Chronic treatment with fluvoxamine desensitizes 5-HT2C receptor-mediated hypolocomotion in rats

Yamauchi, Miki; Tatebayashi, Tomoko; Nagase, Kinuko; Kojima, Maho; Imanishi, Taiichiro

doi:10.1016/j.pbb.2004.05.003

Cited by 57 publications

(38 citation statements)

References 36 publications

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“…The authors suggested that 5-HT 2C receptors might be downregulated after repeated fluoxetine administration. Consistent with this hypothesis is the evidence that chronic treatment with sertraline and other SSRIss, such as sertraline, fluoxetine, fluvoxamine and citalopram, induces tolerance to the hypolocomotor effect of mCPP [168][169][170][171]. This hyposensitivity of 5-HT 2C receptors might be a key step for the achievement of an antidepressant effect.…”

Section: -Ht 2c Recptors and Depressionmentioning

confidence: 76%

Central Serotonin2C Receptor: From Physiology to Pathology

Giovanni¹,

Matteo²,

Pierucci³

et al. 2006

CTMC

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Since the 1950s, when serotonin (5-HT) was discovered in the mammalian central nervous system (CNS), an enormous amount of experimental evidence has revealed the pivotal role of this biogenic amine in a number of cognitive and behavioural functions. Although 5-HT is synthesized by a small group of neurons within the raphe nuclei of the brain stem, almost all parts of the CNS receive serotonergic projections. Furthermore, the importance of 5-HT modulation and the fine-tuning of its action is underlined by the large number of 5-HT binding sites found in the CNS. Hitherto, up to 15 different 5-HT receptors subtypes have been identified. This review was undertaken to summarize the work that has explored the pathophysiological role of one of these receptors, the 5-HT 2C receptor, that has been emerged as a prominent central serotonin receptor subtype. The physiology, pharmacology and anatomical distribution of the 5-HT 2C receptors in the CNS will be firstly reviewed. Finally, their potential involvement in the pathophysiology of depression, schizophrenia, Parkinson's disease and drug abuse will be also discussed.Keywords: Serotonergic receptors, Depression, Schizophrenia, Drug of abuse, selective 5-HT 2C drugs. BASIC ANATOMY OF 5-HT SYSTEMMore than fifty years have passed since Twarog and Page [1] isolated an indole, identified as serotonin (5-HT), in the mammalian brain. Subsequently, Brodie and colleagues [2] suggested that 5-HT might serve as a neurotransmitter in the central nervous system (CNS). The result was one of the most important discoveries in science, giving birth to a new branch of neuroscience [3]. Serotonin is one of the oldest biologically active compound on earth, found in a variety of plants and animals. In vertebrates, the majority of the neurons containing 5-HT are grouped in 9 nuclei named B1 to B9, located in the medial part of the brainstem, generically called the raphe nuclei [4] (Fig. 1). These midline clusters can be divided into two major groups. The caudal or inferior group, localized in the medulla, contains the three nuclei projecting essentially to the grey matter of the spinal cord: the nucleus raphe magnus (NRM, cell group B5), nucleus raphe obscurus (NRO, cell groups B1-B2-B3), and nucleus raphe pallidus (NRP, cell group B4). The rostral or superior group, situated in the pons/mesenchephalon, contains the dorsal raphe nucleus (DRN, cell groups B6 and B7) and the median raphe nucleus (MRN, cell group B8). These nuclei supply about 80% of the serotonergic innervation of the forebrain. Even if in many brain areas, the innervation coming from the two nuclei overlaps, in certain regions the innervation comes exclusively or prevalently from one nucleus only. For example, the dorsal hippocampus receives a serotonergic innervation only from MRN, other areas innervated preferentially from this nucleus are: the medial preoptic area, the suprachiasmatic nucleus, the olfactory bulb *Address correspondence to this author at the Istituto di Ricerche Farmacologiche "Mario Negri", Consor...

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Section: -Ht 2c Recptors and Depressionmentioning

confidence: 76%

Central Serotonin2C Receptor: From Physiology to Pathology

Giovanni¹,

Matteo²,

Pierucci³

et al. 2006

CTMC

View full text Add to dashboard Cite

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“…It has previously been reported that chronic administration of SSRIs, including paroxetine, to rodents (Kennett et al, 1994b;Maj et al, 1996;Yamauchi et al, 2004) and man (Zohar et al, 1988;Hollander et al, 1991;Quested et al, 1997) cause 5-HT 2C receptor desensitization. In the SI test, the anxiogenic effects of the 5-HT 2C receptor agonist mCPP (see Kennett et al, 1989) are inhibited by the coadministration of WAY100635 and fluoxetine for 7 days (Bristow et al, 2000) while no effect is seen with an SSRI alone.…”

Section: Discussionmentioning

confidence: 99%

SB-649915-B, a Novel 5-HT1A/B Autoreceptor Antagonist and Serotonin Reuptake Inhibitor, is Anxiolytic and Displays Fast Onset Activity in the Rat High Light Social Interaction Test

