5-HT2A and 5-HT2C receptors and their atypical regulation properties

Oekelen, Dirk Van; Luyten, Walter; Leysen, Josée E.

doi:10.1016/s0024-3205(03)00141-3

Cited by 202 publications

(114 citation statements)

References 131 publications

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“…This may signify either that drugs of abuse possess a yet unknown common property necessary to induce uncoupling or that non-addictive antidepressants, or their metabolites, exhibit intrinsic pharmacological characteristics, which limit noradrenergic and/or serotonergic transmission. For example, concomitant anti-a1-adrenergic or 5-HT 2A and 5-HT 2C antagonist or agonist properties (Dekeyne and Millan, 2003;Van Oekelen et al, 2003) may block the development of uncoupling and behavioral sensitization. It is also possible that noradrenergic and serotonergic neurons sensitization only occurs following short and intense repeated stimulations of a1b-adrenergic and 5-HT 2A receptors, whereas antidepressants induce only slow and moderate increase in noradrenergic and serotonergic transmissions.…”

Section: Discussionmentioning

confidence: 99%

Drugs of Abuse Specifically Sensitize Noradrenergic and Serotonergic Neurons Via a Non-Dopaminergic Mechanism

Lanteri

Salomon

Torrens

et al. 2007

Neuropsychopharmacol

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A challenge in drug dependence is to delineate long-term neurochemical modifications induced by drugs of abuse. Repeated damphetamine was recently shown to disrupt a mutual regulatory link between noradrenergic and serotonergic neurons, thus inducing long-term increased responses to d-amphetamine and para-chloroamphetamine, respectively. We show here that such a sensitization of noradrenergic and serotonergic neurons also occurs following repeated treatment with cocaine, morphine, or alcohol, three compounds belonging to main groups of addictive substances. In all cases, this sensitization is prevented by a1b-adrenergic and 5-HT 2A receptors blockade, indicating the critical role of these receptors on long-term effects of drugs of abuse. However, repeated treatments with two non-addictive antidepressants, venlafaxine, and clorimipramine, which nevertheless inhibit noradrenergic and serotonergic reuptake, do not induce noradrenergic and serotonergic neurons sensitization. Similarly, this sensitization does not occur following repeated treatments with a specific inhibitor of dopamine (DA) reuptake, GBR12783. Moreover, we show that the effects of SCH23390, a D1 receptor antagonist known to inhibit development of d-amphetamine behavioral sensitization, are due to its 5-HT 2C receptor agonist property. SCH23390 blocks amphetamine-induced release of norepinephrine and RS102221, a 5-HT 2C antagonist, can reverse this inhibition as well as inhibition of noradrenergic sensitization and development of behavioral sensitization induced by repeated damphetamine. We propose that noradrenergic/serotonergic uncoupling is a common neurochemical consequence of repeated consumption of drugs of abuse, unrelated with DA release. Our data also suggest that compounds able to restore the link between noradrenergic and serotonergic modulatory systems could represent important therapeutic targets for investigation.

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Section: Discussionmentioning

confidence: 99%

Drugs of Abuse Specifically Sensitize Noradrenergic and Serotonergic Neurons Via a Non-Dopaminergic Mechanism

Lanteri

Salomon

Torrens

et al. 2007

Neuropsychopharmacol

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“…Specifically, the findings that serotonin reuptake inhibitors are effective in alleviating obsessions and compulsions in patients have directed much attention to the involvement of the serotonergic system in OCD (for review see Sasson and Zohar, 1996;Stein, 2000), with more recent studies implicating specific serotonin receptors (most notably 5-HT1a, 5-HT2a, and 5-HT2c) in the pathophysiology of OCD and in the response to treatment (for review see El Mansari and Blier, 2006;Goddard et al, 2008;Van Oekelen et al, 2003). Abnormalities of the dopaminergic system have been implicated in OCD on the basis of several lines of clinical and preclinical evidence (for review see Denys et al, 2004), including changes in OC symptoms following the administration of amphetamine and cocaine to OCD patients (Insel et al, 1983;Leonard and Rapoport, 1987;McDougle et al, 1989), and the surplus therapeutic benefits obtained with co-administration of SSRIs and dopaminergic blockers (McDougle et al, 1994;Sasson and Zohar, 1996;Saxena et al, 1996).…”

