Apomorphine does not reverse reduced basal dopamine release in rat striatum and nucleus accumbens after chronic haloperidol treatment

138

I¢raln Re~ear,h

(t7 (]';t4t)) 1%,-)-12 r i~.t %1 ,

BRES 23902

Short Communications

Apomorphine does not reverse reduced basal dopamine release in rat striatum and nucleus accurnbens after chronic haloperidol treatment J Ichlkawa and H.Y Meltzer Laboratory of Blologwal Psychiatry, Case Western Reserve Umverstty School of Medicine, Cleveland, OH 44106 (U S A )

(Accepted 19 September 1989) Key words Chronic haloperidol, Dopamlne release, Apomorphme, Autoreceptor, Mlcrodialysis

Chronic administration of halopendol (2 mg/kg x 2t days) m dnnklng water decreased basal dopamme (DA) release and metabolism m rat stnatum and nucleus accumbens m awake, freely moving rats In contrast with previous m vwo voltammetnc studies in chloral hydrate-anesthetized rats, DA release and metabolism decreased in both regions following administration of (-)apomorphme (50 pg/kg, 1 v ) These results demonstrate that stimulation of pre- or postsynaptic DA receptors by apomorphme in rats chronically treated with halopendol further diminishes the release of DA and decreases DA metabolism These results are difficult to reconcde with current concepts of neuroleptlc-mduced depolarization inactivation which predict increased release of DA following DA agomst administration Electrophyslological studies have shown that longt e r m t r e a t m e n t with neurolepttc drugs induces depolarization block in d o p a m l n e ( D A ) neurons with cells of o n g m in the substantla m g r a pars c o m p a c t a (A9) and ventral t e g m e n t a l a r e a (A10) 4 5,9 22 23,26,27 The decrease m s p o n t a n e o u s l y active D A cells in the A10 region might be r e l a t e d to the antipsychottc effect of neurolepttc drugs, whereas the reduction in the n u m b e r of spontaneously active A 9 cells could be causally related to the d e v e l o p m e n t of e x t r a p y r a m i d a l side-effects 9 It has also been suggested that the haloperldol ( H A L ) - l n d u c e d d e p o l a r i z a t i o n block of the A 9 and A10 D A neurons might occur at the level of the cell b o d y or axon, or both, which would then alter D A release In neuron terminals O n the o t h e r hand, in vitro studtes suggest that chronic c l o z a p m e a d m m l s t r a t i o n m a y affect D A release in the s t n a t u m , but not the nucleus accumbens, by an action at the c a r r i e r - m e d i a t e d D A release mechanism m the t e r m m a l region 7 A u t o r e c e p t o r - s e l e c t w e doses of the direct-acting D A agonlst a p o m o r p h l n e causes D A cells in chronically n e u r o l e p U c - t r e a t e d rats to repolarlze and regam the ability to g e n e r a t e s p o n t a n e o u s s p i k e s 4 9 26 27 A p o m o r p h m e also r e v e r s e d the chronic H A L - i n d u c e d decrease in D A release m both the rat strlatum and nucleus accumbens and r e s t o r e d D A release to control levels as d e m o n s t r a t e d by in vlvo v o l t a m m e t r y 3'16 H o w e v e r , these results were o b t a i n e d in chloral hydrate anesthetized animals Recently, it has been shown that general

anesthesia, as well as restraint o r tall-shock stress, alters brain d o p a m m e r g l c activity 1 13 24,30 A d d i t i o n a l l y , A n d 6 n et al 2 o b s e r v e d that chronic H A L t r e a t m e n t , unhke g a m m a - b u t y r o l a c t o n e ( G B L ) , did not increase D A concentratton in rat f o r e b r a m regions and had no effect on the G B L - m d u c e d increase in D A concentrations They concluded that their results were mconslstent with the concept of depolarization block as d e v e l o p e d in anesthetized rats and suggested the n e e d to test the depolarization macttvatlon hypothesis b y further study in conscious animals We dectded to test the hypothesis of neurolepttcinduced d e p o l a r i z a t i o n block by d e t e r m l n m g the abdlty of a p o m o r p h m e to increase D A release m the strtatum and the nucleus accumbens of a w a k e , freely m o v m g rats t r e a t e d with chronic H A L usmg m v w o mtcrodtalysls Male S p r a g u e - D a w l e y rats received H A L (2 mg/ kg/day, McNeil) in their d r m k l n g water in hght-proof bottles for 21 days A control group of rats was given only vehicle D r m k i n g water was changed twice a w e e k and dosages used were corrected by weight and intake volume H A L was dissolved in a minimal a m o u n t of 1 M tartaric acid and diluted with deiontzed water and then adjusted to p H 7 0 - 7 4 with 1 M N a H C O 3 This regimen leads to increased n u m b e r s of D 2 D A receptors m the s t n a t u m (Meltzer et al , u n p u b h s h e d data) On the 21st day of t r e a t m e n t , rats (300-400 g) were anesthetized with sodium p e n t o b a r b i t a l and placed in a stereotaxic frame The skull was e x p o s e d and a hole was

