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5-HT2A and 5-HT2C/2B Receptor Subtypes Modulate

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5-HT2A and 5-HT2C/2B Receptor Subtypes Modulate 5-HT2A and 5-HT2C/2B Receptor Subtypes Modulate Dopamine Release Induced in Vivo by Amphetamine and Morphine in Both the Rat Nucleus Accumbens and Striatum Grégory Porras, M.S., Vincenzo Di Matteo, Ph.D., Claudia Fracasso, B.S., Guillaume Lucas, Ph.D., Philippe De Deurwaerdère, Ph.D., Silvio Caccia, Ph.D., Ennio Esposito, M.D., Ph.D., and Umberto Spampinato, M.D., Ph.D. In vivo microdialysis and single-cell extracellular neuron firing rate in both the ventral tegmental area and recordings were used to assess the involvement of the substantia nigra pars compacta was unaffected by SR serotonin2A (5-HT2A) and serotonin2C/2B (5-HT2C/2B) 46349B (0.1 mg/kg i.v.) but significantly potentiated by SB receptors in the effects induced by amphetamine and 206553 (0.1 mg/kg i.v.). These results show that 5-HT2A morphine on dopaminergic (DA) activity within the and 5-HT2C receptors regulate specifically the activation of mesoaccumbal and nigrostriatal pathways. The increase in midbrain DA neurons induced by amphetamine and DA release induced by amphetamine (2 mg/kg i.p.) in the morphine, respectively. This differential contribution may nucleus accumbens and striatum was significantly reduced be related to the specific mechanism of action of the drug by the selective 5-HT2A antagonist SR 46349B (0.5 mg/kg considered and to the neuronal circuitry involved in their s.c.), but not affected by the 5-HT2C/2B antagonist SB effect on DA neurons. Furthermore, these results suggest 206553 (5 mg/kg i.p.). In contrast, the enhancement of that 5-HT2C receptors selectively modulate the impulse accumbal and striatal DA output induced by morphine (2.5 flow–dependent release of DA. mg/kg s.c.), while insensitive to SR 46349B, was [Neuropsychopharmacology 26:311–324, 2002] significantly increased by SB 206553. Furthermore, © 2002 American College of Neuropsychopharmacology. morphine (0.1–10 mg/kg i.v.)-induced increase in DA Published by Elsevier Science Inc. From the Laboratoire de Neuropsychobiologie des Désadapta- KEY WORDS: Microdialysis; Dopamine release; tions, UMR CNRS 5541-Université Victor Segalen Bordeaux 2, 146 Dopaminergic neuron firing rate; 5-HT2A receptors; rue Léo Saignat, Boîte Postale 31, 33076 Bordeaux Cedex, France 5-HT receptors; Amphetamine; Morphine (GP, GL, PD, US); Istituto di Ricerche Farmacologiche “Mario 2C/2B Negri”, Consorzio “Mario Negri Sud”, Santa Maria Imbaro, Chieti, Several recent studies have focused on the role of Italy (VDM, EEE); and Istituto di Ricerche Farmacologiche “Mario Negri”, via Eritrea 62, 20157 Milano, Italy (CF, SC) serotonin2 (5-HT2) receptors in the regulation of fore- Address correspondence to: Pr. U. Spampinato, Laboratoire de brain dopamine (DA) function and highlight their po- Neuropsychobiologie des Désadaptations, UMR CNRS 5541-Uni- tential as a target for improved treatments of neuropsy- versitéVictor Segalen Bordeaux 2, 146 rue Léo Saignat, Boîte Postale 31, 33076 Bordeaux Cedex, France; E-mail: Umberto.Spampinato chiatric disorders related to central DA neuron @lnpb.u-bordeaux2.fr dysfunction (Kapur and Remington 1996; Walsh and Received February 22, 2001; revised June 21, 2001; accepted July Cunningham 1997; Meltzer 1999). The involvement of 16, 2001. Online publication: 7/18/01 at www.acnp.org/citations/Npp 5-HT2 receptor subtypes, that is, 5-HT2A and 5-HT2C re- 071701152. ceptors, in the control of mesolimbic and nigrostriatal NEUROPSYCHOPHARMACOLOGY 2002–VOL. 26, NO. 3 © 2002 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/02/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(01)00333-5 312 G. Porras et al. NEUROPSYCHOPHARMACOLOGY 2002–VOL. 26, NO. 3 DA neuron activity is now well established (De Deur- antagonist SR 46349B and the 5-HT2C/2B receptor antag- waerdère and Spampinato 1999; Gobert and Millan onist SB 206553 on the release of DA induced by am- 1999; Lucas et al. 2000a), and evidence has been pro- phetamine or morphine in the NAc and striatum of hal- vided that they exert opposite effects on DA release. It othane-anesthetized rats. This experimental procedure has also been suggested that these receptors may con- was chosen because it permits simultaneous monitor- trol DA release by acting at different levels of DA neu- ing of DA outflow in the ipsilateral NAc and striatum ron regulatory mechanisms. On the one hand, 5-HT2A (De Deurwaerdère et al. 1998). To further explore the receptors have been shown to facilitate stimulated but influence of each 5-HT2 receptor subtype on the im- not basal DA release in both the rat nucleus accumbens pulse flow–dependent DA release, we examined, by us- (NAc) and the striatum. Compelling evidence from bio- ing single-unit extracellular recordings, the effect of SR chemical and electrophysiological