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Neurochemistry International 45 (2004) 1029–1038 Changes in extracellular dopamine in the rat globus pallidus induced by typical and atypical antipsychotic drugs Abteilung Tierphysiologie, Biologisches Institut, Universität Stuttgart, Pfaffenwaldring 57, D-70550 Stuttgart, Germany Received 26 March 2004; received in revised form 30 April 2004; accepted 14 May 2004 Abstract
Typical antipsychotic drugs with a high extrapyramidal motor side-effects liability markedly increase extracellular dopamine in the caudate-putamen, while atypical antipsychotic drugs with a low incidence of extrapyramidal motor side-effects have less pronouncedstimulating actions on striatal dopamine. Therefore, it has been suggested that the extrapyramidal motor side-effects liability of antipsychoticdrugs (APD) is correlated with their ability to increase extracellular dopamine in the caudate-putamen.
The globus pallidus (GP) is another basal ganglia structure probably mediating extrapyramidal motor side-effects of typical antipsychotic drugs. Therefore, the present study sought to determine whether extracellular dopamine in the globus pallidus might be a further indicatorto differentiate neurochemical actions of typical and atypical antipsychotic drugs. Using in vivo microdialysis we compared effects onpallidal dopamine induced by typical and atypical antipsychotic drugs in rats. Experiment I demonstrated that systemic administrationof haloperidol (1 mg/kg; i.p.) and clozapine (20 mg/kg; i.p.) induced a significant pallidal dopamine release to about 160 and 180% ofbaseline, respectively. Experiment II revealed that reverse microdialysis of raclopride and clozapine using a cumulative dosing regimen didnot stimulate extracellular dopamine in the globus pallidus if low (1 ␮M) or intermediate (10 and 100 ␮M) concentrations were used. Onlyat a high concentration (1000 ␮M), raclopride and clozapine induced a significant pallidal dopamine release to about 130 and 300% ofbaseline values, respectively. Thus, effects of typical and atypical antipsychotic drugs on pallidal dopamine were similar and thus, may notbe related to their differential extrapyramidal motor side-effects liability. Furthermore, the finding that reverse microdialysis of racloprideover a wide range of concentrations did not stimulate pallidal dopamine concentrations tentatively suggests that pallidal dopamine releaseunder basal conditions is not regulated by D2 autoreceptors.
2004 Elsevier Ltd. All rights reserved.
Keywords: Globus pallidus; Microdialysis; Dopamine; Antipsychotic drugs; Rat 1. Introduction
ical APD. One hypothesis suggests that typical ADP havea higher extrapyramidal motor side-effects liability because Clinical application of antipsychotic drugs (APD) is ac- they generally induce a more pronounced dopamine (DA) companied by extrapyramidal motor side-effects such as D2 receptor occupancy than atypical APD (e.g. parkinsonism. Drugs with a high liability for extrapyrami- dal motor side- effects such as haloperidol were defined as “typical” APD, while drugs be- motor side-effects liability of typical APD as compared to ing largely devoid of extrapyramidal motor side-effects, e.g.
atypical APD may be related to their specific actions on DA release in different forebrain areas. All APD stimulate DA release in the caudate-putamen, nucleus accumbens and pre- A large number of studies have been devoted to differenti- ate the sites and mechanisms of actions of typical and atyp- reflecting a feedback response to the blockade of DA recep-tors (e.g. However, the regional pat- ∗ Corresponding author. Tel.: +49 711 685 5003; tern differs as atypical APD have more prominent actions on extracellular DA in the nucleus accumbens and prefrontal E-mail address: (W. Hauber).
