Central Serotonergic Mechanisms on Head Twitch Response Induced by Benzodiazepine Receptor Agonists

Tadano, Takeshi; Hozumi, Masato; Satoh, Nobunori; Oka, Ryusho; Hishinuma, Takanori; Mizugaki, Michinao; Arai, Yasuhiko; Yasuhara, Hajime; Kinemuchi, Hiroyasu; Niijima, Fukie; Nakagawasai, Osamu; Tan-No, Koichi; Kisara, Kensuke

doi:10.1159/000056089

Cited by 8 publications

(4 citation statements)

References 20 publications

(34 reference statements)

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“…For example, we have shown previously that PKCγ regulates ethanol-stimulated GABA A receptor function in cortex (Harris et al, 1995). It has been shown that GABAergic drugs modulate head twitch behavior in rodents, perhaps through interaction with 5-HT 2 receptors (Handley and Singh, 1985;Moser and Redfern, 1988;Tadano et al, 2001). Feng et al (2001) reported that activation of 5-HT 2 receptors in the prefrontal cortex of rats increased in vitro PKC activity toward GABA A receptor γ 2 subunits.…”

Section: Behavioral Assessments Of 5ht 2a/c Receptorsmentioning

confidence: 97%

Regulation of 5-HT2A/C receptors and DOI-induced behaviors by protein kinase Cγ

Bowers

Miyamoto‐Ditmon

Wehner

2006

Pharmacology Biochemistry and Behavior

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Protein kinase C γ (PKCγ) null mutant mice demonstrate increased behavioral impulsivity and ethanol consumption. Pharmacological studies have shown that 5-HT 2A/C receptors modulate impulsivity and ethanol consumption in rodents and that PKC can regulate 5-HT 2A/C receptors. To determine whether PKCγ plays a selective role in 5-HT 2A/C receptor regulation, biochemical and behavioral experiments were performed in PKCγ mutant and wild-type mice. DOI-stimulated phosphoinositol hydrolysis and [ 125 I]-DOI saturation binding in the PFC, and quantitative autoradiography of [ 125 I]-DOI binding sites in 15 brain regions were analyzed. DOI-induced head twitch responses (HTR) were measured in naïve mice after an acute 2.5 mg/kg injection of DOI. Results indicated that DOI-induced HTR was significantly greater in mutant mice compared to wildtype mice. Results of the phosphoinositol hydrolysis, membrane binding, and autoradiography experiments indicated that in mutant mice, increased HTR was associated with increased 5-HT 2A/C receptor function in the PFC, but not increased receptor number or affinity suggesting that PKCγ regulates receptor function but not receptor number. These data support a role for 5-HT 2A/C receptors in the PFC in mediating some of the behavioral differences observed between PKCγ mutant and wild-type mice.

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Section: Behavioral Assessments Of 5ht 2a/c Receptorsmentioning

confidence: 97%

Regulation of 5-HT2A/C receptors and DOI-induced behaviors by protein kinase Cγ

Bowers

Miyamoto‐Ditmon

Wehner

2006

Pharmacology Biochemistry and Behavior

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“…Nevertheless, there is little evidence to support using the HTR as an animal model of hallucinations or of mental states that are directly relevant to schizophrenia. For example, many non-hallucinogenic compounds that increase 5-HT release and indirectly activate the 5-HT 2A receptor, including d-fenfluramine (Darmani, 1997) and even some benzodiazepines (Tadano et al, 2001), can induce the HTR. Furthermore, although many antipsychotics can block the hallucinogen-induced HTR due to their 5-HT 2A antagonist activity, selective 5-HT 2A antagonists such as M100,907 have only limited efficacy as antipsychotics when administered to schizophrenia patients.…”

