Although dopamine has received little attention in biological research on depression, as compared with other monoamines such as serotonin and noradrenaline, current research on the dopaminergic system is about to change this situation. It is now well established that disturbances of mesolimbic and nigrostriatal DA function are involved in the pathophysiology of depression (Fibiger 1995; Brown and Gershon 1993). Moreover, stress promotes profound and complex alterations involving DA release, metabolism, and receptor densities in the mesolimbic system (Puglisi-Allegra et al. 1991; Cabib and Puglisi-Allegra 1996). It seems that exposure to unavoidable/uncontrollable aversive experiences leads to inhibition of DA release in the mesoaccumbens DA system as well as impaired responding to rewarding and aversive stimuli. These alterations could elicit stress-induced expression and exacerbation of some depressive symptoms in humans (Cabib and Puglisi-Allegra 1996). Thus, in view of the hypothesis that disinhibition of the mesocorticolimbic DA system underlies the mechanism of action of several antidepressant drugs (Cervo and Samanin 1987; Cervo and Samanin 1988; Cervo et al. 1990; D'Aquila et al. 2000; Di Matteo et al. 2000b, c), the disinhibitory effect of SB 206553 and SB 242084 on the mesolimbic DA system might open new possibilities for the employment of 5-HT2C receptor antagonists as antidepressants (Di Matteo et al. 1998, 1999, 2000b, c, 2001). This hypothesis is consistent with the suggestion that 5-HT2C receptor blockers might exert antidepressant activity (Jenck et al. 1998; Di Matteo et al. 2000b, 2001; Giorgetti and Tecott 2004; Baxter et al. 1995). In this respect, it is interesting to note that several antidepressant drugs have been shown to bind with submicromolar affinity to 5-HT2C receptors in the pig brain and to antagonize mCPP-induced penile erections in rats, an effect mediated through the stimulation of central 5-HT2C receptors (Jenck et al. 1993, 1994, 1998). Based on those findings, Di Matteo et al. (2000c) have carried out experiments showing that acute administration of amitriptyline and mianserin, two antidepressants with high affinity for 5-HT2C receptors, enhances DA release in the rat nucleus accumbens by blocking these receptor subtypes, in addition to their other pharmacological properties. Interestingly, ami-triptyline and mianserin have been tested in the chronic mild stress-induced anhedo-nia model of depression and were found to be effective in reversing the stress effects (Sampson et al. 1991; Moreau et al. 1994). The antianhedonic effects of tricyclic antidepressants, mianserin, and fluoxetine were abolished by pretreatment with D2/ D3 receptor antagonists, thus indicating an involvement of DA in the antidepressant effect of various drugs in this model (Sampson et al. 1991; Willner 1995). The ability of antidepressants, such as tricyclics, selective serotonin reuptake inhibitors (SSRIs), and mianserin, to affect DA systems via indirect mechanisms was also reported by studies of Tanda et al. (1994, 1996), suggesting that potentiation of DA release in the rat cortex may indicate its role in the therapeutic action of antidepres-sants. The chronic mild stress procedure, which induces a depression-like state in animals, was shown to enhance 5-HT2C receptor-mediated function, as measured in vivo by mCPP-induced penile erections. In contrast, two different antidepressant treatments [72-h rapid eye movement (REM) sleep deprivation and 10-day administration of moclobemide, a reversible inhibitor of monoamine oxidase type A] resulted in a reduction of this 5-HT2C receptor-mediated function (Moreau et al. 1993). This was interpreted as an indication that the 5-HT2C receptor may be altered and presumably may exist in a dysregulated (hypersensitive) state in depressive illness. Thus, adaptive processes resulting from chronic antidepressant treatment (i.e., desensitization and/or downregulation of 5-HT2C receptors) may play an important role in reversing the 5-HT2C receptor system supersensitivity resulting from a depressive state (Jenck et al. 1998; Moreau et al. 1996).