Section: Ofc Lesionmentioning

confidence: 99%

The Role of the Striatum in Compulsive Behavior in Intact and Orbitofrontal-Cortex-Lesioned Rats: Possible Involvement of the Serotonergic System

Schilman

Klavir

Winter

et al. 2010

Neuropsychopharmacol

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In the signal attenuation rat model of obsessive-compulsive disorder (OCD), 'compulsive' behavior is induced by attenuating a signal indicating that a lever-press response was effective in producing food. We have recently found that lesions to the rat orbitofrontal cortex (OFC) led to an increase in compulsive lever-pressing that was prevented by systemic administration of the selective serotonin reuptake inhibitor paroxetine, and paralleled by an increase in the density of the striatal serotonin transporter. This study further explored the interaction between the OFC, the striatum, and the serotonergic system in the production of compulsive lever-pressing. Experiment 1 revealed that OFC lesions decrease the content of serotonin, dopamine, glutamate, and GABA in the striatum. Experiment 2 showed that intrastriatal administration of paroxetine blocked OFC lesion-induced increased compulsivity, but did not affect compulsive responding in intact rats. Experiments 3 and 4 found that pre-training striatal lesions had no effect on compulsive lever-pressing, whereas post-training striatal inactivation exerted an anticompulsive effect. These results strongly implicate the striatum in the expression of compulsive lever-pressing in both intact and OFC-lesioned rats. Furthermore, the results support the possibility that in a subpopulation of OCD patients a primary pathology of the OFC leads to a dysregulation of the striatal serotonergic system, which is manifested in compulsive behavior, and that antiobsessional/anticompulsive drugs exerts their effects, in these patients, by normalizing the dysfunctional striatal serotonergic system.

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“…may represent a possible therapeutic target for the development of drugs for a range of CNS disorders such as schizophrenia, depression, drug abuse, eating disorders, Parkinson's disease and epilepsy [30][31][32][33]. In fact, 5-HT 2 receptors are major targets for a wide array of psychoactive drugs, ranging from non-classical antipsychotic drugs, anxiolytics and anti-depressants, which have a 5-HT 2 antagonistic action, to hallucinogens, which are agonists of the 5-HT 2 receptors [34][35][36][37]. Furthermore, recently it has been shown that 5-HT 2 receptors have a potential significance in brain development [38], and in experiencedependent plasticity in the visual cortex [39].…”

Section: -Ht 2 Familymentioning

confidence: 99%

“…Studies focusing on the regulation of the 5-HT 2 receptor family have also indicated that 5-HT 2 receptors are non-classically regulated. Indeed, 5-HT 2 receptor responsiveness is not only decreased following chronic agonist exposure but also, paradoxically, after chronic treatment with antagonists such as antipsychotic compounds [37].…”

Section: -Ht 2 Familymentioning

confidence: 99%

“…This mechanism appears to be related to an internalisation process that removes activated cell surface receptors from the plasma membrane involving a phosphorylation step and possible degradation in lysosomes [37]. As a large number of psychotropic drugs, including atypical antipsychotics, antidepressants, and anxiolitics, can all induce down-regulation of 5-HT 2C receptors, it has been suggested that this alteration plays a role in the therapeutic action of these drugs [35,37].…”

Section: -Ht 2c Receptor Structure Signal Trans-duction and Pharmacmentioning

confidence: 99%

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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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5-HT2A and 5-HT2C receptors and their atypical regulation properties

Cited by 202 publications

References 131 publications

Drugs of Abuse Specifically Sensitize Noradrenergic and Serotonergic Neurons Via a Non-Dopaminergic Mechanism

Drugs of Abuse Specifically Sensitize Noradrenergic and Serotonergic Neurons Via a Non-Dopaminergic Mechanism

The Role of the Striatum in Compulsive Behavior in Intact and Orbitofrontal-Cortex-Lesioned Rats: Possible Involvement of the Serotonergic System

Central Serotonin2C Receptor: From Physiology to Pathology

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