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Herbert Y Meltzer - One of the best experts on this subject based on the ideXlab platform.
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5 ht2a and d2 receptor blockade increases cortical da release via 5 ht1a receptor activation a possible mechanism of atypical antipsychotic induced cortical dopamine release
Journal of Neurochemistry, 2001Co-Authors: Junji Ichikawa, Hideo Ishii, Stefania Bonaccorso, Wiley L Fowler, Ian A Olaughlin, Herbert Y MeltzerAbstract:Atypical antipsychotic drugs (APDs), all of which are relatively more potent as serotonin (5-HT)2A than dopamine D2 Antagonists, may improve negative symptoms and cognitive dysfunction in schizophrenia, in part, via increasing cortical dopamine release. 5-HT1A agonism has been also suggested to contribute to the ability to increase cortical dopamine release. The present study tested the hypothesis that clozapine, olanzapine, risperidone, and perhaps other atypical APDs, increase dopamine release in rat medial prefrontal cortex (mPFC) via 5-HT1A receptor activation, as a result of the blockade of 5-HT2A and D2 receptors. M100907 (0.1 mg/kg), a 5-HT2A antagonist, significantly increased the ability of both S(–)-sulpiride (10 mg/kg), a D2 antagonist devoid of 5-HT1A affinity, and R(+)-8-OH-DPAT (0.05 mg/kg), a 5-HT1A agonist, to increase mPFC dopamine release. These effects of M100907 were abolished by WAY100635 (0.05 mg/kg), a 5-HT1A antagonist, which by itself has no effect on mPFC dopamine release. WAY100635 (0.2 mg/kg) also reversed the ability of clozapine (20 mg/kg), olanzapine (1 mg/kg), risperidone (1 mg/kg), and the R(+)-8-OH-DPAT (0.2 mg/kg) to increase mPFC dopamine release. Clozapine is a direct acting 5-HT1A partial agonist, whereas olanzapine and risperidone are not. These results suggest that the atypical APDs via 5-HT2A and D2 receptor blockade, regardless of intrinsic 5-HT1A affinity, may promote the ability of 5-HT1A receptor stimulation to increase mPFC DA release, and provide additional evidence that coadministration of 5-HT2A Antagonists and typical APDs, which are D2 Antagonists, may facilitate 5-HT1A agonist activity.
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direct injection of 5 ht2a receptor agonists into the medial prefrontal cortex produces a head twitch response in rats
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: David L Willins, Herbert Y MeltzerAbstract:The serotonin (5-HT)2A/2c agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), the 5-HT2C agonist 6-chloro-2-[1-piperazinyl]-pyrazine and the 5-HT2A partial agonist m-chloro-phenylpiperazine (mCPP) were injected bilaterally into the medial prefrontal cortex of male rats. DOI and mCPP, but not 6-chloro-2-[1-piperazinly]-pyrazine, elicited a dose-dependent head-twitch response (HTR). DOI-induced HTR had an ED50 of 12.8 nmoles/0.5 μl/side and was inhibited by the 5-HT2A Antagonists ketanserin and MDL 100,907 but was not blocked by pretreatment with the selective 5-HT2C/2B antagonist SDZ SER 082. The HTR to mCPP demonstrated a bell-shaped dose-response curve with an ED50of 1.5 nmoles/0.5 μl/side and a peak effect after 3 nmoles/side. The response to mCPP was greatly diminished by both ketanserin and MDL 100,907 and was partially reversed by SDZ SER 082. These findings suggest that the HTR produced by the direct injection of serotonergic agonists into the medial prefrontal cortex is, in part, mediated by the activation of 5-HT2A receptors. Pretreatment of rats with the 5-HT1A agonist (±)-8-hydroxy-dipropylaminotetralin hydrobromide inhibited the HTR to DOI. This is consistent with other evidence that suggests a functional antagonism between 5-HT1A and 5-HT2A receptor activation. The HTR to DOI was potentiated by the novel 5-HT1A selective antagonist WAY 100,635, which suggests that 5-HT1Areceptors tonically regulate this behavioral response to stimulation of cortical 5-HT2A receptors.
