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Nissar A Darmani - One of the best experts on this subject based on the ideXlab platform.
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central and peripheral mechanisms contribute to the antiemetic actions of delta 9 tetrahydrocannabinol against 5 hydroxytryptophan induced emesis
2004Co-Authors: Nissar A Darmani, Jane C JohnsonAbstract:Delta-9-tetrahydrocannabinol (delta-9-THC) prevents cisplatin-induced emesis via cannabinoid CB1 receptors. Whether central and/or peripheral cannabinoid CB1 receptors account for the antiemetic action(s) of delta-9-THC remains to be investigated. The 5-hydroxytryptamine (5-HT=serotonin) precursor, 5-hydroxytryptophan (5-HTP), is an indirect 5-HT agonist and simultaneously produces the Head-Twitch response (a centrally mediated serotonin 5-HT2A receptor-induced behavior) and emesis (a serotonin 5-HT3 receptor-induced response, mediated by both peripheral and central mechanisms) in the least shrew (Cryptotis parva). The peripheral amino acid decarboxylase inhibitor, carbidopa, prevents the conversion of 5-HTP to 5-HT in the periphery and elevates 5-HTP levels in the central nervous system (CNS). When administered i.p. alone, a 50 mg/kg dose of 5-HTP failed to induce either behaviour while its 100 mg/kg dose produced robust frequencies of both Head-Twitch response and emesis. Pretreatment with carbidopa (0, 10, 20 and 40 mg/kg) potentiated the ability of both doses of 5-HTP to produce the Head-Twitch response in a dose-dependent but bell-shaped manner, with maximal potentiation occurring at 20 mg/kg carbidopa. Carbidopa dose-dependently reduced the frequency of 5-HTP (100 mg/kg)-induced emesis, whereas the 10 mg/kg dose potentiated, and the 20 and 40 mg/kg doses suppressed the frequency of vomits produced by the 50 mg/kg dose of 5-HTP. The peripheral and/or central antiemetic action(s) of delta-9-THC (0, 1, 2.5, 5, 10 and 20 mg/kg) against 5-HTP (100 mg/kg)-induced Head-Twitch response and emesis were investigated in different groups of carbidopa (0, 10 and 20 mg/kg) pretreated shrews. Irrespective of carbidopa treatment, delta-9-THC attenuated the frequency of 5-HTP-induced Head-Twitch response in a dose-dependent manner with similar ID50 values. Although delta-9-THC also reduced the frequency of 5-HTP-induced emesis with similar ID50s, at the 5 mg/kg delta-9-THC dose however, 5-HTP induced significantly less vomits in the 10 and 20 mg/kg carbidopa-treated groups relative to its 0 mg/kg control group. Moreover, increasing doses of carbidopa significantly shifted the inhibitory dose–response effect of delta-9-THC in protecting shrews from 5-HTP-induced emesis to the left. Relatively, a large dose of delta-9-THC (20 mg/kg) was required to significantly reduce the number of vomits produced by direct acting serotonergic 5-HT3 receptor agonists, serotonin and 2-methylserotonin. Low doses of delta-9-THC (0.1–1 mg/kg) nearly completely prevented 2-methylserotonin-induced, centrally mediated, Head-Twitch and ear-scratch responses. The results indicate that delta-9-THC probably acts pre- and postsynaptically to attenuate emesis produced by indirect and direct acting 5-HT3 receptor agonists via both central and peripheral mechanisms. In addition, delta-9-THC prevents 5-HTP-induced Head-Twitch and emesis via cannabinoid CB1 receptors since the CB1 receptor antagonist, SR 141716A [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide], countered the inhibitory actions of an effective dose of delta-9-THC against both behaviours.