1 Present address: Boehringer Ingelheim Pharma GmbH and Co.KG; cortex than in the caudate-putamen, while typical ADP have Birkendorfer Str. 65, D-88397 Biberach a. d. Riss, Germany.
stronger effects in the caudate-putamen ( 0197-0186/$ – see front matter 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.neuint.2004.05.008 H. Fuchs, W. Hauber / Neurochemistry International 45 (2004) 1029–1038 and were approved by the proper authorities in Stuttgart, gested that the less marked actions of atypical APD within Germany. All efforts were made to minimize animal suffer- the caudate-putamen might account for the lower incidence ing and to reduce the number of animals used.
of extrapyramidal motor side-effects In line with this notion, immunohistochemical studies using in-duction of immediate early genes as a marker of neuronal Male CD rats (Charles River, Sulzfeld, Germany) activity showed that atypical APD produced less prominent were housed in groups upto five animals in transparent c-fos expression in the caudate-putamen than typical APD Macrolon® cages (type IV; 35 cm × 55 cm × 10 cm; Ebeco, Castrop-Rauxel, Germany) before surgery. Temperature (20 ± 2 ◦C) and humidity (50 ± 10%) were kept constant in the Most studies addressing possible sites mediating ex- animal house and a 12:12-h light–dark schedule with lights trapyramidal motor side-effects have been focused on the on at 6.00 h was maintained. Rats were given ad libitum ac- caudate-putamen. However, there are other basal ganglia cess to water. Food (standard maintenance chow, Altromin, candidate structures down-stream of the caudate-putamen Lage, Germany) was restricted to 15 g per day and animal.
such as the globus pallidus (GP) which might mediate ex- 2.2. Experiment I: Systemic administration of clozapine trapyramidal motor side-effects. Recent studies revealed that extracellular GABA in the GP is increased after sys-temic administration of haloperidol, but decreased after Rats received intraperitoneal injections of either 1 mg/kg haloperidol (N = 5), 20 mg/kg clozapine (N = 5) or saline In functional models of the basal ganglia, increased (N = 4) in the respective volume. Injections were made at pallidal GABA levels have been linked with parkinsonism the beginning of a microdialysis sampling period.
(Thus, differential neurochemical ac-tions of typical versus atypical APD on pallidal GABA 2.3. Experiment II: Reverse microdialysis of clozapine and might be related to their differential extrapyramidal motor side-effects liability (Apart from GABA, DA in the GP plays a prominent Rats were perfused with increasing concentrations (1, 10, role in mediating motor effects of APD as well. The GP re- 100 and 1000 ␮M) of either clozapine (N = 5) or raclopride ceives a DAergic innervation arising from substantia nigra (N = 5) for 60 min followed by perfusion of artificial cere- brospinal fluid (aCSF) without drug for one additional sam- ronal origin Systemic and intra-GP infusion of D2 receptor an- tagonists increased expression of c-fos in the GP (). Furthermore, Animals were anaesthetized with sodium pentobarbital intra-GP infusion of DA receptor antagonists produced (60 mg/kg, i.p.) (Sigma-Aldrich, Taufkirchen, Germany) following pretreatment with atropine sulphate (0.5 mg/kg, gesting that changes in pallidal DAergic transmission might i.p.) (Sigma-Aldrich, Taufkirchen, Germany) and secured in contribute to extrapyramidal motor side-effects induced by a Kopf stereotaxic apparatus (Kopf Instruments, Tujunga, USA). For experiment I, animals weighing 230–360 g were The present study sought to determine whether extracel- implanted unilaterally with intracranial guide cannulae lular DA in the GP may be an indicator to differentiate neu- (MAB 6.14.IC, Microbiotech/se, Stockholm, Sweden) aim- rochemical actions of atypical and typical APD. Using in ing to the GP at the following coordinates vivo-microdialysis we investigated whether the typical APD haloperidol and the atypical APD clozapine given system- (from dura). For experiment II, animals weighing 240–370 g ically differ in their effects on extracellular pallidal DA in were implanted with intracranial guide cannulae (CMA/12, a similar way as shown previously in the caudate-putamen.
CMA, Solna, Sweden) at the same coordinates as above.