In contrast to most other receptors, 5-HT2C is not classically regulated. Indeed, 5-HT2C receptors appear to decrease their responsiveness not only upon chronic agonist stimulation but also, paradoxically, after chronic treatment with antagonists (Van Oekelen et al. 2003; Serretti et al. 2004). This mechanism appears to be related to an internalization process that removes activated cell surface receptors from the plasma membrane involving a phosphorylation step and possible degradation in lysosomes (Van Oekelen et al. 2003). As a large number of psychotropic drugs, including atypical antipsychotics, antidepressants, and anxiolytics, can all induce downregulation of 5-HT2C receptors, it has been suggested that this receptor adaptation plays a role in the therapeutic action of these drugs (Van Oekelen et al. 2003; Serretti et al. 2004). In this respect, it is interesting to note that chronic treatment with 5-HT2 agonists or antagonists resulted in a paradoxical downregulation at the 5-HT2A and 5-HT2C receptors (Moreau et al. 1996; Van Oekelen et al. 2003; Serretti et al. 2004; Barker and Sanders-Bush 1993; Pranzatelli et al. 1993; Newton and Elliott 1997), and it seems that the downregulation state occurring after chronic exposure to mianserin in isolated systems as well as in cell cultures is a direct receptor-mediated mechanism of this drug at these receptors (Newton and Elliott 1997). Therefore, the downregulating capacity of 5-HT2C agonists and antagonists may play a particularly important role in treating the supersensitivity of 5-HT2C receptors resulting from a depressive state (Jenck et al. 1998; Moreau et al. 1996; Serretti et al. 2004).
The possible involvement of 5-HT2C receptors in the pathogenesis of depressive disorders and in the mode of action of antidepressants is further substantiated by several other observations. For example, acute administration of fluoxetine caused a dose-dependent inhibition of the firing rate of VTA DA neurons (Prisco and Esposito 1995) and a decreased DA release in both the nucleus accumbens and the striatum (Ichikawa and Meltzer 1995), but it did not affect the activity of DA cells in the SNc (Prisco and Esposito 1995). A similar effect, though less pronounced, has been observed with citalopram (Prisco and Esposito 1995). Furthermore, mesu-lergine, an unselective 5-HT2C receptor antagonist (Boess and Martin 1994), as well as the lesion of 5-HT neurons by the neurotoxin 5,7-DHT, prevented fluoxetine-induced inhibition of VTA DA cells (Prisco and Esposito 1995). These results indicate that fluoxetine inhibits the mesolimbic DA pathway by enhancing the extracellular level of 5-HT, which would act through 5-HT2C receptors (Prisco and Esposito 1995). This study also demonstrated that fluoxetine-induced inhibition of DA neurons in the VTA was no longer observed after chronic treatment (21 days) with this drug. Interestingly, mCPP inhibited the firing activity of VTA DA neurons in control animals but not in those chronically treated with fluoxetine (Prisco and Esposito 1995). The authors suggested that 5-HT2C receptors might be downregu-lated after repeated fluoxetine administration. Consistent with this hypothesis is the evidence that chronic treatment with sertraline and citalopram, two SSRIs, induces tolerance to the hypolocomotor effect of mCPP (Maj and Moryl 1992).
This hyposensitivity of 5-HT2C receptors might be a key step for the achievement of an antidepressant effect. Indeed, it is possible to argue that the acute inhibitory effect of fluoxetine on mesolimbic DA system would mask its clinical efficacy in the early stage of treatment. This masking effect disappears when the hyposensitivity of 5-HT2C receptors occurs. A series of studies carried out in our laboratory has shown that acute administration of SSRIs such as paroxetine, sertraline, and fluvoxamine causes a slight but significant decrease in the basal firing rate of VTA DA neurons (Di Mascio et al. 1998). Therefore, it is conceivable that, similar to fluoxetine, these SSRIs could reduce mesocorticolimbic DA transmission by activating 5-HT2C receptors. Furthermore, employing complementary electrophysiological and neurochemical approaches and both acute and chronic administration routes, it was found that mirtazapine, nefazodone, and agomela-tine, three effective and innovative antidepressants, elicit a robust and pronounced enhancement in the activity of mesocorticolimbic DA pathways. These actions were ascribed to their antagonistic properties at inhibitory, tonically active 5-HT2C receptors that desensitize after repeated drug administration (Millan et al. 2000, 2003; Dremencov et al. 2005). Interestingly, agomelatine has shown antidepressant efficacy in clinical trials (Loo et al. 2002; Pandi-Perumal et al. 2006; Zupancic and Guilleminault 2006), and indeed, it was found to be effective in treating severe depression associated with anxiety symptoms, with a better toler-ability and lower adverse effects than other antidepressants such as paroxetine (Loo et al. 2002). Likewise, the novel benzourea derivative S32006 showed potent 5-HT2C receptor antagonistic properties, enhanced the activity of mesocor-tical dopaminergic and adrenergic projections, displaying a broad-based profile of antidepressant properties upon acute and/or repeated administration, and exhibited both rapid and sustained anxiolytic actions (Dekeyne et al. 2008).
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