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      Genotype-Dependent Difference in 5-HT 2C Receptor-Induced Hypolocomotion: Comparison with 5-HT 2A Receptor Functional Activity

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          Abstract

          In the present study behavioral effects of the 5-HT 2C serotonin receptor were investigated in different mouse strains. The 5-HT 2C receptor agonist MK-212 applied intraperitoneally induced significant dose-dependent reduction of distance traveled in the open field test in CBA/Lac mice. This effect was receptor-specific because it was inhibited by the 5-HT 2C receptor antagonist RS102221. To study the role of genotype in 5-HT 2C receptor-induced hypolocomotion, locomotor activity of seven inbred mouse strains was measured after MK-212 acute treatment. We found that the 5-HT 2C receptor stimulation by MK-212 decreased distance traveled in the open field test in CBA/Lac, C57Bl/6, C3H/He, and ICR mice, whereas it failed to affect locomotor activity in DBA/2J, Asn, and Balb/c mice. We also compared the interstrain differences in functional response to 5-HT 2C and 5-HT 2A receptors activation measured by the quantification of receptor-mediated head-twitches. These experiments revealed significant positive correlation between 5-HT2C and 5-HT2A receptors functional responses for all investigated mouse strains. Moreover, we found that 5-HT 2A receptor activation with DOI did not change locomotor activity in CBA/Lac mice. Taken together, our data indicate the implication of 5-HT 2C receptors in regulation of locomotor activity and suggest the shared mechanism for functional responses mediated by 5-HT 2C and 5-HT 2A receptors.

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          Most cited references75

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          Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior.

          Hallucinogens, including mescaline, psilocybin, and lysergic acid diethylamide (LSD), profoundly affect perception, cognition, and mood. All known drugs of this class are 5-HT(2A) receptor (2AR) agonists, yet closely related 2AR agonists such as lisuride lack comparable psychoactive properties. Why only certain 2AR agonists are hallucinogens and which neural circuits mediate their effects are poorly understood. By genetically expressing 2AR only in cortex, we show that 2AR-regulated pathways on cortical neurons are sufficient to mediate the signaling pattern and behavioral response to hallucinogens. Hallucinogenic and nonhallucinogenic 2AR agonists both regulate signaling in the same 2AR-expressing cortical neurons. However, the signaling and behavioral responses to the hallucinogens are distinct. While lisuride and LSD both act at 2AR expressed by cortex neurons to regulate phospholipase C, LSD responses also involve pertussis toxin-sensitive heterotrimeric G(i/o) proteins and Src. These studies identify the long-elusive neural and signaling mechanisms responsible for the unique effects of hallucinogens.
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            Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission.

            The neurotransmitter dopamine (DA) has a long association with normal functions such as motor control, cognition, and reward, as well as a number of syndromes including drug abuse, schizophrenia, and Parkinson's disease. Studies show that serotonin (5-HT) acts through several 5-HT receptors in the brain to modulate DA neurons in all 3 major dopaminergic pathways. There are at least fourteen 5-HT receptor subtypes, many of which have been shown to play some role in mediating 5-HT/DA interactions. Several subtypes, including the 5-HT1A, 5-HT1B, 5-HT2A, 5-HT3 and 5-HT4 receptors, act to facilitate DA release, while the 5-HT2C receptor mediates an inhibitory effect of 5-HT on DA release. Most 5-HT receptor subtypes only modulate DA release when 5-HT and/or DA neurons are stimulated, but the 5-HT2C receptor, characterized by high levels of constitutive activity, inhibits tonic as well as evoked DA release. This review summarizes the anatomical evidence for the presence of each 5-HT receptor subtype in dopaminergic regions of the brain and the neuropharmacological evidence demonstrating regulation of each DA pathway. The relevance of 5-HT receptor modulation of DA systems to the development of therapeutics used to treat schizophrenia, depression, and drug abuse is discussed. Lastly, areas are highlighted in which future research would be maximally beneficial to the treatment of these disorders.
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              Serotonin 5-HT(2C) receptors regulate anxiety-like behavior.

              Central serotonin (5-hydroxytryptamine, 5-HT) systems have been implicated in the pathophysiology and treatment of anxiety disorders, which are among the world's most prevalent psychiatric conditions. Here, we report that the 5-HT(2C) receptor (5-HT(2C)R) subtype is critically involved in regulating behaviors characteristic of anxiety using male 5-HT(2C)R knockout (KO) mice. Specific neural substrates underlying the 5-HT(2C)R KO anxiolytic phenotype were investigated, and we report that 5-HT(2C)R KO mice display a selective blunting of extended amygdala corticotropin-releasing hormone neuronal activation in response to anxiety stimuli. These findings illustrate a mechanism through which 5-HT(2C)Rs affect anxiety-related behavior and provide insight into the neural circuitry mediating the complex psychological process of anxiety.
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                Author and article information

                Journal
                Neural Plast
                Neural Plast
                NP
                Neural Plasticity
                Hindawi Publishing Corporation
                2090-5904
                1687-5443
                2015
                26 August 2015
                : 2015
                : 846589
                Affiliations
                1Institute of Cytology and Genetics, Siberian Division of Russian Academy of Sciences, Novosibirsk 630090, Russia
                2Cellular Neurophysiology, Hannover Medical School, 30625 Hannover, Germany
                Author notes

                Academic Editor: Michel Baudry

                Article
                10.1155/2015/846589
                4563107
                26380122
                94725f8d-a97a-4c07-9bf3-1bab30449a63
                Copyright © 2015 Darya V. Bazovkina et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 12 March 2015
                : 9 August 2015
                Categories
                Research Article

                Neurosciences
                Neurosciences

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