Furthermore, we analysed by reverse microdialysis whether After the surgery rats were housed individually in the effects of a typical and an atypical APD on pallidal DA Macrolon® cages (type III; 37 cm × 21 cm × 30 cm; Ebeco, Castrop-Rauxel, Germany) with raised solid-walled lids.
Each rat was given at least one week to recover from surgery.
2. Material and methods
The animal experiments described in this study were con- Microdialysis was performed in the home cage of the ducted according to the German Law on Animal Protection animal with the lid replaced by a metal frame bearing a H. Fuchs, W. Hauber / Neurochemistry International 45 (2004) 1029–1038 counterbalanced arm with the swivel assembly. Dual channel liquid swivels, either Tsumura TCS2-23 (Pronexus, Skärhol-men, Sweden) or Instech low torque swivels (375/D22/QM, Dialysates were analysed for DA, DOPAC and HVA us- Instech Laboratory, Plymouth Meeting, USA) were used.
ing HPLC with electrochemical detection. The mobile phase Attachment to the swivel was achieved by a spring tether used in experiment I consisted of 2 g/l sodium acetate, 5 g/l connected directly to the head mount via a self-made citric acid, 200–600 mg/l 1-heptanesulfonic acid, 110 mg/l Na2-EDTA and 12.5% (v/v) methanol with pH at 3.9 before A microdialysis probe either MAB 6.14.2 (Microbiotech/ methanol addition. In experiment II, the mobile phase had se, Stockholm, Sweden, experiment I) or CMA/12 (CMA, a higher concentration of methanol (18.5%, v/v) and HSA Solna, Sweden, experiment II) with an exposed membrane (2000 mg/l). Minor modifications in the concentrations of length of 2 mm was inserted through the guide cannula at HSA and methanol were made to optimise DA peak sep- least 7 h before sampling of the first baseline value and aration, if necessary. The HPLC apparatus consisted of a perfused with aCSF (145 mM Na+, 2.5 mM K+, 2.4 mM Flux Rheos 2000 pump (Flux Instruments, Basel, Switzer- Ca2+ [experiment I] or 1.2 mM Ca2+ [experiment II] and land), a refrigerated CMA/200 autosampler (CMA, Solna, 0.9 mM Mg 2+) delivered by a CMA/100 microdialysis Sweden), a Nucleosil C18 column (Bischoff, Leonberg, Ger- pump (CMA, Solna, Sweden) at 2.0 ␮l/min. ACSF for exper- many; 5 ␮m particles, length × i.d. 125 mm × 3 mm) and a iment I contained 3 ␮M nomifensine, a catecholamine reup- dual electrode BAS LC4C amperometric detector (Bioana- take inhibitor. Samples were collected every 30 min. Basal lytical Systems, Lafayette, USA) with the electrode poten- levels were determined 60 min before drug administration tial set to 600 mV at high gain to quantify DA and 700 mV at a low gain to measure the metabolites. Filter setting was0.1 Hz. The separation was performed at room temperatureand sample run time was less than 7 min. The detection limit of DA in a standard solution was about 2 pg per injection orlower.
In experiment I, sterile saline (Fresenius, Bad Homburg, Germany), haloperidol (Haldol-Janssen, Janssen, Neuss, 2.8. Reconstruction of probe location Germany), and clozapine (Tocris, Ellisville, USA) wereused for systemic administration. Clozapine was diluted After the experiments, animals were euthanised by an with 0.1 M HCl to a final concentration of 10 mg/ml and overdose of sodium pentobarbital, the brains removed, fixed aliquots were stored frozen (−70 ◦C). Artificial CSF in for at least 2 h in formalin and immersed in 30% (w/v) su- experiment I contained nomifensine (3 ␮M). A stock so- crose for several days. Cryosections (60 ␮m) were taken and lution of nomifensine maleate (RBI, Natick, USA) at a stained with cresyl violet. Only data from animals with cor- concentration of 887 ␮M was prepared in ultra pure water, rect probe location, i.e. most of the exposed dialysis mem- stored in frozen (−70 ◦C) aliquots and added to the aCSF.