Bryan L. Roth - One of the best experts on this subject based on the ideXlab platform.
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evidence for the preferential involvement of 5 ht2a serotonin receptors in stress and drug induced dopamine release in the rat medial prefrontal cortex
Neuropsychopharmacology, 2006Co-Authors: Elizabeth A Pehek, Bryan L. Roth, Christine Nocjar, Tara A Byrd, Omar S MabroukAbstract:The mechanism(s) by which serotonin modulates dopamine release in the medial prefrontal cortex is not known, although studies suggest an involvement of 5-HT2 family receptors. We employed in vivo microdialysis and putatively selective 5-HT2A Antagonists (M100907, MDL 11,939, SR46349B) to determine if 5-HT2A receptors are responsible for both drug- and stress-induced DA release in the medial prefrontal cortex. MDL 11,939 and SR46349B receptor-binding studies indicated, for the first time, that only MDL 11,939 had greater selectivity for the 5-HT2A vs the 5-HT2C receptor subtypes similar to M100907, and that both showed low or no affinity for non-5-HT2 receptors. Reverse dialysis with 5-HT2A Antagonists had little or no effect on basal dopamine efflux. However, intracortical administration of MDL 11,939 or M100907 attenuated dopamine release induced by systemic administration of the 5-HT2 agonist DOI. Dual-probe microdialysis demonstrated that systemic DOI also increased glutamate concentrations in the ventral tegmental area (VTA). This was blocked by intracortical M100907. Cortical perfusion with M100907, or the atypical antipsychotic drug risperidone, but not the 5-HT2B/C ligand SB 206553, also decreased dopamine release induced physiologically by stress. These results indicate that stimulation of cortical 5-HT2A receptors increases the release of dopamine from the mesocortical system. They suggest that this effect may be mediated by increases in glutamate release from corticotegmental projections to the VTA. Additionally, they indicate that cortical 5-HT2A receptors modulate evoked dopamine release, such as that observed physiologically following mild stress. These findings may have implications for the pharmacological treatment of disorders resulting from or exacerbated by stress.
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Serotonergic Antagonist Effects on Trafficking of Serotonin 5‐HT2A Receptors in Vitro and in Vivoa
Annals of the New York Academy of Sciences, 1998Co-Authors: David L Willins, L. Alsayegh, Sally A. Berry, Jon R. Backstrom, Elaine Sanders-bush, Lee Friedman, Naseem Khan, Bryan L. RothAbstract:: The mechanism by which Antagonists down-regulate 5-HT2A receptors is unknown. We here report that a variety of 5-HT2A Antagonists induce a change in the subcellular distribution of 5-HT2A receptors both in vitro and in vivo. In a stably transfected NIH 3T3 cell-line, brief exposure to 1 μM clozapine caused a 2.5-fold increase in intracellular 5-HT2A-like immunoreactivity, as measured by confocal microscopy. Confirmatory studies utilizing a biotin-trap technique, demonstrated that the increase in intracellular immunoreactivity results from internalization of receptor from the cell surface. Exposure of transfected cells to other 5-HT2A receptor Antagonists produced similar increases in intracellular 5-HT2A-like immunoreactivity. In vivo administration of clozapine (20 mg/kg, sc, ×7 days) caused a greater than twofold increase in intracellular immunoreactivity in cell bodies of cortical pyramidal neurons. Additionally, chronic clozapine administration was associated with a decrease in labeling of apical dendrites on pyramidal cells. These results show that clozapine causes a change in subcellular distribution of 5-HT2A receptors in vitro and in vivo.
Omar S Mabrouk - One of the best experts on this subject based on the ideXlab platform.
