eJD European Journal of Pharmacology molecular pharmacology

Molecular Pharmacology Section 289 (1995) 97-101 ELSEVIER

Dizocilpine enhances striatal tyrosine hydroxylase and aromatic L-amino acid decarboxylase activity

Maria Hadjiconstantinou a.b,c,*, Zvani L. Rossetti b, Trina A. Wemlinger b, Norton H. Neff b,c a Department of Psychiatry, The Ohio State Unicersity College of Medicine, 333 W. lOth Acenue, Columbus, OH 43210, USA

h Department of Pharmacology, The Ohio State Unicersity College of Medicine, Columbus, OH 43210, USA c Neuroscience Program, The Ohio State University College of Medicine. Columbus, OH 43210, USA

Received 31 August 1994; revised 28 November 1994; accepted 6 December 1994

Abstract

Dizocilpine administration enhances dopamine metabolism in the rat striatum, nucleus accumbens, olfactory tubercle, and prefrontal cortex. Concomitant with increased metabolism is enhanced tyrosine hydroxylase and aromatic L-amino acid decarboxylase activities in the striatum and increased mRNA for the two enzymes in the midbrain. Activation of dopaminergic neurons may, in part, explain increased locomotor activity in normal animals and the ability of dizocilpine to potentiate the antiparkinsonian action of L-3,4-dihydroxyphenylalanine in an animal model.

Keywords: Dizocilpine; Tyrosine hydroxylase; Aromatic L-amino acid decarboxylase; Dopamine; Parkinson's disease

1. Introduct ion

Dizocilpine (MK-801) is a non-competitive antago- nist of the glutamate N-methyl-D-aspartate (NMDA) excitatory amino acid receptor (Wong et al., 1986). Administration of dizocilpine to rodents increases the firing rate of dopaminergic neurons (Zhang et al., 1992; French et al., 1993), enhances dopamine metabolism (Hiramatsu et al., 1989; Rao et al., 1990; Liljequist et al., 1991; L6scher et al., 1991) and in- creases locomotor activity (Clineschmidt et al., 1982; Carlsson and Carlsson, 1989; Svensson et al., 1991; Liljequist et al., 1991; Ouagazzal et al., 1994). The neurochemical substrate(s) for the dizocilpine-induced locomotion is unclear (L6scher and Honack, 1992). Based on the marked locomotor activity induced by dizociipine Carlsson and Carlsson (1990) proposed a hypothetical neuronal feedback loop model where NMDA receptor antagonists might by useful in treat- ing Parkinson's disease and NMDA receptor agonists might be useful for treating schizophrenia (Kornhubcr and Weller, 1993). Subsequently, it was reported that

' Corresponding author. Tel.: 614-292-8608; Fax: 614-292-7232.

0922-4106/95/$09.50 © 1995 Elsevier Science B.V. All rights reserved SSDI 0922-4106(94)00199-5

NMDA and non-NMDA glutamate receptor antago- nists had a synergistic effect with I.-DOPA (L-3,4-dihy- droxyphenylalanine) for ameliorating the parkinsonian symptomatology in animal models of the disease (Klockgether and Turski, 1990; L6schmann et ai., 1991). Interestingly, non-competitive NMDA receptor antago- nists appear to be effective in reversing motor symp- toms in animal models of parkinsonism even when given alone (Klockgether and Turski, 1990; Graham et al., 1990; Elliott et al., 1990).

Aromatic L-amino acid decarboxylase is an obliga- tory enzyme for the conversion of exogenous L-DOPA to dopamine in the striatum of parkinsonians. As the disease progresses and dopaminergic neurons are lost, there is a loss of aromatic L-amino acid decarboxylase and dopamine in the striatum (Gjedde et al., 1993). Loss of aromatic L-amino acid decarboxylase would be expected to coincide with decreased conversion of ex- ogenous L-DOPA to dopamine. There is now evidence that aromatic L-amino acid decarboxylase activity is modulated in vivo by neuronal activity (Hadjiconstan- tinou et al., 1988), drugs that act at dopamine recep- tors (Rossetti et al., 1990; Hadjiconstantinou et al., 1993; Zhu et al., 1992; Zhu et al., 1993), compounds that activate protein kinase A (Young et al., 1993) and