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reversal of sr 141716a induced Head Twitch and ear scratch responses in mice by δ9 thc and other cannabinoids
2002Co-Authors: Jano J Janoyan, Jennifer L Crim, Nissar A DarmaniAbstract:Abstract Recently, we have shown that cannabinoids of diverse structure block the ability of the selective 5-HT 2A/C agonist DOI to produce the Head-Twitch response (HTR) and the ear-scratch response (ESR) in mice. The cannabinoid CB 1 antagonist/inverse agonist SR 141716A also induces these behaviors in mice. The purposes of the present study were: (1) to investigate whether Δ 9 -tetrahydrocannabinol (Δ 9 -THC) and other cannabinoids HU-210 and WIN 55, 212-2 can prevent SR 141716A-induced HTR and ESR and (2) to evaluate any correlation between the ID 50 potency order of the cited cannabinoids in blocking SR 141716A-induced HTR and ESR and their ED 50 order of potency in reducing spontaneous locomotor activity and rearing behavior. For the SR 141716A reversal study, different groups of mice were injected intraperitoneally with either vehicle or varying doses of the following cannabinoids: Δ 9 -THC (2.5–20 mg/kg), Δ 8 -THC (5-20 mg/kg), HU-210 (0.05–0.5 mg/kg), CP 55, 940 (0.5–2.5 mg/kg) and WIN 55, 212–2 (2.5–10 mg/kg). Thirty minutes later, each mouse received SR 141716A (2.5 mg/kg ip) and the frequencies of the induced behaviors (mean±S.E.M.) were recorded for the next 30 min. The effects of the cited doses of cannabinoids were also examined on spontaneous locomotor activity and rearing frequency for a 20-min duration 10 min after cannabinoid injection. The tested cannabinoids reduced the frequencies of HTR and ESR in SR 141716A-injected mice. These agents also attenuated the cited naturally occurring repertoire of motor parameters in mice. Although large potency differences were observed among the cited cannabinoids, each tested cannabinoid was relatively equipotent in preventing locomotor parameters and SR 141716A-induced behaviors. The ID 50 potency order of cannabinoids in blocking SR 141716A-induced HTR and ESR were similar (HU-210>CP 55, 940>WIN 55, 212-2≥Δ 9 -THC=Δ 8 -THC), and are comparable with: (1) their ED 50 potency order in attenuating both spontaneous locomotor activity and rearing behavior (HU-210>CP 55, 940>WIN 55, 212-2>Δ 9 -THC=Δ 8 -THC) and (2) their published ED 50 potency order for producing the tetrad of behaviors in mice as well as their rank order of binding affinities for cannabinoid CB 1 receptors. The present data show that cannabinoids of diverse structure prevent SR 141716A-induced HTR and ESR, and inhibition of these behaviors by cannabinoids could be used as a new index of cannabimimetic activity.
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nicotine attenuates doi induced Head Twitch response in mice implications for tourette syndrome
2001Co-Authors: Yousef Tizabi, Lemuel T Russell, Michael Johnson, Nissar A DarmaniAbstract:Abstract 1. Tourette syndrome (TS), a chronic neuropsychiatric disorder, is characterized by motor and vocal tics. Preliminary clinical studies indicate possible therapeutic benefits of nicotine in the treatment of Tourette's syndrome (TS). It has been proposed that Twitches of the Head in mice or Twitches of Head and shoulders in rats following administration of the selective 5HT 2A/C agonist DOI (1-)2,5-dimethoxy-4-iodophenyl-2-aminopropane, can serve as an animal model of tics in TS. 2. In this study, the effects of acute and chronic administration of nicotine on DOI-induced Head Twitch response (HTR) in male albino ICR mice were evaluated. 3. Both acute and chronic nicotine (daily injections for 10 days) reduced the DOI-induced HTR. Moreover, chronic administration of DOI (1 mg/kg/day for 10 days) resulted in 65% increase in [ 125 I]α-bungarotoxin binding in cerebellum and 41% increase in striatal [ 3 H]cytisine binding. However, the acute inhibitory effects of nicotine were not blocked by pretreatment with the nicotinic antagonist, mecamylamine. Indeed, at higher doses, mecamylamine also reduced the DOI-induced HTR. 4. The data suggest that both nicotine and mecamylamine may be of therapeutic potential in the treatment of some symptoms of TS.
