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Differential Actions of Antiparkinson Agents at Multiple Classes of Monoaminergic Receptor

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Differential Actions of Antiparkinson Agents at Multiple Classes of Monoaminergic Receptor 0022-3565/02/3032-815–822$7.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 303, No. 2 Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics 39883/1021572 JPET 303:815–822, 2002 Printed in U.S.A. Differential Actions of Antiparkinson Agents at Multiple Classes of Monoaminergic Receptor. III. Agonist and Antagonist Properties at Serotonin, 5-HT1 and 5-HT2, Receptor Subtypes ADRIAN NEWMAN-TANCREDI, DIDIER CUSSAC, YANN QUENTRIC, MANUELLE TOUZARD, LAURENCE VERRIELE,` NATHALIE CARPENTIER, and MARK J. MILLAN Department of Psychopharmacology, Institut de Recherches Servier, Paris, France Received June 14, 2002; accepted July 22, 2002 Downloaded from ABSTRACT Although certain antiparkinson agents interact with serotonin line, and pergolide displayed potent (7.6–8.8) agonist proper- (5-HT) receptors, little information is available concerning func- ties (49–103%), whereas apomorphine and roxindole were an- tional actions. Herein, we characterized efficacies of apomor- tagonists and piribedil was inactive. Only pergolide (113%/8.2) phine, bromocriptine, cabergoline, lisuride, piribedil, pergolide, and cabergoline (123%/8.6) displayed pronounced agonist jpet.aspetjournals.org roxindole, and terguride at human (h)5-HT1A, h5-HT1B, and properties at h5-HT2B receptors. At 5-HT2C receptors, lisuride, Ј 35 h5-HT1D receptors [guanosine 5 -O-(3-[ S]thio)triphosphate bromocriptine, pergolide, and cabergoline were efficacious 35 ␥ ([ S]GTP S) binding], and at h5-HT2A, h5-HT2B, and h5-HT2C (75–96%) agonists, apomorphine and terguride were antago- receptors (depletion of membrane-bound [3H]phosphatydili- nists, and piribedil was inactive. MDL100,907 and SB242,084, nositol). All drugs stimulated h5-HT1A receptors with efficacies selective antagonists at 5-HT2A and 5-HT2C receptors, respec- (compared with 5-HT, 100%) ranging from modest (apomor- tively, abolished these actions of pergolide, cabergoline, and phine, 35%) to high (cabergoline, 93%). At h5-HT1B receptors, bromocriptine. In conclusion, antiparkinson agents display efficacies varied from mild (terguride, 37%) to marked (caber- markedly different patterns of agonist and antagonist proper- at ASPET Journals on January 23, 2020 goline, 102%) and potencies were modest (pEC50 values of ties at multiple 5-HT receptor subtypes. Although all show 5.8–7.6): h5-HT1D sites were activated with a similar range of modest (agonist) activity at 5-HT1A sites, their contrasting ac- efficacies and greater potency (7.1–8.5). Piribedil and apomor- tions at 5-HT2A and 5-HT2C sites may be of particular signifi- phine were inactive at h5-HT1B and h5-HT1D receptors. At cance to their functional profiles in vivo. h5-HT2A receptors, terguride, lisuride, bromocriptine, cabergo- Several lines of evidence implicate serotonergic pathways their influence upon the motor, mood, and cognitive symptoms in the etiology and treatment of Parkinson’s disease. First, of Parkinson’s disease, although serotonergic properties do not patients exhibit decreased levels of 5-HT reuptake sites and underlie their ability to restore motor function per se (see Dis- of the 5-HT metabolite 5-hydroxyindoleacetic acid, observa- cussion). The significance of individual subtypes of 5-HT recep- tions possibly related to depressive symptoms comorbid with tor to Parkinson’s disease and its management may be outlined motor dysfunction (Mayeux, 1990). Second, the neurotoxin as follows. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, which depletes 5-HT1A receptors are enriched in regions controlling motor nigrostriatal pools of dopamine (DA) and induces a Parkinson’s function, such as the striatum, nucleus accumbens, and fron- disease-like syndrome, reduces striatal levels of 5-HT (Pe´rez- tal cortex (Barnes and Sharp, 1999; Millan et al., 2000): in Otan˜o et al., 1991). Third, the antiparkinson agent and DA the striatum, the density of 5-HT1A receptors is elevated precursor L-dihydroxyphenylacetic acid (L-DOPA) displaces after damage to nigrostriatal dopaminergic pathways (Fre- 5-HT from serotonergic neurons innervating the striatum, chilla et al., 2001). Both presynaptic 5-HT autoreceptors wherein it is transformed into DA (Arai et al., 1996; Kannari et 1A and their postsynaptic counterparts exert a modulatory in- al., 2001). Fourth, actions of antiparkinson agents at 5-HT receptors (Newman-Tancredi et al., 2002) may participate in fluence upon dopaminergic transmission, motor function, mood, and cognition (Wadenberg, 1996; Barnes and Sharp, 1999; Meneses, 1999; Millan, 2000). Notably, 5-HT1A ago- Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. nists reverse reserpine-induced hypoactivity (Ahlenius and DOI: 10.1124/jpet.102.039883. Salmi, 1995) and abrogate the motor disruption elicited by ABBREVIATIONS: 5-HT, serotonin; DA, dopamine; L-DOPA, L-dihydroxyphenylacetic acid; [35S]GTP␥S, guanosine 5Ј-O-(3-[35S]thio)triphosphate; h, human; PI, phosphatidylinositol; CHO, Chinese hamster ovary. 