98 AI. ttadjiconstantinou et aL / European Journal <~1" t'harmacoh)gy - 3,h~h'cuhtr Pharmucoh~.ey .~~,~ tton 2,~#) (Iq~15) q7- I01

C (Young et al., 1994) or that inhibit phosphatasc activity (Young ct al., 1994). Indeed, evidence suggest that modulation is by enzyme induction a n d / o r by enzyme phosphorylation (Hadjiconstantinou ct al., 1988; Rossetti et al., 1990; Young c ta l . , 1993; Young et al., 1994).

Wc now present evidence that treatment with di- zocilpinc, in addition to enhancing locomotor activity, enhanccs dopaminc metabolism and increases tyrosine hydroxylasc and aromatic L-amino acid decarboxylase activitics in the striatum. Increased aromatic L-amino acid dccarboxylase activity with increased conversion of L-DOPA to dopaminc may explain the decreased symptomatology reported for animal models of Parkin- son's disease treated with glutamate receptor antago- nists and I.-DOPA (Klockgether and Turski, 1990; L6schmann et al., 1991).

1.1. Materials and methods"

Adult male Spraguc-Dawley rats (Zivic-Miller Labo- ratories, Zelienople, PAl were maintained at constant room temperature on a 12 h l ight /dark cyclc with lights on at 6:00 am. Dizocilpine, 1 mg /kg i.p., dis- solved in saline was administered and the animals decapitated 1 h later when locomotor activity appeared maximal. The brain was micro-dissected into striatum (caudate-putamcn), nucleus accumbens, olfactory tu- bercle, prefrontal cortex (Palkovits and Brownstein, 1988) and midbrain. The midbrain consisted of thc region bounding the substantia nigra. Dopaminc and DOPAC content as well as tyrosine hydroxylase and aromatic L-amino acid decarboxylasc activity were esti- mated in tissue samples from the same animal. Mid- brain was used for extracting RNA for tyrosine hydrox- ylase and aromatic L-amino acid dccarboxylase mRNA northern analysis.

1.2. Analysis of dopamine and DOPAC

Catechols were analyzed by high performance liquid chromatography with electrochemical detection as wc have described previously (Hadjiconstantinou et al., 1983).

1.3. Analysis of aromatic L-amino acid decarbox.vlase

Aromatic L-amino acid decarboxylase activity was assayed by a modification of the method of Nagatsu et al. (Nagatsu et al., 1979). The assay is bascd on the enzymatic conversion of L-3,4-dihydroxyphcnylanine (L-DOPA) to dopaminc with the measurement of dopamine by high performance liquid chromatography (Hadjiconstantinou et al., 1993). The concentration in the incubation medium of I_-DOPA was 500/zM and of pyridoxal-5'-phosphate 10/xM.

1.4. Analysis of tyrosine hydroxy&se actitio'

A modification of the method of Reinhard et al., (1986) was used to assay tyrosine hydroxylase activity. Thc assay is based on the conversion of [3,53H]-i.-tyro - sine to DOPA with the production of [~H]H20. The [3H]H~O produccd was counted in a /3 spectromcter. The concentration in the incubation medium of tyro- sine was 200 p.M and of DL-6-methyl-5,6,7,8-tctrahy- dropteridine 1 mM.