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cocaine and selective monoamine uptake blockers sertraline nisoxetine and gbr 12935 prevent the d fenfluramine induced Head Twitch response in mice
1998Co-Authors: Nissar A DarmaniAbstract:Abstract Serotonin release subsequent to 5-HT precursor loading mainly occurs via exocytosis. Acute cocaine or sertraline administration promote the ability of 5-HT precursors (e.g. l -tryptophan) to induce the 5-HT2A receptor-mediated Head-Twitch response (HTR) in rodents. The 5-HT releaser, d-fenfluramine, at behaviorally active doses, can induce the Head-Twitch response in rodents by releasing cytoplasmic 5-HT via the serotonin uptake carrier working in reverse. The purpose of the present study was to utilize the d-fenfluramine–induced HTR to determine the serotonergic and nonserotonergic components of cocaine’s actions on the d-fenfluramine–sensitive pool of cytoplasmic 5-HT. Because a dramatic differential potentiation in HTR frequency is obtained when cocaine is administered prior relative to after l -tryptophan injection, the effects of varying doses of cocaine and the selective serotonin (sertraline), dopamine (DA) (GBR 12935), and norepinephrine (NE) (nisoxetine) uptake blockers were investigated on the d-fenfluramine–induced behavior in two experimental protocols. Thus, each uptake inhibitor was administered either 10 min following (protocol 1) or 10 min prior to (protocol 2) d-fenfluramine injection. All the tested uptake inhibitors attenuated the d-fenfluramine–induced HTR in a dose-dependent manner in both experimental protocols. However, their order of potency in either protocol 1 (nisoxetine > GBR 12935 > cocaine > sertraline) or protocol 2 (cocaine > GBR 12935 > nisoxetine = sertraline) does not agree with in vitro affinity of these drugs for the 5-HT transporter. In addition, the potency order for cocaine and nisoxetine in protocol 1 was significantly reversed in protocol 2. The inhibitory effects of the cited drugs on the d-fenfluramine–induced HTR are discussed in terms of: 1) high doses of selective monoamine uptake blockers may not exhibit as much selectivity for their target uptake sites as indicated by in vitro tests; and 2) possible pharmacokinetic interactions between d-fenfluramine and the monoamine uptake blockers.
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withdrawal from chronic cocaine administration causes prolonged deficits in l tryptophan induced Head Twitch response in mice
1997Co-Authors: Nissar A DarmaniAbstract:Abstract Withdrawal from chronic cocaine exposure potentiates the ability of direct 5-HT2A agonists to induce the Head-Twitch response (HTR) in rodents. This supersensitivity is assumed to be a consequence of cocaine-induced deficits in presynaptic serotonin neurochemistry. The present study utilized the HTR produced by L-tryptophan (TP) to investigate the dose- and time-response effects of cocaine-induced 5-HT deficit. Thus, different groups of mice were injected with cocaine twice daily (0, 0.1, 0.5, 2.5, 5 or 10 mg kg , i.p.) for 7 or 13 days. During HTR testing procedure, at 24 h after last chronic injection, treated-mice received either: 1) no cocaine; 2) their corresponding daily dose; or 3) a 10 mg kg dose. In paradigm 1, the frequency of TP-induced HTR was attenuated in a dose-dependent manner in both chronic cocaine regimens. In paradigm 2, small challenge doses (0.1–2.5 mg kg ) of cocaine in their respective pretreatment groups failed to alter HTR, but larger challenge doses (5 and 10 mg kg ) potentiated the behavior. In paradigm 3, the 10 mg kg challenge dose potentiated the HTR to a similar degree in both chronically exposed vehicle and various cocaine-treated groups in both treatment regimens. Extended withdrawal studies from cocaine exposure (0, 0.5 and 5 mg kg twice daily for 7 or 13 days) indicated attenuations in HTR persisted up to 96 h postcocaine abstinence in paradigm 1, whereas paradigm 2 revealed significant attenuations between 48–72 h for 0.5 mg kg dose; and potentiations for the 5 mg kg dose persisted throughout the 96 h abstinence. In paradigm 3, no significant effect was observed at 96 h abstinence, but the 10 mg kg challenge dose significantly potentiated HTR in chronically exposed 10 mg kg cocaine group 10 days following cocaine abstinence in both exposure regimens. Overall, these results support the notion that chronic cocaine exposure produces prolonged deficits in presynaptic serotonin neurochemistry. Furthermore, serotonergic mechanisms appear to be exquisitely sensitive to chronic administration of both low and high doses of cocaine.
Clinton E Canal - One of the best experts on this subject based on the ideXlab platform.