studies has shown 46349B and SB 206553 on the increase in VTA and SNc that 5-HT2A receptors may modulate either impulse DA neuron firing rate induced by morphine. Finally, in flow–independent or –dependent release of DA a separate group of experiments, plasma and brain con- through mechanisms involving regulation of either DA centrations of amphetamine and morphine were mea- synthesis or DA neuron firing rate, respectively sured to evaluate possible pharmacokinetic interactions (Schmidt et al. 1992; Gudelsky et al. 1994; Schmidt and between the probe drugs and the 5-HT-agents used. Fadayel 1996). On the other hand, several neurochemi- cal studies have shown that 5-HT2C receptors exert in- hibitory control on both basal and stimulated DA re- MATERIALS AND METHODS lease (Di Giovanni et al. 1999; Hutson et al. 2000; Lucas Animals et al. 2000a). In addition, electrophysiological studies have shown that basal firing rate of DA neurons located Male Sprague Dawley rats (IFFA CREDO, Lyon, in both the ventral tegmental area (VTA) and substantia France and Consorzio Mario Negri Sud, Chieti, Italy) nigra pars compacta (SNc) is increased by 5-HT2C recep- weighing 330–380 g were used. Animals were kept at Ϯ Њ tor antagonists and inhibited by 5-HT2C receptor ago- constant room temperature (21 2 C) and relative hu- nists (Di Matteo et al. 2000; Gobert et al. 2000). Interest- midity (60%) with a 12-h light/dark cycle (dark from 8 ingly, it has recently been proposed that 5-HT2C P.M.) and had free access to water and food. All ani- receptors may selectively regulate the impulse flow– mals use procedures conformed to International Euro- dependent release of DA (Willins and Meltzer 1998; Lu- pean Ethical Standards (86/609-EEC) and the French cas et al. 2000a). National Committee (décret 87/848) for the care and The above-reported arguments that 5-HT2A and 5-HT2C use of laboratory animals. All efforts were made to receptors regulate DA release through different mecha- minimize animal suffering and to reduce the number nisms may be of considerable interest when discussing of animals used. the effect of drugs of abuse, such as psychostimulants or opiates, on DA function. Indeed, the fact that drugs Drugs of abuse increase DA release through different cellular mechanisms leads to the possibility that their effect on The following compounds were used: SR 46349B (trans- DA release could be modulated differentially by each of 4-{(3Z)3-[(2-dimethylaminoethyl)oxiimino]-3-(2-fluorophe- the 5-HT2 receptor subtypes, depending on the mecha- nyl)propen-1-yl}-phenol) hemifumarate (Sanofi Recher- nism of action of the drug considered. Thus, amphet- che, Montpellier, France) and SB 206553 (5-methyl-1-(3- amine-induced DA release, which occurs indepen- pyridylcarbamoyl)-1,2,3, 5-tetrahydropyrrolo[2,3-f]indole) dently from DA neuron firing rate and involves (SmithKline Beecham Pharmaceuticals, Harlow, UK), increase in DA synthesis (Seiden et al. 1993; Cadoni et which were kindly provided by the producers. Morphine al. 1995), could be sensitive to 5-HT2A but not 5-HT2C re- sulfate and d-amphetamine sulfate (amphetamine) were ceptor regulation. Conversely, morphine-stimulated from Sigma (St Louis, MO). d-norfenfluramine hydro- DA release, thought to be a consequence of its excita- chloride was a generous gift from I.R.I.S. Laboratories tory effect on DA neuron firing rate (Di Chiara and (Courbevoie, France). All other chemicals and reagents North 1992), could be controlled by 5-HT2A and 5-HT2C were the purest commercially available (Merck; Sigma). receptors. Although some studies have already investi- gated the role of 5-HT receptors on amphetamine- or 2 Microdialysis morphine-induced DA release, the poor selectivity of the 5-HT compounds used does not allow a clear con- Surgery and perfusion procedures were performed as clusion concerning this issue (Ichikawa and Meltzer previously described (De Deurwaerdère et al. 1998), 1992; Willins and Meltzer 1998). with minor modifications. Briefly, rats were anesthe- Thus, in this study, we examined, by in vivo mi- tized with a mixture of halothane and nitrous oxide- crodialysis, the effect of the selective 5-HT2A receptor oxygen (1%; 2:1 v/v). After tracheotomy for artificial NEUROPSYCHOPHARMACOLOGY 2002–VOL. 26, NO. 3 5-HT2A and 5-HT2C/2B Receptors and DA Neuron Activity 313 ventilation, the animals were placed in a stereotaxic interaural line, for placement of the recording electrode frame, and their rectal temperature was monitored and in the areas studied were (in millimeters), for the VTA, maintained at 37.3ЊC Ϯ 0.1 with a heating pad. Two mi- AP ϭ 2.7–3.4, L ϭ 0.3–0.5, V ϭ 7–8 ventral to the level of crodialysis probes, 2 and 3 mm long, (CMA/11, 240 ␮m exposed tissue; and for the SNc, AP ϭ 2.7–3.4, L ϭ 1.8–2.2, outer diameter, Cuprophan; Carnegie Medicin, Phymep, V ϭ 6.5–7.5 (Paxinos and Watson 1986).
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