Starr

Price

Watson

et al. 2007

Neuropsychopharmacol

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Preclinically, the combination of an SSRI and 5-HT autoreceptor antagonist has been shown to reduce the time to onset of anxiolytic activity compared to an SSRI alone. In accordance with this, clinical data suggest the coadministration of an SSRI and (7) pindolol can decrease the time to onset of anxiolytic/antidepressant activity. Thus, the dual-acting novel SSRI and 5-HT 1A/B receptor antagonist, SB-649915-B, has been assessed in acute and chronic preclinical models of anxiolysis. SB-649915-B (0.1-1.0 mg/kg, i.p.) significantly reduced ultrasonic vocalization in male rat pups separated from their mothers (ED 50 of 0.17 mg/kg). In the marmoset human threat test SB-649915-B (3.0 and 10 mg/kg, s.c.) significantly reduced the number of postures with no effect on locomotion. In the rat high light social interaction (SI), SB-649915-B (1.0-7.5 mg/kg, t.i.d.) and paroxetine (3.0 mg/kg, once daily) were orally administered for 4, 7, and 21 days. Ex vivo inhibition of [ 3 H]5-HT uptake was also measured following SI. SB-649915-B and paroxetine had no effect on SI after 4 days. In contrast to paroxetine, SB-649915-B (1.0 and 3.0 mg/kg, p.o., t.i.d.) significantly (po0.05) increased SI time with no effect on locomotion, indicative of an anxiolytic-like profile on day 7. Anxiolysis was maintained after chronic (21 days) administration by which time paroxetine also increased SI significantly. 5-HT uptake was inhibited by SB-649915-B at all time points to a similar magnitude as that seen with paroxetine. In conclusion, SB-649915-B is acutely anxiolytic and reduces the latency to onset of anxiolytic behavior compared to paroxetine in the SI model.

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“…Treatment with psychedelic drugs possessing potent 5-HT 2A/2C agonist action properties appears to have favorable results on OCD patients (Moreno and Delgado, 1997;Delgado and Moreno 1998a, b;Delgado, 2000), and 5-HT 2C receptor antagonism has been suggested to play a role in the generation of obsessive-compulsive symptoms in patients with comorbid psychiatric disorder, although this effect was not reported in patients suffering from primary/ pure OCD (Khullar et al, 2001; see Sareen et al, 2004 for review). Furthermore, the 5-HT 2 antagonist ritanserin reversed the therapeutic effect of fluvoxamine (Erzegovesi et al, 1992), while studies which assessed the behavioral response to mCPP following chronic treatment with SSRIs have shown attenuated response to mCPP suggesting that chronic treatment with SSRIs leads to desensitization of 5-HT 2C receptors (Kennedy et al, 1993;Kennett et al, 1994;Maj et al, 1996;Yamauchi et al, 2004). This latter hypothesis has been strengthened from reports on 5-HT 2C downregulation following chronic treatment with SSRIs (van Oekelen et al, 2003;Serretti et al, 2004).…”

Section: Obsessive-compulsive Disorder and Reversal Learningmentioning

confidence: 95%

Dissociable Effects of Selective 5-HT2A and 5-HT2C Receptor Antagonists on Serial Spatial Reversal Learning in Rats

Boulougouris

Glennon

Robbins

2007

Neuropsychopharmacol

195

183

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Serotonin (5-hydroxytryptamine, or 5-HT) is strongly implicated in the ability to shift behavior in response to changing stimulus-reward contingencies. However, there is little information on the contribution of different 5-HT receptors in reversal learning. Thus, we investigated the effects of systemic administration of the 5-HT 2A antagonist M100907 (0, 0.01, 0.03, and 0.1 mg/kg, i.p.) and the 5-HT 2C antagonist SB 242084 (0, 0.1, 0.3, and 1.0 mg/kg, i.p.) on the performance of an instrumental two-lever spatial discrimination and serial spatial reversal learning task, where both levers were presented and only one was reinforced. The rat was required to respond on the reinforced lever under a fixed ratio 3 schedule of reinforcement. Following attainment of criterion, a series of within-session reversals was presented. Neither M100907 nor SB 242084 altered performance during spatial discrimination and retention of the previously reinforced contingencies. M100907 significantly impaired reversal learning by increasing both trials to criterion (only at the highest dose) and incorrect responses to criterion in Reversal 1, a pattern of behavior manifested as increased perseverative responding on the previously reinforced lever. In contrast, SB 242084 improved reversal learning by decreasing trials and incorrect responses to criterion in Reversal 1, with significantly fewer perseverative responses. These data support the view that 5-HT 2A and 5-HT 2C receptors have distinct roles in cognitive flexibility and response inhibition. The improved performance in reversal learning observed following 5-HT 2C receptor antagonism suggests these receptors may offer the potential for therapeutic advances in a number of neuropsychiatric disorders where cognitive deficits are a feature, including obsessive-compulsive disorder.

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Chronic treatment with fluvoxamine desensitizes 5-HT2C receptor-mediated hypolocomotion in rats

Cited by 57 publications

References 36 publications

Central Serotonin2C Receptor: From Physiology to Pathology

Central Serotonin2C Receptor: From Physiology to Pathology

SB-649915-B, a Novel 5-HT1A/B Autoreceptor Antagonist and Serotonin Reuptake Inhibitor, is Anxiolytic and Displays Fast Onset Activity in the Rat High Light Social Interaction Test

Dissociable Effects of Selective 5-HT2A and 5-HT2C Receptor Antagonists on Serial Spatial Reversal Learning in Rats

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