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support for 5 ht2c receptor functional selectivity in vivo utilizing structurally diverse selective 5 ht2c receptor ligands and the 2 5 dimethoxy 4 iodoamphetamine elicited Head Twitch response model
2013Co-Authors: Clinton E Canal, Raymond G Booth, Drake MorganAbstract:There are seemingly conflicting data in the literature regarding the role of serotonin (5-HT) 5-HT2C receptors in the mouse Head-Twitch response (HTR) elicited by the hallucinogenic 5-HT2A/2B/2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI). Namely, both 5-HT2C receptor agonists and antagonists, regarding 5-HT2C receptor-mediated Gq-phospholipase C (PLC) signaling, reportedly attenuate the HTR response. The present experiments tested the hypothesis that both classes of 5-HT2C receptor compounds could attenuate the DOI-elicited-HTR in a single strain of mice, C57Bl/6J. The expected results were considered in accordance with ligand functional selectivity. Commercially-available 5-HT2C agonists (CP 809101, Ro 60-0175, WAY 161503, mCPP, and 1-methylpsilocin), novel 4-phenyl-2-N,N-dimethyl-aminotetralin (PAT)-type 5-HT2C agonists (with 5-HT2A/2B antagonist activity), and antagonists selective for 5-HT2A (M100907), 5-HT2C (SB-242084), and 5-HT2B/2C (SB-206553) receptors attenuated the DOI-elicited-HTR. In contrast, there were differential effects on locomotion across classes of compounds. The 5-HT2C agonists and M100907 decreased locomotion, SB-242084 increased locomotion, SB-206553 resulted in dose-dependent biphasic effects on locomotion, and the PATs did not alter locomotion. In vitro molecular pharmacology studies showed that 5-HT2C agonists potent for attenuating the DOI-elicited-HTR also reduced the efficacy of DOI to activate mouse 5-HT2C receptor-mediated PLC signaling in HEK cells. Although there were differences in affinities of a few compounds at mouse compared to human 5-HT2A or 5-HT2C receptors, all compounds tested retained their selectivity for either receptor, regardless of receptor species. Results indicate that 5-HT2C receptor agonists and antagonists attenuate the DOI-elicited-HTR in C57Bl/6J mice, and suggest that structurally diverse 5-HT2C ligands result in different 5-HT2C receptor signaling outcomes compared to DOI.
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Head Twitch response in rodents induced by the hallucinogen 2 5 dimethoxy 4 iodoamphetamine a comprehensive history a re evaluation of mechanisms and its utility as a model
2012Co-Authors: Clinton E Canal, Drake MorganAbstract:Two primary animal models persist for assessing hallucinogenic potential of novel compounds and for examining the pharmacological and neurobiological substrates underlying the actions of classical hallucinogens, the two-lever drug discrimination procedure and the drug-induced Head-Twitch response (HTR) in rodents. The substituted amphetamine hallucinogen, serotonin 2 (5-HT2) receptor agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI) has emerged as the most popular pharmacological tool used in HTR studies of hallucinogens. Synthesizing classic, recent, and relatively overlooked findings, addressing ostensibly conflicting observations, and considering contemporary theories in receptor and behavioural pharmacology, this review provides an up-to-date and comprehensive synopsis of DOI and the HTR model, from neural mechanisms to utility for understanding psychiatric diseases. Also presented is support for the argument that, although both the two-lever drug discrimination and the HTR models in rodents are useful for uncovering receptors, interacting proteins, intracellular signalling pathways, and neurochemical processes affected by DOI and related classical hallucinogens, results from both models suggest they are not reporting hallucinogenic experiences in animals. Copyright © 2012 John Wiley & Sons, Ltd.
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the serotonin 2c receptor potently modulates the Head Twitch response in mice induced by a phenethylamine hallucinogen
2010Co-Authors: Paul J Gresch, Elaine Sandersbush, Uade Olaghere B Da Silva, Clinton E Canal, Erin E Watt, David C. AireyAbstract:Hallucinogenic serotonin 2A (5-HT2A) receptor partial agonists, such as (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI), induce a frontal cortex-dependent Head-Twitch response (HTR) in rodents, a behavioral proxy of a hallucinogenic response that is blocked by 5-HT2A receptor antagonists. In addition to 5-HT2A receptors, DOI and most other serotonin-like hallucinogens have high affinity and potency as partial agonists at 5-HT2C receptors. We tested for involvement of 5-HT2C receptors in the HTR induced by DOI. Comparison of 5-HT2C receptor knockout and wild-type littermates revealed an approximately 50% reduction in DOI-induced HTR in knockout mice. Also, pretreatment with either the 5-HT2C receptor antagonist SB206553 or SB242084 eradicated a twofold difference in DOI-induced HTR between the standard inbred mouse strains C57BL/6J and DBA/2J, and decreased the DOI-induced HTR by at least 50% in both strains. None of several measures of 5-HT2A receptors in frontal cortex explained the strain difference, including 5-HT2A receptor density, Gαq or Gαi/o protein levels, phospholipase C activity, or DOI-induced expression of Egr1 and Egr2. 5-HT2C receptor density in the brains of C57BL/6J and DBA/2J was also equivalent, suggesting that 5-HT2C receptor-mediated intracellular signaling or other physiological modulators of the HTR may explain the strain difference in response to DOI. We conclude that the HTR to DOI in mice is strongly modulated by 5-HT2C receptor activity. This novel finding invites reassessment of hallucinogenic mechanisms involving 5-HT2 receptors.
Robert R Luedtke - One of the best experts on this subject based on the ideXlab platform.