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evidence for the preferential involvement of 5 ht2a serotonin receptors in stress and drug induced dopamine release in the rat medial prefrontal cortex
Neuropsychopharmacology, 2006Co-Authors: Elizabeth A Pehek, Bryan L. Roth, Christine Nocjar, Tara A Byrd, Omar S MabroukAbstract:The mechanism(s) by which serotonin modulates dopamine release in the medial prefrontal cortex is not known, although studies suggest an involvement of 5-HT2 family receptors. We employed in vivo microdialysis and putatively selective 5-HT2A Antagonists (M100907, MDL 11,939, SR46349B) to determine if 5-HT2A receptors are responsible for both drug- and stress-induced DA release in the medial prefrontal cortex. MDL 11,939 and SR46349B receptor-binding studies indicated, for the first time, that only MDL 11,939 had greater selectivity for the 5-HT2A vs the 5-HT2C receptor subtypes similar to M100907, and that both showed low or no affinity for non-5-HT2 receptors. Reverse dialysis with 5-HT2A Antagonists had little or no effect on basal dopamine efflux. However, intracortical administration of MDL 11,939 or M100907 attenuated dopamine release induced by systemic administration of the 5-HT2 agonist DOI. Dual-probe microdialysis demonstrated that systemic DOI also increased glutamate concentrations in the ventral tegmental area (VTA). This was blocked by intracortical M100907. Cortical perfusion with M100907, or the atypical antipsychotic drug risperidone, but not the 5-HT2B/C ligand SB 206553, also decreased dopamine release induced physiologically by stress. These results indicate that stimulation of cortical 5-HT2A receptors increases the release of dopamine from the mesocortical system. They suggest that this effect may be mediated by increases in glutamate release from corticotegmental projections to the VTA. Additionally, they indicate that cortical 5-HT2A receptors modulate evoked dopamine release, such as that observed physiologically following mild stress. These findings may have implications for the pharmacological treatment of disorders resulting from or exacerbated by stress.
David L Willins - One of the best experts on this subject based on the ideXlab platform.
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Serotonergic Antagonist Effects on Trafficking of Serotonin 5‐HT2A Receptors in Vitro and in Vivoa
Annals of the New York Academy of Sciences, 1998Co-Authors: David L Willins, L. Alsayegh, Sally A. Berry, Jon R. Backstrom, Elaine Sanders-bush, Lee Friedman, Naseem Khan, Bryan L. RothAbstract:: The mechanism by which Antagonists down-regulate 5-HT2A receptors is unknown. We here report that a variety of 5-HT2A Antagonists induce a change in the subcellular distribution of 5-HT2A receptors both in vitro and in vivo. In a stably transfected NIH 3T3 cell-line, brief exposure to 1 μM clozapine caused a 2.5-fold increase in intracellular 5-HT2A-like immunoreactivity, as measured by confocal microscopy. Confirmatory studies utilizing a biotin-trap technique, demonstrated that the increase in intracellular immunoreactivity results from internalization of receptor from the cell surface. Exposure of transfected cells to other 5-HT2A receptor Antagonists produced similar increases in intracellular 5-HT2A-like immunoreactivity. In vivo administration of clozapine (20 mg/kg, sc, ×7 days) caused a greater than twofold increase in intracellular immunoreactivity in cell bodies of cortical pyramidal neurons. Additionally, chronic clozapine administration was associated with a decrease in labeling of apical dendrites on pyramidal cells. These results show that clozapine causes a change in subcellular distribution of 5-HT2A receptors in vitro and in vivo.
