5-HT2C and GABAB receptors influence handling-induced convulsion severity in chromosome 4 congenic and DBA/2J background strain mice.
- Authors
- Reilly, Matthew T; Milner, Lauren C; Shirley, Renee L; Crabbe, John C; Buck, Kari J
- Year
- 2008
- Journal
- Brain research
- PMID
- 18262506
- DOI
- 10.1016/j.brainres.2008.01.024
- PMCID
- PMC2322873
Progress towards elucidating the underlying genetic variation for susceptibility to complex central nervous system (CNS) hyperexcitability states has just begun. Genetic mapping analyses suggest that a gene(s) on mid-chromosome 4 has pleiotropic effects on multiple CNS hyperexcitability states in mice, including alcohol and barbiturate withdrawal and convulsions elicited by chemical and audiogenic stimuli. We recently identified Mpdz within this chromosomal region as a gene that influences alcohol and barbiturate withdrawal convulsions. Mpdz encodes the multi-PDZ domain protein (MPDZ). Currently, there is limited information available about the mechanism by which MPDZ influences drug withdrawal and/or other CNS hyperexcitability states, but may involve its interaction with 5-HT2C and/or GABAB receptors. One of the most useful tools we have developed thus far is a congenic strain that possesses a segment of chromosome 4 from the C57BL/6J (donor) mouse strain superimposed on a genetic background that is >99% from the DBA/2J strain. The introduced segment spans the Mpdz gene. Here, we demonstrate that handling-induced convulsions are less severe in congenic vs. background strain mice in response to either a 5-HT2C receptor antagonist (SB242084) or a GABAB receptor agonist (baclofen), but not a GABAA receptor channel blocker (pentylenetetrazol). These data suggest that allelic variation in Mpdz, or a linked gene, influences SB242084- and baclofen-enhanced convulsions. Our results are consistent with the hypothesis that Mpdz's effects on CNS hyperexcitability, including alcohol and barbiturate withdrawal, involve MPDZ interaction with 5-HT2C and/or GABAB receptors. However, additional genes reside within the congenic interval and may also influence CNS hyperexcitability.
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In this knowledge base
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|---|---|---|
| Genetic research: who is at risk for alcoholism. | 2010 | 23579937 |
External
| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| The Cerebellar GABA<sub>A</sub>R System as a Potential Target for Treating Alcohol Use Disorder. | Rossi DJ et al. | — | 2018 | → |
| Genetic studies of alcohol dependence in the context of the addiction cycle. | Reilly MT et al. | — | 2017 | → |
| Effective Reduction of Acute Ethanol Withdrawal by the Tetracycline Derivative, Tigecycline, in Female and Male DBA/2J Mice. | Martinez JM et al. | — | 2016 | → |
| Assessment of seizure liability of Org 306039, a 5-HT2c agonist, using hippocampal brain slice and rodent EEG telemetry. | Markgraf CG et al. | — | 2014 | → |
| Ethosuximide reduces electrographical and behavioral correlates of alcohol withdrawal seizure in DBA/2J mice. | Riegle MA et al. | — | 2014 | → |
| Mpdz expression in the caudolateral substantia nigra pars reticulata is crucially involved in alcohol withdrawal. | Kruse LC et al. | — | 2014 | → |
| Discovering genes involved in alcohol dependence and other alcohol responses: role of animal models. | Buck KJ et al. | — | 2012 | → |
| Role of PDZ proteins in regulating trafficking, signaling, and function of GPCRs: means, motif, and opportunity. | Romero G et al. | — | 2011 | → |
| Substantia nigra pars reticulata is crucially involved in barbiturate and ethanol withdrawal in mice. | Chen G et al. | — | 2011 | → |
| Genetic research: who is at risk for alcoholism. | Foroud T et al. | — | 2010 | → |
| Focus on HTR2C: A possible suggestion for genetic studies of complex disorders. | Drago A et al. | — | 2009 | → |
| Pregnancy outcomes for women with epilepsy and bipolar disorder could be improved with intraventricular or intrathecal medication administration. | Alisky JM | — | 2009 | → |
| Involvement of the limbic basal ganglia in ethanol withdrawal convulsivity in mice is influenced by a chromosome 4 locus. | Chen G et al. | — | 2008 | → |