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dysregulated corticostriatal activity in open field behavior and the Head Twitch response induced by the hallucinogen 2 5 dimethoxy 4 iodoamphetamine
2017Co-Authors: Claudia Rangelbarajas, Ana Maria Estradasanchez, Scott J Barton, Robert R Luedtke, George V RebecAbstract:Abstract The substituted amphetamine, 2,5-dimethoxy-4-iodoamphetamine (DOI), is a hallucinogen that has been used to model a variety of psychiatric conditions. Here, we studied the effect of DOI on neural activity recorded simultaneously in the primary motor cortex (M1) and dorsal striatum of freely behaving FvB/N mice. DOI significantly decreased the firing rate of individually isolated neurons in M1 and dorsal striatum relative to pre-drug baseline. It also induced a bursting pattern of activity by increasing both the number of spikes within a burst and burst duration. In addition, DOI increased coincident firing between simultaneously recorded neuron pairs within the striatum and between M1 and dorsal striatum. Local field potential (LFP) activity also increased in coherence between M1 and dorsal striatum after DOI in the low frequency gamma band (30–50 Hz), while corticostriatal coherence in delta, theta, alpha, and beta activity decreased. We also assessed corticostriatal LFP activity in relation to the DOI-induced Head-Twitch response (HTR), a readily identifiable behavior used to assess potential treatments for the conditions it models. The HTR was associated with increased delta and decreased theta power in both M1 and dorsal striatum. Together, our results suggest that DOI dysregulates corticostriatal communication and that the HTR is associated with this dysregulation.
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the effect of the sigma 1 receptor selective compound ls 1 137 on the doi induced Head Twitch response in mice
2016Co-Authors: Maninder Malik, Claudia Rangelbarajas, Robert H. Mach, Robert R LuedtkeAbstract:Several receptor mediated pathways have been shown to modulate the murine Head Twitch response (HTR). However, the role of sigma receptors in the murine (±)-2,5-dimethoxy-4-iodoamphetamine (DOI)-induced HTR has not been previously investigated. We examined the ability of LS-1-137, a novel sigma-1 vs. sigma-2 receptor selective phenylacetamide, to modulate the DOI-induced HTR in DBA/2J mice. We also assessed the in vivo efficacy of reference sigma-1 receptor antagonists and agonists PRE-084 and PPCC. The effect of the sigma-2 receptor selective antagonist RHM-1-86 was also examined. Rotarod analysis was performed to monitor motor coordination after LS-1-137 administration. Radioligand binding techniques were used to determine the affinity of LS-1-137 at 5-HT2A and 5-HT2C receptors. LS-1-137 and the sigma-1 receptor antagonists haloperidol and BD 1047 were able to attenuate a DOI-induced HTR, indicating that LS-1-137 was acting in vivo as a sigma-1 receptor antagonist. LS-1-137 did not compromise rotarod performance within a dose range capable of attenuating the effects of DOI. Radioligand binding studies indicate that LS-1-137 exhibits low affinity binding at both 5-HT2A and 5-HT2C receptors. Based upon the results from these and our previous studies, LS-1-137 is a neuroprotective agent that attenuates the murine DOI-induced HTR independent of activity at 5-HT2 receptor subtypes, D2-like dopamine receptors, sigma-2 receptors and NMDA receptors. LS-1-137 appears to act as a sigma-1 receptor antagonist to inhibit the DOI-induced HTR. Therefore, the DOI-induced HTR can be used to assess the in vivo efficacy of sigma-1 receptor selective compounds.
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pharmacological modulation of abnormal involuntary doi induced Head Twitch response movements in male dba 2j mice ii effects of d3 dopamine receptor selective compounds
2015Co-Authors: Claudia Rangelbarajas, Maninder Malik, Robert H. Mach, Robert R LuedtkeAbstract:We recently reported on the characterization of the hallucinogen 2,5-dimethoxy-4-methylamphetamine's (DOI) ability to elicit a Head Twitch response (HTR) in DBA/2J mice and the ability of D2 vs. D3 dopamine receptor selective compounds to modulate that response. For these studies, the ability of D3 vs. D2 dopamine receptor selective compounds to attenuate the DOI-dependent HTR was examined. WC 10, a D3 dopamine receptor weak partial agonist with 40-fold binding selectivity for D3 vs. D2 dopamine receptors, produced a dose-dependent decrease in the DOI-induced HTR (IC50 = 3.7 mg/kg). WC 44, a D3 receptor selective full agonist, also inhibited the DOI-induced HTR (IC50 = 5.1 mg/kg). The effect of two D3 receptor selective partial agonists, LAX-4-136 and WW-III-55, were also evaluated. These analogs exhibit 150-fold and 800-fold D3 vs. D2 binding selectivity, respectively. Both compounds inhibited the HTR with similar potency but with different maximum efficacies. At 10 mg/kg WW-III-55 inhibited the HTR by 95%, while LAX-4-136 administration resulted in a 50% reduction. In addition, DOI (5 mg/kg) was administered at various times after LAX-4-136 or WW-III-55 administration to compare the duration of action. The homopiperazine analog LAX-4-136 exhibited greater stability. An assessment of our test compounds on motor performance and coordination was performed using a rotarod test. None of the D3 dopamine receptor selective compounds significantly altered latency to fall, suggesting that these compounds a) did not attenuate the DOI-dependent HTR due to sedative or adverse motor effects and b) may have antipsychotic/antihallucinogenic activity.
