HT2C Receptors and Dopamine Function

Ugedo et al. (1989) showed that systemic administration of ritanserin, a 5-HT2 antagonist, was capable of increasing both the firing rate and the bursting activity of DA neurons in the SNc and the VTA. These effects were prevented by 5-HT depletion induced by PCPA (Ugedo et al. 1989). These authors concluded that "... these results suggest that 5-HT exerts an inhibitory control of midbrain DA cell activity mediated by 5-HT2 receptors ..." (Ugedo et al. 1989), obviously referring to 5-HT2 as the receptors that were subsequently defined 5-HT2A (Hoyer et al. 2002). However, it is important to point out that the doses of ritanserin (0.5-2.0 mg/kg i.v.) used in the study of (Ugedo et al. 1989) were too high to selectively block 5-HT2A receptors, in that it has been shown that ritanserin is a potent 5-HT antagonist, which also binds with high affinity to 5-HT2C receptors (Boess and Martin 1994). It is therefore impossible to discriminate the relative contribution of 5-HT2A and 5-HT2C in the disinhibitory effect of ritanserin reported in the study by Ugedo et al. (1989). In a subsequent study, the same research group (Andersson et al. 1995) found that ritanserin (1.0 mg/kg i.v.) increased the firing rate, the burst firing, and the variation coefficient of DA neurons in the VTA but not in the SNc. Moreover, ritanserin pre-treatment significantly enhanced the stimulatory effects of low doses of raclopride (10-20 mg/kg i.v.) on the burst firing of VTA DA neurons (Andersson et al. 1995). These data indicated that unselective blockade of 5-HT2 receptors by ritanserin can preferentially increase the activity of DA neurons in the VTA, but they did not clearly establish which receptor subtype (5-HT2A or 5-HT2C or both?) is involved in this effect. This picture was further complicated by the evidence that ritanserin (0.1-6.4 mg/kg i.v.) had no consistent effects on the basal firing rate of SNc DA neurons but significantly reversed the inhibition induced by both direct and indirect DA agonists (Shi et al. 1995). However, the effect of ritanserin was apparently mediated by a mechanism independent of 5-HT, but it was due to its ability to selectively block DA autoreceptors (Shi et al. 1995). Although 5-HT2A receptors are localized on a subset of DA cells in the VTA (Nocjar et al. 2002), the use of selective ligands has not revealed a clear role for these receptors in modulating dopaminergic neuronal activity within the nuclei. Blockade of 5-HT2A receptors by the potent and selective 5-HT2A antagonist MDL 100907 {R(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol} (Shi et al. 1995; Minabe et al. 2001)

and SR 46349B {but-2-enedioic acid; 4-[(E)-3-(2-dimethylaminoethoxyamino)-3-(2-fluorophenyl)prop-2-enylidene]cyclohexa-2,5-dien-1-one} (Di Giovanni et al. 1999), or their activation with the agonist (±)-DOI (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (Di Matteo et al. 2000a), had no significant effect on the basal activity of SNc and VTA DA neurons and on their inhibition of direct and indirect DA agonists (Shi et al. 1995). A cell-per-track study showed that MDL 100907 behaves as an atypical APD (Sorensen et al. 1993). MDL 100907 (1.0 mg/kg, i.p.) produced only small increases in the number of active SNc and VTA DA neurons after acute administration (Sorensen et al. 1993) but at 0.1 mg/kg, i.p. significantly increased the number of spontaneously active SNc and VTA DA neurons. When administered chronically, MDL 100907 (1.0 mg/kg, i.p.) selectively reduced the number of spontaneously active VTA neurons (Sorensen et al. 1993), whereas at lower doses (0.03-0.1 mg/kg, i.p.) it was active in reducing the number of the cells in both the DA nuclei.

In spite of these findings, a functional role for 5-HT2A receptors localized on VTA DA neurons has yet to be determined. However, in another study 5-HT2A antagonists were found to block the inhibitory effect of amphetamine on the basal firing rate of DA neurons, in both the SNc and the VTA (Sorensen et al. 1993) or the amphetamine-induced DA release in the nucleus accumbens and striatum (Porras et al. 2002). Conversely, the selective blockade of 5-HT2A does not modify the effect of morphine (Porras et al. 2002). Thus, this receptor subtype might modulate the activity of both the nigro-striatal and mesocorticolimbic dopaminergic systems only when specific neuronal circuitry mechanisms are activated. Further investigations into the circuitry of this regulation indicated that 5-HT2A receptors on cortical projections regulate DA cellular activity. 5-HT2A receptors seem to be unable to modulate DA function under resting conditions (Porras et al. 2002; Di Giovanni et al. 2000).