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direct injection of 5 ht2a receptor agonists into the medial prefrontal cortex produces a head twitch response in rats
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: David L Willins, Herbert Y MeltzerAbstract:The serotonin (5-HT)2A/2c agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), the 5-HT2C agonist 6-chloro-2-[1-piperazinyl]-pyrazine and the 5-HT2A partial agonist m-chloro-phenylpiperazine (mCPP) were injected bilaterally into the medial prefrontal cortex of male rats. DOI and mCPP, but not 6-chloro-2-[1-piperazinly]-pyrazine, elicited a dose-dependent head-twitch response (HTR). DOI-induced HTR had an ED50 of 12.8 nmoles/0.5 μl/side and was inhibited by the 5-HT2A Antagonists ketanserin and MDL 100,907 but was not blocked by pretreatment with the selective 5-HT2C/2B antagonist SDZ SER 082. The HTR to mCPP demonstrated a bell-shaped dose-response curve with an ED50of 1.5 nmoles/0.5 μl/side and a peak effect after 3 nmoles/side. The response to mCPP was greatly diminished by both ketanserin and MDL 100,907 and was partially reversed by SDZ SER 082. These findings suggest that the HTR produced by the direct injection of serotonergic agonists into the medial prefrontal cortex is, in part, mediated by the activation of 5-HT2A receptors. Pretreatment of rats with the 5-HT1A agonist (±)-8-hydroxy-dipropylaminotetralin hydrobromide inhibited the HTR to DOI. This is consistent with other evidence that suggests a functional antagonism between 5-HT1A and 5-HT2A receptor activation. The HTR to DOI was potentiated by the novel 5-HT1A selective antagonist WAY 100,635, which suggests that 5-HT1Areceptors tonically regulate this behavioral response to stimulation of cortical 5-HT2A receptors.
Stevin H Zorn - One of the best experts on this subject based on the ideXlab platform.
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5 ht1a receptor activation contributes to ziprasidone induced dopamine release in the rat prefrontal cortex
Biological Psychiatry, 2000Co-Authors: Hans Rollema, Anne W Schmidt, Jeffrey Sprouse, Stevin H ZornAbstract:Background: Ziprasidone (Zeldox) is a novel antipsychotic with a unique combination of antagonist activities at monoaminergic receptors and transporters and potent agonist activity at serotonin 5-HT1A receptors. 5-HT1A receptor agonism may be an important feature in ziprasidone’s clinical actions because 5-HT1A agonists increase cortical dopamine release, which may underlie efficacy against negative symptoms and reduce dopamine D2 antagonist-induced extrapyramidal side effects. This study investigated the in vivo 5-HT1A agonist activity of ziprasidone by measuring the contribution of 5-HT1A receptor activation to the ziprasidone-induced cortical dopamine release in rats. Methods: Effects on dopamine release were measured by microdialysis in prefrontal cortex and striatum. The role of 5-HT1A receptor activation was estimated by assessing the sensitivity of the response to pretreatment with the 5-HT1A antagonist, WAY-100635. For comparison, the D2/5-HT2A Antagonists clozapine and olanzapine, the D2 antagonist haloperidol, the 5-HT2A antagonist MDL 100,907 and the 5-HT1A agonist 8-OHDPAT were included. Results: Low doses (<3.2 mg/kg) of ziprasidone, clozapine, and olanzapine increased dopamine release to approximately the same extent in prefrontal cortex as in striatum, but higher doses (≥3.2 mg/kg) resulted in an increasingly preferential effect on cortical dopamine release. The 5-HT1A agonist 8-OHDPAT produced a robust increase in cortical dopamine (DA) release without affecting striatal DA release. In contrast, the D2 antagonist haloperidol selectively increased striatal DA release, whereas the 5-HT2A antagonist MDL 100,907 had no effect on cortical or striatal DA release. Prior administration of WAY-100635 completely blocked the cortical DA increase produced by 8-OHDPAT and significantly attenuated the ziprasidone- and clozapine-induced cortical DA increase. WAY-100635 pretreatment had no effect on the olanzapine-induced DA increase. Conclusions: The preferential increase in DA release in rat prefrontal cortex produced by ziprasidone is mediated by 5-HT1A receptor activation. This result extends and confirms other in vitro and in vivo data suggesting that ziprasidone, like clozapine, acts as a 5-HT1A receptor agonist in vivo, which may contribute to its activity as an antipsychotic with efficacy against negative symptoms and a low extrapyramidal side effect liability.
