Abstract
The glycine receptor (GlyR), a ligand-gated ion channel, is critical for inhibitory neurotransmission in brainstem, spinal cord, and in supraspinal regions. Recent data from several laboratories have shown that GlyRs are expressed in the brain reward circuitry and that α1 and α2 are the principal subunits expressed in the nucleus accumbens (nAc). In the present study, we studied the sensitivity to ethanol of homomeric and heteromeric α3 GlyR subunits in HEK293 cells and dissociated neurons from the nAc. Finally, we explored ethanol-related behaviors in a Glra3 knockout mouse (Glra3–/–). Studies in HEK293 cells showed that while homomeric α3 GlyR subunits were insensitive to ethanol, heteromeric α3β GlyR subunits showed higher sensitivity to ethanol. Additionally, using electrophysiological recordings in dissociated accumbal neurons, we found that the glycine current density increased in Glra3–/– mice and the GlyRs were less affected by ethanol and picrotoxin. We also examined the effect of ethanol on sedation and drinking behavior in Glra3–/– mice and found that the duration in the loss of righting reflex (LORR) was unchanged compared to wild-type (WT) mice. On the other hand, using the drinking in the dark (DID) paradigm, we found that Glra3–/– mice have a larger ethanol consumption compared to WT mice, and that this was already high during the first days of exposure to ethanol. Our results support the conclusion that heteromeric α3β, but not homomeric α3, GlyRs are potentiated by ethanol. Also, the increase in GlyR and GABAAR mediated current densities in accumbal neurons in the KO mice support the presence of compensatory changes to α3 knock out. The increase in ethanol drinking in the Glra3–/– mice might be associated to the reduction in β and compensatory changes in other subunits in the receptor arrangement.
Highlights
The nucleus accumbens is a key region in the mesolimbic dopaminergic system and is important in the mediation of goaldirected behaviors, motivational processes, and addiction-related behaviors
In the mammalian central nervous system, the glycine receptor (GlyR) α3 subunit is expressed as two splice variants known as α3L and α3S subunits, which differ in that α3L contains a 15amino acid insertion (TEAFALEKFYRFSDT) within the TM3TM4 intracellular domain (Nikolic et al, 1998; Eichler et al, 2009)
We sought to examine the effect of co-expressing the β subunit in the effect of ethanol potentiation on GlyR α3 subunits using HEK293 cells
Summary
The nucleus accumbens (nAc) is a key region in the mesolimbic dopaminergic system and is important in the mediation of goaldirected behaviors, motivational processes, and addiction-related behaviors. Recent studies have demonstrated the presence of GlyRs in higher brain regions such as the prefrontal cortex (Lu and Ye, 2011; Salling and Harrison, 2014), nAc (Martin and Siggins, 2002; Munoz et al, 2018), and VTA (Ye et al, 2001; Li et al, 2012). Unlike the present study, using brain slice and local glycine application, the authors reported that mice with a deletion in Glra (Glra3−/− mice) lacked tonic glycinergic currents in the striatum suggesting that α3 subunits play a role in the activation of tonically activated GlyRs. Interestingly, Glra3−/− mice showed increased ethanol intake and preference in the 24h intermittent access protocols (Blednov et al, 2015). It is possible that ethanol potentiates α3β, but not α3 homomeric complexes, a subunit arrangement that is likely present in the nAc, but this possibility has not yet been examined
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