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Mechanism of hallucinogenic drug act...

Benneyworth, Michael Andrew.

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Mechanism of hallucinogenic drug action: Modulation of glutamatergic signaling.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Mechanism of hallucinogenic drug action: Modulation of glutamatergic signaling./
Author:	Benneyworth, Michael Andrew.
Description:	208 p.
Notes:	Adviser: Elaine Sanders-Bush.
Contained By:	Dissertation Abstracts International68-12B.
Subject:	Biology, Neuroscience. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3293859
ISBN:	9780549381921

Mechanism of hallucinogenic drug action: Modulation of glutamatergic signaling.
Benneyworth, Michael Andrew.

Mechanism of hallucinogenic drug action: Modulation of glutamatergic signaling. - 208 p.

Adviser: Elaine Sanders-Bush.

Thesis (Ph.D.)--Vanderbilt University, 2007.

Recent clinical studies reveal that selective agonists of group II metabotropic glutamate (mGlu) receptors (mGlu2 and mGlu3 subtypes) have robust efficacy in treating positive and negative symptoms in schizophrenia patients. Group II mGlu receptor agonists also modulate the in vivo activity of psychotomimetic drugs and reduce the ability of psychotomimetic hallucinogens, via activation of serotonin (5-HT) subtype 2A receptors, to increase glutamatergic transmission. The use of mouse models provides an opportunity to investigate the dynamic action that mGlu2/3 receptors play in regulating the behavioral effects of hallucinogens, through both pharmacological and genetic manipulations. The current studies sought to characterize for the first time the subjective effects of hallucinogens in mice using the two-lever drug discrimination paradigm in mice, investigating the classical hallucinogen lysergic acid diethylamide (LSD) and the hallucinogenic 5-HT2A/2C receptor agonist (-)2,5-dimethoxy-4-bromoamphetamine [(-)DOB)] as stimulus drugs. Complete pharmacological evaluation of these drugs was performed, examining their temporal and dose-dependent properties, generalization of the stimuli to other hallucinogens, and pharmacological interventions with selective receptor antagonists. Additionally, the ability of mGlu2/3 receptors to regulate the hallucinogen discriminative stimulus was examined, using various drugs and mice with the selective deletion of either mGlu2 or mGlu3 receptors. The present work also thoroughly examined the regulation of a stereotyped hallucinogen-induced head twitch response. These experiments showed that the discriminative stimuli of hallucinogens is not regulated by mGlu2/3 receptors, as opposed to the head twitch response which was robustly antagonized by mGlu2/3 receptor agonists. Additionally, this regulation of the head twitch response by mGlu2/3 receptor agonists was attributed to the selective activation of mGlu2 receptors in the medial prefrontal cortex, using a positive allosteric modulator of mGlu2 receptors, a novel pharmacological mechanism of activating metabotropic receptors. Furthermore experiments demonstrated that repeated hallucinogen treatment causes a loss of sensitivity to mGlu2/3 receptor agonists, likely resultant of persistent activation of mGlu2/3 receptors by a hallucinogen-induced hyperglutamatergic state. All of these studies shed significant light on the behavioral effects of hallucinogens in mice, the interaction between hallucinogens and glutamatergic neurotransmission and the action of mGlu2/3 receptors to regulate hallucinogen-induced neurotransmission and behavior.

ISBN: 9780549381921Subjects--Topical Terms:

1017680
Biology, Neuroscience.

Mechanism of hallucinogenic drug action: Modulation of glutamatergic signaling.
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100 1 $a Benneyworth, Michael Andrew. $3 1262943
245 1 0 $a Mechanism of hallucinogenic drug action: Modulation of glutamatergic signaling.
300 $a 208 p.
500 $a Adviser: Elaine Sanders-Bush.
500 $a Source: Dissertation Abstracts International, Volume: 68-12, Section: B, page: 7948.
502 $a Thesis (Ph.D.)--Vanderbilt University, 2007.
520 $a Recent clinical studies reveal that selective agonists of group II metabotropic glutamate (mGlu) receptors (mGlu2 and mGlu3 subtypes) have robust efficacy in treating positive and negative symptoms in schizophrenia patients. Group II mGlu receptor agonists also modulate the in vivo activity of psychotomimetic drugs and reduce the ability of psychotomimetic hallucinogens, via activation of serotonin (5-HT) subtype 2A receptors, to increase glutamatergic transmission. The use of mouse models provides an opportunity to investigate the dynamic action that mGlu2/3 receptors play in regulating the behavioral effects of hallucinogens, through both pharmacological and genetic manipulations. The current studies sought to characterize for the first time the subjective effects of hallucinogens in mice using the two-lever drug discrimination paradigm in mice, investigating the classical hallucinogen lysergic acid diethylamide (LSD) and the hallucinogenic 5-HT2A/2C receptor agonist (-)2,5-dimethoxy-4-bromoamphetamine [(-)DOB)] as stimulus drugs. Complete pharmacological evaluation of these drugs was performed, examining their temporal and dose-dependent properties, generalization of the stimuli to other hallucinogens, and pharmacological interventions with selective receptor antagonists. Additionally, the ability of mGlu2/3 receptors to regulate the hallucinogen discriminative stimulus was examined, using various drugs and mice with the selective deletion of either mGlu2 or mGlu3 receptors. The present work also thoroughly examined the regulation of a stereotyped hallucinogen-induced head twitch response. These experiments showed that the discriminative stimuli of hallucinogens is not regulated by mGlu2/3 receptors, as opposed to the head twitch response which was robustly antagonized by mGlu2/3 receptor agonists. Additionally, this regulation of the head twitch response by mGlu2/3 receptor agonists was attributed to the selective activation of mGlu2 receptors in the medial prefrontal cortex, using a positive allosteric modulator of mGlu2 receptors, a novel pharmacological mechanism of activating metabotropic receptors. Furthermore experiments demonstrated that repeated hallucinogen treatment causes a loss of sensitivity to mGlu2/3 receptor agonists, likely resultant of persistent activation of mGlu2/3 receptors by a hallucinogen-induced hyperglutamatergic state. All of these studies shed significant light on the behavioral effects of hallucinogens in mice, the interaction between hallucinogens and glutamatergic neurotransmission and the action of mGlu2/3 receptors to regulate hallucinogen-induced neurotransmission and behavior.
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