Compelling evidence has been given about the lack of influence on DA cell function by the selective blockade of central 5-HT2B receptors (Di Giovanni et al. 1999; Di Matteo et al. 2000a; Gobert et al. 2000).

Sixteen years ago, the issue regarding the role of 5-HT on the control of the electrical activity of DA neurons in the SNc and the VTA was quite confused and controversial. At that time, a study undertaken in our laboratory shed some light on the subject (Prisco et al. 1994). Systemic administration of mesulergine produced a significant increase in the basal firing rate of VTA DA neurons, whereas ritanserin, used at doses that selectively block 5-HT2A receptors, caused a slight, statistically significant decrease in the basal activity of these neurons (Prisco et al. 1994). These data, although obtained by using partially selective antagonists, represent the first evidence of a differential effect of 5-HT2A and 5-HT2C receptors upon DA-containing neurons in the VTA (Prisco et al. 1994). Thus, the data obtained by Prisco et al. (1994) supported the conclusion that 5-HT exerts an inhibitory action on DA neurons in the VTA through the 5-HT2C receptor subtype (which at that time was still named 5-HT1C). Subsequent studies confirmed a selective involvement of 5-HT2C receptors on the basis of the evidence that the inhibitory effect of the mixed 5HT2A/2B/2C receptor agonists 1-(meta-chlorophenyl)piperazine (mCPP) and 6-chloro-2-(1-piperazinyl) piperazine (MK 212) on the activity of VTA DA-containing neurons and on accumbal

DA release was completely prevented by SB 242084 {6-chloro-5-methyl-1-[2-(2-methylpyridiyl-3-oxy)-pyrid-5-yl carbamoyl] indoline}, a selective 5-HT2C receptor antagonist (Di Giovanni et al. 2000). Moreover, SB 242084 blocked the inhibitory action of RO 60-0175 [(S)-2-(chloro-5-fluoro-indol-1-yl)-1-methylethylamine 1:1 C4H4O4], a selective 5-HT2C receptor agonist (Di Matteo et al. 2000a; Martin et al. 1998). Another series of studies clearly indicated a selective involvement of 5-HT2C receptors for the suppressive influence of 5-HT on the activity of dopaminergic pathways. In fact, a series of in vivo electrophysiological and neurochemical studies showed that 5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f ]indole (SB 206553), a selective 5-HT2C/2B receptor inverse agonist (Kennett et al. 1996; De Deurwaerdère et al. 2004), and 6-chloro-5-methyl-l-[2-(2-methylpyridiyl-3-oxy)-pyrid-5-yl carbamoyl] indoline (SB 242084), the most potent and selective 5-HT2C receptor antagonist available (Kennett et al. 1996), increased the basal firing rate and the bursting activity of VTA DA neurons (Fig. 11.1) and enhanced DA release in both rat nucleus accumbens (Fig. 11.2) and prefrontal cortex (Di Giovanni et al. 1999; Gobert et al. 2000; De Deurwaerdère et al. 2004; De Deurwaerdère and Spampinato 1999; Di Matteo et al. 1999; Gobert and Millan 1999). Conversely, systemic administration of RO 60-0175 had opposite effects (Figs. 11.3 and 11.5) (Kennett et al. 1996; Di Matteo et al. 1999; Millan et al. 1998). SB 206553 and SB 242084 were also found to potentiate pharmacological-induced accumbal DA release (Porras et al. 2002; Hutson et al. 2000; Navailles et al. 2004) and stress-stimulated DA outflow in

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Fig. 11.1 Effect of SB242084 on the firing rate of SNc and VTA DA neurons. (a) and (c) Histograms showing mean percentage of change (±SEM) in firing rate of DA neurons in the SNc (a) and the VTA (c) after i.v. SB 242084 (n = 6-8) (b) and (d) Representative rate histograms showing the lack of effect of i.v. SB 242084 (640 mg/kg) in the SNc (b) and the typical excitatory response in the VTA (d). *P < 0.05, **P < 0.01 compared with control group; one-way ANOVA followed by Tukey test (Modified from Di Matteo et al. 1999)

Fig. 11.1 Effect of SB242084 on the firing rate of SNc and VTA DA neurons. (a) and (c) Histograms showing mean percentage of change (±SEM) in firing rate of DA neurons in the SNc (a) and the VTA (c) after i.v. SB 242084 (n = 6-8) (b) and (d) Representative rate histograms showing the lack of effect of i.v. SB 242084 (640 mg/kg) in the SNc (b) and the typical excitatory response in the VTA (d). *P < 0.05, **P < 0.01 compared with control group; one-way ANOVA followed by Tukey test (Modified from Di Matteo et al. 1999)

