5-HT2C and GABAB receptors influence handling-induced convulsion severity in chromosome 4 congenic and DBA/2J background strain mice

Abstract

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-HT 2C and/or GABA B 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-HT 2C receptor antagonist (SB242084) or a GABA B receptor agonist (baclofen), but not a GABA A 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-HT 2C and/or GABA B receptors. However, additional genes reside within the congenic interval and may also influence CNS hyperexcitability.

Ethosuximide reduces electrographical and behavioral correlates of alcohol withdrawal seizure in DBA/2J mice

“…However, other reports suggest that the kindling phenomenon is only one potential mechanism for the development of alcohol withdrawal symptoms and is relevant only in certain situations (Wojnar, Bizoń, & Wasilewski, 1999). T channels are one of many factors that may contribute to hyperexcitability and regional specific effects of ethanol withdrawal (Chen, Reilly, Kozell, Hitzemann, & Buck, 2009; Reilly, Milner, Shirley, Crabbe, & Buck, 2008). The observation of “kindling-like” effects, while they may be due to multiple targets of ethanol, nevertheless underscores the importance of early intervention.…”

Genetic studies of alcohol dependence in the context of the addiction cycle

“…In addition, serotonin specific neuronal reduction in expression of Htr1A in mice contributes to cocaine seeking behavior and inhibition of dorsal raphe 5-HT1A autoreceptors attenuates cocaine self-administration in rats with prolonged extended access, but not 1 h access to the drug (You et al, 2016). Finally, a quantitative trait gene, the multiple PDZ domain protein (MPDZ), mediates drug withdrawal responses in mice and humans (Shirley et al, 2004; Fehr et al, 2002; Reilly et al, 2008; Milner et al, 2015; Chen and Buck, 2010; Chen et al, 2011). MPDZ is critical for serotonin type 2 receptor signaling and likely mediates variation in alcohol withdrawal severity via alterations in serotonin signaling fidelity (Reilly et al, 2008; Chen et al, 2009; Buck et al, 2004).…”

“…Finally, a quantitative trait gene, the multiple PDZ domain protein (MPDZ), mediates drug withdrawal responses in mice and humans (Shirley et al, 2004; Fehr et al, 2002; Reilly et al, 2008; Milner et al, 2015; Chen and Buck, 2010; Chen et al, 2011). MPDZ is critical for serotonin type 2 receptor signaling and likely mediates variation in alcohol withdrawal severity via alterations in serotonin signaling fidelity (Reilly et al, 2008; Chen et al, 2009; Buck et al, 2004). Thus, SNPs within HTR1A associated with alcohol dependence (Zuo et al, 2012) could alter compulsive drug seeking behavior which predominates during the preoccupation-anticipation stage of addiction.…”

Role of PDZ Proteins in Regulating Trafficking, Signaling, and Function of GPCRs: Means, Motif, and Opportunity

“…These reactions, however, exhibit shorter duration, suggesting a modulatory role for receptor–PDZ protein interactions (Balasubramanian et al, 2007). Importantly, recent work examining the genetic basis of hyperexcitability in mouse congenic strains identified the Mupp1 gene as an important regulator of sensitivity to 5-HT2CR antagonists and to GABA B agonists (Reilly et al, 2008). …”