Correspondence J Ichlkawa, Laboratory of Biological Psychiatry, Case Western Reserve University School of Medicine, 2040 Abmgton Road. Cleveland. OH 44106 U S A

139 drilled to allow implantation of a dialysis p r o b e into either the strtatum or the nucleus accumbens by K o m g and K h p p e l ~4 (strtatum coordinates A + 1 0, L + 3 5, V - 6 5, nucleus accumbens A + 3 0 , L + 2 0 , V - 7 5 mm relative to b r e g m a ) A dialysis p r o b e (4 m m length l o o p e d fiber for the strlatum, 2 m m for the nucleus accumbens, 225/xm o d , molecular weight cut-off level 10,000 D a , Cordts Dow) was inserted slowly mto each b r a m region A n lndwelhng catheter (MRE033, Bramtree Scientific) was placed in the left femoral vein The p r o b e was perfused at 2 5 /d/ram with Ringer's solution (144 m M Na +, 3 8 m M Ca 2+, 4 0 m M K +, 156 6 m M CI-, p H 6 0) 24 h after surgery (one day after drug withdrawal) Dlalysates were collected every 20 mm into small vmls with 40/xl 0 2 M p e r c h l o n c acid contalnmg 0 002% 1-cystelne (Sigma) Samples were applied directly into H P L C with electrochemical detection and analyzed for D A , dlh~droxyphenylacettc acid ( D O P A C ) , homovanllhc acid ( H V A ) and 5-hydroxylndoleacetlc acid (5H I A A ) The detection hmlt of assays was 5-10 fmol per sample Details of the H P L C m e t h o d will be published elsewhere The location of dialysis probes was verified after each e x p e r i m e n t ( - ) A p o m o r p h l n e hydrochloride (50 /xg/kg, Research Biochemlcals) dissolved in physiological saline with 100 /gM ascorbic acid was a d m m i s t e r e d intravenously (i v ) after o b t a i n m g 3 - 5 stable baseline values The m e a n ot the basal effluxes during this p e r i o d was taken as 100% Chronic a d m l n i s t r a n o n ot H A L decreased basal effiux of D A (36% and 50% vs controls), D O P A C (51% and 69%) and H V A (35% and 57%) in the strlatum and the nucleus accumbens, respectively, but had no effect on 5 - H I A A etflux levels In either region (Table I) ( - ) A p o m o r p h i n e slgnlticantly reduced D A and D O P A C effiux in both the striatum and the nucleus accumbens of vehicle and chronic H A L - t r e a t e d rats (Fig l) The results for H V A were not significantly different t r o m those for D O P A C and will no be further discussed