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Fig. 11.2 Time course of the effect of i.p. administration of 5 (▲) and 10 mg/kg SB 242084 (■) on extracellular DA and DOPAC levels in the striatum (left column) and the nucleus accumbens (right column). (□) Control group treated with vehicle. SB 242084 was administered at the time indicated by vertical arrows. Each data point represents mean percentage ± SEM of the baseline value calculated from three samples before SB 242084 injection. Each experiment was carried out on five to six animals per group. *P < 0.05, **P < 0.01 compared with control group; two-way ANOVA followed by Tukey test (Modified from Di Matteo et al. 1999)

the rat prefrontal cortex (Pozzi et al. 2002), while stimulation of 5-HT2C receptors by RO 60-0175 in the VTA suppressed it (Pozzi et al. 2002), suggesting a role of these receptors on evoked accumbal DA release also. On the other hand, 5-HT2C receptor agonists such as mCPP, MK 212, and RO 60-0175 did not significantly affect the activity of SNc DA neurons and the in vivo DA release in the striatum (Figs. 11.4 and 11.5) (Gobert et al. 2000; Di Matteo et al. 1999), and the mixed 5HT2B/2C antagonist SB 206553 caused only a slight increase in the basal activity of DA neurons in the nigros-triatal pathway (Di Giovanni et al. 1999), suggesting that the serotonergic system controls both basal and stimulated impulse flow-dependent release of DA preferentially in the mesocorticolimbic system by acting through 5-HT2C receptors. Consistently, it has been reported that SB 243213 {5-methyl-1-[[-2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-6-trifluoromethylindoline hydrochloride}, a new selective 5-HT2C receptor inverse agonist (Wood et al. 2001; Berg et al. 2006), at a dose of 3 mg/kg, i.p.

Fig. 11.3 Effect of mCPP, MK 212, and RO 60-0175 on the firing rate of VTA DA neurons and the blockade by SB 242084 of their inhibitory actions. Representative rate histograms showing the typical inhibitory effects produced by i.v. administration of mCPP and MK 212 (5, 5, 10, 20, 40, 80, 160 mg/kg at arrows) and RO 60-0175 (320 mg/kg at arrows) in control rats (a), (d), and (f) Representative rate histograms showing that i.v. SB 242084 (200 mg/kg) prevents the inhibitory effects of mCPP and MK 212 (5, 5, 10, 20, 40, 80, 160 mg/kg at arrows) (b), (e), and (g) (Modified from references Di Giovanni et al. 2000; Di Matteo et al. 1999, respectively)

Fig. 11.3 Effect of mCPP, MK 212, and RO 60-0175 on the firing rate of VTA DA neurons and the blockade by SB 242084 of their inhibitory actions. Representative rate histograms showing the typical inhibitory effects produced by i.v. administration of mCPP and MK 212 (5, 5, 10, 20, 40, 80, 160 mg/kg at arrows) and RO 60-0175 (320 mg/kg at arrows) in control rats (a), (d), and (f) Representative rate histograms showing that i.v. SB 242084 (200 mg/kg) prevents the inhibitory effects of mCPP and MK 212 (5, 5, 10, 20, 40, 80, 160 mg/kg at arrows) (b), (e), and (g) (Modified from references Di Giovanni et al. 2000; Di Matteo et al. 1999, respectively)

significantly decreased only the number of spontaneously active VTA DA neurons and modified the pattern discharge but did not affect the number of spontaneously active SNc DA cells, whereas the 10 mg/kg, i.p. dose altered the firing pattern of DA neurons in both the SNc and the VTA (Blackburn et al. 2002).

Moreover, a study carried out in our laboratory has shown that mCPP excites non-DA (presumably GABA-containing) neurons in both the SNr and the VTA by activating 5-HT2C receptors (Di Giovanni et al. 2001). One interesting finding of that study was the differential effect exerted by mCPP on subpopulations of SNr neurons. Thus, mCPP caused a marked excitation of presumed GABA-ergic SNr projection neurons, whereas it did not affect SNr GABA-containing interneurons that exert a direct inhibitory influence on DA neurons in the substantia nigra (Di Giovanni et al. 2001). On the other hand, all non-DA neurons in the VTA were equally excited by mCPP. It is tempting to speculate that this differential response to mCPP might be the basis of the preferential inhibitory effect of 5-HT2C agonists on the mesocorticolimbic versus the nigrostriatal DA function. Other in vivo electrophysiological and neurochemical studies have confirmed and extended the above mentioned data, namely, that 5-HT exerts a direct excitatory effect on GABA-ergic neurons in the substantia nigra pars reticulata and VTA by acting on 5-HT2C receptors (Invernizzi et al. 2007; Bankson and Yamamoto 2004). In fact, about 50% of SNr neurons are excited by the selective

