Attenuation of haloperidol‐induced catalepsy by a 5‐HT<sub>2C</sub> receptor antagonist

Reavill, C.; Kettle, Anthony J.; Holland, Vicky; Riley, Graham J.; Blackburn, T.P.

doi:10.1038/sj.bjp.0702350

Cited by 126 publications

(72 citation statements)

References 12 publications

(13 reference statements)

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“…However, a concern is that dopaminergic suppression via 5-HT 2C agonism in the mesocortical pathway could potentially worsen cognition, 22 whereas, in the nigrostriatal pathway the same action might cause EPS. [23][24][25] On the other hand, 5-HT 2C antagonism at inhibitory gamma-aminobutyric acid (GABA) interneurons in the brain stem may be expected to reduce depression and improve cognition by disinhibiting dopamine and norepinephrine release in the prefrontal cortex. 2,26 Receptors associated with weight gain are H 1 histamine receptors and 5-HT 2C receptors in the hypothalamus.…”

Section: -Ht 2c : Agonist or Antagonist?mentioning

confidence: 99%

Building a Better Antipsychotic: Receptor Targets for the Treatment of Multiple Symptom Dimensions of Schizophrenia

Kim¹,

Maneen²,

Stahl

2009

Neurotherapeutics

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Summary: Attempts to develop selective ("magic bullet") drugs for the treatment of schizophrenia have been frustrated by the complex etiology of the disease. The symptomatology of schizophrenia does not appear to arise from a single neurobiological entity, but rather may be derived from pathology at one or more receptor types. This has prompted multifactorial approaches to the development of new therapeutics, as embodied by polypharmacy and an alternative (or augmentative) strategy known as "intramolecular polypharmacy," in which a single drug possesses the capacity to affect multiple receptor types.Atypical antipsychotics are a well-known example of this approach; each atypical possesses a unique portfolio of activities at receptors that may contribute to therapeutic effects (as well as side effects). In this article we present a discussion of some of the receptor targets that are currently thought to mediate symptoms of schizophrenia, as well as their possible implications for the design of future multifunctional antipsychotics.

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Section: -Ht 2c : Agonist or Antagonist?mentioning

confidence: 99%

Building a Better Antipsychotic: Receptor Targets for the Treatment of Multiple Symptom Dimensions of Schizophrenia

Kim¹,

Maneen²,

Stahl

2009

Neurotherapeutics

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“…Behavioural studies with SB 228537, a selective 5-HT 2B/2C receptor antagonist and using selective 5-HT 2A and 5-HT 2B receptor antagonists as controls indicate that 5-HT 2C receptor antagonism can produce a significant reversal of haloperidolinduced catalepsy [197]. However, not all atypical APDs are 5-HT 2C receptor antagonists, for example, risperidone [181].…”

Section: -Ht 2c Recptors and Schizophreniamentioning

confidence: 99%

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 receptor antagonism may confer on antipsychotic drugs atypicality with relatively weaker D2 receptor antagonism (or partial D2 receptor agonism) because of the ability of 5-HT2A receptors to differentially modulate the activity of dopaminergic neurones depending on regions of the brain. Furthermore, some evidences suggest that the combination of 5-HT2A and 5-HT2C receptor blockade may be a more efficient means to augment antipsychotic action than either alone (Reavill et al, 1999;Meltzer et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

YKP1447, A Novel Potential Atypical Antipsychotic Agent

Dong

Heo

et al. 2009

Korean J Physiol Pharmacol

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(S)-Carbamic acid 2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-1-phenyl-ethyl ester hydrochloride (YKP1447) is a novel "atypical" antipsychotic drug which selectively binds to serotonin (5-HT2A, Ki=0.61 nM, 5-HT2C, Ki=20.7 nM) and dopamine (D2, Ki=45.9 nM, D3, Ki=42.1 nM) receptors with over 10∼ 100-fold selectivity over the various receptors which exist in the brain. In the behavioral studies using mice, YKP1447 antagonized the apomorphine-induced cage climbing (ED50=0.93 mg/kg) and DOI-induced head twitch (ED50=0.18 mg/kg) behavior. In the dextroamphetamine-induced hyperactivity and conditioned avoidance response (CAR) paradigm in rats, YKP1447 inhibited the hyperactivity induced by amphetamine (ED50=0.54 mg/kg) and the avoidance response (ED50=0.48 mg/kg); however, unlike other antipsychotic drugs, catalepsy was observed only at much higher dose (ED50=68.6 mg/kg). Based on the CAR and catalepsy results, the therapeutic index (TI) value for YKP1447 is over 100 (i.p.). These results indicate that YKP1447 has an atypical profile and less undesirable side effects than currently available drugs.

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Attenuation of haloperidol‐induced catalepsy by a 5‐HT_2C receptor antagonist

Cited by 126 publications

References 12 publications

Building a Better Antipsychotic: Receptor Targets for the Treatment of Multiple Symptom Dimensions of Schizophrenia

Building a Better Antipsychotic: Receptor Targets for the Treatment of Multiple Symptom Dimensions of Schizophrenia

Central Serotonin2C Receptor: From Physiology to Pathology

YKP1447, A Novel Potential Atypical Antipsychotic Agent

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Attenuation of haloperidol‐induced catalepsy by a 5‐HT2C receptor antagonist

Cited by 126 publications

References 12 publications

Building a Better Antipsychotic: Receptor Targets for the Treatment of Multiple Symptom Dimensions of Schizophrenia

Building a Better Antipsychotic: Receptor Targets for the Treatment of Multiple Symptom Dimensions of Schizophrenia

Central Serotonin2C Receptor: From Physiology to Pathology

YKP1447, A Novel Potential Atypical Antipsychotic Agent

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Product

Resources

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Attenuation of haloperidol‐induced catalepsy by a 5‐HT_2C receptor antagonist