here During the first 60 mln atter injection, the decrease m D A release m both groups was virtually identical in each of the regions D A effiux levels gradually recovered to the pre-drug basal levels at 100 mln in both brain regions in the vehicle-treated groups H o w e v e r , lower D A effiux levels persisted in the H A L - t r e a t e d groups A N O V A revealed significant differences at specific later time periods between the vehicle- and H A L - t r e a t e d rats (Fig 1) We confirmed our previous r e p o r t ~ and some electrophyslological studies 3 ~ ~' that basal D A release is lowered in both the striatum and the nucleus accumbens after chronic H A L t r e a t m e n t The percentage decrease m basal D A release in both regions r e p o r t e d here is virtually identified w~th that r e p o r t e d by Lane and Biaha 1~ using in VlVO v o l t a m m e t r y We also observed reduced basal etflux of D O P A C and H V A in both regions (Table I) D O P A C is r e g a r d e d as an indicator ot m t r a n e u r o n a l D A metabolism because D O P A C is derived from an intraneuronal pool ot newly synthesized D A or results from o v e r p r o d u c t i o n ot non-released lntraneuronal D A ~° Chronic H A L administration had no effect on basal 5 - H I A A effiux in either region The finding that chronic H A L t r e a t m e n t decreases basal D A release and m e t a b o h s m in both the strlatum and the nucleus accumbens is c o m p a t i b l e with the hypothesis of depolarization block in both A 9 and A I 0 D A neurons H o w e v e r , o t h e r In vivo mlcrodlalysts studies have r e p o r t e d differing results Thus chronic H A L t r e a t m e n t was r e p o r t e d to increase basal D A release in the striatum ~°, to decrease basal D A release and m e t a b o h s m in the prefrontal cortex but not the nucleus accumbens, and to decrease D O P A C and H V A onl'~ in the strlatum ~° F u r t h e r investigation is n e e d e d to reconcile these discrepant results The concept of d e p o l a r i z a t i o n block is s u p p o r t e d by previous reports that a p o m o r p h l n e , in doses c o m p a r a b l e to those used here, which are believed to be autorecep-

TABLE I Basal efflu r after ch romc halopendol (mean +_ ~ E M pmol/20 ram) n

DA

DOPA (

HVA

S-HI4 4

6 8

0353_+0048 0 128_+01120 36**

34 67_+367 17 60_+307 51"*

25 32_+1 72 880_+ 1 q5 35* ~

6~;1+_047 6119_+076 97

6 9

0136+0008 0068+0009 50**

25 19+1 39 17 39_+241 69*

1273_+074 726_+080 57**

427+(148 S88+_085 138

ftrtatum (long-loop)

Vehicle Halopendol ~ of Vehicle N accumbens (short-loop)

Vehicle Halopendol % of Vehicle

Differences b~.t~een treatment and vehicle groups were determined bv mulnple ANOVA and Student s t-test *P < 0 02, **P ~ (I 002 vs vehicle, respecUve]~

140

tor.selectweZO 2~ h y p e r p o l a n z e d the cell m e m b r a n e and

have been achieved 11 The percentage decrease m L)O-

restored spontaneous actw~ty of D A neurons, m chronic H A L - t r e a t e d rats 9 and reversed the HAL-reduced reduction m D A release to control levels 1~ 1~

P A C efflux following a p o m o r p h m e was smaller than that for D A The percentage decrease m D A was greater m

In this study, ( - ) a p o m o r p h m e (50/ag/kg) was admmnstered i v to rats This dose should have an e q m p o t e n t effect on D 2 D A receptors as the dose of 100 ktg/kg racem~c a p o m o r p h m e used by Lane et al ~6 As shown m Fig 1, contrary to expectations based on the work ctted above, ( - ) a p o m o r p h m e stgnlficantly decreased D A and D O P A C efflux m both the strmtum and the nucleus accumbens of chromc H A L - t r e a t e d rats and the percentage decrease was greater than that observed following a p o m o r p h m e admmmtrat~on to vehncle-treated rats We have prewously reported that the efflux of D A and D O P A C in vehicle and H A L - t r e a t e d rats remams stable during the 3-h period after stable levels of D A release

the H A L - p r e t r e a t e d group than the controls at some ot the later time pertods A p o m o r p h l n e had no effect on 5 - H I A A etflux levels m etther regaon These results suggest that admmlstratlon of low doses of a p o m o r p h m e to chromc H A L - p r e t r e a t e d rats does not restore the release of D A and, hence may not revere the depolarization block which may have developed durmg the course of H A L treatment Low doses of a p o m o r p h l n e have been shown to decrease D A efflux in naive rats, presumably by stimulating presynaptlc D A autoreceptors 12'8 Many radloreceptor binding studies have shown chronic H A L - m d u c e d supersensitivity of pre- and postsynaptic brain D2 D A receptors 6 17 1921 Thus, the e n h a n c e d decrease tn D A

STRIATUN

N AC~

J25

]25

(-)APO50/R/kg a.v.

