12) 66.6 + 3.3 42.9 + 2.6
were spared, the possibility that I A had some effect on catecholaminergic terminals cannot be precluded. M P F C deafferentation induced a transient but nonspecific increase in l o c o m o t o r behavior, evident during the p e r i o d of normal exploration as well as after saline and D-amphetamine administration. The effect of excitotoxic M P F C lesions on such behaviors has not, to our knowledge, been previously evaluated. Increases in spontaneous 3,9,28,3°,34,48,56,57,72'91 activity, as well as amp h e t a m i n e - i n d u c e d locomotion or stereotypy 1'26'27'37-39' ~5,57 have been observed after ablative frontocortical lesions, most of which either exceeded the boundaries of the M P F C 3'9'26'27'30'37'72"91 or spared it considerably while affecting adjacent areas 1'38"39'56'57. Ablations confined to the M P F C 28"34'35"48 damage fibers of passage 64 to regions also involved in l o c o m o t o r activity 61. A s has been noted by others 36, conclusions drawn from such studies about the role of the M P F C in modulating locomotor and
exploratory behaviors r e m a i n e d to be confirmed. O u r results are consistent with earlier inferences. Although probably not unique in this regard (see refs. 1, 38, 39, 56, 57, 83), under certain testing conditions intrinsic M P F C neurons contribute to inhibition of l o c o m o t o r exploratory activity. The time course of behavioral changes following I A lesion of the M P F C paralleled several neurochemical changes. F o u r t e e n days postoperatively H V A and N A levels were elevated in the cingulate cortex. It may be that the I A lesion affected some N A e r g i c fibers which pass through the forebrain before innervating the cingulate cortex 64. The increase in H V A m a y thus represent a c o m p e n s a t o r y increase in N A synthesis in a subset of unimpaired N A neurons. Alternatively, the H V A change may reflect an increase in local D A turnover unrelated to the N A system. D A , D O P A C and H V A were transiently increased within the anterior striatum. With one exception 65, most authors have not found such changes in striatal D A or its metabolites after ablative frontocortical lesions 38'69'8°. Available descriptions suggest that in those studies the dissection techniques were considerably different from ours, and that the lesions either exceeded M P F C boundaries 65 or primarily affected areas (e.g. area 10 of Krieg) 5~ o t h e r than the the M P F C 38'69"8°. Christie et al. 16 induced selective M P F C lesions using N M D A and assayed several brain regions at 2, 6 and 12 days. By day 12 nucleus accumbens N A was increased but no significant changes in D A , D O P A C or the D O P A C / D A utilization ratio could b e d e t e c t e d in the M P F C , nucleus accumbens, c a u d a t e - p u t a m e n or ventral t e g m e n t a l areas. H o w e v e r , the dissection technique used yielded mean weights of 19.6 + 0.2 mg and 61.7 + 2.9 mg for nucleus accumbens and corpus striatum, respectively, in earlier experiments 4. These are several times greater than ours, and may be an important variable given the t o p o g r a p h y of M P F C corticostriatal projections. The M P F C projects most densely to the a n t e r o m e d i a l striatum 5"32'6°'79, the area in which we detected elevations of D A and its metabolites. Given that c o m p a r a b l e changes were not found in the lateral striatum it is likely that subtle regional elevations would not have been d e t e c t e d had a less specific striatal dissection been e m p l o y e d . There are several routes by which an M P F C lesion could influence the striatal D A system. The M P F C projects directly to the substantia nigra 1° and the ventral tegmental area 15, the nuclei of origin of striatal D A 23. These mesencephalic nuclei are anatomically linked 21 and topographically project to forebrain structures 23. While it is of interest that changes in D A indices following M P F C lesion were confined to that part of the striatum where the projection fields of the M P F C and ventral tegmental
269 area overlap 53, the ineractions of the MPFC with mesencephalic nuclei are poorly understood. The corticostriatal system has been more extensively studied. Corticostriatal neurons form synapses at the heads, whereas nigrostriatal DA terminals synapse at the necks of dendritic spines of spiny striatal projection neurons 7'25. While there is no evidence for axo-axonic synapses between corticostriatal and nigrostriatal terminals, glutamate, the putative neurotransmitter of the corticostriatal system 59'9° appears to influence striatal DA release 13. If as some studies suggest, glutamate simply facilitates striatal DA release 73, alterations in presynaptic striatal DAergic activity might be expected to parallel changes in impulse dependent corticostriatal glutamate release. The latter is consistent with the augmentation of striatal transmission observed following DA depletion of the MPFC 58'7°, given that DA is inhibitory to most cells of the MPFC 8'87. However, we find that a non-specific deefferentation of the MPFC which destroys glutamatergic projections to the striatum, not only does not reduce but appears to increase striatal DA release, albeit transiently. Striatal glutamate-DA interactions are complex and a simple facilitatory role for glutamate on DA release is unlikely. Depending on the concentrations used, glutamate may stimulate or inhibit nigrostriatal DA release 13. Studies of the glutamate receptor subtype responsible for affecting DA release have also yielded conflicting results 