brane located within the GP, were evaluated ( Nomifensine was included to the aCSF in this experimentto achieve reliable measurement of basal dialysate levels ofDA which were close to the detection limit. In the presence 2.9. Data expression and statistics of nomifensine, the DA release induced by DA antagonistsis probably enhanced (e.g. Data are expressed as mean percentages of control values but major pharmacological properties of DA release, i.e. its (±standard error of the mean, S.E.M.). The average con- Ca2+ and tetrodotoxin sensitivity, are not altered centration of three samples before drug administration (not corrected for probe recovery) was taken as control and set clozapine were perfused by reverse microdialysis. A stock to 100%. Data were analysed by a one-way ANOVA for re- solution of clozapine (Tocris, Ellisville, USA) was prepared peated measurements followed by Least square differences in 0.1 M HCl (50 mM) and aliquots were stored frozen.
(LSD) post hoc test. The last baseline sample was taken as At the experimental day, they were diluted with aCSF to reference. An α-level of P < 0.05 was regarded to represent a concentration of 1 mM. After adjustment of the pH 6–7 statistical significances. Statistical analysis were made with with NaOH, they were further diluted with aCSF to final Statistica 5.5 (StatSoft, Tulsa, USA).
concentrations of 100, 10 and 1 ␮M. Stock solutions withraclopride (s(−)-raclopride tartrate, Sigma Deisenhofen,Germany) were prepared in aCSF (1 mM) and aliquots were 3. Results
stored frozen (−70 ◦C). At the experimental day, they werefurther diluted with aCSF to final concentrations of 100, 10 and 1 ␮M. Nomifensine was not included to the aCSFin this experiment due to an increased sensitivity of the In experiment I, basal dialysate DA concentrations were 27.7 ± 4.4 pg/60 ␮l in saline-treated animals (N = 4), H. Fuchs, W. Hauber / Neurochemistry International 45 (2004) 1029–1038 3.2. Experiment I: Systemic administration of clozapineand haloperidol i.p.) produced a significant increase (F1,6 = 4.57, P = 0.0031) of dialysate DA to about 180% of baseline,administration of haloperidol (1 mg/kg, i.p.) a significantincrease to about 160% of baseline (F1,6 = 48.24, P <0.00001). Statistical analysis further revealed a significanteffect in the saline group (F1,6 = 3.29, P < 0.023), but therewere no significant differences of samples after saline treat-ment relative to the baseline value (T = 0 min) as revealedby post hoc LSD-test.
Administration of clozapine and haloperidol produced in- creases in dialysate DOPAC (F1,6 = 5.68, P < 0.00086 andF1,6 = 12.21, P < 0.00001, respectively) and HVA (F1,6 = 2.59, P = 0.044 and F1,6 = 2.72, P < 0.037, respectively)levels. In saline controls no significant changes in DOPAC Fig. 1. Microdialysis probe placements in the GP. Numbers indicate the (F1,6 = 0.56, P = 0.76) or HVA (F1,6 = 0.50, P = 0.797) distance (in mm) from bregma. Schematics are adapted from the atlas of 3.3. Experiment II: Reverse microdialysis of clozapine and 16.0 ± 5.3 pg/60 ␮l in clozapine-treated animals (N = 5) and 36.8 ± 3.8 pg/60 ␮l in raclopride-treated animals (N = 5). In experiment II, basal dialysate DA concentrations were 8.5 ± 0.7 pg/60 ␮l in clozapine-treated animals (N Raclopride and clozapine significantly elevated dialysate = 5) and 4.9 ± 0.3 pg/60 ␮l in raclopride-treated animals DA levels (F1,11=3.19, P = 0.003 and F1,11 = 14.51, P < 0.00001, respectively) Post hoc LSD Fig. 2. Effects of systemic administration of clozapine (20 mg/kg i.p.), haloperidol (1 mg/kg i.p.) or saline (1 ml/kg i.p.) on pallidal extracellular DAconcentrations. ∗: clozapine, §: haloperidol and #: saline indicate significant differences relative to the last baseline sample (T = 0 min) (P < 0.05,ANOVA for repeated measurements followed by post hoc LSD test).