,oo[ s0 °

. . . . . . . . . . 0

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22[

20 40 60 80 100120140t60180

t25

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20 40 60 80 100120t40160180

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g,o0

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,~

75

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50

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25

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0 20 40 60 80 100120t40160t80 mznutes after injection

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0 20 40 60 80 100120140160180 mznutee after injection

Fng 1 The time course effect of (-) apomorphlne (APO, 50/~g/kg, 1 v ) on DA (above) and DOPAC (below) effiux m rat stnatum (left) and nucleus accumbens (right) APO slgmficantly decreased DA and DOPAC efflux levels m the stnatum and the accumbens of chromcally halopendol (HAL, 2 mg/kg/day)-treated rats more than in both regions of controls Open (HAL) or closed (controls) circles show the mean + S E M from groups of 5-8 rats per each treatment and arc expressed as a percentage of the mean pre-drug basehne efflux value of DA and DOPAC respectively, as measured in each group This value is designated as 100% (Ume 0) Statnstacallystgmficant differences were determined by multiple analyses of variance (ANOVA) and Student's t-test * and ** indicate P < 0 04 and P < 0 004 vs controls, respectwely

141 release following a p o m o r p h m e may be due to Increased

decreases D A release, could be an indication that m

sensitivity of D A autoreceptors In n e u r o n terminals in both the strlatum and nucleus accumbens, or to postsyn-

these

rats,

a p o m o r p h l n e rapidly hyperpolarlzes D A

neurons, including the population of D A n e u r o n s not previously inactivated by depolarization 9 This would be

aptic D 2 D A receptors' supersensitivity The failure to reverse the decrease in D A release in both the striatum and nucleus accumbens folJowmg a p o m o r p h m e cannot be due to the use of too low a dose of a p o m o r p h l n e The dose used here, 50 ktg/kg, 1 v of

expected to further decrease D A release The difference in the effect of a p o m o r p h m e on D A release in this study and that of Lane and Blaha 15 could be due to the effect of anesthesia on the extent of repolarizatlon of the cell

( - ) a p o m o r p h l n e , is similar or identical to that employed by Grace and B u n n e y9 and Lane et ai 16 The dose of

m e m b r a n e This inactivation of a larger group of D A n e u r o n s by a hyperpolarlzatlon mechanism could occur

H A L we used, 2 m g / k g / d a y , was considerably higher than that employed by these authors However, the tissue levels of H A L at the time this study was conducted, were apparently not sufficiently high to block the effect of apomorphlne The results reported here illustrate an important issue concerning data analys~s in chronic treatment studies using In wvo mIcrodmlysis It is standard procedure to report the results of microdlalysls studies as a percentage of pre-drug basal D A levels, as was done here However, when slgmficant differences between pre-drug basal D A levels between groups are present, as was the case for the chronic H A L - t r e a t e d rats compared to the vehicletreated controls, the smaller absolute decrease in D A effiux In the H A L - t r e a t e d rats might be interpreted as evidence for subsensltlvlty of D A receptors rather than supersensitivity, as concluded on the basis of the percentage decrease m basal D A effiux Since there is no evidence consistent w~th the development of subsens~t~v~ty of D A autoreceptors or postsynaptlc D A receptors following chronic neuroleptlc treatment, the practice of expressing In VlVO dmlysls results as percentage change m D A efflux Is likely to be vahd, at least m this case B u n n e y and colleagues 4 9 have previously shown, using

vm actions at supersenslttve somatodendritlC autoreceptors A p o m o r p h l n e could also further decrease D A release by an i n d e p e n d e n t effect at supersensitive terminal autoreceptors ~9 A n o t h e r posslblhty to explain our results is that a p o m o r p h i n e might increase the firing rate of D A n e u r o n s by repolarlzatlon but still decrease the release of D A by an action at supersensttlve terminal D A autoreceptors It seems unlikely that the results found here should be taken as evidence against the depolarization Inactivation hypothesis, although there are other data 2 which are not consistent with the hypothesis These results suggest a rationale for the reported abdlty of apomorphine or other D A agonlsts such as bromocrlptlne to produce a synergistic antlpsychotlc effect xn some neuroleptlc-treated schlzophremc patients l~ The DA-agonlsts might further decrease D A release xn the striatum and nucleus accumbens In summary, we have found that chromc H A L treatment decreased basal D A release and metabolism m the strlatum and the nucleus accumbens in awake, freely moving rats This decrease in D A release was enhanced rather than reversed by low dose i v a p o m o r p h l n e This suggests that the mechanisms controlhng D A release can be affected by DA-agonlsts i n d e p e n d e n t l y ot any possible depolarization block produced by chronic H A L treatment No m a j o r differences were found in the effect of chromc H A L followed by a p o m o r p h l n e on the efflux of D A , D O P A C or H V A in the s t n a t u m and nucleus accumbens consistent with previous evidence that chromc H A L treatment produces similar effects in both regions