Fig. 11.4 Lack of effect of mCPP, MK 212, and RO 60-0175 on the firing rate of SNc DA neurons. Representative rate histograms showing the typical effects produced by i.v. administration of mCPP and MK 212 (5, 5, 10, 20, 40, 80, 160 mg/kg at arrows) and RO 60-0175 (5, 10, 20, 40, 80, 160, 320, 640 mg/kg at arrows) (Modified from Di Giovanni et al. 2000; Di Matteo et al. 1999, respectively)

Fig. 11.4 Lack of effect of mCPP, MK 212, and RO 60-0175 on the firing rate of SNc DA neurons. Representative rate histograms showing the typical effects produced by i.v. administration of mCPP and MK 212 (5, 5, 10, 20, 40, 80, 160 mg/kg at arrows) and RO 60-0175 (5, 10, 20, 40, 80, 160, 320, 640 mg/kg at arrows) (Modified from Di Giovanni et al. 2000; Di Matteo et al. 1999, respectively)

5-HT2C receptors agonist RO 60-0175, and this effect is counteracted by SB 243213; moreover, microiontophoretic application of RO 60-0175 clearly showed a direct effect of the 5-HT2C receptors on the SNr neurons, antagonized by SB 243213 (Invernizzi et al. 2007). Infusion of RO 60-0175 and mCPP by reverse dialysis significantly increased extracellular levels of GABA in the SNr (Invernizzi et al. 2007). Nevertheless, intra-VTA infusion of SB 206553 has been shown to attenuate 3,4-methylenedioxymethamphetamine (MDMA)-induced increase GABA levels in the VTA and to potentiate the concurrent increase in accumbal DA release (Bankson and Yamamoto 2004).

Fig. 11.5 Time course of the effect of i.p. administration of 1 mg/kg RO 60-0175 (■) on extracellular DA and DOPAC levels in the striatum (left column) and in the nucleus accumbens (right column). (□) Control group treated with vehicle. RO 60-0175 was administered at the time indicated by vertical arrows. Each data point represents mean percentage ± SEM of the baseline value calculated from three samples before RO 60-0175 injection. Each experiment was carried out on five animals per group. *P < 0.05, **P < 0.01 compared with control group; two-way ANOVA followed by Tukey test (Modified from reference Di Matteo et al. 1999)

Fig. 11.5 Time course of the effect of i.p. administration of 1 mg/kg RO 60-0175 (■) on extracellular DA and DOPAC levels in the striatum (left column) and in the nucleus accumbens (right column). (□) Control group treated with vehicle. RO 60-0175 was administered at the time indicated by vertical arrows. Each data point represents mean percentage ± SEM of the baseline value calculated from three samples before RO 60-0175 injection. Each experiment was carried out on five animals per group. *P < 0.05, **P < 0.01 compared with control group; two-way ANOVA followed by Tukey test (Modified from reference Di Matteo et al. 1999)

Although recent studies showed that systemic administration of 5-HT2C receptor agonists, including RO 60-0175, do not significantly decrease the activity of nigros-triatal dopaminergic neurons (Di Giovanni et al. 2000; Di Matteo et al. 1999), such treatment decreases DA efflux in the striatum (Gobert and Millan 1999; Navailles et al. 2004; Alex et al. 2005), while systemic administration of SB 206553 and SB 242084 enhance it (Porras et al. 2002; Di Giovanni et al. 2000; De Deurwaerdere and Spampinato 1999; Navailles et al. 2004). A recent study has shown that the 5-HT2C receptor inverse agonist-induced increase in accumbal and striatal DA release is insensitive to the depletion of extracellular 5-HT, suggesting that constitutive activity of the 5-HT2C receptors participates in the tonic inhibitory control that they exert upon DA release in both the nucleus accumbens and striatum (De Deurwaerdere et al. 2004). Furthermore, biochemical evidence indicates that both VTA and accumbal 5-HT2C receptors participate in the phasic inhibitory control exerted by central 5-HT2C receptors on mesoaccumbens DA neurons (Navailles et al. 2006a, 2008) and that the nucleus accumbens shell region constitutes the major site for the expression of the tonic inhibitory control involving the constitutive activity of 5-HT2C receptors (Navailles et al. 2006a). There is also evidence that 5-HT2C receptors can modulate the phasic activity of the dopaminergic nigrostriatal system. Indeed, SB 206553 has been shown to potentiate cocaine-, morphine-, and haloperidol-induced increases in DA outflow in the rat striatum (Porras et al. 2002; Navailles et al. 2004, 2006b), and systemic administration of RO 60-0175 was found to attenuate haloperidol-induced DA release in the same area (Navailles et al. 2004), as well as nicotine-induced increase in DA activity in the nigrostriatal system (Di Matteo et al. 2004; Pierucci et al. 2004).

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