Efficacy of 5HT2C Antagonists Alone and in Combination with SSRIs in Clinical Treatment of Depression

Several compounds that are clinically effective antidepressants are potent 5-HT2C antagonists (Millan 2006). Nefazodone, trazodone, and remeron all block 5-HT2C receptors however, their pharmacological profile also encompasses blockade of 5-HT2A receptors as well as histamine 1 and alpha 2 receptors (Hyttel 1982). Agomelatonine is a potent 5-HT2C antagonist that has been shown to be effective in treatment of major depression. However, this compound also activates melatonin receptors, which...

Heterodimerization Splice Variants and Isoforms

Splice variants, lacking the full complement of TMDs, have been described for many different GPCR. These truncated receptors have been reported to have a dominant negative effect on wild-type receptor function through dimerization, resulting in trapping of wild-type receptors in the ER (Benkirane et al. 1997 Karpa et al. 2000 Grosse et al. 1997). Therefore, heterodimerization between wild-type receptors and splice variants may play an important role in normal physiological regulation of...

Mutant Mice2C

Central serotonergic systems have long been appreciated to have key roles in the regulation of feeding and body weight (for review, see Lam and Heisler 2007 Nelson and Gehlert 2006 Heisler et al. 2003). Studies of mutant mice with functional alterations of 5-HT2CR activity have elucidated some of the mechanisms underlying this important regulation. In the hypothalamus, 5-HT2CRs are prominently expressed on POMC-containing neurons of the ventrolateral arcuate nucleus (Wright et al. 1995...

Nicotine

The pharmacological actions and physiological effects of nicotine are complex. It is widely accepted that the reinforcing effects of nicotine are mediated in part by interactions between nicotinic acetylcholine receptors (nAChRs), GABA, glutamate, and DA in the VTA (for reviews, see Markou 2008 Di Matteo et al. 2007). A major neurochemical event that is involved in the behavioral effects of nicotine, including locomotor activity and reinforcement, is indirect activation of mesolimbic DA neurons...

Effects of Typical and Atypical Antipsychotics on Sleep in Schizophrenia Patients

Typical and atypical antipsychotic drugs bind to a wide variety of CNS receptors including the 5-HT2A and 5-HT2C receptors. Thus, it seems pertinent to analyze the effects of antipsychotic drugs on sleep variables and the mechanisms involved in their actions on sleep and W. It should be noted that Monti and Monti (2004) and Winokur and Kamath (2008) have provided detailed reviews of work carried out in this area. Our analysis will be limited to the effects on sleep variables of the typical...

Drugs of Abuse

Substantial evidence indicates that the mesolimbic pathway, particularly the dopaminergic system innervating accumbal areas, is implicated in the reward value of both natural and drug reinforcers, such as sexual behavior or psychostimulants, respectively (Koob 1992 Di Chiara and Imperato 1988 Salamone et al. 2007 Spanagel and Weiss 1999). The fact that drugs of abuse act through different cellular mechanisms leads to the possibility that their effects on DA release could be modulated...

HT Receptors Feeding Behavior and Body Weight in Rodents

5ht2c Receptor Alzheimer

The role of 5-HT in the control of appetite on the structure of rodent feeding behavior were first examined in a series of studies using the 5-HT releasing and reuptake-inhibiting drug fenfluramine (Blundell 1977). Fenfluramine produced reductions in caloric intake that corresponded to changes in feeding behavior normally brought about by ingestion, rather than hyperactivity, sedation, or malaise. Measurements Fig. 17.1 Functional divergence in 5-HT2C receptor pathway. Serotonin (5-HT) inhibits...

Effects of 5HT2C Inverse Agonists in Animal Models of Psychosis

There are three commonly used models for antipsychotic activity blockade of conditioned avoidance response, antagonism of locomotor activity produced by amphetamine or the N-methyl-d-asparate (NMDA)-receptor antagonists, phencyclidine (PCP) or MK-801, and blockade of the disruption of prepulse inhibition by indirect or direct DA agonists or NMDA receptor antagonists. Atypical and typical antipsy-chotic drugs are active in all these models, with atypical antipsychotic drugs, apparently because...

References

Aita VM, Liu J, Knowles JA, et al (1999) A comprehensive linkage analysis of chromosome 21q22 supports prior evidence for a putative bipolar affective disorder locus. Am J Hum Genet 64 210-217. Amore M, Strippoli P, Laterza C, et al (2004) Sequence analysis of ADARB1 gene in patients with familial bipolar disorder. J Affect Disord 81 79-85. Bass BL (2002) RNA editing by adenosine deaminases that act on RNA. Annu Rev Biochem 71 817-846. Berg KA, Clarke WP, Sailstad C, et al (1994) Signal...

Therapeutic Potential of 5HT2C Receptor Drugs for Reward Related Behavioral Problems

Pharmaceutical research into the identification of subtype selective 5-HT2C agonists has been an ongoing effort since the mid-1990s, driven largely by the potential of such drugs to treat obesity (Nilsson 2006). This has not been an immediately successful enterprise, largely because of the high sequence homology between the 5-HT2A, 5-HT2B, and 5-HT2C receptor subtypes (Hoyer et al. 2002 Barnes and Sharp 1999) and the negative impact of direct 5-HT2A and 5-HT2B receptor activation. The...

