Serotonin‐3 Receptors in the Actions of Alcohol, Alcohol Reinforcement, and Alcoholism

McBride, William J.; Lovinger, David M.; Machu, Tina K.; Thielen, Richard J.; Rodd, Zachary A.; Murphy, James M.; Roache, John D.; Johnson, Bankole A.

doi:10.1097/01.alc.0000113419.99915.da

Cited by 74 publications

(60 citation statements)

References 83 publications

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“…5-HT 3 receptors are widely distributed throughout the CNS and peripheral nervous system, with particularly high concentrations in the nucleus tractus solitarius, area postrema, and dorsal motor nucleus of the vagus nerve in which they play an important role in mediating emesis (Barnes et al, 1990a,b;Steward et al, 1993). 5-HT 3 receptors are also thought to be important targets of alcohols and to play a role in alcohol addiction (Hodge et al, 2004;Johnson, 2004;McBride et al, 2004). Additionally, 5-HT 3 receptors modulate certain behavioral functions, including cognition, anxiety, and depression, as well as the baroreflex, carotid chemoreflex, and the Bezold-Jarisch reflex (Costall and Naylor, 2004;Farber et al, 2004;Haus et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Differential Effects of Serotonin and Dopamine on Human 5-HT_3AReceptor Kinetics: Interpretation within an Allosteric Kinetic Model

Solt

Ruesch²,

Forman³

et al. 2007

J. Neurosci.

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Serotonin type 3 (5-HT 3 ) receptors are members of the pentameric Cys-loop superfamily of receptors that modulate synaptic neurotransmission. In response to agonist binding and unbinding, members of this superfamily undergo a series of conformational transitions that define their functional properties. In this study, we report the results of electrophysiological studies using rapid solution exchange designed to characterize and compare the actions of the high-efficacy agonist serotonin and the low-efficacy agonist dopamine on human 5-HT 3A receptors expressed in human embryonic kidney HEK293 cells. In the case of serotonin, receptor activation rates varied with agonist concentration, and deactivation occurred as a single-exponential process with a rate that was similar to the maximal rate of desensitization. Receptors recovered slowly from long desensitizing pulses of serotonin with a sigmoidal time course. In the case of dopamine, receptor activation rates were independent of agonist concentration, receptor deactivation occurred as a complex process that was significantly faster than the maximal rate of desensitization, and recovery from desensitization occurred more quickly than with 5-HT and its time course was not sigmoidal. We developed an allosteric kinetic model for 5-HT 3A receptor activation, deactivation, desensitization, and resensitization. Interpretation of our results within the context of this model indicated that the distinct modulatory actions of serotonin versus dopamine are largely attributable to the vastly different rates with which these two agonists induce channel opening and dissociate from open and desensitized states.

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Section: Introductionmentioning

confidence: 99%

Differential Effects of Serotonin and Dopamine on Human 5-HT_3AReceptor Kinetics: Interpretation within an Allosteric Kinetic Model

Solt

Ruesch²,

Forman³

et al. 2007

J. Neurosci.

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“…25 Alterations in brain serotonin (5-hydroxytryptamine) levels as well as disturbances in central serotonergic transmission are important contributing factors in the pathogenesis of many psychiatric disorders 26,27 including alcoholism. [28][29][30] Tryptophan hydroxylase 1 alone has been reported to have a genetic association with and represent a major candidate gene for various psychiatric disorders 31 such as bipolar disorder, 32 alcohol dependence, 33 affective disorders and alcoholism. [34][35][36] However, no reports on TFs involved in the expression of Tph1 were found.…”

Section: Zinc Ion Homeostasismentioning

confidence: 99%

Ethanol-responsive genes: identification of transcription factors and their role in metabolomics

Uddin

Singh

2006

Pharmacogenomics J

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Transcription factors (TFs) and their combinatorial control on cis-regulatory elements play critical role in the co-expression of genes. This affects the interaction of genes in the transcriptome and thus may affect signals that cascade through cellular pathways. Using a combination of bioinformatic approaches, we sought to identify such common combinations of TFs in a set of ethanol-responsive (ER) genes and assess the role of ethanol in affecting multiple pathways through their co-regulation. Our results show that the metallothionein genes are regulated by TF motifs cAMP responsive element binding protein (CREB) and metal-activated transcription factor 1 and primarily involved in zinc ion homeostasis. We have also identified new target genes, Synaptojanin 1 and tryptophan hydroxylase 1, potentially regulated by this module. Altered arrangement of TF-binding sites in the module may direct the action of these and other target genes in intracellular signaling cascades, cell growth and/or maintenance. In addition to CREB, other key TFs identified are ecotropic viral integration site-1 and SP1. These modulate the contribution of the target ER genes in cell cycle regulation and apoptosis or programmed cell death. Multiple lines of evidence confirm the above findings and indicate that different groups of ER genes are involved in different biological processes and their co-regulation most likely results from different sets of regulatory modules. These findings associate the role of the ER genes studied and their potential TF modules with alcohol response pathways and phenotypes.