12'77. Moreover, mechanisms of glutamate-DA interactions have been largely inferred from acute manipulations of these systems. Following a chronic disturbance of glutamatergic innervation, as would be induced by a cortical lesion, compensatory processes occur. Accordingly, the mechanism by which our MPFC lesion transiently increased presynaptic striatal DA indices remains to be clarified. No changes were detected in mesolimbic DA or its metabolites. This is puzzling for several reasons. The nucleus accumbens receives excitatory amino acid input from the MPFC 14'17 as well as DA innervation from the mesencephalic nuclei 23 and has other similarities to the medial striatum 22,32. The recent observation that tetrodotoxin blockade of transmission from the ventral MPFC acutely elevates DOPAC levels in the nucleus accumbens, has suggested that cortico-accumbal projections tonically inhibit mesolimbic DA release 54. We, as well as others 71 have not, however, detected any changes in basal presynaptic DA indices within the nucleus accumbens following chronic interruption of innervation from the MPFC. It is possible that tolerance develops to the partial destruction of glutamatergic input more rapidly or effectively in the nucleus accumbens than in the striatum. Loss of MPFC projections can perhaps be compensated
for by excitatory input to the nucleus accumbens from other structures17'74'88. The absence of mesolimbic neurochemical changes is also odd in light of the behavioral changes observed. Although DA release in the corpus striatum has been linked to locomotor activity24, D A transmission in the nucleus accumbens is believed to be of primary importance in determining locomotion 19'47. Yet, the time course of augmented locomotor activity paralleled increases in striatal DA and its metabolites. That mesolimbic DA systems were also involved cannot, however, be definitively precluded. Given that MPFC DA terminals are highly stress-sensitive 76, and that the behavioral effects of ablative MPFC lesions vary with testing conditions 34'35, it may be relevant that the rats we used for neurochemical analysis were well acclimatized before euthanasia, whereas animals undergoing behavioral assessment were exposed to mild stresses (novel open field, i.p. injections). In other experiments, MPFC lesions have been found to alter behavioral and biochemical responses to stressful stimuli T M . Accordingly, it is possible that neurochemical changes not present in acclimatized rats, but evoked by the mildly stressful conditions of testing, may be associated with the increased locomotor activity evident 14 days postoperatively. Similar considerations may also account for some of the inconsistent findings following DA depletion of the MPFC 29'44'52'58'67'70'75. Although amphetamine-induced locomotion as well as levels of DA and its metabolites normalized by 1 month, postoperatively, it would be premature to conclude that IA lesions of the MPFC have no enduring effects on subcortical DA systems. Animals were tested following a single dose of D-amphetamine, an agent which amplifies release of serotonin and NA, as well as of DA 2. Postsynaptic indices of DA transmission in the nucleus accumbens or corpus striatum were not assessed. Experiments were completed by the 28th postoperative day. Other striatal denervation paradigms suggest that lesioninduced changes in DA transmission may continue beyond the fourth postoperative week 31,32. Moreover, the response of an apparently 'compensated' system to an activation demand or pharmacological challenge remains to be determined. Some enduring effects of MPFC deefferentation might only become evident under conditions that normally require activation of the MPFC DA system and/or participation of MPFC terminal projection fields. For instance, abnormal locomotor and biochemical responses to stressful stimuli can be elicited several months after MPFC lesion 4°,41. In summary, increases in spontaneous and amphetamine-induced locomotor activity as well as in DA and its metabolites within the medial corpus striatum are evident 14 days after bilateral destruction of intrinsic MPFC
270 n e u r o n s . T h e s e changes a t t e n u a t e by the f o u r t h w e e k .
useful in c h a r a c t e r i z i n g the p a t h o p h y s i o l o g y of a com-
T h e d a t a are consistent with earlier studies implicating
p r o m i s e d brain u n d e r c o n d i t i o n s w h i c h n o r m a l l y elicit a
M P F C n e u r o n s in the m o d u l a t i o n of c a t e c h o l a m i n e t u r n o v e r in o t h e r brain areas 54'7°. T h e n a t u r e of this
c o o r d i n a t e d r e s p o n s e of c e r e b r a l D A systems.
m o d u l a t i o n and t h e c o n d i t i o n s u n d e r which it b e c o m e s
Acknowledgements. The authors wish to thank Mrs. E. Krauthamer for preparing the histological specimens, Mr. J. Aarons for his drawings, Mr. R. Alexander for helping with biochemical analyses and Dr, M. Casanova for his assistance in producing the photomicrographs. Parts of this work were presented at the 141st Annual Meeting of the American Psychiatric Association, Montreal, 1988 and at the 17th Annual Meeting of the Society for Neuroscience, New Orleans, 1987.
i m p o r t a n t r e m a i n to be d e t e r m i n e d . It has b e e n postulated that s o m e psychiatric s y m p t o m s m a y result w h e n the i n t e g r a t e d f u n c t i o n of several D A cannot
be
maintained
in the
t e r m i n a l fields
face of an
activation
d e m a n d s9. T h u s the animal m o d e l d e s c r i b e d m a y p r o v e
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