815 816 Newman-Tancredi et al. agonists (dyskinesias) and antagonists (catalepsy) at dopa- tiate actions of dopaminergic agonists in models of Parkin- minergic receptors (Wadenberg, 1996; Bibbiani et al., 2001). son’s disease (Fox and Brotchie, 1999). Activation of 5-HT2C 5-HT1B receptors are highly expressed in the substantia receptors is also implicated in processes underlying the in- nigra, striatum, and corticolimbic structures wherein they duction of tremor (Sarkar et al., 2000) and (at subthalamic modify the activity of serotonergic, cholinergic, and glutama- loci) dyskinesias (Eberle-Wang et al., 1996; Barwick et al., tergic pathways (Bruinvels et al., 1993; Barnes and Sharp, 2000). Finally, 5-HT2C antagonist properties alleviate de- 1999). Although 5-HT1B receptors inhibit DA release in the pressive and anxious states (Kennett et al., 1996; Millan et striatum (Sarhan et al., 2000), they are facilitatory to DA al., 2000). release in the nucleus accumbens wherein, in interaction Because a detailed characterization of the serotonergic with dopaminergic terminals, they influence motor function properties of antiparkinson agents has yet to be undertaken, (Przegalinski et al., 2001; Yan and Yan, 2001). However, we investigated the efficacies of diverse antiparkinson agents activation of mesolimbic DA release is implicated in reward at h5-HT1A, h5-HT1B, h5-HT1D, h5-HT2A, h5-HT2B, and h5- mechanisms as well as disturbances of cognition and mood HT2C receptors Efficacy at “5-HT1 ” receptor subtypes was associated with schizophrenia: this is of note because psycho- determined by measuring G protein activation with estab- sis is a serious problem in Parkinson’s disease (Friedman and lished [35S]GTP␥S binding methodologies (Newman-Tan- Factor, 2000; Audinot et al., 2001). Inasmuch as dendritic credi et al., 1999). Efficacy at “5-HT2 ” receptor subtypes was 5-HT1D receptors complement the inhibitory influence of (ter- determined using a measure of phospholipase C activation, 3 Downloaded from minal) 5-HT1B receptors upon serotonergic transmission, depletion of membrane-bound [ H]phosphatidylinositols (PI) they may mimic certain of their functional roles. Further- (Cussac et al., 2002b). more, their high concentration in the basal ganglia is of potential pertinence to antiparkinson agents (Bruinvels et al., 1993, Barnes and Sharp, 1999). Materials and Methods There is a high concentration of 5-HT2A receptors in corti- Determination of Agonist Efficacy at Recombinant h5- colimbic structures controlling motor function and mood as jpet.aspetjournals.org 35 ␥ well as in the striatum, wherein they are up-regulated upon HT1A, h5-HT1B, and h5-HT1D Receptors by [ S]GTP S Bind- ing. Efficacy at cloned h5-HT , h5-HT , and h5-HT receptors elimination of nigrostriatal dopaminergic input (Numan et 1A 1B 1D was determined by measuring stimulation of [35S]GTP␥S binding, as al., 1995; Barnes and Sharp, 1999; Gresch and Walker, described previously (Newman-Tancredi et al., 1999). Briefly, mem- 1999). Some 5-HT2A receptors are located on substance P- branes prepared from Chinese hamster ovary (CHO) cells stably containing output neurons, but the majority are localized on expressing h5-HT1A, h5-HT1B, or h5-HT1D receptors were incubated corticostriatal and pallidostriatal afferents: antagonism of at 22°C for 20 min (h5-HT1A) or 30 min (h5-HT1B and h5-HT1D) with the latter sites may reduce the induction of dyskinesias by drugs or 5-HT in the following buffer: 20 mM HEPES pH 7.4, 10 mM at ASPET Journals on January 23, 2020 ␮ 35 ␥ antiparkinson agents (Gresch and Walker, 1999; Bubser et NaCl, 3 M GDP, 3 mM MgCl2, and 0.1 nM [ S]GTP S. Agonist efficacy is expressed relative to that of 5-HT (defined as 100%), which al., 2001; Naidu and Kulkarni, 2001). Activation of 5-HT2A receptors enhances DA release in the striatum (Ng et al., was tested at a maximally effective concentration (10 ␮M) in each 1999; De Deurwaerde`re and Spampinato, 2001), frontal cor- experiment. Experiments were terminated by rapid filtration tex (Millan, 2000; Millan et al., 2000), and nucleus accum- through GF/B filters (Whatman, Maidstone, UK) using a Packard Instrument Company, Inc. (Downers Grove, IL) 96-well cell har- bens (Bowers et al., 2000; Yan et al., 2000), actions underly- vester and radioactivity determined by liquid scintillation counting. ing their complex, facilitatory influence upon motor function Binding densities (Bmax values) at h5-HT1A, h5-HT1B, and h5-HT1D (Millan et al., 1999; McMahon and Cunningham,
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