1.5. Northern blot analysis

Total RNA was isolated by the method of Chom- czynski and Sacchi (1987). The isolated RNA was sepa- rated by denaturating electrophoresis on a 0.66 M formaldchydc, 1.4 percent agarose gel and blotted for hybridization to Genc Screen Plus membrane (NEN, Boston, MA). Blots were hybridized overnight at 42°C with ~2p-labellcd tyrosine hydroxylasc or aromatic L- amino acid decarboxylasc cRNA. Betwcen hybridiza- tions radioactive probes were removed from the Gene Scrccn Plus membranes by thorough washing. North- crn blots were placed in apposition with Kodak X-O- Mat AR film. For aromatic L-amino acid decarboxy- lase, a 286 bp mouse aromatic L-amino acid decarboxy- lasc eDNA was subcloncd into a pGEMaZ vector and an anti-sense RNA probe was lincarizcd with Xho 1 and transcribed with SP6 polymerasc. For tyrosinc hydroxylase, a 0.3 Kb PStl-Kpnl restriction fragment from clonc pTH.4, a gift from Dr. D. Chikaraishi, was subcloncd into a pGEM-4Z vector and antiscnse probes synthesized from Hindlll-l incarized plasmid using SP6 polymerase.

After washing membranes were rehybridized with a probc for /3-actin which was used to normalize the Northern blot signals. Thc /3-actin signal served as an internal standard to correct between sample variation for the extraction of mRNA. Autoradiograms were scanned using an LKB Ultrascan XL, enhanced laser densitometer. Data arc expressed as thc ratio of the density for the probe of interest to that of /3-actin (Ambion, Austin, TX) on the same blot.

1.6. Statistical analysis

Statistical evaluation of the neurochemical data were by analysis of variance followed by a Newman-Keuls test. The non-parametric Mann Whitney U-test was used for the statistical analysis of the mRNA blot data.

2. Results

One h following the administration of dizocilpine, 1 mg /kg i.p., there was a significant rise of both

M. Hadjiconstantinou et al. / European Journal of Pharmacology - Molecular Pharmacology Section 289 (1995) 97-101 99

Table 1 Dizocilpine increases dopamine and D O P A C content in the rat brain

Brain region Vehicle Dizocilpine A A A D Dopamine D O P A C Dopamine DOPAC

( p m o l / m g protein + S.E.M.)

Striatum 431 + 17 56_+3 736+-74 a 98+_9 ~ Nucleus accumbens 290± 16 37± 1 2925:27 64_+4 ~ Olfactory tubercle 263 +_ 18 29 + 1 239 + 20 40 _+ 4 a Prefrontal cortex 195:1 16+ I 3 0 ± 2 a 38_+3 a

Rats were treated with dizocilpine, 1 m g / k g i.p., and killed 1 h later. N = 7-12. a p < 0.05 compared with vehicle.

Table 2 Dizocilpine increases tyrosine hydroxylase activity in the striatum of the rat

Brain region Vehicle Dizocilpine

( n m o l / m g pro te in /20 min + S.E.M.)

Striatum 2.4 + 0.1 3,6 ± 0.2 a

Nucleus accumbens 2.0 + 0.2 1.9 -+ 0.1 Olfactory aubercle 1.6 ± 0.1 1.7 + 0.1

Rats were treated with dizocilpine, 1 m g / k g i.p., and killed 1 h later. N = 7-12. " P < 0.05 compared with vehicle.

dopamine and DOPAC in the striatum and prefrontal cortex (Table 1). In the accumbens and olfactory tuber- cle only DOPAC increased.

In the striatum, but not in the accumbens or olfac- tory tubercle, there was a significant rise of tyrosine hydroxylase activity one h after dizocilpine treatment (Table 2). Activity in the prefrontal cortex was too low for reliable quantitation with the method used. In addition, there was a significant rise of aromatic L- amino acid decarboxylase activity in the striatum (Ta- ble 3), but not the other regions of brain evaluated.

The rise of tyrosine hydroxylase and aromatic L- amino acid decarboxylase activity was not a direct effect of dizocilpine on the enzymes as adding it, 10 nM-10 p,M, to the assay medium had no effect on activity (data not shown).

Concomitant with the rise of tyrosine hydroxylase and aromatic L-amino acid decarboxylase activity in the striatum was a significant increase of both tyrosine hydroxylase mRNA and aromatic L-amino acid decar- boxylase mRNA abundance in the midbrain (Figs. 1 and 2).

Table 3 Dizocilpine increases aromatic L-amino acid decarboxylase activity in the str iatum of the rat

Brain region Vehicle Dizocilpine

( n m o l / m g pro te in /20 min + S.E.M.)