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pharmacological modulation of abnormal involuntary doi induced Head Twitch response in male dba 2j mice i effects of d2 d3 and d2 dopamine receptor selective compounds
2014Co-Authors: Claudia Rangelbarajas, Maninder Malik, Suwanna Vangveravong, Robert H. Mach, Robert R LuedtkeAbstract:Abstract Because of the complexity and heterogeneity of human neuropsychiatric disorders, it has been difficult to identify animal models that mimic the symptoms of these neuropathologies and can be used to screen for antipsychotic agents. For this study we selected the murine 5HT2A/2C receptor agonist-induced Head Twitch response (HTR) induced by the administration of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), which has been proposed as an animal model of symptoms associated with a variety of behavioral and psychiatric conditions. We investigated the DOI-induced HTR in male DBA/2J mice using a panel of D2-like (D2, D3 and D4) and D2 dopamine receptor selective compounds. When DBA/2J mice were administered a daily dose of DOI (5 mg/kg), tolerance to the DOI occurs. However, administrations of the same dose of DOI every other day (48 h) or on a weekly basis did not lead to tolerance and the ability to induce tolerance after daily administration of DOI remains intact after repeated weekly administration of DOI. Subsequently, a panel of D2-like dopamine receptor antagonists was found to effectively inhibit the DOI-induced HTR in DBA/2J mice. However, the benzamide eticlopride, which is a high affinity D2-like antagonist, was a notable exception. SV 293, SV-III-130s and N-methylbenperidol, which exhibit a high affinity for D2 versus the D3 dopamine receptor subtypes (60- to 100-fold binding selectivity), were also found to inhibit the HTR in DBA/2J mice. This observation suggests a functional interaction between dopaminergic and serotonergic systems through D2 dopamine receptors and the 5-HT2A serotonin receptors in vivo.
Junzo Kamei - One of the best experts on this subject based on the ideXlab platform.
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involvement of diazepam insensitive benzodiazepine receptors in the suppression of doi induced Head Twitch responses in diabetic mice
2006Co-Authors: Shigeo Miyata, Shoko Hirano, Junzo KameiAbstract:Rationale We previously reported that the Head-Twitch responses induced by the 5-HT2 receptor agonist (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) (DOI-HTRs) were decreased in streptozotocin-induced diabetic mice.
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involvement of diazepam insensitive benzodiazepine receptors in the suppression of doi induced Head Twitch responses in diabetic mice
2006Co-Authors: Shigeo Miyata, Shoko Hirano, Junzo KameiAbstract:We previously reported that the Head-Twitch responses induced by the 5-HT2 receptor agonist (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) (DOI-HTRs) were decreased in streptozotocin-induced diabetic mice. We examined the involvement of γ-aminobutyric acid (GABA)/benzodiazepine system on the suppression of DOI-HTRs in diabetic mice. The benzodiazepine receptor antagonist flumazenil (0.1–1 mg/kg, i.v.) dose-dependently and significantly increased DOI-HTRs in diabetic mice to the same levels as in nondiabetic mice. However, flumazenil (0.1–1 mg/kg, i.v.) did not affect DOI-HTRs in nondiabetic mice. The benzodiazepine receptor agonist diazepam (0.1–1 mg/kg, i.p.) had no effect on DOI-HTRs in either nondiabetic or diabetic mice. The GABAA receptor antagonist bicuculline (0.1–1 mg/kg, i.p.) and the benzodiazepine receptor partial inverse agonist Ro 15-4513 (0.1–1 mg/kg, i.v.) dose-dependently and significantly suppressed DOI-HTRs in nondiabetic mice to the same levels as in diabetic mice. Ro 15-4513-induced reduction of DOI-HTRs in nondiabetic mice was completely antagonized by flumazenil (1 mg/kg, i.v.), but not diazepam (0.3 mg/kg, i.p.). We suggest that the abnormal diazepam-insensitive benzodiazepine receptor function partly underlies the suppression of DOI-HTRs in diabetic mice.