Section: Introductionmentioning

confidence: 99%

Serotonergic hallucinogens as translational models relevant to schizophrenia

Halberstadt

Geyer

2013

International Journal of Neuropsychopharmacology

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One of the oldest models of schizophrenia is based on the effects of serotonergic hallucinogens such as mescaline, psilocybin, and (+)-lysergic acid diethylamide (LSD), which act through the serotonin 5-HT2A receptor. These compounds produce a “model psychosis” in normal individuals that resembles at least some of the positive symptoms of schizophrenia. Based on these similarities, and because evidence has emerged that the serotonergic system plays a role in the pathogenesis of schizophrenia in some patients, animal models relevant to schizophrenia have been developed based on hallucinogen effects. Here we review the behavioral effects of hallucinogens in four of those models, the receptor and neurochemical mechanisms for the effects, and their translational relevance. Despite the difficulty of modeling hallucinogen effects in nonverbal species, animal models of schizophrenia based on hallucinogens have yielded important insights into the linkage between 5-HT and schizophrenia and have helped to identify receptor targets and interactions that could be exploited in the development of new therapeutic agents.

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“…Most importantly, selective 5-HT 2A antagonists block the HTR induced by DOI and other hallucinogens (Schreiber et al, 1995; Fantegrossi et al, 2005, 2006, 2008, 2010), and hallucinogens do not induce the HTR in 5-HT 2A knockout mice (Gonzalez-Maeso et al, 2003, 2007; Keiser et al, 2009; Halberstadt et al, 2011). Although phencyclidine (Nabeshima et al, 1987), benzodiazepines (Tadano et al, 2001), the CB 1 antagonist SR 14176A (Darmani and Pandya, 2000), the 5-HT 1A antagonist WAY-100635 (Darmani, 1998), and thyrotropin-releasing hormone analogs (Fone et al, 1989) induce the HTR, these effects are blocked by 5-HT 2A receptor antagonists. Because of this specificity, this behavior has been widely adopted as an animal behavioral assay for 5-HT 2A activation and hallucinogen-like effects.…”

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confidence: 99%

Characterization of the head-twitch response induced by hallucinogens in mice

2013

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Rationale The head-twitch response (HTR) is a rapid side-to-side rotational head movement that occurs in rats and mice after administration of serotonergic hallucinogens and other 5-HT2A agonists. The HTR is widely used as a behavioral assay for 5-HT2A activation and to probe for interactions between the 5-HT2A receptor and other transmitter systems. Objective High-speed video recordings were used to analyze the head movement that occurs during head twitches in C57BL/6J mice. Experiments were also conducted in C57BL/6J mice to determine whether a head-mounted magnet and a magnetometer coil could be used to detect the HTR induced by serotonergic hallucinations based on the dynamics of the response. Results Head movement during the HTR was highly rhythmic and occurred within a specific frequency range (mean reciprocation frequency of 90.3 Hz). Head twitches produced wave-like oscillations of magnetometer coil voltage that matched the frequency of head movement during the response. The magnetometer coil detected the HTR induced by the serotonergic hallucinogens 2,5-dimethoxy-4-iodoamphetamine (DOI; 0.25, 0.5, and 1.0 mg/kg, IP) and lysergic acid diethylamide (LSD; 0.05, 0.1, 0.2, and 0.4 mg/kg, IP) with extremely high sensitivity and specificity. Magnetometer coil recordings demonstrated that the non-hallucinogenic compounds (+)-amphetamine (2.5 and 5.0 mg/kg, IP) and lisuride (0.8, 1.6, and 3.2 mg/kg, IP) did not induce the HTR. Conclusions These studies confirm that a magnetometer coil can be used to detect the HTR induced by hallucinogens. The use of magnetometer-based HTR detection provides a high-throughput, semi-automated assay for this behavior, and offers several advantages over traditional assessment methods.

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Central Serotonergic Mechanisms on Head Twitch Response Induced by Benzodiazepine Receptor Agonists

Cited by 8 publications

References 20 publications

Regulation of 5-HT2A/C receptors and DOI-induced behaviors by protein kinase Cγ

Regulation of 5-HT2A/C receptors and DOI-induced behaviors by protein kinase Cγ

Serotonergic hallucinogens as translational models relevant to schizophrenia

Characterization of the head-twitch response induced by hallucinogens in mice

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