Striatum 26 +- 1 38 ± 2 "

Nuc l eus accumbens 24 +- 0.5 21 _+ 2 Olfactory tubercle 6 ± 0.5 6 _+ 0.5 Prefrontal cortex 195:1 18± 1

Rats were treated with dizocilpine, 1 m g / k g i.p., and killed 1 h later. N = 7-12. ~ P < 0.05 compared with vehicle.

. 4:

• . . . TH

1 2 1 2 Fig. 1. Dizocilpine-induced increase of aromatic L-amino acid decar- boxylase and tyrosine hydroxylase m R N A in midbrain. Representa- tive Northern blots. Aromatic L-amino acid decarboxylase: Lane 1, vehicle treated; Lane 2. dizocilpine treated. Tyrosine hydroxylase: Lane I, vehicle treated; Lane 2, dizocilpine treated. Animals were treated as described in the Tables. Total m R N A from the mid-brain of an animal was sequentially hybridized with aromatic L-amino acid decarboxylase, tyrosine hydroxylase and /3 actin probes as described in Materials and methods.

3. Discussion

Dizocilpine is a non-competitive NMDA receptor antagonist which exerts its effects, presumably, by in- teracting with the NMDA receptor-associated ion channel (Wong et al., 1986,1988). Dizocilpine induces a characteristic behavioral syndrome in rodents consist- ing of hyperlocomotion, stereotypies and ataxia, which are thought to result, in part, from an interaction between glutaminergic and dopaminergic transmission (Lodge and Johnson, 1990; Kulkarni and Verma, 1991). Although dizocilpine increases dopaminergic tone (Hiramatsu et al., 1989; Liljequist et al., 1991; L6scher et al., 1991; Rao et al., 1990; L6scher and Honack, 1992), there is not universal agreement on the involve- ment of dopaminergic neurons in the dizocilpine-in- duced locomotor activity (Carlsson and Carlsson, 1989; Lfscher et al., 1991; Liljequist et al., 1991; Ouagazzal et al., 1993; L6scher and Honack, 1992). Apparently dizocilpine exerts its locomotor effects via dopamine- dependent and dopamine-independent neuronal mech-

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Fig. 2. Dizocilpine-induced increase of aromatic L-amino acid decar- boxylase and tyrosine hydroxylase m R N A in mid-brain. Quantitative repre~n ta t ion of optic densities as percent of vehicle control. Sig- nals were normalized against /3-actin on the same blot. Blots, N = 5, were from 2 separate studies. "P < 0.05 compared to vehicle.

1110 M. IhJdjiconstanttnot¢ ~'t aL / European Journal ~f lJharmacoh~gy - Moh'c'tdar Pharma('¢~h~gy 3)'~'ti~m 289 (19q5) 97-. 101

anisms. The neurochcmical substrates and the site(s) for the behavioral actions of dizocilpinc arc dcbatable. Whilc the basal ganglia appear to be important for the locomotor action of the compound, the exact anatomi- cal site of this action and whether dizocilpinc elicits locomotion by acting dircctly or indirectly on nigrostri- atal or mesolimbic dopaminergic neurons is unclear (Klockgethcr and Turski, 19911: Elliott ct al., 1990; Zhang ct al., 1992; Ouagazzal et al., 1993).