Dysregulated Function of Mesoaccumbal and Nigrostriatal Dopamine Systems in 5HT2CR Mutant Mice

Nucleus Accumbens

5-HT2CR mRNA is prominently expressed in the striatum (Str) and nucleus accumbens (NAc) (Eberle-Wang et al. 1997), two subcortical regions vital for coordinating many important behaviors such as motor program selection and responses to appetitive stimuli. The Str and NAc also play vital roles in how the phenotypes of Parkinson's disease and substance abuse, two highly morbid and difficult-to-treat clinical conditions, are expressed. Studies of basal ganglia physiology and behavior in 5-HT2CR...

Introduction

From an evolutionary perspective, reinforcement of natural stimulation that enhances survival or the perpetuation of genes (such as food and sex) would be beneficial to the continuation of the species. The system of conditioning through reward and gratification remains one of the most fundamental examples of such reinforcement. However, there is a small fraction of pharmacological substances that possess the ability to abnormally intensify this reward function in the brain, known as drugs of...

WAY 163969 A 5HT2C Agonist Treatment for Schizophrenia

The 5-HT2C-selective receptor agonist, WAY-163909 12 1,4 diazepino 12 indole ,was reported to be active in various animal models of schizophrenia (Marquis et al. 2007). At doses of 1.7-30 mg kg IP, it decreased apomorphine-induced climbing and behaved like an atypical in that it did not cause catalepsy. Similar to 5-HT2A antagonists, e.g., M100907, WAY 163909 (0.3-3 mg kg subcutaneous SC ) was reported to be more effective in inhibiting PCP-induced locomotor activity than d-amphetamine with no...

Serotonergic Modulation of Cortical Neuronal Excitability

Serotonin, by activating different receptor subtypes, regulates membrane excitability in the central nervous system in a complex manner (Andrade 1998). The involvement of various voltage-gated ion channels in this action of serotonin receptors has been demonstrated (Carr et al. 2002 Colino and Halliwell 1987 Haj-Dahmane and Andrade 1996 Penington and Kelly 1990). However, application of a low concentration of a 5-HT1A or 5-HT2A 2C agonist alone fails to alter the action potential firing...

Homodimer Biogenesis

There are several lines of evidence suggesting that GPCR dimerization occurs prior to receptor expression on the plasma membrane. The most notable example involves heterodimerization of class C GABAbR1 and GABAbR2 receptors, which has been demonstrated to be essential for receptor trafficking from the ER to the plasma membrane (Jones et al. 1998 Kaupmann et al. 1998 White et al. 1998 Margeta-Mitrovic et al. 2000). Dimerization has been proposed as a general mechanism necessary for proper...

Features of Prader Willi Syndrome

Prader-Willi syndrome is a congenital disease with an incidence of about 1 in 8,000 to 20,000 live births. Prader-Willi syndrome is the most common genetic cause of marked obesity in humans. The excess weight causes type II diabetes as a major complication. This makes PWS the most frequent genetic cause for type II diabetes (Butler et al. 2006). Early PWS is characterized by a failure to thrive, feeding difficulties and hypogonadism. Later, the patients are characterized by short stature and...

Constitutive Activity of 5HT2C Receptors In vitro Consideration and Pharmacology

The constitutive activity of seven-transmembrane receptor is a concept now widely accepted and well characterized in heterologous recombinant systems in vitro Costa and Herz 1989 Milligan et al. 1995 Berg et al. 2001 Kenakin 2001, 2004 . The capacity of this receptor to regulate cellular signaling systems in the absence of occupancy by a ligand could be considered as an artificial property as it depends on the density of the receptor at cell surface and the total absence of the endogenous...

Role of 5HT2A and 5HT2C Receptors in the Regulation of the Behavioral State

Several approaches have been followed to characterize the role of the 5-HT2A and 5-HT2C receptors in the regulation of sleep and W. They include Table 20.1 Distribution of the 5-HT2A receptor in rat brain From Mengod et al. 1990 Abramowski et al. 1995 Duxon et al. 1997 Cornea-Hebert et al. 1999 Clemett et al. 2000 Frontal Parietal Occipital Piriform Olfactory bulb Medial and lateral septal nuclei Hippocampal formation Amygdala Nucleus of the diagonal band of Broca Ventral pallidum Nucleus...

Role of 5HT2C Receptors in the Regulation of Monoamine Neurotransmission

It is well established that monoamine systems play a central role in pathophysio-logy of affective disorders and in antidepressant response Monoamine neurons densely innervate the limbic areas of the brain, modulate behavioral and emotional Brains On-Line BV, Groningen, The Netherlands e-mail e.dremencov brainsonline.org Brains On-Line US LLC, San-Francisco, CA, USA e-mail thomas.cremers brainsonline.org G. Di Giovanni et al. eds. , 5-HT2C Receptors in the Pathophysiology of CNS Disease, 249...

HT2C Effects on Factors Influencing Learning Processes 2451 Anxiety

The 5-HT2 receptor family seems to be particularly involved in anxiety because several drugs effective for the treatment of anxiety disorders interact with this type of receptor Mora et al. 1997 Peroutka 1995 . Mora et al. 1997 tested mCPP, ritanserin and propen-1-yl phenol hemifumarate SR-463496A , a selective 5-HT2A 2C receptor antagonist Rinaldi-Carmona et al. 1992 on two types of fear. The authors used a paradigm in which the same rat in one experimental session was exposed to two types of...