H. Fuchs, W. Hauber / Neurochemistry International 45 (2004) 1029–1038 Fig. 3. Effect of systemic administration of clozapine (20 mg/kg i.p.), haloperidol (1 mg/kg i.p.) or saline (1 ml/kg i.p.) on pallidal extracellular DOPAC(upper panel) and HVA (lower panel) concentrations. ∗: clozapine, §: haloperidol indicate significant differences relative to the last baseline sample (T = 0 min) (P < 0.05, ANOVA for repeated measurements followed by post hoc LSD test).
test revealed significant increases of dialysate DA at P = 0.028), while raclopride had no significant effects (F1,11 the highest concentration of raclopride and clozapine 4. Discussion
Dialysate DOPAC levels were increased significantly by raclopride or clozapine at the highest concentration (1 mM) The present study demonstrates that a typical and an atyp- (F1,11 = 3.11, P = 0.0056 and F1,11 = 2.37, P = 0.028, ical APD can increase the extracellular DA concentration respectively). Clozapine at the highest concentration (1 mM) in the GP if administered systemically. However, local ad- had also significant effects on dialysate HVA (F1,11 = 2.37, ministration of a typical and an atypical ADP by reverse H. Fuchs, W. Hauber / Neurochemistry International 45 (2004) 1029–1038 Fig. 4. Effect of reverse microdialysis of clozapine or raclopride in increasing concentrations from 1 to 1000 ␮M on pallidal extracellular DA concentrations.
∗: clozapine, §: raclopride indicate significant differences relative to the last baseline sample (T = 0 min) (P < 0.05, ANOVA for repeated measurementsfollowed by post hoc LSD test).
microdialysis did not stimulate extracellular DA concentra- tion in the GP except at a very high concentration.
Moreover, typicalAPD produce much higher expression of immediate early 4.1. APD effects after systemic administration genes, e.g. c-fos, in the caudate-putamen than atypical APD( Doses of clozapine at least 10 times higher than haloperi- dol were considered to be equipotent and generally used the high liability of typical APD for extrapyramidal motor to compare neurochemical effects of both drugs (e.g.
side-effects might be related to their prominent actions on we administered a dose of clozapine 20-fold higher than haloperidol. Results demonstrate that both drugs induced a has stronger stimulating effects on pallidal DA than cloza- significant pallidal DA release with an onset at the initial pine. However, our data provide no evidence in support of post-administration sample. Thus, a typical and an atypi- this notion. Thus, effects of typical and atypical APD on cal APD given systemically in about equipotent doses can pallidal DA may not account for their differential motor elicit a similar pallidal DA efflux. In addition, clozapine side-effects liability. This does not argue against the GP as a and haloperidol elevated pallidal DOPAC indicating drug possible site of such effects as systemic administration and effects on pallidal DA metabolism as extracellular DOPAC intra-GP infusion of haloperidol increased, while clozapine is considered to be a marker for cytoplasmatic DA synthesis decreased pallidal GABA, effects that might be associated with their respective extrapyramidal motor side-effect pro- dialysate HVA levels which might reflect the fact that most extracellular DOPAC is rapidly converted to HVA by the ferential motor side-effects liability of typical and atypical A large number of studies revealed that haloperidol APD may not be solely related to their preferential action on is more effective in increasing extracellular DA in the striatal DA. Positron emission tomography (PET) binding studies revealed that high D2 receptor occupancies (>80%) are necessary to produce extrapyramidal motor side-effects response to the blockade of D2 receptors (e.g. easily achieved with typical than atypical APD (e.g. evidence for a clear-cut dissociation of the effects of cloza- H. Fuchs, W. Hauber / Neurochemistry International 45 (2004) 1029–1038 Fig. 5. Effect of reverse microdialysis of clozapine or raclopride in increasing concentrations from 1 to 1000 ␮M on pallidal extracellular DOPAC (upperpanel) and HVA (lower panel) concentrations. ∗: clozapine indicate significant differences relative to the last baseline sample (T = 0 min) (P < 0.05,ANOVA for repeated measurements followed by post hoc LSD test).