Despite the unresolved nature of the behavioral pharmacology of dizocilpine, it exerts pronounced ef- fects on dopaminergic ncuronal activity. Dizocilpinc, increases the firing of dopaminergic neurons (Zhang et al., 1992; French et al., 1993), enhances dopamine mctabolism in various regions of brain (Hiramatsu et al., 1989; Rao ct al., 1990; Liljcquist et al., 1991; L6scher c t a l . , 1991) and potentiates the effects of L-DOPA in an animal model of Parkinson's diseasc (Klockgcther and Turski, 1990; lJ~schmann ct al., 1991). Based on these reports, we investigated whether a dose of dizocilpinc, 1 mg /kg i.p., which clcarly cnhances locomotor activity and reduces limb rigidity in an ani- mal modcl of Parkinson's disease (Klockgether and Turski, 1990), affectcd the activities of thc dopaminc synthetic enzymes tyrosine hydroxylase and aromatic L-amino acid decarboxylase. Tyrosine hydroxylase ac- tivity is apparently rate-limiting for the synthesis of catecholamincs (Nagatsu ct al., 1964) whilc aromatic L-amino acid dccarboxylase is thought to bc present in cxcess (Pletscher and Gcy, 1963). With the treatment conditions used, dizocilpine increascd dopaminc and DOPAC content in the striatum and prefrontal cortex and increased DOPAC in the nuclcus accumbcns and olfactory tubercle, evidence for increased synthesis and metabolism of dopamine. In addition, dizocilpine, in- creased the activity of tyrosine hydroxylase and aro- matic L-amino acid dccarboxylasc in the striatum. The enzyme increascs were accompanied by enhanced tyro- sine hydroxylase and aromatic L-amino acid decarboxy- lase mRNA in the midbrain implicating ncw protein synthesis. Increased enzyme activity may be an attempt to maintain neurotransmitter content and availability in response to heightened demand. Failure to find increased enzyme activity in the terminal fields of the vcntral tegmental dopamincrgic neurons suggest differ- ential modulation of tyrosine hydroxylasc and aromatic l,-amino acid decarboxylasc in the various dopaminer- gic systems or a diffcrencc in the timc-course for the rcsponsc.

it has been suggested that NMDA receptor antago- nists might be useful adjuncts for treating parkinson- ism. This is based on observations that intrastriatal administration of dizocilpine and phencyclidine pre- vent neurolcptic-induced catalepsy (Elliott et al., 1990), that injection of dizocilpine into the medial pallidal segment of MPTP (l-methyl-4-phenyl-l,2,3,6-tetrahy-

dropyridine)-treated primates reverses motor symp- toms (Graham ct al., 1990), that dizocilpinc potentiates thc effect of I,-DOPA in a catecholaminc-dcpletcd model of parkinsonism (Klockgether and Turski, 1090) and that the antiparkinsonian drugs amantadine and memantine are non-competitive NMDA receptor an- tagonists (Bormann, 1989, Kornhuber ct al., 1991). Increased dopaminc synthesis and rcleasc is a possiblc mechanism for thc putativc antiparkinsonian action of these compounds. Our observation that dizocilpine in- creases aromatic L-amino acid dccarboxylase activity offers yet another mechanism, The reports that gluta- mate rcceptor antagonists potcntiatc the effcct of ~- DOPA in an animal model of Parkinson's discase (Klockgethcr and Turski, 1990; ~ischmann et al., 1991) might be interpreted to suggcst that either more l.- DOPA is available in striatum for dccarboxylation or that morc aromatic L-amino acid decarboxylasc is available to dccarboxylate a given dosc of J-DOPA. Our results suggest that the non-competitivc NMDA rcceptor antagonist, dizc~ilpine, activates nigrostriatal ncurons and as a consequence dopaminergic synthetic cnzymes arc enhanced. Decarboxylation of cxogcnous ~,-DOPA is a function of thc tissuc content of aromatic L-amino acid decarboxylase (Xu ct al., 1985), thus morc enzyme results in greater decarboxylation of a given dose of L-DOPA to form more dopamine (Xu et al., 1985). Based on our results, the report of Klock- gethcr and Turski (1990) wherc the antiparkisonian action of t_-DOPA was potentiated by dizocilpinc and CPP (3-[2-carboxypiperazin-4-yl]-propyl-l-phosphonic acid), might be, in part, the consequence of cnhanced convcrsion of n.-DOPA to dopamine by enhanced stri- atal decarboxylating activity.

h~ conclusion, wc provide evidence that the non- competitive NMDA receptor antagonist dizocilpinc en- hances the activity of the dopamine synthetic enzymes tyrosinc hydroxylase and aromatic L-amino acid dccar- boxylasc as well as mRNA. This information adds to our understanding of the pharmacology and potential thcrapeutic application of dizocilpine.

Acknowledgement

This work was supported, in part, by NHS grant MH43374.

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