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Diabetes inhibits the DOI-induced Head-Twitch response in mice.
2004Co-Authors: Shigeo Miyata, Shoko Hirano, Junzo KameiAbstract:Clinical studies suggest that the prevalence of psychiatric disorders is higher in diabetic patients than in the general population. It has been reported that central serotonin(2A) (5-HT(2A)) receptors may be involved in the pathogenesis and treatment of psychiatric disorders. We examined the effect of streptozotocin-induced diabetes on the function of central 5-HT(2A) receptors in mice. Male ICR mice were rendered diabetic by an injection of streptozotocin (200 mg/kg, i.v.). The experiments were conducted 2 weeks after the injection of streptozotocin. To evaluate the central 5-HT(2A) receptor function, Head-Twitch responses were measured for 15 min immediately after the treatment with (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI) (0.1-1 mg/kg, s.c.), a selective 5-HT(2) receptor agonist. Significantly fewer Head-Twitch responses were induced by DOI in diabetic mice than in non-diabetic mice. The number and affinity of 5-HT(2A) receptors in the mouse frontal cortex were not affected by diabetes. The corticosterone response to DOI (1 mg/kg and 3 mg/kg, s.c.) was not different between non-diabetic and diabetic mice, although the baseline of plasma corticosterone levels was significantly higher in diabetic than in non-diabetic mice. Our results suggest that a neuronal network that causes Head-Twitch responses by triggering by the activation of 5-HT(2A) receptors may be altered by type-1 diabetes in mice.
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diabetes inhibits the doi induced Head Twitch response in mice
2004Co-Authors: Shigeo Miyata, Shoko Hirano, Junzo KameiAbstract:Rationale Clinical studies suggest that the prevalence of psychiatric disorders is higher in diabetic patients than in the general population. It has been reported that central serotonin2A (5-HT2A) receptors may be involved in the pathogenesis and treatment of psychiatric disorders.
Takeshi Tadano - One of the best experts on this subject based on the ideXlab platform.
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Enhanced Head-Twitch response to 5-HT-related agonists in thiamine-deficient mice
2007Co-Authors: Osamu Nakagawasai, A. Ohba, Kazuo Wakui, S. Mitazaki, A. Murata, Fukie Niijima, Y. Arai, Takeshi TadanoAbstract:While many studies suggest an involvement of brain serotonergic systems in neuro-psychiatric disorders such as schizophrenia and depression, their role in Wernicke-Korsakoff syndrome (WKS) remains unclear. Since dietary thiamine deficiency (TD) in mice is considered as a putative model of WKS, it was used in the present study to investigate the function of serotonergic neurons in this disorder. After 20 days of TD feeding, the intensity of tryptophan hydroxylase immunofluorescence was found to be significantly decreased in the dorsal and medial raphe nuclei. In addition, the Head-Twitch response (HTR) elicited by the intracerebroventricular administration of the 5-HT_2A agonist 2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) was significantly increased in TD versus control mice, whereas the injection of ketanserin, a 5-HT_2A receptor antagonist, prevented this enhancement. A single injection of thiamine HCl on the 19th day of TD feeding did not reduce the enhanced DOI-induced HTR. On the other hand, the administration of d-fenfluramine, a 5-HT releaser, did not enhance the HTR in TD mice. Together, our results indicate that TD causes a super-sensitivity of 5-HT_2A receptors by reducing presynaptic 5-HT synthesis derived from degenerating neurons projecting from the raphe nucleus.
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monoamine oxidase and Head Twitch response in mice mechanisms of α methylated substrate derivatives
2004Co-Authors: Osamu Nakagawasai, Masashi Hozumi, Shinetsu Satoh, Mitsuro Neda, Hajime Hiraga, Yuichiro Arai, Nobunori Satoh, Takeshi TadanoAbstract:Abstract It is well known that Head-Twitch response (HTR) in mice represents hallucinations, since administration of lysergic acid diethylamide (LSD) produces hallucinations in humans, and the HTR in mice is induced by administration of LSD as a hallucinogen. The HTR is produced by excitation of 5-hydroxytryptamine (5-HT)2A receptors. In this paper, we review the mechanisms of HTR induced by various drugs such as 5-HT precursor, 5-HT receptor agonist, 5-HT releaser, hallucinogenic compounds, benzodiazepins and cannabinoid. The response induced by HTR-inducers is significantly enhanced by combined treatment with a non-selective form of monoamine oxidase (MAO) inhibitor. Thus, the relationship between MAO activity and HTR caused by these drugs (especially, α-methylated analogous compounds which 5-fluoro-α-methyltryptamine, 6-fluoro-α-methyltryptamine and p-hydroxyamphetamine) is presented in detail.