4.2. APD effects after reverse microdialysis into the GP qualitative comparisons of results from both experimentsperformed here.
Comparisons of results from experiments I and II have to Results of experiment II revealed that clozapine and raclo- take into account that microdialysis conditions differ in some pride failed to induce a significant pallidal DA release at aspects, e.g. the perfusion fluid in experiment II contained a concentrations up to 100 ␮M. However, at concentration of lower calcium concentration, no nomifensine and different 1 mM, clozapine produced a prominent, raclopride a moder- microdialysis probes were used. Furthermore, in experiment ate albeit significant pallidal DA release. The fact that palli- II we used the selective D2 antagonist raclopride instead of dal perfusion of the highly selective D2 receptor antagonist haloperidol as typical APD for reverse microdialysis due to its superior solubility in aCSF with neutral pH. However, stimulated extracellular DA only at a very high concentra- raclopride and haloperidol bind in vivo almost exclusively tion suggests that a pallidal D2 receptor blockade does not account for the increase of pallidal DA induced by systemic H. Fuchs, W. Hauber / Neurochemistry International 45 (2004) 1029–1038 haloperidol. Rather, this effect might be mediated by D2 re- tor antagonist, increased DA in the GP (Fuchs and Hauber, ceptors located on midbrain DA cell bodies. In contrast, the unpublished observations) and ventral pallidum ( moderate increase of pallidal DA after perfusion of 1 mM raclopride might be due to unspecific effects of this veryhigh concentration.
Another implication of the almost complete failure of pal- lidal raclopride to enhance extracellular DA is that the GP Taken together, the present data show that raclopride did might lack presynaptic D2 receptors. Blockade of these re- not stimulate pallidal DA efflux when administered by re- ceptors localized on nerve terminals in the caudate-putamen verse microdialysis in a wide range of concentrations. This or prefrontal cortex stimulates DA efflux ( tentatively suggests that pallidal DA release under basal con- ditions is not regulated by D2 autoreceptors, which may be explained: (i) by a general lack of autoreceptors in the GP; or, (ii) by a DAtone too low to stimulate autoreceptors under basal conditions. Furthermore, our results demonstrate that systemic administration of a typical and an atypical APD existence of presynaptic D2 receptors located on nigropal- stimulated pallidal DA and DA metabolism with a similar lidal terminals. Thus, our findings point to the view that magnitude. Therefore, effects of typical and atypical APD D2 autoreceptors might not be involved in regulation of ex- on pallidal DA seem to be similar and thus, may not be re- tracellular pallidal DA. Alternatively, the DA tone acting lated to their differential extrapyramidal motor side-effects on D2 autoreceptors might be very low under basal condi- tions, because the GP receives only a “sparse” DA innerva-tion (In line with this notion, pallidalD2 receptor blockade did not decrease pallidal GABA lev- Acknowledgements
els (despite the presence of presy-naptic D2 receptors on striatopallidal terminals GP bears D3 receptors Supported by the Deutsche Forschungsgemeinschaft (Ha 2340/4-2). The authors are grateful for the generous tech- display an unusually high affinity to DA ( nical support of Dr. K. Drescher (Abbott, Ludwigshafen, Germany) and N. Wenkel (Axel Semrau, Sprockhövel, Ger- Thus, D3 receptors could act as pallidal autore- ceptors, however, their ultrastructural localization and rolein regulation of extracellular DA in the GP is yet unknown.
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