extracellular and Intracellular recording techmques, that systemic a p o m o r p h m e causes D A neurons inactivated by chronic H A L administration to increase their firing rate A p o m o r p h m e has been shown to decrease the firing rate of D A n e u r o n s in naive rats s These findings, together with the a p o m o r p h l n e - m d u c e d increase in D A release in rats chronically treated with H A L is , has been advanced as evidence for the depolarization Inactivation hypothesis 9 The effects of a p o m o r p h m e m H A L - p r e t r e a t e d rats were interpreted as due to repolarlzatlon of the depolarized n e u r o n s Our finding that in awake, freely moving rats previously treated with H A L , apomorphlne further

This research was supported, m part, by USPHS MH 41684 MH 41594, GCRC MOIRR00080 and grants from the Laureate Foundation (NARSAD) and Sawyer Foundations H Y M is the recipient of a USPHS Research Career Sclenust Av~ard MH 478(18 We are grateful to Mr Matthew A Schre~ber for techmcal assistance and to Ms Lee Mason for typing the manuscript

1 Abercromble, E D Keefe K A , D1Fnshcla, D S and Z~gmond, M J Dltferentml effect of stress on m vwo dopamme release m strLatum, nucleus accumbens and medial frontal cortex J Neurochem , 52 (1989) 1655-1658 2 And6n, N -E Grendhoff, J and Svensson, T H Does treatment w~th halopendol for 3 weeks produce depolarization block m m~dbram dopamme neurons of unanestheuzed rats~ P~vcho-

pharmacology, 96 (1988) 558-560 3 Blaha C D and Lane R F Chronic treatment wtth classical and atypical antlpsychot~e drugs differentially decreases dopamine release in strlatum and nucleus accumbens in vivo, Neurosct Lett, 78 (1987) 199-204 4 Bunney B S and Grace A A Acute and chromc halopendol treatment comparison of eflects on mgral dopammerglc cell

,

142 actlwty Life Scz 23 (19781 1715-1728 5 Chmdo L A and Bunney, B S , Typical and dtyplcal neurolept~cs dlfferentml effects of chronic admmlstratmn on tht actwlty of A9 and AI0 midbram dopammergm neurons J lVeurosct, 8 (19831 1607-1619 6 Chlpkm, R E McQuade, R D and lono L C D~ and D 2 dopamme binding site up-regulatmn and apomorphme-mduced stereotypv Pharmacol Btochem Beha~ , 28 (19871 477-482 7 Compton, D R and Johnson K M Etfects of acute and chrome chlozapme and halopendol on in wtro release ol acetylchohne and dopamme from stnatum and nucleus accumbens J Pharmacol Erp The~ , 248 (1989)521-53(I 8 Grace, A A and Bunney, B S , Low doses of apomorphme ehcJt two opposing influences on dopamme cell electrophysmlogv, Bratn Research, 33 (1985) 285-298 9 Grace, A A and Bunne) B S , Induction of depolanzatmn block in mldbram dopamme neurons b~ repeated admm~stratmn of halopendol dnalysls using m vwo mtracellular recording J Pharmacol E:tp Ther, 238 (1986) 1092-1100 10 Hernandez, L and Hoebel, B G Halopendol given chronically decreases basal dopamlne m the prefrontal cortex more than the stnatum or nucleus accumbens as s~multaneously measured by mlcrodmlysls, Bratn Res Bull, 22 (1989) 763-769 11 Ichlkawa, J and Meltzer H Y The effect ot chromc clozapme and halopendol on basal dopamme release and metabohsm m rat strmtum and nucleus accumbens stud~ed b'~ m vwo mmrodmlysls Eur J Pharmacol, submitted 12 Imperato, A Tanda, G , Frau, R and DiChlara, G , Pharmacologmal profile of dopamlne receptor agomsts as studmd by brain dmlysls m behaving rats, J Pharmacol Exp Ther 245 (1988) 257-264 13 Kelland, M D Freeman A S and Chmdo, L A Chloral hydrate anesthesia alters the responsweness of ~dennfied m~dbrain dopamme neurons to dopamme agomst admm~stratmn S Y N A P T E 3 (19891 30-37 14 Komg, J F R and Khppel, R A The Rat Bram a 5tereotaxu Atlaa of the Forebram and Lower Parts of the Bram Stem Wdhams and Wdkms, Baltimore, 1963 15 Lane R F and Blaha, C D , Chromc halopendol decreases dopamme release m strmtum and nucleus accumbens m vwo depolarization block as a possible mechamsm of action, Brain Res Bull, 18 (1987) 135-138 16 Lane, R F , Blaha, C D and R~et, J M , Selective mh~b~tmn of mesohmbm dopamme release following chronic admm~stratmn of elozapme involvement of a:noradrenerg~c receptors demonstrated by m wvo voltammetrv, Bram Research 460 (1988) 398-401 17 MacLennan, A J Atmadja, S , Lee N and F~blger H (-