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“…Activation of 5-HT 3 receptors enhances the release of the neurotransmitters dopamine and GABA, which are believed to be the principal neurotransmitters for addiction and intoxication, respectively (McBride et al, 2004). The role of 5-HT 3 receptors in the neuronal circuitry of drug dependence has been known for some time (Grant, 1995).…”

mentioning

confidence: 99%

Ethanol Stabilizes the Open State of Single 5-Hydroxytryptamine_3A(QDA) Receptors

Feinberg-Zadek

Davies²

2010

J Pharmacol Exp Ther

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Ethanol enhancement of 5-hydroxytryptamine (5-HT) 3A receptor-mediated responses may have important consequences in the intoxicating and addictive properties of ethanol. Although the exact mechanism is unknown, ethanol-mediated enhancement of 5-HT 3 receptor current has been proposed to occur due to stabilization of the open-channel state. It has not been possible to directly measure the open state of the channel due to the extremely low single-channel conductance of 5-HT 3A channels. Recently, three arginine residues within the large intracellular loop of the 5-HT 3A subunit were substituted by their equivalent residues (glutamine, aspartate, and alanine) of the 5-HT 3B subunit to produce a 5-HT 3A (QDA) subunit that forms functional homomeric channels exhibiting a measurable single-channel conductance. Using whole-cell rapid-agonist application techniques and the cell-attached single-channel recording configuration, we examined human 5-HT 3A (QDA) receptors expressed in human embryonic kidney 293 cells. The agonist sensitivity, macroscopic kinetics, and modulation by ethanol were similar between mutant and wild-type channels, suggesting the substitutions had not altered these channel structure-function properties. The open time histogram for single-channel events mediated by 5-HT 3A (QDA) receptors in the presence of maximal 5-HT was best fit by three exponentials, but in the presence of ethanol a fourth open state was evident. In summary, the QDA substitution greatly enhanced singlechannel conductance with little effect on 5-HT 3A channel's kinetic properties and ethanol enhances agonist action on 5-HT 3A receptors by inducing a new, long-lived open-channel state. Furthermore, the 5-HT 3A (QDA) receptor appears to be suitable for pharmacological studies of 5-HT 3A receptor modulation at a single-channel level.

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Serotonin‐3 Receptors in the Actions of Alcohol, Alcohol Reinforcement, and Alcoholism

Cited by 74 publications

References 83 publications

Differential Effects of Serotonin and Dopamine on Human 5-HT_3AReceptor Kinetics: Interpretation within an Allosteric Kinetic Model

Differential Effects of Serotonin and Dopamine on Human 5-HT_3AReceptor Kinetics: Interpretation within an Allosteric Kinetic Model

Ethanol-responsive genes: identification of transcription factors and their role in metabolomics

Ethanol Stabilizes the Open State of Single 5-Hydroxytryptamine_3A(QDA) Receptors

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Serotonin‐3 Receptors in the Actions of Alcohol, Alcohol Reinforcement, and Alcoholism

Cited by 74 publications

References 83 publications

Differential Effects of Serotonin and Dopamine on Human 5-HT3AReceptor Kinetics: Interpretation within an Allosteric Kinetic Model

Differential Effects of Serotonin and Dopamine on Human 5-HT3AReceptor Kinetics: Interpretation within an Allosteric Kinetic Model

Ethanol-responsive genes: identification of transcription factors and their role in metabolomics

Ethanol Stabilizes the Open State of Single 5-Hydroxytryptamine3A(QDA) Receptors

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Differential Effects of Serotonin and Dopamine on Human 5-HT_3AReceptor Kinetics: Interpretation within an Allosteric Kinetic Model

Differential Effects of Serotonin and Dopamine on Human 5-HT_3AReceptor Kinetics: Interpretation within an Allosteric Kinetic Model

Ethanol Stabilizes the Open State of Single 5-Hydroxytryptamine_3A(QDA) Receptors