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enhancement of 5 hydroxytryptamine induced Head Twitch response after olfactory bulbectomy
2003Co-Authors: Osamu Nakagawasai, Yuichiro Arai, Kensuke Kisara, Soichi Hozumi, Hajime Yasuhara, Koichi Tanno, Takeshi Tadano, Lars OrelandAbstract:Abstract 5-Hydroxytryptamine 2A receptor agonists evoke the Head-Twitch response in mice. The Head-Twitch response in olfactory bulbectomized mice elicited by the administration of 5-hydroxytryptamine (40 μg/mouse, i.c.v.) was increased about threefold as compared with controls on the 14th day after the operation. The injection of ketanserin (1 mg/kg, i.p.), a 5-hydroxytryptamine 2A receptor antagonist, inhibited this enhancement of 5-hydroxytryptamine-induced Head-Twitch response after olfactory bulbectomized. On the 14th day, the number of Head-Twitch response induced by 5-hydroxytryptophan (40, 80 and 160 mg/kg, i.p.), a precursor of 5-hydroxytryptamine, did not differ between olfactory bulbectomized and control mice. Monoamine oxidase-B activity in the forebrain of olfactory bulbectomized mice was higher than that in controls while monoamine oxidase-A activities were unchanged. The 5-hydroxytryptamine uptake into synaptosomes in the forebrain homogenates of olfactory bulbectomized mice was lower than that in controls. These findings indicate that olfactory bulbectomized causes the enhancement of Head-Twitch response by a supersensitivity of 5-hydroxytryptamine 2A receptors in cerebral cortex derived from degeneration of neurons projecting from the olfactory bulb.
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suppressive effect of nantenine isolated from nandina domestica thunberg on the 5 hydroxy l tryptophan plus clorgyline induced Head Twitch response in mice
2002Co-Authors: Bachtiar Indra, Yuichiro Arai, Hajime Yasuhara, Osamu Nakagawasai, Yasushi Ohizumi, Takeshi Tadano, Kensuke KisaraAbstract:Abstract We investigated the effects of nantenine (9,10-Methylenedioxy-1, 2 dimethoxyaporphine), a major alkaloid isolated from the fruit of Nandina domestica Thunb (Berberidaceae), on the 5-HT 2A receptor-mediated Head-Twitch response (HTR) in mice. Intraperitoneal (i.p.) injection of nantenine (13.3, 20 and 30 mg/kg) as well as the 5-HT 2A receptor antagonist ketanserin (0.0625, 0.25 and 1 mg/kg) inhibited the 5-hydroxy-L-tryptophan ( l -5-HTP; 75 mg/kg, i.p.) plus monoamine oxidase inhibitor, clorgyline (1 mg/kg, i.p.)-induced HTR in a dose-dependent manner. In contrast, neither l -5-HTP plus clorgyline nor 5-HT 1A agonist, 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT; 5 μg/mouse, i.c.v.)-induced Head weaving was affected by nantenine or ketanserin. Furthermore, neither nantenine (up to 30 mg/kg) nor ketanserin (up to 1 mg/kg) affect on the locomotor activity. In the receptor binding studies, nantenine showed affinity to the 5-HT 2A receptors ( K i = 0.4 μM), while it had less affinity toward α 1 -adrenergic ( K i = 2.1 μM) and D 2 -dopaminergic ( K i = 1.7 μM) receptors of the mouse brain. These results suggest that nantenine inhibits l -5-HTP plus clorgyline-induced Head-Twitch response by blocking 5-HT 2A receptors in the central nervous system.
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central serotonergic mechanisms on Head Twitch response induced by benzodiazepine receptor agonists
2001Co-Authors: Takeshi Tadano, Masashi Hozumi, Takanori Hishinuma, Hiroyasu Kinemuchi, Yuichiro Arai, Nobunori Satoh, Hajime Yasuhara, Michinao Mizugaki, Fukie Niijima, Osamu NakagawasaiAbstract:Intraperitoneal injection of benzodiazepine receptor agonists (estazolam, zopiclone, triazolam: 0.03–0.24 mmol/kg) induces the Head Twitch response (HTR). The present study was undertaken to examine t