18

19

20 21 22

23

24

25

26

27

28

29

30

Chromc haloperldol administration lncrea,,Ls the densw~ ol 11 dopamme receptors m medial pretrontaI cortex ol the rat P~vchopharmacologv 95 (19881 255-257 Meltzer H Y Relevance ot dopamme autoreceptor~ tor p~,,chlatr) cllmcal and prechmcal studm~ ~cht2ophr Bull 6 ( 19801 456-475 Nowak, J Z , Arbdla, S Galzm A M dnd Langcr 5 Z Changes m sensitivity of lelease-modulatlng dopamme autoreceptors after chromc treatment with halopendol J Pharmacol E,.p Ther , 226 (19831 558-564 Roth R H CNS dopamme autoreceptors dlstnbutmn, pharmacology and functmn Ann N Y Acad Set 430 (1984) 27-5~ Seeman, P , Brain dopamln~ receptors Pharma¢ol Rein 32 (19801 229-313 Skarsfeldt T Dffferenttal eftects after repeated treatment w~th halopendol, clozapme, thmndazme and tefludazme on SNC and VTA dopamme neurons m rats Ltfe Scz , 42 (1988) 1037-1044 Skarsfeldt T Effect oI chromc treatment wtth SCH 23390 and halopendol on spontaneous actlwty of dopamlne neurons m substantm mgra pars compacta (SNC) and ventral tegmental area (VTA) m rats, Eur J Pharmacol, 145 (1988) 239-243 Spamplnato, U , Glrault, J - A Dangmr, J , Savakl, H E , Glowmskl, J and Besson, M -J Apomorphme and haloperldol effects on strmtal [~H]dopamme release m anesthetized, awake, restrained and freely moving rats, Brain Res Bull, 16 (19861 161-166 Ungerstedt, U Herrera-Marschmtz, M Jungnehus, U Stahle, L , Tossman U and Zetterstrom, T , Dopamme synapuc mechanisms reflected m stu&es combining behavmral recordings and brain dmlysls Adv Btoscl, ~7 (1982) 219-231 White FJ and Wang, R Y , Comparison of the effects o! chromc haloperldol treatment on A9 and A 10 dopamme neurons m the rat, Lzfe Scl, 32 (1982) 983-903 White F J and Wang, R Y Dffferentml effects of classical and atypical antlpsychotlc drugs on A9 and A10 dopamme neuron~, Sctence, 221 (1983) 1054-1057 Zetterstrom T and Ungerstedt, U , Effects of apomorphme on the m vwo release of dopamme and its metabohtes, studmd by brain dmlysls, Eur J Pharmacol, 97 (1984) 29-36 Zetterstrom, T , Sharp T Colhn, A K and Ungerstedt, U In wvo measurement of extracellular dopamme and DOPAC m rat ~tnatum after various dopamme-releasmg drugs, lmphcatmn for the ongm of extracellular DOPAC, Eur J Pharmacol 148 (1988) 327-334 Zhang W , Tdson, H , Stachowmk, M K and Hong J S , Repeated halopendol administration changes basal release of stnatal dopamme and subsequent responses to halopendol challenge, Bram Research, 484 (1989) 389-392